CN105561292A - Composition for healing skin wound and application method of composition - Google Patents
Composition for healing skin wound and application method of composition Download PDFInfo
- Publication number
- CN105561292A CN105561292A CN201510629278.XA CN201510629278A CN105561292A CN 105561292 A CN105561292 A CN 105561292A CN 201510629278 A CN201510629278 A CN 201510629278A CN 105561292 A CN105561292 A CN 105561292A
- Authority
- CN
- China
- Prior art keywords
- wound
- wound healing
- composition
- polypeptide
- compositions
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
-
- 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
Abstract
The invention discloses a composition for healing a skin wound. The composition comprises a polypeptide compound. The polypeptide compound comprises polypeptide chains, and each polypeptide chain comprises 5-120 amino acid units. The composition further comprises a medicinal medium for loading the polypeptide compound, and the medicinal medium can be aqueous solution, suspension, dispersion, ointment, gel, cream, lotion, spray or paste. In addition, the invention discloses a method which applies the composition to the skin wound according to the concentration of about 1-100 microgram/ml to heal the skin wound.
Description
The divisional application that the application is the applying date is on November 3rd, 2010, application number is 201080070970.9, denomination of invention is the Chinese invention patent application of " skin wound healing compoistion and method of use ".
About the statement of federal funding research
The present invention makes under the contract number that NIH (NationalInstitutesofHealth) authorizes is the governmental support of GM67100 and AR46538.U.S. government enjoys certain right in the present invention.
Background of invention
Technical field
The disclosure belongs to the field of Wound healing compositions and application thereof.Specifically, the disclosure relates to peptide composition and these compositionss surface applied to skin, with by promoting that the migration of all Skin Cells carrys out accelerating wound healing.
Background technology
Wound healing or wound repair are the complicated processes that skin repairs self after injury.In normal skin, epidermis (outermost layer) and corium (inner or darker layer) exist with homeostasis state, form the protective barrier for external environment condition.Normal wound healing process can be divided into three phases substantially, i.e. inflammatory stage, multiplicative stage and maturation period.Inflammatory stage continues 0-2 days, and relates to cell and raise wound area in order.Thereafter be the multiplicative stage of 2-6 days, during this period, the fibroblast in wound bed, keratinocyte and other cells start active proliferation with wound closure.In the first stage of tissue repair, there is acute inflammation response and cell migration.At front 24-48 hour, neutrophil cell is occupied an leading position; By the 3rd day, macrophage came to life.Neutrophil cell and macrophage phagocytic also digest pathological organisms and fragment of tissue.Maturation period, peak value appeared at the 21st day after the multiplicative stage, now by rebuilding initial scar tissue, wound was healed completely.
Serious wounds does not defer to the normal time table of above-mentioned agglutination.The longer time needed for serious wounds can cause undesired cost and slow down relevant pain to healing, and the reduction of ability to work and overall quality of life.Suffer from the people of decubital ulcer make a definite diagnosis every year 2,000,000,900,000 people has the ulcer of the lower limb of disunion.According to estimates, the age has the patient of 18% to have foot ulcers that is chronic, disunion suffering from the patient of diabetes of over-65s.In addition, because shank chronic wounds infects, 50,000 routine lower extremity amputation operation is carried out every year.Due to wound abnormal flavour, infection and pain, cause quality of life significantly impaired by the morbidity of the leg ulcer of disunion.In addition, these problems also cause society to isolate and self-image reduction in the patient with chronic skin wounds.Economically, the expense for managing the wound healing postponed in U.S. old people is annual 9000000000 dollars according to estimates.
A large amount of time and moneys has been employed in chronic wound care field.Akella etc. are at U.S. Patent number 7,081, disclose the application of the protein mixture for the treatment of wound in 240, wherein said mixture is separated from skeleton, or comes from recombiant protein such as bone morphogenetic protein, transforming growth factor and fibroblast growth factor.But the overall clinical result of factor therapy is disappointed, and little somatomedin finally obtains FDA approval.
Kiss discusses the application of non-growth factor protein in wound healing, and described non-growth factor protein is shifted and α by mankind's alpha1-antitrypsin, human placental alkaline's phosphatase, the mankind
1-sour glycoprotein is formed.But the shortcoming of the method is that it needs the order of the complexity of the several agents worked in different step to use, and may need according to each treatment adjustment compositions.Similarly, the use of Graftskin does not have cost benefit.
It is critical events in human skin wound healing that epithelium is formed again, and wherein epidermal keratinocytes lateral migration is with wound closure.In chronic wounds, keratinocyte migration is blocked, and wound keeps open, causes morbidity and even death.
During human skin wound healing, crucial rate-limiting step is that the intrinsic epidermis at edge of wound place and hypodermal cell start to move in wound bed.Human keratinocytes (HKC) strides across wound bed lateral migration from notching edge, final wound closure, and this process is called as epithelium and is again formed.Hypodermal cell comprises dermal fibroblast (DF) and microvascular dermal endothelial cell (HDMEC), they start to move in wound after HKC migration, these cells are deposition substrate albumen in wound, shrinks and reinvent the new wound closed, building new blood vessel.HKC migration drives primarily of the TGF α in serum human, and not by the impact of the high concentration TGF 'beta ' family cytokine coexisted in serum human.On the contrary, even if under somatomedin such as PDGF-BB and VEGF existent condition, the existence of TGF β still blocks the migration of hypodermal cell.Therefore, for where start before DF and HDMEC migration, under abundant TGF β exists, how DF and HDMEC moves in wound bed, is still unsolved mystery although be appreciated that to move at wound healing period HKC.
Other research relates to use heat shock protein to promote wound healing.Such as, Srivastava etc. at U.S. Patent number 6,475, disclose a kind of compositions in 490, it comprises non-compound or the heat shock protein with the non-covalent compound of antigenic molecule, comprises gp96, hsp90 and hsp70.But, in pharmaceutical composition, use these macromole of total length, cause effect of per unit weight protein to reduce.
Summary of the invention
In order to overcome the problems referred to above, the disclosure identifies a kind of Wound healing compositions, and it comprises the polypeptide compound that a class has relative small size polypeptide chain.In a kind of embodiment of the present disclosure, described polypeptide chain has every bar chain 5 to 120 Amino Acid Units.Optionally, described compositions comprises the medicinal medium for polypeptide compound described in load, such as aqueous solution, suspension, dispersion, ointment, ointment, gel, cream, lotion, spray or paste.
In another kind of embodiment of the present disclosure, described polypeptide chain has every bar chain 20 to 60 Amino Acid Units.Optionally, polypeptide chain comprises the aminoacid sequence from 236 to 350 amino acids, EEKEDKEEEKEKEEKESEDKPEIEDVGSDEEEEKKDGDKKKKKKIKEKYIDQEE or SDEEEEKKDGDKKKKKKIKEKYIDQEE of hsp90 α peptide.Optionally, the described compositions mixture of the polypeptide chain of specific amino acid unit that can comprise 5 to 120 Amino Acid Units, a 20-60 Amino Acid Unit or show above.
The disclosure also relates to the method for healing skin wound, and described method comprises and being contacted with skin wound by the pharmaceutical composition of the first effective dose, and described pharmaceutical composition is made up of the polypeptide compound with polypeptide chain.Described polypeptide chain is every bar chain 5 to 120 Amino Acid Units, every bar chain 20 to 60 Amino Acid Units, or the aminoacid sequence from 236 to 350 amino acids, EEKEDKEEEKEKEEKESEDKPEIEDVGSDEEEEKKDGDKKKKKKIKEKYIDQEE or SDEEEEKKDGDKKKKKKIKEKYIDQEE that comprise hsp90 α peptide.
Described method optionally uses the pharmaceutical composition of the medicinal medium had for polypeptide compound described in load, and described medicinal medium is made up of aqueous solution, suspension, dispersion, ointment, ointment, gel, cream, lotion, spray or paste.
In another embodiment, described polypeptide compound is formulated in described medicinal medium with the concentration of about 10 μ g/ml to about 3mg/ml.Optionally, described polypeptide compound is formulated in described medicinal medium with the concentration of about 30 μ g/ml to about 500 μ g/ml.
In a kind of embodiment of wound healing method, described compositions was littlely applied to wound up to about every 72 hours by about every 6.Optionally, described compositions was littlely applied to wound up to about every 48 hours by about every 24.
Other advantages of the present disclosure and other features are partly set forth in the following description, and for the person of ordinary skill of the art, after have studied following content, part becomes apparent by other advantages of the present disclosure and other features, or can recognize from practice of the present disclosure.Can realize by what specifically note in claims and obtain advantage of the present disclosure.
As would be recognized, the disclosure can have other different embodiments, and details more of the present disclosure can various obvious in modify, it does not all deviate from the disclosure.Therefore, drawing and description should be considered to be exemplary and not restrictive in essence.
Accompanying drawing explanation
Fig. 1 show polypeptide compound various effect and with contrast cream compared with in mice on the bar diagram of the impact of wound healing.
Fig. 2 a-f be there are 115 amino acid whose peptide chains polypeptide compared with contrast cream, the photo of the skin wound healing result of mice.
Fig. 3 a-3e is the compound (Regranex of FDA approval
tM, PDGF-BB) and compared with contrast cream, the photo of the skin wound healing result of mice.
Detailed description of the invention
Without being limited by theory, it is believed that after skin injury, the TGF α of paracrine or autocrine release stimulates film transposition and the secretion of the hsp90 α albumen be pre-existing in HKC.The hsp90 α of secretion starts HKC migration by the CD91/LRP-1 receptor be incorporated on cell surface, and HKC migration is the critical events of epithelium forming process again.When extracellular hsp90 α to be diffused in wound bed and to reach finite concentration wherein, it starts to induce DF and HDMEC to move to wound bed from notching edge, even under " danger " condition: do not have ATP and ATPase active, and there is Universal Cell depressomotor such as TGF 'beta ' family cytokine.Therefore, hsp90 α in extracellular is used to skin wound healing.But when there is chronic wounds, skin can not produce the hsp90 α for wound healing.Therefore, must apply to wound the additive promoting skin wound healing.
Just as can be seen in Figure 1, compared with control media, total length (WT) hsp90 α demonstrates significant prokinetic activity.Central domain adds that electrically charged sequence (M-1) demonstrates the activity with WThsp90 α similarity degree.But the central domain lacking electrically charged sequence demonstrates significantly reduced activity (M-2), but electrically charged sequence adds whole N '-terminal domains, and (N ') does not demonstrate stimulating activity.Two C '-terminal domains (C '-1 and C '-2, for guaranteeing prepared by result) all demonstrate the prokinetic activity of moderate.Therefore, hsp90 α mainly through in the middle of it and carboxy-terminal domain promote that HKC moves, this is consistent with their surface locations in hsp90 α.Therefore, the compositions of the central domain of hsp90 α is comprised by wound healing character similar for the compositions shown to comprise separately hsp90 α.
But, as what can see in FIG, not that whole central domain and the electrically charged part of all complete hsp90 α albumen or hsp90 α albumen is all required for promotion wound healing yet.The F-3 fragment be made up of 115 Amino Acid Units coming from 236 to 350 amino acids and the F-5 fragment (sequence EEKEDKEEEKEKEEKESEDKPEIEDVGSDEEEEKKDGDKKKKKKIKEKYIDQEE) with 54 Amino Acid Units coming from 236 to 289 amino acids show the activity similar to total length hsp90 α, and the impact of its on cell migration is 100%.Therefore, the non-essential parts of hsp90 α does not need to be comprised in the compositions for wound healing, thus allows effect of the active wound consolidant of the per unit weight of compositions higher.In addition, more cheap and conventional synthetic method can be used to obtain the less polypeptide chain of chain length, and the separation and extraction method that need not depend on complexity add electrically charged part to the central domain obtaining hsp90 α albumen or hsp90 α albumen.
In order to confirm effect of the polypeptide compound of 115 Amino Acid Units and 54 Amino Acid Units, them are synthesized by conventional means.By containing 100 μ l10% carboxymethyl cellulose cream of 100 μ gF-3 fragments and independent cream surface applied every day to the 1cmx1cm wound on nude mice back, use 5 days altogether, and every two days analyze to wound.The selected wound photo of representative experiment is illustrated in Fig. 2 A-2F.Can find out, compared with contrasting with cream, beginning in the 4th day and at the 6th day, the 8th day, the 11st day, the 13rd day and the 15th day, closing of the remarkable accelerated in wounds of F-3.
Embodiment
In the following embodiments, following conditioned disjunction method is employed.
Mix 100 medicinal μ l10% carboxymethyl celluloses cream (aseptic), and the 1cmx1cm wound on surface coverage nude mice back.After such processing, wound several antibiotic and Flexibi fabric bandages (bandi) are covered, and wrap up mice fix Flexibi fabric bandages by twining surgical bandage (coban) with self-adhesion.Then add F-3 compound mixture every day until 5 days, and every two days analyze to wound.
In order to prepare for F-3 surface-treated mice, by 8 to 10 week age mice back central authorities tweezers pick up skin and remove full thickness cutaneous with shears, manufacture 1.0-cmx1.0-cm through thickness excise wound.With not carrying out surface coverage containing (in contrast) or the 100 μ l10% carboxymethyl celluloses containing 300 μ g restructuring F-3 compounds to wound.Then wound area Flexibi fabric bandages (Band-Aid) and self-adhesion are twined surgical bandage Coban to cover, to prevent drying.The F-3 compound of a dosage is only used to wound.In order to measure wound area, within the 4th, 6,8,11,13 and 15 day after wound, obtain the standardized digital photo of wound, and use image analyzer (AlphaEaseFC4.1.0 version, AlphaInnotechCorporation) to determine the area of open wound.By the area of wound in healing and the area of original wound being compared, determine the percentage rate of wound area.StudentT inspection is used to carry out statistical analysis.The scheme using committee (UniversityofSouthernCaliforniaInstitutionalAnimalUseComm ittee) to ratify by University of Southern California's laboratory animal is used to carry out all zooscopies.
There is provided the following examples to be for exemplary purposes, instead of intend to limit the scope of the invention.
1.0-cm is manufactured in the back central authorities of the nude mouse in 8 to 10 ages in week
2(1cmx1cm) square through thickness excision wound, and every day surface applied F-3 pharmaceutical composition, use altogether 5 days (n=often organizes 10 mices).(A) the representative wound of the 4th, 6,8,11,13 and 15 day is shown.With in the cream surface-treated mice containing F-3, wound size significantly reduces (right figure), but does not significantly reduce (left figure) when using independent cream.(B) after wound the 4th, 6,8,11,13 and 15 day, the meansigma methods ± SD (n=often organizes 10 mices) of wound size measurement result.
In order to compare effect of F-3 compound, use the Regenerex of FDA approval
tMstudy.Use said method, by the PDGF-BB (Regenerex of 40 μ g dosage
tM) be administered on mice, use altogether 5 days (n=often organizes 10 mices), and compare with F-3 compound.(A) the representative wound of the 0th, 5,7,10 and 12 day has been shown in Fig. 3 A-3E.As what can see from figure, with in the cream surface-treated mice containing F-3, wound size significantly reduces (upper figure), but at use Regenerex
tMwhen not significantly reduce (figure below).
The disclosure can be put into practice by use conventional material, method and apparatus.Therefore, the details of such material, equipment and method is not listed in this article in detail.The such as concrete material of a large amount of detail, structure, chemicals, method etc. are listed, to provide thorough understanding of the present disclosure in superincumbent description.But, should be realized that, can without the need to taking the details specifically listed to put into practice the disclosure.In other cases, known process structure is not described in detail, in order to avoid unnecessarily obscure the disclosure.
Only illustrate and describe several embodiment of the present disclosure in this article.Should be appreciated that, the disclosure can be incorporated in other environment various with other groups various and use, and can carry out changing or revising in the scope of the inventive concept such as stated herein.
Claims (9)
1. Wound healing compositions, it comprises:
The polypeptide be made up of aminoacid sequence EEKEDKEEEKEKEEKESEDKPEIEDVGSDEEEEKKDGDKKKKKKIKEKYIDQEE.
2. Wound healing compositions, it comprises:
The polypeptide be made up of aminoacid sequence SDEEEEKKDGDKKKKKKIKEKYIDQEE.
3. the Wound healing compositions of claim 1, it also comprises the medicinal medium for polypeptide compound described in load, and wherein said medicinal medium is that at least one is selected from following medium: aqueous solution, suspension, dispersion, ointment, ointment, gel, cream, lotion, spray or paste.
4. the Wound healing compositions of claim 2, it also comprises the medicinal medium for polypeptide compound described in load, and wherein said medicinal medium is that at least one is selected from following medium: aqueous solution, suspension, dispersion, ointment, ointment, gel, cream, lotion, spray or paste.
5. the Wound healing compositions of claim 1 or 2 is for the preparation of the purposes in the medicament of skin wound healing.
6. the Wound healing compositions of claim 3, wherein said polypeptide is present in described medicinal medium with the concentration of 10 μ g/ml to 3mg/ml or with the concentration of 30 μ g/ml to 500 μ g/ml.
7. the Wound healing compositions of claim 4, wherein said polypeptide is present in described medicinal medium with the concentration of 10 μ g/ml to 3mg/ml or with the concentration of 30 μ g/ml to 500 μ g/ml.
8. the Wound healing compositions of claim 1-4 and any one of 6-7, for the treatment of wound, wherein described compositions was littlely applied to described wound up to every 72 hours by every 6.
9. the Wound healing compositions of claim 1-4 and any one of 6-7, for the treatment of wound, wherein described compositions was littlely applied to described wound up to every 48 hours by every 24.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201080070970.9A CN103458914B (en) | 2010-11-03 | 2010-11-03 | Skin wound healing compoistion and method of use |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201080070970.9A Division CN103458914B (en) | 2010-11-03 | 2010-11-03 | Skin wound healing compoistion and method of use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105561292A true CN105561292A (en) | 2016-05-11 |
Family
ID=55880980
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510629278.XA Pending CN105561292A (en) | 2010-11-03 | 2010-11-03 | Composition for healing skin wound and application method of composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105561292A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000023093A1 (en) * | 1998-10-19 | 2000-04-27 | Fordham University | Compositions and methods for promoting tissue repair using heat shock proteins |
| WO2008086358A1 (en) * | 2007-01-08 | 2008-07-17 | University Of Southern California Usc Stevens | Skin wound healing compositions and methods of use thereof |
-
2010
- 2010-11-03 CN CN201510629278.XA patent/CN105561292A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000023093A1 (en) * | 1998-10-19 | 2000-04-27 | Fordham University | Compositions and methods for promoting tissue repair using heat shock proteins |
| WO2008086358A1 (en) * | 2007-01-08 | 2008-07-17 | University Of Southern California Usc Stevens | Skin wound healing compositions and methods of use thereof |
Non-Patent Citations (1)
| Title |
|---|
| XIAOMINSONG等: "The regulatory mechanism of Hsp90α secretion from endothelial cells and its role in angiogenesis during wound healing", 《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103458914B (en) | Skin wound healing compoistion and method of use | |
| Scardovi et al. | Epidermal growth factor in the topical treatment of traumatic corneal ulcers | |
| US8455443B2 (en) | Methods of use of skin wound healing compositions | |
| JP2022513418A (en) | Skin regeneration and healing mixture of peptide components and their use | |
| Mai et al. | Synergistic effect of bismuth subgallate and borneol, the major components of Sulbogin®, on the healing of skin wound | |
| EP0443224B1 (en) | Use of thrombospondin to promote wound healing | |
| EP2145623A1 (en) | Pharmaceutical and cosmetic compositions for accelerated healing of wounds and other surface damages | |
| CN114903981A (en) | Wound repair formula containing recombinant type III collagen | |
| Gibello et al. | First pilot case-control interventional study using autologous extracellular vesicles to treat chronic venous ulcers unresponsive to conventional treatments | |
| KR101820519B1 (en) | Use of sulglycotide for promoting skin-wound-healing, and composition for external application comprising the same | |
| CN105561292A (en) | Composition for healing skin wound and application method of composition | |
| Shashikumara et al. | Efficacy of 15% lysine cream in treating diabetic foot ulcers: a randomized interventional study | |
| EP2070531B1 (en) | Pharmaceutical preparation containing histamine H2-receptor antagonists having wound healing activity at low doses | |
| Cellini et al. | Epidermal growth factor in the topical treatment of herpetic corneal ulcers | |
| EP3288579A1 (en) | A novel skin medical and cosmetic care product | |
| Hong et al. | Skin necrosis after filler‐associated vascular compromise: successful treatment with topical epidermal growth factor | |
| US20240016893A1 (en) | Compositions and methods for treating wounds | |
| KR102638405B1 (en) | Composition Comprising Cimifugin for Wound Healing | |
| DE60212352T2 (en) | PEPTIDES FOR THE TREATMENT OF WOUND CONTRACTION | |
| Marlinawati et al. | The Effect of Papaya Leaf Extract Gel (Carica papaya) on Interleukin-1β Expression and Collagen Density (Col1A1) in the Back Incision Wound Healing of Wistar Rats (Rattus norvegicus). | |
| KR20220069909A (en) | Wound healing coposition comprising verafamil | |
| Ferreira et al. | Effect of high-voltage electrical stimulation and topical insulin on experimental cutaneous lesions | |
| Copenhagen | 7th Joint Meeting of the European Tissue Repair Society (ETRS) with the Wound Healing Society | |
| KR20010023154A (en) | USE OF 17-α-ESTRADIOL FOR THE TREATMENT OF AGED OR SUNDAMAGED SKIN AND/OR SKIN ATROPHY | |
| WO2018026264A2 (en) | Medicament for wound treatment |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160511 |