CN109646709A - A kind of medical hemostatic closed material of degradable absorption - Google Patents
A kind of medical hemostatic closed material of degradable absorption Download PDFInfo
- Publication number
- CN109646709A CN109646709A CN201910087916.8A CN201910087916A CN109646709A CN 109646709 A CN109646709 A CN 109646709A CN 201910087916 A CN201910087916 A CN 201910087916A CN 109646709 A CN109646709 A CN 109646709A
- Authority
- CN
- China
- Prior art keywords
- succinimide ester
- succinimide
- high molecular
- acid
- medical hemostatic
- 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
- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/043—Mixtures of macromolecular materials
-
- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
-
- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0042—Materials resorbable by the body
-
- 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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/04—Materials for stopping bleeding
Landscapes
- Health & Medical Sciences (AREA)
- Surgery (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention discloses a kind of medical hemostatic closed materials of degradable absorption, belong to a kind of Medical absorbable material, by using succinimide group activation high molecular material or chain material, it is formed and contains multiple activated carboxyl group polyhydroxy succinimide esters, be uniformly mixed with the high molecular material containing multiple amino.Using succinimide group and amino fast reaction occurs for the present invention, good hemostasis seals effect can be played when being attached to wound site surface by forming fine and close macromolecule reticular structure, and the material formed has good degradable absorbability, has high clinical value.Meanwhile the high molecular material of selection has certain viscosity, can preferably be attached at tissue, prevent from falling.
Description
Technical field
The present invention relates to pharmaceutical technology field, in particular to a kind of medical hemostatic closed material of degradable absorption.
Background technique
With the continuous development of science and technology, the non-absorbable hemostasia material such as bone wax has been widely used in clinic, but this
The infection of art area and other complication caused by a little non-absorbable hemostasia materials are unavoidable.Medical absorbable hemostatic material in recent years
Material causes the great attention of various countries' medical field and industrial circle, and many large-scale medical companies are devoted to study novel hemostatic material
Material.Existing market has developed the hemostatic material of a variety of different compositions and different mechanisms, applies because of its different characteristics different.
There are many surgical hemostasis closed materials for medical treatment or medical research, including PU, polyester, polyethylene at present
The raw materials such as alcohol, fibrinogen, gelatin, chitosan or glucan, but that there are still operation processings early period is complicated, degradation speed is slow or
Be not thorough, forming material it is really up to the mark lead to problems such as and organize sticking nature it is bad.
Patent WO2000062827 uses four arm polyethylene glycol as core element for representative, connects a variety of reactive groups of branch
(group containing succinimide and amino), forms reticular structure, and corresponding product is hundred special medical closed agent.Meanwhile in market
It is upper to be used there are also the tissue sealant based on collagen with the sealer based on alpha-cyanoacrylate ester material.
Tissue sealant needs based on collagen are used in conjunction with aldehydes, and aldehydes is big for the irritation of tissue,
Sealer based on alpha-cyanoacrylate ester material has certain cytotoxicity, and as existing hundred special sealers, film forming compared with
Firmly, tissue sticking nature is bad.
Summary of the invention
Above-mentioned technical problem to be solved by this invention is to provide a kind of medical hemostatic closed material of degradable absorption,
By way of by albumen or polysaccharide activation, the glycoprotein that can be cross-linked in situ or albuminoid structure are prepared, has good group
Knit sticking nature and degradable metabolic capability.
The medical hemostatic closed material of the degradable absorption, by use succinimide group activation high molecular material or
Chain material forms the polyhydroxy succinimide ester for containing multiple activated carboxyl groups, with the macromolecule for containing multiple amino
Material is uniformly mixed.
Preferable, when being used in mixed way, pH is controlled between 6-12.
Preferable, it is described that high molecular material or chain material are activated as Sodium Hyaluronate, sulphur by succinimide group
Aching and limp ossein sodium, glutelin, poly-aspartate, dermatan sulfate, suberic acid, decanedioic acid, four arm polyethylene glycol, in glutaric acid
It is one or more.
Preferable, the polyhydroxy succinimide ester containing multiple activated carboxyl groups is hyaluronic acid succinyl
Imines ester, chondroitin sulfate succinimide ester, glutelin succinimide ester, poly-aspartate succinimide ester, sulfuric acid
Dermatan succinimide ester, disuccinimidyl suberate, two succinimide ester of decanedioic acid, four arm polyethylene glycol ambers
One of acid imide, glutarate are a variety of.
Preferable, the high molecular material containing multiple amino is the Sodium Hyaluronate of deacetylation processing, sulfuric acid
Chondroitin sodium, chitin, polylysine, collagen, albumin, fibrin, one in the amido modified polyethylene glycol of four arms
Kind is a variety of.
By the present invention in that being combined with mucopolysaccharide, modification protide raw material and four arm polyethylene glycol products, greatly improve
The softness of film forming enhances tissue sticking nature, and the mucopolysaccharide used, protide raw material and four arm polyethylene glycol raw materials carry out
Polysuccinimated or amination modification, makes it have very high reactivity, has very strong reactivity after mixing, keeps away
Exempt from the use of aldehydes raw material, reduces cytotoxicity.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.
Embodiment one
Carbonyl dimidazoles and the hydroxysuccinimide-activated hyalomitome of N are used first in a certain amount of hyaluronic acid solution
Acid, after the reaction was completed, using ethyl alcohol carry out alcohol precipitation operation, sediment alcohol is washed, dissolve, dialysis, be freeze-dried product is transparent
Matter acid succinimide ester.
Then at 50-60 DEG C, hydrazine hydrate is added in a certain amount of hyaluronic acid and its sulfate stirs 72h, ethyl alcohol
Precipitation and separation collects precipitating vacuum drying and obtains polymeric articles.Polymeric articles are dissolved in the acetic acid of l5%, iodine is added
Acid, mixture react 1-2h at 4 DEG C.The iodic acid solution for being then added 57% continues to be stirred to react.Addition ether is extracted to molten
Liquid layering and it is completely colorless, adjustings solution layer pH be 7.0-7.5.Sediment alcohol is washed, is dissolved, dialysis is freeze-dried to obtain product
Deacetylated processing hyaluronic acid contains carboxyl and amino on strand.
The hyaluronic acid succinimide ester that reaction obtains is dissolved into formation uniformly with deacetylated processing hyaluronic acid respectively
Gel uniformly mixes two kinds of solution wherein deacetylated hyaluronic acid solution pH is 9, and system pH is 7.5-8.5 when mixing.
Succinimide group reacts rapidly with amino, forms highly cross-linked hyaluronic acid derivatives network, both
The medical hemostatic closed material of degradable absorption.Hyaluronic acid derivatives structure and extracellular matrix structure height are similar, have good
Good histocompatbility, and hyaluronic acid has good organizational coherence and water absorbing capacity, the promotion of the degree of cross linking is so that this stop
Blood closed material has good water resistant dissolubility, guarantees its continual and steady performance hemostasis seals effect.
Embodiment two
Then at 50-60 DEG C, hydrazine hydrate is added in a certain amount of hyaluronic acid and its sulfate stirs 72h, ethyl alcohol
Precipitation and separation collects precipitating vacuum drying and obtains polymeric articles.Product is dissolved in the acetic acid of l5%, acid iodide, mixing is added
Object reacts 1-2h at 4 DEG C.The iodic acid solution for being then added 57% continues to be stirred to react.Be added ether be extracted to solution layering and
Completely colorless, adjusting solution layer pH is 7.0-7.5；Sediment progress alcohol is washed, is dissolved, dialysis, the de- second of product is freeze-dried to obtain
Acyl hyaluronic acid contains carboxyl and amino on strand.
Two succinimide ester of decanedioic acid is prepared using decanedioic acid, and the deacetylated hyaluronic acid that reaction obtains is matched
Gel is made to mix with two succinimide ester of decanedioic acid, system pH is 7-9 when mixing.
Succinimide group reacts rapidly with amino, forms highly cross-linked hyaluronic acid derivatives network, both
The medical hemostatic closed material of degradable absorption.Decanedioic acid structural molecule amount is smaller, and the hemostasis seals material structure of formation is fine and close
It is compact, there is good mechanical strength and elasticity, be suitable for being used as filler, while hyaluronic acid assigns the strong water absorbing capacity of structure
Power and adhesive capacity, while ensure that the safety and degradable ability of product.
Embodiment three
It is soft using carbonyl dimidazoles and the hydroxysuccinimide-activated sulfuric acid of N first in a certain amount of hyaluronic acid solution
Ossein carries out alcohol precipitation operation using ethyl alcohol, sediment alcohol is washed, dissolve after the reaction was completed, and dialysis is freeze-dried to obtain the product sulfur
Aching and limp ossein succinimide ester；
Chondroitin sulfate succinimide ester and polylysine that reaction obtains are dissolved respectively and form homogeneous gel, wherein
Polylysin solution pH is 8-9, and two kinds of solution are uniformly mixed, and system pH is 7.5-8.5 when mixing.
Succinimide group reacts rapidly with amino, forms highly cross-linked glycoprotein gel network, and both obtaining can
The medical hemostatic closed material that degradation absorbs.Chondroitin sulfate has good water suction and lubricating ability, and polylysine can be with
Anion interaction with tissue generates stronger cohesive force, and has good sterilizing ability and thermal stability.
Example IV
Glutelin succinimide ester will be prepared with glutelin and collagen dissolves form homogeneous gel respectively,
Middle collagen solution pH is 8-9, and two kinds of solution are uniformly mixed, and system pH is 7.5-8.5 when mixing.
Succinimide group reacts rapidly with amino, forms highly cross-linked albuminoid gel network, and both obtaining can
The medical hemostatic closed material that degradation absorbs.This material can degrade rapidly to amino acid and each by the effect of vivo protein enzyme
Kind of peptides, by body using or as metabolism of energy substances.
Above with respect to specific descriptions of the invention, it is merely to illustrate the present invention and is not limited to the embodiment of the present invention and is retouched
The technical solution stated, those skilled in the art should understand that, it still can modify to the present invention or equivalent replacement,
Have reached same technique effect；Needs are used as long as meeting, all within protection scope of the present invention.
Claims (4)
1. a kind of medical hemostatic closed material of degradable absorption, which is characterized in that by using the activation of succinimide group high
Molecular material or chain material, formed contain multiple activated carboxyl groups polyhydroxy succinimide ester, with contain multiple ammonia
The high molecular material of base is uniformly mixed；
It is described that high molecular material or chain material are activated as Sodium Hyaluronate, sodium chondroitin sulfate, paddy by succinimide group
One of albumen, poly-aspartate, dermatan sulfate, suberic acid, decanedioic acid, four arm polyethylene glycol, glutaric acid are a variety of.
2. the medical hemostatic closed material of degradable absorption according to claim 1, which is characterized in that described containing multiple
The polyhydroxy succinimide ester of activated carboxyl group is hyaluronic acid succinimide ester, chondroitin sulfate succinimide
Ester, glutelin succinimide ester, poly-aspartate succinimide ester, dermatan sulfate succinimide ester, suberic acid two
One of succinimide ester, two succinimide ester of decanedioic acid, four arm polyethylene glycol succinimides, glutarate are more
Kind.
3. the medical hemostatic closed material of degradable absorption according to claim 1 or 2, which is characterized in that described to contain
Sodium Hyaluronate, sodium chondroitin sulfate, chitin of the high molecular material of multiple amino for deacetylation processing, polylysine,
Collagen, albumin, fibrin, one of amido modified polyethylene glycol of four arms or a variety of.
4. the medical hemostatic closed material of degradable absorption according to claim 1, which is characterized in that when being used in mixed way,
PH is controlled between 6-12.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910087916.8A CN109646709A (en) | 2019-01-29 | 2019-01-29 | A kind of medical hemostatic closed material of degradable absorption |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910087916.8A CN109646709A (en) | 2019-01-29 | 2019-01-29 | A kind of medical hemostatic closed material of degradable absorption |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109646709A true CN109646709A (en) | 2019-04-19 |
Family
ID=66120880
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910087916.8A Pending CN109646709A (en) | 2019-01-29 | 2019-01-29 | A kind of medical hemostatic closed material of degradable absorption |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109646709A (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110917385A (en) * | 2019-11-20 | 2020-03-27 | 山东百多安医疗器械有限公司 | Self-repairing quick-sealing medical adhesive and preparation method thereof |
| CN110935058A (en) * | 2019-11-20 | 2020-03-31 | 山东百多安医疗器械有限公司 | Double-component medical glue for rapid hemostasis and preparation method thereof |
| CN111467580A (en) * | 2020-03-05 | 2020-07-31 | 诺一迈尔(山东)医学科技有限公司 | Temperature-sensitive composition for treating periodontal diseases and preparation method thereof |
| CN112007201A (en) * | 2020-08-12 | 2020-12-01 | 山东百多安医疗器械股份有限公司 | Adhesive antibacterial hemostatic sponge and preparation method thereof |
| CN112076341A (en) * | 2019-05-27 | 2020-12-15 | 戴建英 | Self-curing self-adhesive digestive tract injury mucosa protective adhesive and application thereof |
| CN113041164A (en) * | 2021-03-12 | 2021-06-29 | 广州武州制药有限公司 | Application of succinimide stearate in preparation of anti-friction skin care masking liquid and anti-friction skin care masking liquid containing succinimide stearate |
| CN113209357A (en) * | 2021-05-14 | 2021-08-06 | 南方科技大学 | Composite styptic powder |
| CN113274544A (en) * | 2021-05-14 | 2021-08-20 | 南方科技大学 | PEG styptic powder |
| CN115177779A (en) * | 2022-06-14 | 2022-10-14 | 深圳凡旻生物科技有限公司 | Biological glue and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1694903A (en) * | 2002-07-26 | 2005-11-09 | 株式会社Lg生命科学 | Hyaluronic acid derivative gel and method for preparing the same |
| CN1723046A (en) * | 2003-02-13 | 2006-01-18 | 独立行政法人物质·材料研究机构 | Biodegradable and pressure-sensitive material for medical use |
| CN105963792A (en) * | 2016-04-29 | 2016-09-28 | 深圳迈普再生医学科技有限公司 | Medical hydrogel composition, medical hydrogel as well as preparation method and application of medical hydrogel |
| CN106075549A (en) * | 2016-06-17 | 2016-11-09 | 广州迈普再生医学科技有限公司 | Tissue closes glue composition, and tissue closes glue and its preparation method and application |
-
2019
- 2019-01-29 CN CN201910087916.8A patent/CN109646709A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1694903A (en) * | 2002-07-26 | 2005-11-09 | 株式会社Lg生命科学 | Hyaluronic acid derivative gel and method for preparing the same |
| CN1723046A (en) * | 2003-02-13 | 2006-01-18 | 独立行政法人物质·材料研究机构 | Biodegradable and pressure-sensitive material for medical use |
| CN105963792A (en) * | 2016-04-29 | 2016-09-28 | 深圳迈普再生医学科技有限公司 | Medical hydrogel composition, medical hydrogel as well as preparation method and application of medical hydrogel |
| CN106075549A (en) * | 2016-06-17 | 2016-11-09 | 广州迈普再生医学科技有限公司 | Tissue closes glue composition, and tissue closes glue and its preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| 徐元清等: "《有机化学实验》", 31 December 2017 * |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112076341A (en) * | 2019-05-27 | 2020-12-15 | 戴建英 | Self-curing self-adhesive digestive tract injury mucosa protective adhesive and application thereof |
| CN110917385B (en) * | 2019-11-20 | 2022-01-11 | 山东百多安医疗器械股份有限公司 | Self-repairing quick-sealing medical adhesive and preparation method thereof |
| CN110935058A (en) * | 2019-11-20 | 2020-03-31 | 山东百多安医疗器械有限公司 | Double-component medical glue for rapid hemostasis and preparation method thereof |
| CN110917385A (en) * | 2019-11-20 | 2020-03-27 | 山东百多安医疗器械有限公司 | Self-repairing quick-sealing medical adhesive and preparation method thereof |
| CN111467580A (en) * | 2020-03-05 | 2020-07-31 | 诺一迈尔(山东)医学科技有限公司 | Temperature-sensitive composition for treating periodontal diseases and preparation method thereof |
| CN111467580B (en) * | 2020-03-05 | 2022-05-17 | 诺一迈尔(山东)医学科技有限公司 | Temperature-sensitive composition for treating periodontal diseases and preparation method thereof |
| CN112007201A (en) * | 2020-08-12 | 2020-12-01 | 山东百多安医疗器械股份有限公司 | Adhesive antibacterial hemostatic sponge and preparation method thereof |
| CN113041164A (en) * | 2021-03-12 | 2021-06-29 | 广州武州制药有限公司 | Application of succinimide stearate in preparation of anti-friction skin care masking liquid and anti-friction skin care masking liquid containing succinimide stearate |
| CN113274544A (en) * | 2021-05-14 | 2021-08-20 | 南方科技大学 | PEG styptic powder |
| CN113209357A (en) * | 2021-05-14 | 2021-08-06 | 南方科技大学 | Composite styptic powder |
| CN113209357B (en) * | 2021-05-14 | 2023-02-17 | 南方科技大学 | Composite styptic powder |
| CN115177779A (en) * | 2022-06-14 | 2022-10-14 | 深圳凡旻生物科技有限公司 | Biological glue and preparation method and application thereof |
| CN115177779B (en) * | 2022-06-14 | 2023-12-05 | 深圳凡旻生物科技有限公司 | Biological glue and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109646709A (en) | A kind of medical hemostatic closed material of degradable absorption | |
| Zhong et al. | A mussel-inspired carboxymethyl cellulose hydrogel with enhanced adhesiveness through enzymatic crosslinking | |
| JP7014845B2 (en) | Preparation and / or formulation of proteins cross-linked by polysaccharides | |
| Bu et al. | Cohesion mechanisms for bioadhesives | |
| Tang et al. | A review on recent advances of Protein-Polymer hydrogels | |
| ES2900605T3 (en) | Fast Acting Dry Sealant and Methods of Use and Manufacture | |
| AU2005283282B2 (en) | Photoreactive polysaccharide, photocrosslinked polysaccharide products, the method of making them and medical materials therefrom | |
| US9446166B2 (en) | Fibrin sealant compositions with chemical crosslinking | |
| Zheng et al. | Recent progress in surgical adhesives for biomedical applications | |
| CN101716366A (en) | Biocolloid hemostatic prepared by aldehyde-modified sodium alginate and amine-modified gelatine | |
| CN105833337A (en) | Fibrous tissue sealant and method of using same | |
| US20230348699A1 (en) | Hydrophobically modified chitosan compositions | |
| Yang et al. | Advances in adhesive hydrogels for tissue engineering | |
| JP2013537050A (en) | Mercapto-modified biocompatible polymer derivatives with low degree of mercapto modification, their cross-linking materials, and methods of use thereof | |
| Liang et al. | Injectable protocatechuic acid based composite hydrogel with hemostatic and antioxidant properties for skin regeneration | |
| JP2019216755A (en) | Hemostatic material | |
| Sharma et al. | Nano/micro-formulations of keratin in biocomposites, wound healing and drug delivery systems; recent advances in biomedical applications | |
| Xing et al. | Injectable hydrogel based on modified gelatin and sodium alginate for soft-tissue adhesive | |
| US20100260845A1 (en) | Biocompatible and Biodegradable Biopolymer Matrix | |
| Shao et al. | Recent research advances on polysaccharide-, peptide-, and protein-based hemostatic materials: A review | |
| CN112143410A (en) | Injectable biological adhesive and preparation method and application thereof | |
| CA2706701C (en) | Biocompatible phase invertible proteinaceous compositions | |
| Bu et al. | Recent trends in natural polymer-based hydrogels for biomedical applications | |
| WO2023109329A1 (en) | Medical tissue adhesive, and preparation method therefor and use thereof | |
| Kumari et al. | Hydrogel as a prospective substance for wound healing and sealing |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190419 |
|
| RJ01 | Rejection of invention patent application after publication |