CN111281978A - Hyaluronic acid-based carrier and application of preparation method thereof in anti-scar - Google Patents
Hyaluronic acid-based carrier and application of preparation method thereof in anti-scar Download PDFInfo
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- CN111281978A CN111281978A CN201910771137.XA CN201910771137A CN111281978A CN 111281978 A CN111281978 A CN 111281978A CN 201910771137 A CN201910771137 A CN 201910771137A CN 111281978 A CN111281978 A CN 111281978A
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- hyaluronic acid
- based carrier
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/52—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
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Abstract
A hyaluronic acid-based carrier is in the form of granule, has an average particle diameter of 80nm + -10 nm, and is prepared by coating hyaluronic acid matrix with silicon dioxide. The target compound with medical activity is loaded on the hyaluronic acid-based carrier provided by the invention, and the characteristic of imbibing and swelling hyaluronic acid is utilized, so that the silicon dioxide material coated on the hyaluronic acid-based carrier is gradually broken, and free target molecules are released. On the other hand, along with the swelling and degradation of the hyaluronic acid, the target molecules loaded in the hyaluronic acid-based carrier are further released, so that the problem that the target compound molecules are quickly released in vivo is solved, and the hyaluronic acid-based carrier is suitable for anti-scar treatment by taking the hyaluronic acid-based carrier.
Description
Technical Field
The invention relates to a composite material, in particular to a carrier mainly based on hyaluronic acid groups and application of the carrier in scar resistance.
Background
Hyaluronic acid is an acidic mucopolysaccharide that exhibits a variety of important physiological functions in the body with unique molecular structures and physicochemical properties, such as: lubricating joints, regulating permeability of vessel walls, regulating diffusion and operation of proteins and water electrolytes, promoting wound healing, etc. More importantly, hyaluronic acid has a special water retention effect, is the substance which is found to have the best moisture retention in nature at present, and is called an ideal Natural Moisturizing Factor (NMF).
Hyaluronic acid is a good biocompatible material and is suitable as a carrier. Practice shows that in the anti-scar administration, only hyaluronic acid is used as a carrier, related drug molecules are rapidly released in vivo, the drug molecules can be detected in tissues within 24 hours after the administration, and 40-50% of the drug is eliminated.
The Chinese invention patent ZL201410673636.2 discloses a mesoporous nano silicon sphere compound targeted drug delivery system, and the preparation method comprises the following steps of 1) preparing amino functionalized drug-loaded mesoporous silica microspheres; 2) preparing hyaluronic acid-sulfhydryl polypeptide-adriamycin (HA-RGD-DOX); 3) preparing mesoporous microspheres-hyaluronic acid-sulfhydryl polypeptide-adriamycin-paclitaxel (MSNs-HA-RGD-DOX-PTX); 4) preparing a fluorescent marker modified mesoporous microsphere-hyaluronic acid-thiol-polypeptide-adriamycin-paclitaxel complex (MSNs-HA-RGD-DOX-PTX). The drug delivery system has the characteristics of realizing multi-target synergistic drug delivery, excellent blood stability, good invisibility, drug release property, controlled release property and the like.
Chinese patent application 201610594428.2 discloses a hyaluronic acid modified lipid mesoporous silicon core-shell nano-assembly and a preparation method thereof. The method comprises the following specific steps: 1) mixing mesoporous silicon and a drug in an organic solvent to obtain drug-loaded mesoporous silicon; 2) dispersing the drug-loaded mesoporous silicon by PBS, adding liposome into the drug-loaded mesoporous silicon, hydrating the drug-loaded mesoporous silicon at 30-80 ℃, and homogenizing the drug-loaded mesoporous silicon under 500-1200 Pa to obtain liposome-coated mesoporous silicon nanoparticles; 3) Activating hyaluronic acid HA by using EDC and NHS, and reacting the activated hyaluronic acid HA with the mesoporous silicon nanoparticles wrapped by the liposome to obtain the hyaluronic acid modified lipid mesoporous silicon core-shell nano-assembly. The assembly of the invention achieves rapid release and high concentration accumulation of the drug by proton exchange.
Chinese patent application 201611114226.X discloses a preparation method of a short peptide/silicon dioxide/hyaluronic acid composite hydrogel, which comprises the following steps: firstly, self-assembling amphiphilic short peptide in an aqueous solution to form a stable self-assembled body; mixing the silicon dioxide precursor with the assembled short peptide solution, and reacting under a proper condition to obtain short peptide/silicon dioxide hydrogel; finally, compounding the short peptide/silicon dioxide/hyaluronic acid composite hydrogel with a hyaluronic acid solution with a certain concentration to obtain the short peptide/silicon dioxide/hyaluronic acid composite hydrogel. The fibers formed by self-assembly of the short peptide molecules are protected by the silicon dioxide layer, and the fibers are connected by Si-O-Si chemical bonds to form a cross-linked network, so that the mechanical strength is improved. The surface of the silicon dioxide in the gel contains a large number of hydroxyl groups, so that some functional molecules including drug molecules, antibacterial biomolecules or bioactive factors and the like can be conveniently loaded and slowly released, and the gel is suitable for being used as a three-dimensional scaffold material of medical dressings.
Another commonly used biocompatible and biodegradable material is PLGA, but the long degradation period of its molecules also produces an inflammatory response locally upon administration, and is not suitable for use as a carrier in anti-scarring applications.
Disclosure of Invention
It is an object of the present invention to provide a hyaluronic acid-based carrier that retains the properties of hyaluronic acid and is effective in delaying the release of molecules encapsulated therein.
It is another object of the present invention to provide a hyaluronic acid based carrier, effective in delaying the release of anti-scarring molecules, and use in anti-scarring,
it is still another object of the present invention to provide a hyaluronic acid-based carrier preparation method to produce carriers suitable for anti-scarring drug molecules as needed.
The hyaluronic acid-based carrier provided by the invention is granular, the average grain diameter of the hyaluronic acid-based carrier is 80nm +/-10 nm, and a hyaluronic acid matrix is coated with silicon dioxide.
Silanization reagents were used, such as: but are not limited to, Tetraethoxysilane (TOEs) coated silica on hyaluronic acid matrices.
The invention provides another hyaluronic acid-based carrier, which is also loaded with magnetic particles in hyaluronic acid matrix, such as: fe3O4And targeting of the vector is achieved.
When the target compound needs to be transported, the hyaluronic acid and the target compound are blended, and then the silica is coated on the hyaluronic acid matrix by using a silanization reagent. The target molecule also covalently binds to the hyaluronic acid, and the covalent bond can be hydrolyzed or acid-cleaved, thereby allowing the target compound to be separated from the hyaluronic acid phase.
The target compound includes protein (such as bovine serum albumin and human serum albumin), polypeptide, polymer and organic small molecule, and also includes compound obtained by combining active molecule with medical function and another carrier.
The hyaluronic acid-based carrier provided by the invention has a liquid absorption effect, gradually swells after liquid absorption, and the coated silicon dioxide can be obviously observed (observed by instruments such as an electron microscope and the like) to break after 5 minutes, so that the hyaluronic acid-based carrier extends outwards. Over time, the hyaluronic acid-based carrier is gradually degraded by the cells or tissues, during which the target compound loaded therein is released.
The present invention also provides a method for preparing a hyaluronic acid-based carrier for preparing carrier particles for loading a target compound, comprising:
a target compound (e.g., HSA) is mixed with hyaluronic acid (e.g., an aqueous hyaluronic acid solution) and stirred (e.g., for 10 minutes), magnetic particles (e.g., 2.8mg) are added, pH is adjusted to be higher than 7, and then absolute ethanol and tetraethoxysilane are added, and stirred at 2,500rpm + -50 rpm for 10 hours + -0.5 hours.
The compound with the anti-scar activity is loaded in a hyaluronic acid-based carrier, so that the release of anti-scar molecules can be effectively delayed, and the compound can be applied to anti-scar treatment, such as: making into anti-scar medicine or cosmetic.
The invention also provides a preparation method of the hyaluronic acid-based carrier, which is used for preparing the anti-scar carrier and comprises the following steps:
the compound having anti-scarring activity (shown as SEQ ID No 1) is mixed with hyaluronic acid and stirred (e.g., for 10 minutes), the pH is adjusted to be more than 7, and after adding absolute ethanol and a silylation agent, stirring is carried out overnight at 2,500 rpm. + -. 50 rpm. The stirring time is preferably 10 hours. + -. 0.5 hours, so as to favour the swelling of the hyaluronic acid and the release of the compound with anti-cicatricial activity.
During the alkylation, 120. mu.l tetraethoxysilane per 15ml of anhydrous ethanol was added.
From the anti-scar effect and the swelling and degradation time of hyaluronic acid, the compound with the anti-scar activity and the hyaluronic acid are preferentially selected, and the dosage is 1: 6 according to the weight.
The present invention also provides another hyaluronic acid-based carrier for use in the preparation of an anti-scarring carrier, comprising:
3mg of the compound represented by SEQ ID No1 was mixed with 0.5mg of hyaluronic acid (e.g., 5mL of an aqueous solution having a concentration of 0.1 mg/mL) and stirred (e.g., 10 minutes), the pH was adjusted to more than 7 (e.g., pH 9. + -.1), and then 15mL of absolute ethanol and 120. mu.l of tetraethoxysilane were added and stirred at 2,500 rpm. + -. 50rpm for 10 hours. + -. 0.5 hours.
The hyaluronic acid-based carrier loaded with the anti-scar active molecules is directly applied to the surface of the wound, or is matched with other auxiliary materials to be prepared into a medicament and then is applied to the surface of the wound.
The technical scheme of the invention has the following beneficial effects:
the hyaluronic acid-based carrier provided by the invention utilizes the imbibition and swelling characteristics of hyaluronic acid to enable the silicon dioxide material coated on the hyaluronic acid-based carrier to be gradually broken, so that free target molecules are released. On the other hand, as hyaluronic acid swells and degrades, the target molecule loaded in the hyaluronic acid-based carrier is further released. Thereby solving the problem that the target compound molecules are rapidly released in vivo.
For the anti-scar treatment of a wound part, the hyaluronic acid-based carrier provided by the invention can effectively solve the problem that when hyaluronic acid is used as the carrier, a related anti-scar active compound is quickly released in vivo, so that the time of the anti-scar active compound acting on the wound part is effectively prolonged, and the anti-scar effect is effectively improved.
Drawings
FIG. 1 is a hyaluronic acid-based carrier of the present invention, silica being coated thereon, wherein: the number "1" is designated as the transparent acid moiety and the number "2" is designated as the silica moiety;
FIG. 2 is a graph showing the swelling and degradation state of the hyaluronic acid-based carrier of the present invention 10 minutes after imbibition;
FIG. 3 is a graph showing the results of the growth inhibition of fibroblasts and embryonic stem cells by the hyaluronic acid-based drug carrier of the present invention.
Detailed Description
The technical scheme of the invention is described in detail in the following with reference to the accompanying drawings. Although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the spirit and scope of the invention as defined in the appended claims.
EXAMPLE 1 preparation of the support
1mg of the chemically synthesized compound represented by SEQ ID No1 and 6mg of hyaluronic acid (5mL of 1.2mg/mL aqueous solution) were mixed and stirred for 10 minutes, pH was adjusted to 10, and then 15mL of absolute ethanol and 120. mu.l of tetraethoxysilane were added and stirred at 2,500 rpm. + -. 50rpm for 10 hours.
By observing the morphology through an electron microscope, as shown in fig. 1, the silica (gray area) and the hyaluronic acid (black area) can be respectively clear, and the silica is coated outside the hyaluronic acid.
Example 2 degradation test
The hyaluronic acid-based carrier prepared in example 1 was left in the tissue fluid for 5 minutes or more, and the form of the hyaluronic acid-based carrier was observed, as shown in fig. 2. As shown in fig. 2, hyaluronic acid absorbs liquid and swells, and then the silica layer is broken, hyaluronic acid expands to the outside, and the particle state disappears, and the boundary between silica and hyaluronic acid is difficult to be washed and recognized.
Example 3 Water swelling test
Water absorption test: taking 0.2g of sample into a dry bag, weighing the dry bag by using an electronic balance (m1), slowly dripping distilled water until the sample does not absorb water any more, squeezing off excessive water, weighing the sample by using the electronic balance (m2), and calculating the water absorption rate Q according to the following formula, wherein the result shows that the water absorption expansion of the hyaluronic acid is an important factor for cracking the drug carrier.
Example 4 cytotoxicity assays
MTT method is adopted to research the growth inhibition of hyaluronic acid-based drug carrier on fibroblasts and embryonic stem cells. The result shows that the biocompatibility is good, and no obvious toxic effect exists. See fig. 3.
Sequence listing
<110> Shanghai university of traffic medical college affiliated ninth people hospital
<120> hyaluronic acid-based carrier and application of preparation method thereof in scar resistance
<141>2019-08-14
<160>1
<170>SIPOSequenceListing 1.0
<210>1
<211>31
<212>PRT
<213>Artificial Sequence
<400>1
Gln Gln Gln Gln Gln Gln Ala Asn Phe Ser Leu Gly Pro Ser Pro Trp
1 5 10 15
Ile Trp Ser Leu Asp Thr Gln Trp Ser Arg Val Leu Ala Leu Trp
20 25 30
Claims (10)
1. A hyaluronic acid-based carrier characterized by being in the form of particles having an average particle diameter of 80nm + -10 nm, and being coated with silica on a hyaluronic acid matrix.
2. The hyaluronic acid-based carrier according to claim 1, characterized in that the silica is coated on the hyaluronic acid matrix using a silanization reagent.
3. The hyaluronic acid-based carrier of claim 1, characterized in that magnetic particles are also loaded within the hyaluronic acid matrix.
4. The hyaluronic acid-based carrier according to claim 1, wherein the hyaluronic acid-based carrier has a imbibing effect and gradually swells after imbibing, and the coated silica is visibly broken after 5 minutes, and the hyaluronic acid matrix is spread outward.
5. Use of a hyaluronic acid-based carrier according to any of claims 1-4 for the preparation of an anti-scarring drug or cosmetic.
6. An anti-scar product, characterized in that an anti-scar compound is used as an active ingredient, and the hyaluronic acid-based carrier of claims 1-4 is loaded in the hyaluronic acid-based carrier.
7. Anti-scarring product according to claim 6, characterised in that said anti-scarring compound is represented by SEQ ID No 1.
8. A method for preparing a hyaluronic acid-based carrier for anti-scarring, comprising:
mixing and stirring a compound with anti-scar activity and hyaluronic acid, adjusting the pH to be more than 7, adding absolute ethyl alcohol and a silanization reagent, and stirring at 2 rpm +/-50 rpm for 10 hours +/-0.5 hours; .
Adding 120 mu l of the silylation reagent into every 15ml of the absolute ethyl alcohol, wherein the alkylation reagent is tetraethoxysilane.
9. The method for preparing a hyaluronic acid-based carrier for anti-scarring according to claim 8, wherein the compound having the anti-scarring activity and the hyaluronic acid are used in an amount of 1: 6 by weight.
10. The method for preparing a hyaluronic acid-based carrier for anti-scarring according to claim 8, characterized in that the compound having an anti-scarring activity is represented by SEQ ID No 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910771137.XA CN111281978A (en) | 2019-08-19 | 2019-08-19 | Hyaluronic acid-based carrier and application of preparation method thereof in anti-scar |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910771137.XA CN111281978A (en) | 2019-08-19 | 2019-08-19 | Hyaluronic acid-based carrier and application of preparation method thereof in anti-scar |
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| CN111281978A true CN111281978A (en) | 2020-06-16 |
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| CN201910771137.XA Pending CN111281978A (en) | 2019-08-19 | 2019-08-19 | Hyaluronic acid-based carrier and application of preparation method thereof in anti-scar |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010081800A2 (en) * | 2009-01-13 | 2010-07-22 | Pharmasurgics In Sweden Ab | New pharmaceutical compositions |
| CN107019706A (en) * | 2017-03-31 | 2017-08-08 | 福州大学 | A kind of cis-platinum aldehyde radical hyaluronic acid nanometer compound and preparation method thereof |
| CN110123741A (en) * | 2019-06-24 | 2019-08-16 | 中国医学科学院基础医学研究所 | A kind of iron cross-linked-hyaluronic acid nanogel, preparation method and purposes |
-
2019
- 2019-08-19 CN CN201910771137.XA patent/CN111281978A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010081800A2 (en) * | 2009-01-13 | 2010-07-22 | Pharmasurgics In Sweden Ab | New pharmaceutical compositions |
| CN107019706A (en) * | 2017-03-31 | 2017-08-08 | 福州大学 | A kind of cis-platinum aldehyde radical hyaluronic acid nanometer compound and preparation method thereof |
| CN110123741A (en) * | 2019-06-24 | 2019-08-16 | 中国医学科学院基础医学研究所 | A kind of iron cross-linked-hyaluronic acid nanogel, preparation method and purposes |
Non-Patent Citations (1)
| Title |
|---|
| MO-ZHEN WANG ET AL.: "Preparation of Hollow Silica Microspheres via Poly(N-isopropylacrylamide)" * |
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Application publication date: 20200616 |