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WO2018190613A1 - Composition de poudre hydrogélifiée pour la cicatrisation de plaies et son procédé de production - Google Patents

Composition de poudre hydrogélifiée pour la cicatrisation de plaies et son procédé de production Download PDF

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Publication number
WO2018190613A1
WO2018190613A1 PCT/KR2018/004191 KR2018004191W WO2018190613A1 WO 2018190613 A1 WO2018190613 A1 WO 2018190613A1 KR 2018004191 W KR2018004191 W KR 2018004191W WO 2018190613 A1 WO2018190613 A1 WO 2018190613A1
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Prior art keywords
wound
powder composition
parts
weight
powder
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PCT/KR2018/004191
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English (en)
Korean (ko)
Inventor
유진욱
이주호
Original Assignee
부산대학교 산학협력단
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Priority claimed from KR1020180019353A external-priority patent/KR102086150B1/ko
Application filed by 부산대학교 산학협력단 filed Critical 부산대학교 산학협력단
Publication of WO2018190613A1 publication Critical patent/WO2018190613A1/fr

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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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form

Definitions

  • the present invention relates to a powder composition for treating wounds that is hydrogelized when applied to a wound and a method for preparing the wound.
  • a wound is a state in which the anatomical continuity of a human tissue has lost its original continuity by external action.
  • our skin is composed of epidermis, dermis, and subcutaneous fat, and the loss of continuity such as epidermis, dermis, and subcutaneous fat by trauma such as cut or falling is called wound.
  • wound dressing In general, dressing is used to effectively treat wounds of the skin such as wounds and traumas.
  • Wound dressings have the following characteristics: adequate moisture retention in contact with wounds, ability to control wound discharge, ease of attachment and removal of dressings to wounds, air and vapor permeability between external wounds, external Insulation of wounds, resistance to bacteria invasion, non-toxicity to human body, excellent mechanical properties, etc. are required.
  • GSNO S-nitrosoglutathione
  • a hydrogel-type formulation may be more useful than a film-type formulation.
  • most nitric oxide donors including S-nitrosoglutathione have high moisture content. Since it is unstable and rapidly decomposed in an environment, there is a problem that it is very difficult to ensure the stability of the formulation to be formulated into a film.
  • the powder is excellent in stability, but can not provide a wet environment of the wound site, there is a problem that it is difficult to maintain a concentration that can maintain a therapeutic effect for a long time because the release pattern of NO also rapidly made.
  • S-Nitrosoglutathione S-nitrosoglutathione
  • Another object of the present invention is to provide a method for preparing a powder composition for treating wounds that is hydrogelized rapidly upon application of wounds.
  • the present invention provides a powder composition for wound treatment comprising S-nitrosoglutathione (GSNO), alginate salt, pectin and polyethylene glycol (PEG) as an active ingredient do.
  • GSNO S-nitrosoglutathione
  • alginate salt alginate salt
  • pectin polyethylene glycol
  • PEG polyethylene glycol
  • the present invention comprises the steps of (1) grinding each of the powder form of GSNO, alginate salt, pectin and PEG; (2) mixing all the pulverized products prepared in step (1); And (3) passing the mixture prepared in step (2) through a sieve.
  • the present invention relates to a powder composition for treating wounds and a method for producing the same which is hydrogelized when applied to a wound, and the powder composition of the present invention can be hydrogelized to effectively treat a wound area having a larger area than a film-type preparation.
  • the exudates such as bedsores and burns are more susceptible to infections and have wider potential for wounds than conventional commercialized products.
  • the manufacturing process is simple and easy for mass production, and is also stable at room temperature when stored in a sealed container.
  • Figure 1 shows the moisture absorption and thus the morphological changes of the nitric oxide-containing wound treatment powder composition to be hydrogelized when applying the wound of the present invention.
  • Figure 2 shows the storage stability of the powder composition of the present invention.
  • Pseudomonas Pseudomonas of the powder composition of the present invention aeruginosa shows wound healing test results in an infected animal model.
  • Figure 7 shows the results of the quantification of bacteria in the wound in the in vivo animal model.
  • Figure 8 shows the results of the Wort's gram staining on the wound surface at 14 days after the start of treatment (normal skin (A), untreated group (B, C), powder carrier treated group (D) , Powder composition treatment group (E) of the present invention).
  • Figure 9 shows a comparison of the degree of tissue recovery through histological staining (A, B, C, D is H & E staining, E, F, G, H is a Masson's trichrome staining technique, A , E is a normal tissue, B, F is an untreated group, C, G is a group treated only with a powder carrier, D, H is a group treated with a powder composition of the present invention E: epidermis, F: fiber Fibrous tissue G: granulation tissue, H: hair follicle, I: immune cells, M: muscle).
  • the wound recovery is excellent and the antimicrobial effect can be effectively converted into gel form by effectively absorbing exudates at the wound site, which is why the present invention is more effective than film-type preparations.
  • the present invention has been completed by discovering that powder formulations may be useful for treating large area wounds.
  • the present invention provides a powder composition for wound treatment comprising S-nitrosoglutathione (S-Nitrosoglutathione; GSNO), alginate salt, pectin, and polyethylene glycol (PEG) as an active ingredient.
  • S-Nitrosoglutathione S-Nitrosoglutathione
  • GSNO S-nitrosoglutathione
  • alginate salt alginate salt
  • pectin polyethylene glycol
  • alginate is used as a gelling agent, so that the nitric oxide donor GSNO having a wound healing promoting effect and an antibacterial effect can absorb the exudates at the wound site and quickly change into a gel form, thereby forming hydrogel in in situ. It is possible.
  • the main active ingredient in the powder composition is a nitric oxide donor that is also present in the body, and is involved in cell differentiation, collagen synthesis, and the like by nitric oxide (NO) generated during decomposition, thereby promoting and helping to recover from a wound.
  • NO nitric oxide
  • the oxidative stress caused by the nitric oxide generated has an antimicrobial effect, and this mechanism rarely causes resistance and exhibits an antimicrobial effect without a gram negative / positive distinction and thus is suitable for use in skin wound infection.
  • the powder composition based on 100 parts by weight of the powder composition, 2 parts by weight of GSNO to 10 parts by weight, 10 parts to 40 parts by weight of alginate salt, 5 parts to 20 parts by weight of pectin and 50 parts by weight to PEG
  • 2 parts by weight of GSNO to 10 parts by weight 10 parts to 40 parts by weight of alginate salt, 5 parts to 20 parts by weight of pectin and 50 parts by weight to PEG
  • the numerical range it can be included in the 80 parts by weight, it is preferable because the modification to the uniform and durable gel at the wound site is made quickly, and the wound healing effect is maximized.
  • the GSNO: alginate salt: pectin: PEG may be included in a weight ratio of 4: 21: 11: 64.
  • the powder composition may be modified in a hydrogel form within 1 to 3 minutes at the wound site, the powder composition according to the present invention solves the problems appearing in powder form or film form, all of the advantages of each form Can be represented.
  • the powder composition is used to treat wounds by slowly releasing nitric oxide (NO) at the wound site, or Pseudomonas aeruginosa ) or methicillin-resistant Staphylococcus aureus (MRSA) exhibits antimicrobial activity against any one or more of the bar can be treated wound, in one embodiment of the present invention, the powder composition of the present invention.
  • NO nitric oxide
  • MRSA methicillin-resistant Staphylococcus aureus
  • the sustained release of nitric oxide was improved, and the bactericidal effect of more than 99.99% was observed for two species of Gram-positive bacteria, MRSA and Gram-negative bacteria, P. aeruginosa , which are the most problematic infections in the hospital.
  • the wound may be any one or more selected from abrasions, lacerations, burns, cuts, cuts, crystallizations, penetrating wounds, and left wounds, but is not limited thereto.
  • the present invention comprises the steps of (1) milling GSNO, alginate salt, pectin and PEG in powder form, respectively; (2) mixing all the pulverized products prepared in step (1); And (3) passing the mixture prepared in step (2) through a sieve.
  • the sieve may be a porous structure having an average diameter of 80 ⁇ m to 100 ⁇ m, but is not limited thereto.
  • the prepared wound composition may include GSNO: alginate salt: pectin: PEG in a weight ratio of 4: 21: 11: 64.
  • GSNO, sodium alginate, pectin and PEG were first ground to a standard No. 170 (average diameter of the hole is 90 ⁇ m). Thereafter, GSNO: alginate salt: pectin: PEG was mixed at a weight ratio of 4: 21: 11: 64, and then passed through No. 170 to prepare a powder composition for wound treatment according to the present invention.
  • a gelling powder (Comparative Example 1) prepared by mixing GSNO, sodium alginate, pectin, and PEG (MW: 8000) without grinding in the same weight ratio was used.
  • sodium alginate: pectin: PEG were prepared by mixing in a weight ratio of 2: 1: 6.
  • the in vitro test method was as follows: First, the cellulose membrane was contacted on a simulated wound fluid (SWF) mimicking the wound exudate, and then 40 mg of the powder composition prepared in Example 1 was added to cellulose. Evenly distributed over the membrane. At this time, since the water molecules are diffused over the cellulose membrane and absorbed in the powder composition, the photographs were taken every designated time, and the weight of the absorbed fluid (exudate) was measured.
  • SWF simulated wound fluid
  • Example 1 storage stability was analyzed.
  • the specific experimental method was as follows: The powder composition prepared in Example 1 was placed in a microtube of 10 mg each and then placed in a 4 ° C. refrigerator and 37 ° C. incubator. Thereafter, three microtubes were taken out at regular intervals, dissolved in water, and the absorbance at 335 nm was measured using an ultraviolet visible absorbance spectrometer to quantify and compare the amount of GSNO.
  • the amount of GNSO released according to the degree of moisture absorption was confirmed. Specifically, the following experimental method was carried out: 50 mg of the powder composition prepared in Example 1 was uniformly dispersed on the bottom of a 2 ml microtube having a flat bottom surface, and the exudate was absorbed less (200% absorption). ), The most absorbed state (350%), and the amount of SWF that would have been exposed to more exudates (500%) than the absorbable amount was added to each tube. Thereafter, three microtubes were taken in a 37 ° C. incubator and dissolved in water, and then the remaining amount of GSNO was measured and analyzed using an ultraviolet-visible spectrophotometer.
  • the antimicrobial experiment was performed in vitro with respect to the powder composition prepared in Example 1. Specifically, the following experimental method was carried out: P. aeruginosa (PAO1, purchased from KCTC) and MRSA (USA 300, purchased from ATCC) were incubated for 12 hours, and then the maximum absorption amount was prepared in Example 1 10 8 CFU / ml bacteria were added to the powder composition and incubated for 24 hours, and the CFU was measured and compared. In addition, using the Baclight live / dead kit was stained bacteria exposed to the powder composition prepared in Example 1 for 24 hours, photographed by confocal laser fluorescence microscope.
  • P. aeruginosa P. aeruginosa
  • MRSA USA 300
  • the wound recovery ability was confirmed in the bacterial infection ICR mouse model. Specifically, the following experimental methods were carried out: 6-week-old ICR mice were purchased, acclimated for 1 week, then anesthetized and hair removed. Whole layer wounds were created using 8 mm biopsy punches on the back, and 10 9 CFU of P. aeruginosa was added to each wound, and the wounds were sealed and left for 2 days to make infected whole layer wounds. Thereafter, every two days, the powder composition prepared in Example 1, the powder composition without GSNO (powder carrier) and the untreated group were divided into a total of three groups, and photographed each time, the size was compared and analyzed. It was.
  • the number of bacteria in the wound in the mouse model was quantified.
  • the following experimental methods were performed: 6-week-old ICR mice were purchased, acclimated for 1 week, anesthetized, and hair was removed.
  • Whole layer wounds were created using 8 mm biopsy punches on the back, and 10 9 CFU of P. aeruginosa was added to each wound, and the wounds were sealed and left for 2 days to make infected whole layer wounds.
  • the powder composition prepared in Example 1 and the powder composition without GSNO (powder carrier) were divided into a total of three groups of non-treated groups, and euthanized three mice every fixed day to tear off the wound site. Finely ground and diluted, P. aeruginosa
  • the bacteria were cultured in cetrimide medium where only bacteria were selectively grown, and CFU was measured.
  • Hematoxylin & Eosin staining H & E staining
  • Mason's trichrome staining technique masson's trichrome staining
  • H & E staining hematoxylin and eosin were sequentially stained, and in the case of Mason's trichrome staining, staining was performed according to the staining method sequence provided by ABCAM. Thereafter, tissues were compared, observed and photographed at a magnification of 200 times using an optical microscope.
  • Example 1 The content uniformity of the powder composition prepared in Example 1 and Comparative Example 1 prepared without undergoing grinding was confirmed. That is, each powder was unfolded and randomly sampled at 10 places to measure the content of GSNO. At this time, the weight of the powder of about 10 mg was measured and dissolved in water, and the absorbance at 335 nm by using an ultraviolet visible spectrophotometer to measure and compare the content of GSNO. In addition, the Hausner ratio calculated
  • Example 1 As a result, as shown in FIG. 10, the powder composition of Example 1, which was subjected to the grinding process, was found to have a more uniform distribution of GNSO, thereby preparing a highly uniform formulation. Since the fluidity is lowered in, it was confirmed that when applied to the actual wound it can further reduce the phenomenon of the powder flowing down before it turns into a gel.
  • Powder carrier compositions containing various gelling agents were prepared in the same manner as in Example 1 except that GSNO was not mixed in order to determine whether the gelling ability was different when using other gelling agents instead of alginate. .
  • GSNO hyaluronic acid, carrageenan, poloxamer, gelatin, guar gum, CMC-Na or chitosan are used instead of alginate as a gelling agent, respectively.
  • a powder carrier composition of Comparative Examples 2 to 8. At this time, the content ratio of each composition was the same as the excipient ratio except the GSNO of the powder composition of Example 1, the gelling agent: pectin: PEG 2: 1: 6.
  • the gelling agent except for alginate and hyaluronic acid is 10 minutes until gel formation. Since the above has passed, it can be seen that it is not suitable as a gelling agent of the in situ hydrogel-forming powder. In other words, alginate and hyaluronic acid showed in situ hydrogel formation, but hyaluronic acid showed a slower gelation rate than alginate, and thus alginate was the most optimal gelling agent for rapid gel formation.
  • Sample Average gel formation time S.D Remarks Alginate 0.86 minutes 0.11 NO / GP Hyaluronate 3.27 minutes 0.17 - Carrageenan Not suitable (10 minutes or more) - Not suitable for in situ hydrogel forming powder formulations which must form gels quickly Poloxamer Not suitable (10 minutes or more) - Gelatin Not suitable (10 minutes or more) - Guar gum Not suitable (10 minutes or more) - CMC-Na Not suitable (10 minutes or more) - Chitosan Not suitable (10 minutes or more) -
  • a powder composition is prepared according to the method described in Example 1, but the alginate content is 10% (relative to the total weight), and the effect is verified.
  • a powder containing 2% GSNO and a powder containing 10% GSNO were prepared.
  • the GSNO: alginate salt: pectin: PEG as a content ratio was prepared so that 2: 10: 5: 83 and 10: 10: 5: 75.
  • a powder containing 40% alginate was prepared (GSNO: alginate salt: pectin: PEG 4: 4: 20: 36), and in Example 1 The mouse animal model was treated in the same manner as the prepared powder composition.
  • the specific experimental method was as follows: 6 weeks old ICR mice were purchased and allowed to acclimate for 1 week, followed by anesthesia and hair removal. Whole layer wounds were made using 8 mm biopsy punches on the back, and the drug was treated into the above-mentioned drug and GSNO-free carrier powder composition, and the non-treated group, and the drugs were taken and photographed every two days to compare and analyze the size. .
  • the specific method was as follows: Each powder prepared was evenly spread by 50 mg in a small dish, and then 1 ml of distilled water was evenly added to observe and photograph the shape of the gel formed.

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  • Engineering & Computer Science (AREA)
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Abstract

La présente invention concerne une composition de type poudre pour la cicatrisation des plaies comprenant du S-nitrosoglutathion (GSNO), un sel d'alginate, de la pectine et du polyéthylène glycol (PEG) à titre de principes actifs, et son procédé de production. L'utilisation par la présente invention de GSNO en association avec un système formant hydrogel in situ basé sur un alginate ayant une capacité appropriée de libération contrôlée de médicament permet à la composition de présenter les avantages à la fois d'un acide et d'un film de sorte que la stabilité de la formulation est élevée en stockage ; qu'elle peut rapidement se convertir en gel pour couvrir une plaie ou créer un environnement humide quand elle est appliquée sur une plaie ; qu'elle peut efficacement éliminer les germes présents dans les plaies exsudatives ; et peut favoriser la cicatrisation des plaies par promotion de la différenciation cellulaire et synthèse de collagène.
PCT/KR2018/004191 2017-04-10 2018-04-10 Composition de poudre hydrogélifiée pour la cicatrisation de plaies et son procédé de production WO2018190613A1 (fr)

Applications Claiming Priority (4)

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KR20170046153 2017-04-10
KR10-2017-0046153 2017-04-10
KR10-2018-0019353 2018-02-19
KR1020180019353A KR102086150B1 (ko) 2017-04-10 2018-02-19 하이드로겔화 되는 창상 치료용 파우더 조성물 및 이의 제조방법

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113398062A (zh) * 2021-06-18 2021-09-17 苏州大学 促进创面愈合的可吸收水凝胶组合物及其制备方法与应用
CN115252884A (zh) * 2022-07-11 2022-11-01 湖北工业大学 一种粉剂组合物及在制备宠物伤口粉剂敷料中的应用

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KR20050077464A (ko) * 2004-01-28 2005-08-02 최재철 대나무 표피 분말을 포함하는 화상치료제 및 이의 제조방법
KR20100021564A (ko) * 2007-03-27 2010-02-25 노랩스 에이비 산화 질소 전달을 위한 국소 피부 전달 장치
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113398062A (zh) * 2021-06-18 2021-09-17 苏州大学 促进创面愈合的可吸收水凝胶组合物及其制备方法与应用
CN115252884A (zh) * 2022-07-11 2022-11-01 湖北工业大学 一种粉剂组合物及在制备宠物伤口粉剂敷料中的应用

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