WO2012144678A1 - 생체적합성 히알루론산 가교물을 포함하는 약물 전달 조성물 - Google Patents

생체적합성 히알루론산 가교물을 포함하는 약물 전달 조성물 Download PDF

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Publication number
WO2012144678A1
WO2012144678A1 PCT/KR2011/003070 KR2011003070W WO2012144678A1 WO 2012144678 A1 WO2012144678 A1 WO 2012144678A1 KR 2011003070 W KR2011003070 W KR 2011003070W WO 2012144678 A1 WO2012144678 A1 WO 2012144678A1
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WO
WIPO (PCT)
Prior art keywords
hyaluronic acid
drug delivery
delivery composition
drug
hydrogel
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PCT/KR2011/003070
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English (en)
French (fr)
Korean (ko)
Inventor
김은진
신일균
김동곤
Original Assignee
주식회사 엠아이텍
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Publication of WO2012144678A1 publication Critical patent/WO2012144678A1/ko

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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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • 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
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a composition comprising a biocompatible hyaluronic acid crosslinked product.
  • hydrogels are suitable for constructing similar substrates for such tissue engineering.
  • the hydrogel's properties allow for excellent flow of nutrients into cells and product flow outside the cells to promote cell adhesion, proliferation and growth in hydrogels.
  • the main characteristics are the possibility of modifying the surface by bonding.
  • Hyaluronic acid generally has a molecular weight of about 1,000 ⁇ 10,000,000 Da and has the unique physicochemical properties and specific biological functions as mentioned above.
  • the hyaluronic acid-based biomaterial is very suitable as a tissue support for biocompatibility and cell growth induction. Nevertheless, hyaluronic acid alone is not very elastic and has a disadvantage in that it easily breaks down. Limited. In addition, the surfaces of these skeletons are so hydrophilic that they have poor adhesion and cell differentiation. For this reason, a method of modifying hyaluronic acid by mixing or crosslinking hyaluronic acid with biocompatible natural polymers such as collagen and gelatin, or by modifying hyaluronic acid with a hydrophobic group has been proposed.
  • crosslinking agent A small amount of crosslinking agent must be used to obtain biomaterials for physiological use and sufficient purification is required when using an excess of crosslinking agent. It is also important that the crosslinking agent used does not itself cause toxicity to the living body.
  • Background Art Many biocompatible polymer materials have been of interest as carriers for efficiently transporting drugs into the human body. Various techniques have been developed for the purpose of increasing the bioabsorption rate of the existing drug, or targeted drug delivery to release the drug specifically to the required area.
  • S. Patent No. 5416071 discloses a sustained release formulation of interferon, including hyaluronic acid and plasma protein, but reported that blood concentration rapidly decreased to 1/10 of the initial concentration within 24 hours.
  • hyaluronic acid microparticles were prepared, coated with a lipophilic substance such as lecithin, and then dispersed in oil to control drug release.
  • oil in water of lecithin-coated microparticles was controlled. emulsion). Therefore, there is a need for the development of formulations and compositions that exhibit excellent sustained release effects over a period of time while maintaining the physiological activity of protein drugs.
  • the present invention was created to solve the problems of the prior art as described above, it is possible to physically enclose a protein drug or anti-inflammatory drug and to control the drug release, such as inducing drug release for a certain period of time to effect the effect of the drug It is an object of the present invention to provide an excellent drug delivery composition including a hydrogel by cross-linking of hyaluronic acid polymer that maximizes and solves the cytotoxicity problem generated during crosslinking.
  • the biodegradable polymer is characterized in that it is selected from homopolymers of lactic acid having a molecular weight ranging from 6,000 to 100,000, copolymer derivatives of lactic acid and glycolic acid, or mixtures thereof.
  • the anti-inflammatory drug is characterized in that it is selected from the group consisting of pyroxicam, meloxium, ibuprofen, metoprofen, diclofenac, indomethacin, tetracycline, monocycline, doxycycline and mixtures thereof.
  • the present invention has the following effects.
  • the drug delivery composition according to the present invention may exhibit long-term persistence while the protein drug or anti-inflammatory agent maintains biological activity.
  • the drug delivery composition according to the present invention can be prepared in a biocompatible, biodegradable scaffold to control the inflammatory response that may occur when the biomaterial is inserted into the human body as a support for tissue engineering to increase histological healing power.
  • the manufacturing process for the final composition is simple and simple compared to other methods, the manufacturing cost can be much reduced.
  • 1 is a graph showing the water content according to the weight fraction of hyaluronic acid in the cross-linked hyaluronic acid / polysaccharide hydrogel component.
  • Figure 2 is a cytotoxicity test results of hyaluronic acid and cross-linked hyaluronic acid hydrogel prepared by the present invention.
  • 1% (w / v) hyaluronic acid solution was prepared and 50mM EDC (1-Ethyl-3- (3-dimethylaminopropyl) -carbodiimide) was added thereto, and the solution was stirred at 4 o C for 24 hours. Thereafter, 1% (w / v) gelatin solution was mixed, stirred well for about 5 minutes, and then crosslinked for 6 hours. pH was adjusted to 7.4.
  • 1% (w / v) hyaluronic acid solution was prepared and 50mM EDC (1-Ethyl-3- (3-dimethylaminopropyl) -carbodiimide) was added thereto, and the solution was stirred at 4 o C for 24 hours. Thereafter, the 1% (w / v) collagen solution was mixed and stirred well for about 5 minutes, and then crosslinked for 6 hours. pH was adjusted to 7.4.
  • the water content of the hydrogel was stably increased between 20 to 80% by weight of the hyaluronic acid in the crosslinked hyaluronic acid hydrogel.
  • These experimental results were confirmed in all crosslinked hydrogels such as gelatin, chitosan and collagen. This confirms that the basic swelling characteristics that should be present as drug carriers are relatively well implemented.
  • aqueous solution was prepared by using albumin powder at a constant concentration.
  • the crosslinked hyaluronic acid hydrogel was placed therein so that all of the albumin solution was absorbed into the hydrogel.
  • the loading amount of albumin could be adjusted by changing the initial albumin concentration in aqueous solution.
  • Albumin-containing hyaluronic acid hydrogel was dried for 24 hours.
  • the crosslinked hyaluronic acid / gelatin hydrogel prepared as in Preparation Example 1 was placed in an aqueous albumin solution so that all the albumin solution was absorbed into the hydrogel.
  • the crosslinked hyaluronic acid collagen hydrogel containing albumin was dried for 24 hours.
  • the crosslinked hyaluronic acid / chitosan hydrogel prepared as in Preparation Example 3 was placed in an aqueous albumin solution so that all the albumin solutions were absorbed into the hydrogel.
  • Albumin-sealed crosslinked hyaluronic acid / collagen hydrogel was dried for 24 hours.
  • the crosslinked hyaluronic acid / collagen hydrogel prepared as in Preparation Example 4 was placed in an albumin aqueous solution so that all the albumin solutions were absorbed into the hydrogel.
  • the crosslinked hyaluronic acid collagen hydrogel containing albumin was dried for 24 hours.
  • the albumin-containing crosslinked hyaluronic acid / gelatin hydrogel was placed in PBS at 37 ° C. and a predetermined amount of solution was taken at a predetermined time to measure the amount of albumin released from the hyaluronic acid hydrogel using a UV spectrometer (FIG. 3).
  • a 1% w / v hyaluronic acid solution was prepared at room temperature, followed by adding 1 mol% adipic dihydrazide and mixing at room temperature to proceed the crosslinking reaction.
  • the cross-linked hyaluronic acid prepared by using adipic dihydrazide (AD) as a crosslinking agent was sufficiently washed with distilled water and then crosslinked hyaluronic acid was dried in a vacuum dryer and subjected to cytotoxicity experiments in the same manner as in Experimental Example 2. ( Figure 2)
  • hyaluronic acid cross-linked using adipic dihydrazide (AD) and poly (ethylene glycol) diglycidyl ether (PEGDE) as crosslinking agents showed cytotoxicity potential from very low cellular activity compared to control. Therefore, the composition according to the present invention was found to be extremely safe in order to be implanted or injected in vivo to express the pharmaceutical function.
  • hyaluronic acid / gelatin hyaluronic acid / chitosan cross-linked hydrogel prepared using EDC as shown in Figure 2, although the general differentiation and proliferation of cells after 24 hours has been confirmed using AD and PEGDE as a crosslinking agent Hyaluronic acid cross-linked products have been shown to inhibit cell proliferation due to toxicity.
  • a 1% w / v hyaluronic acid solution was prepared at room temperature, mixed with an aqueous albumin solution to prepare hyaluronic acid containing albumin, and then dried for 48 hours.
  • the amount of drug released from hyaluronic acid cross-linked hyaluronic acid prepared by the present invention shows a slowly increasing pattern over 12 hours.
  • the initial drug burst occurred in the non-crosslinked hyaluronic acid and drug mixture phase.
  • the hyaluronic acid / polysaccharide cross-linked hydrogel as shown in Figure 4 when changing the weight fraction of hyaluronic acid in the cross-linked hydrogel was confirmed the effect on drug release.
  • the weight fraction of hyaluronic acid in the cross-linked hydrogel is 30 to 80%, the drug is slowly released over 12 hours, but when 20% or less, or 90% or more, it was confirmed that the drug release mechanism was not expressed.
PCT/KR2011/003070 2011-04-19 2011-04-27 생체적합성 히알루론산 가교물을 포함하는 약물 전달 조성물 WO2012144678A1 (ko)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020110035989A KR101379380B1 (ko) 2011-04-19 2011-04-19 생체적합성 히알루론산 가교물을 포함하는 약물 전달 조성물
KR10-2011-0035989 2011-04-19

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WO (1) WO2012144678A1 (zh-CN)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10369101B2 (en) 2013-03-15 2019-08-06 Latitude Pharmaceuticals Inc. Parenteral diclofenac composition
CN115427023A (zh) * 2020-02-03 2022-12-02 Mnh生物技术株式会社 用于治疗听力损失的控释配制物及其制备方法

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101477021B1 (ko) * 2013-03-20 2014-12-30 강릉원주대학교산학협력단 약물이 탑재된 치과용 나노섬유 칩의 제조방법
KR101806735B1 (ko) * 2015-09-11 2017-12-07 성균관대학교산학협력단 약물 전달용 조성물 및 이의 제조 방법
KR101877894B1 (ko) * 2016-12-09 2018-07-12 서울대학교병원 난청 치료용 복합 주사 제제 및 그의 제조 방법
KR102201482B1 (ko) * 2019-07-29 2021-01-13 주식회사 피움바이오 주입력이 우수한 가교된 히알루론산 기반 기능성 생체 적합성 고분자 복합체의 제조 방법
WO2024049058A1 (ko) * 2022-09-01 2024-03-07 (주)시지바이오 경조직 재생용 조성물

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050226937A1 (en) * 1998-06-01 2005-10-13 Chiron Corporation Use of hyaluronic acid polymers for mucosal delivery of vaccine and adjuvants
US20060024373A1 (en) * 2000-11-14 2006-02-02 N.V.R. Labs Ltd. Cross-linked hyaluronic acid-laminin gels and use thereof in cell culture and medical implants
US20060280797A1 (en) * 2005-04-25 2006-12-14 Shoichet Molly S Blends of temperature sensitive and anionic polymers for drug delivery
WO2009005790A2 (en) * 2007-06-29 2009-01-08 Carbylan Biosurgery, Inc. Sterile thiol-derivatized hyaluronic acid polymer compositions and uses thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050226937A1 (en) * 1998-06-01 2005-10-13 Chiron Corporation Use of hyaluronic acid polymers for mucosal delivery of vaccine and adjuvants
US20060024373A1 (en) * 2000-11-14 2006-02-02 N.V.R. Labs Ltd. Cross-linked hyaluronic acid-laminin gels and use thereof in cell culture and medical implants
US20060280797A1 (en) * 2005-04-25 2006-12-14 Shoichet Molly S Blends of temperature sensitive and anionic polymers for drug delivery
WO2009005790A2 (en) * 2007-06-29 2009-01-08 Carbylan Biosurgery, Inc. Sterile thiol-derivatized hyaluronic acid polymer compositions and uses thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10369101B2 (en) 2013-03-15 2019-08-06 Latitude Pharmaceuticals Inc. Parenteral diclofenac composition
CN115427023A (zh) * 2020-02-03 2022-12-02 Mnh生物技术株式会社 用于治疗听力损失的控释配制物及其制备方法

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KR20120118559A (ko) 2012-10-29
KR101379380B1 (ko) 2014-04-02

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