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WO1996007420A1 - Composition stimulant les macrophages contenant un tensio-actif non ionique - Google Patents

Composition stimulant les macrophages contenant un tensio-actif non ionique Download PDF

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Publication number
WO1996007420A1
WO1996007420A1 PCT/GB1995/002077 GB9502077W WO9607420A1 WO 1996007420 A1 WO1996007420 A1 WO 1996007420A1 GB 9502077 W GB9502077 W GB 9502077W WO 9607420 A1 WO9607420 A1 WO 9607420A1
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WO
WIPO (PCT)
Prior art keywords
ionic surfactant
poloxamer
poloxamine
use according
administration
Prior art date
Application number
PCT/GB1995/002077
Other languages
English (en)
Inventor
Seyed Moein Moghimi
Stanley Stewart Davis
Original Assignee
The University Of Nottingham
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by The University Of Nottingham filed Critical The University Of Nottingham
Priority to AU33940/95A priority Critical patent/AU3394095A/en
Publication of WO1996007420A1 publication Critical patent/WO1996007420A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/77—Polymers containing oxygen of oxiranes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen

Definitions

  • Mononuclear phagocytes are widely distributed in the body, being present in blood, bone marrow, connective tissue, liver, lungs, lymphoid tissue, nervous tissue and serous cavities. These cells constitute an important part of the defence mechanism of the body (the reticuloendothelial system, RES) by clearing the blood, the lymph and other tissues of particulate pollutants, for instance microorganisms and damaged body constituents.
  • RES reticuloendothelial system
  • the RES also participates in a myriad of other host functions such as secretion of numerous biochemical products that affect a wide range of functions (complement components, coagulation factors, colony stimulating factors, enzymes like lysozyme and elastase, enzyme inhibitors such as plasmin, serum amyloid A and P factors, etc.), determining the host response to he orrhagic, traumatic, septic and endotoxin shock, burns, surgery, X-irradiation, prolonged tissue ischemia, response to drugs, bacteria and viral infections, tumour growth, atherosclerosis and immunological depression (reviewed by Altura, B. M. , 1980, Adv. Microcirc lation 9, 252).
  • the hepatic Kupffer cells manifest 80-90% of total reticuloendothelial activity, and thus a direct or an indirect depression of Kupffer cell function will have a significant effect on the defence mechanisms of the body.
  • Factors that depress Kupffer cell function, particularly phagocytic function include age, traumatic shock, sepsis, neoplastic diseases, X- irradiation.
  • aflatoxin B alcohol, diabetes, obstructive jaundice, etc.
  • Efforts have been directed to develop systems that can stimulate the phagocytic function of the RES, particularly the Kupffer cells.
  • Factors or signals that activate Kupffer cells include zymosan, glucan (soluble and paniculate forms), estrogen, colony- stimulating factor, lymphokines, somatostatin, Corynebacterium parvum with or without phorbol myristate, endotoxin, bacillus Calmette-Guerin, hydroxyethyl starch, partial hepatectomy and 3-palmitoyl-(-)-)-catechin.
  • Kupffer cell proliferation causes Kupffer cell proliferation and some will cause enhanced expression of certain plasma membrane receptors [reviewed by Jones, E. A. and Summerfield, J.A. In: The Liver - Biology and Pathobiology, (Arias, I. M., Jakoby, W. B., Popper, H., Schachter, D. and Shafritz, D. A., eds). Raven Press, New York, pp 683-704; de V Amsterdam, W. J. S. et al. 1994, J. Exp. Med. 180, 705].
  • Agents that stimulate Kupffer cells increase their ability to mediate cytotoxicity against tumour cells and their antibacterial properties (Nomoto, K. et al. 1985, J. Gin. Lab.
  • Increased respiratory burst activity induced by agents that stimulate Kupffer cells is usually characterized by glucose oxidation via the hexose monophosphate shunt, luminol-dependent chemiluminescence and production of superoxide oxygen and hydrogen peroxide.
  • Kupffer cell phagocytic function Some factors which stimulate Kupffer cell phagocytic function also exert radioprotective activity (usually via production of cytokines). These include a genetically engineered (atypical) ⁇ -glucan from a variant of S. cerevisiae (Alpha Beta Technology, WO9103248-A. 1991), polysaccharides from plant sources, for example extracts of ginseng root (Takeda, A. et al. 1981 , J. Radiat.
  • the present invention therefore provides the use of a substantially endotoxin-free non-ionic surfactant having a molecular weight of 1200 or greater in the manufacture of a medicament for stimulating the phagocytic function of macrophages of the reticuloendothelial system.
  • endotoxin-free we mean that the composition is not toxic when administered in beneficial doses to humans.
  • the endotoxin level is of OJng/ml or below (for example when measured using the Endotec Kit (ICN Biomedical, UK)).
  • the non-ionic surfactant is preferably a polymeric material containing polyethylene oxide or polypropylene oxide or a combination of both subunits at any molar ratio, or contains polyethylene glycol.
  • the non-ionic surfactant may be provided as a conjugate. It is preferably coupled to another biologically active material, such as a protein, peptide, sugar or phospholipid.
  • the non-surfactant part of the conjugate need not itself be immunologically active and, in particular, need not be an immunoglobulin. If the conjugate is itself a non-ionic surfactant then clearly it can be used as it is.
  • the invention also encompasses conjugates or derivatives which are not themselves non-ionic surfactants but which are, for example, metabolized in the body to form or release a non-ionic surfactant following administration. In such a conjugate, it is preferably the surfactant part which has a m.w. of 1200 or greater.
  • Preferred non-ionic surfactants are poloxamers and poloxamines with a molecular weight of 1200 or more, the Pluronic and Tetronic block co- polymers (Registered Trademarks, BASF, USA).
  • Poloxamines are preferred, especially poloxamine-908. Also preferred are polyethylene glycols of molecular weight greater than 1200. Preferred polyoxyethylene-comprising conjugates of surfactants include Tweens 40, 60 and 80 (poloxyethylene sorbitan mono-palmitate, -stearate and -oleate, respectively). The molecular weight of the non-ionic surfactant is preferably at least 3000, more preferably at least 5000 or 10000.
  • Preferred non-ionic surfactants having a molecular weight of 1200 or greater are Pluronics L35, L42, L43, L44, L61, L62, L63, L64, Tetronic 304 and Tween 80.
  • Preferred surfactants having a molecular weight of 3000 or greater are Pluronics F68, F38, F65, P84, P85, F87 and Tetronics 904, 908, 1304, 1307 and 1504.
  • Activation can be achieved by a single administration of 0.3 g/kg body weight or higher of the non-ionic surfactant.
  • the dose will generally be chosen to cause stimulation of the phagocytic function of macrophages within 4 days after administration. The effect can last up to 10 days after administration.
  • the surfactant is administered at 3 mg/kg body weight, more preferably 6 or 18.5 mg/kg body weight.
  • the activation of the RES has been found to be obtained three days after intravenous administration of the polymer solution.
  • the activation is defined as enhanced phagocytosis by macrophages of the RES, particularly the Kupffer cells.
  • the activation is achieved either directly on cells or via cytokine release (hence the polymer may exert radioprotective activity) and may cause proliferation of Kupffer cells and up-regulate certain Kupffer cell plasma membrane antigens and receptors such as ED2 and scavenger receptor respectively. Similar effects may occur on other macrophages (lymph nodes, spleen, etc).
  • the surfactant is preferably administered by intravenous administration, but may also be administered by other parenteral routes such as subcutaneous, intramuscular and intraperitoneal, or non parenteral routes such as orally.
  • the surfactant can be administered in water, saline, or any other non-toxic solution containing electrolytes, for example dextrose or other sugars, as will be appreciated by those skilled in the art.
  • the surfactant may be administered in a solid or liquid dosage form made with standard components known to those skilled in the art.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (compound of the invention) with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations in accordance with the present invention suitable for oral administration may be presented as discrete units such as capsules. -cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (eg povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (eg sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide desired release profile.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouth-washes comprising the active ingredient in a suitable liquid carrier.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the additior of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose or an appropriate fraction thereof, of an active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • the enhanced phagocytic activity of macrophages following administration of the surfactant can be demonstrated by measuring clearance of "phagocyte-resistant" substrates from the blood.
  • substrates include certain poloxamer and poloxamine coated polystyrene and gold particles (Ilium, L., US4904479, Davis, S. S. et al. WO9402122,; Moghimi, S. M. et al. 1983, Biochem. Biophys. Acta 1179, 157) and other sterically-stabilized colloids such as polyethyleneglycol-coated liposomes, etc.
  • test-substrate is below 100 nm in diameter which under normal conditions is not cleared effectively from the blood by organs of the RES.
  • not cleared we mean that there is a total liver uptake of test-substrate of not more than 10-15 % of the administered dose within 3 h after intravenous administration or 2 h after subcutaneous administration by the liver in normal control subjects. In test subjects the following should preferably be achieved:
  • phagocyte-resistant substrate is injected intravenously, within 3 h at least 25% of the administered dose is cleared by the liver (compared to less than 10-15% of the administered dose in control subjects) and 4-5 % of the dose by the spleen (compared to less than 3 % of the administered dose in the control subjects);
  • liver and spleen should retain their ability to efficiently remove "phagocyte-resistant” particles up to 10 days after administration of the polymer.
  • the non-ionic surfactant used in the invention should therefore preferably have minimal effect on the activation of human serum complement activity and preferably should give a residual total complement hemolytic activity of surfactant-treated human serum of 50% or less than that of the residual total complement activity of poloxamer- 188 treated human serum when measured by the method described by Devine, C.V. et al. in 1994 Biochem. Biophys. Acta. 1191, 43.
  • compositions of the invention may be used to enhance the phagocytic activity of macrophages of the RES in any patient who requires a strengthened immune system, for example elderly, malnourished or diabetic patients or patients with compromised immunity because of other illnesses, for example AIDS, and those given immuno-suppressive agents such as cyclosporin.
  • the compositions may also be administered 3-10 days before surgery, especially abdominal surgery, to reduce the risk of post-operative infection.
  • the compositions can also be used to prevent or treat infections, whether viral, bacterial, fungal, protozoal or parasitic, as an alternative to, or as well as, treatment with other anti-infective agents.
  • compositions of the invention include: interfering with the clotting mechanism or reducing the blood viscosity; decreasing the incidence of tumour metastases; reducing the endothelial adherence of tumour cells and improving the rheology of the sickle erythrocytes; and radioprotective activity.
  • FIG. 1 shows the effect of poloxamer-188 and poloxamine-908 on residual total human complement hemolytic activity.
  • Example 1 Removal of any endotoxin associated with polymer solutions was achieved using polymyxin-B-agarose as described in Moghimi. S. M. et al.. 1993 Biochim. Biophys. Acta 1157, 233). Briefly, solutions of non- ionic surfactants (2.0% w/v) were passed ten times through a column of polymyxin-B-agarose. The procedure was repeated to ensure complete removal of endotoxins employing a new column.
  • Endotec Kit ICN Biomedical. UK
  • the kit is based on the Limulus lysate reaction with the endotoxin (the sensitivity is 0.06 - 0J ng/ml).
  • the residual total complement activity of poloxamine-908 was compared to that of poloxamer- 188 treated human serum according to established methods, using sheep erythrocyte stroma sensitized with rabbit antibody as described in detail elsewhere (Devine, D. V. et al., 1994, Biochim. Biophys. Acta 1191, 43).
  • the results are presented in Figure 1.
  • the human serum must have a CH ⁇ , (complement half-life of 50%) of 200-220 units (1 in 30 dilution).
  • Serum was serially diluted to obtain an optimal concentration for the detection of changes in complement levels.
  • the residual complement activity is expressed as a percentage of the hemolytic activity of human serum diluted with the standard DGNB 2+ buffer (isotonic veronal buffered saline).
  • the results show minimum activation of complement by poloxamine-908 when compared to that of poloxamer- 188 (50% or less than that of poloxamer- 188 up to 0J2 ⁇ mole of polymer).
  • Example 2 Groups of three male Wistar rats (body weight 150+ 10 g) were injected intravenously with 18.5 mg/kg of body weight of endotoxin- free poloxamine-908 1.0% (w/v) via the lateral tail vein. Control animals received intravenous administration of sterile saline. At 3 h and then at daily intervals, all animals received an intravenous dose of poloxamine- 908 coated [ I25 I]-radiolabelled polystyrene nanospheres of 60 nm in diameter (Moghimi, S. M. et al., 1993, Biochim. Biophys Acta 1157, 233).
  • Organ distribution of nanospheres were the same in saline-treated rats 3 h and 10 days prior to administration of test-nanospheres.
  • Poloxamine-908 coated nanospheres which are resistant to phagocytosis by lymph node macrophages (Moghimi. S. M. et al. 1994, FEBS Lett. 344, 25), were also sequestered by the phagocytic cells of the subcapsular sinus of the cortex and the classical macrophages of the medulla in both the popliteal and iliac nodes 2 h after subcutaneous administration into the footpad of polymer-treated rats when compared to control animals (data not shown). A large fraction of the nanospheres reached the systemic circulation of both animal groups but only in polymer-treated rats were particles rapidly cleared from the body by Kupffer cells.
  • Example 3 Groups of three male or female Wistar rats (body weight 150 ⁇ 10 g) were injected intravenously with 17 mg/kg body weight of endotoxin-free L31 , PEG-1000. L121 , F68. PEG-20000 and tetronic 908 via the lateral tail-vein. Control animals received i.v. administration of sterile saline. 4 days later all animals received an intravenous dose of poloxamine-908 control ( l2i I)-radiolabelled polystyrene nanospheres of 60nm in diameter. The circulatory activity of nanospheres was monitored and animals were killed 3 hours post administration for the analysis of radioactivity associated with organs of the RES.
  • results demonstrate that polymers with m.w. of less than 1200 are not effective in stimulating nanosphere clearance by liver and spleen.
  • results demonstrate that the most effective polymers in stimulating nanosphere clearance by liver and spleen have m.w. of greater than 3000 (eg. L121 , F68, PEG-20000 and 908).
  • Example 4 The method of Example 3 was repeated using endotoxin-free Tween-80 (sorbitan onooleate (ethylene oxide 20)). The liver and spleen uptake of nanospheres was found to be 31.9 ⁇ 3.6 and 8.9 ⁇ 1.2% of the administered dose. This is compared to values of 7.7 ⁇ 2.5 and 1.6 ⁇ 8.3 for liver and spleen in saline (control) treated animals.
  • Tween-80 sorbitan onooleate (ethylene oxide 20)
  • Poloxamer 181 100 mg Lactose 200 mg Starch 50 mg
  • Tablets are prepared from the foregoing ingredients by wet granulation followed by compression.
  • formulations A and B are prepared by wet granulation of the ingredients with a solution of povidone, followed by addition of magnesium stearate and compression.
  • formulations D and E are prepared by direct compression of the admixed ingredients.
  • the lactose used in formulation E is of the direction compression type.
  • the formulation is prepared by wet granulation of the ingredients (below) with a solution of povidone followed by the addition of magnesium stearate and compression. mg/tablet
  • a capsule formulation is prepared by admixing the ingredients of Formulation D in Example C above and filling into a two-part hard gelatin capsule.
  • Formulation B (infra) is prepared in a similar manner.
  • Capsules are prepared by melting the Macrogol 4000 BP, dispersing the active ingredient in the melt and filling the melt into a two-part hard gelatin capsule. Formulation D mg/capsule
  • Capsules are prepared by dispersing the active ingredient in the lecithin and arachis oil and filling the dispersion into soft, elastic gelatin capsules.
  • the following controlled release capsule formulation is prepared by extruding ingredients a, b, and c using an extruder, followed by spheronisation of the extrudate and drying. The dried pellets are then coated with release-controlling membrane (d) and filled into a two-piece, hard gelatin capsule.
  • the active ingredient is dissolved in most of the phosphate buffer (35- 40°C), then made up to volume and filtered through a sterile micropore filter into a sterile 10 ml amber glass vial (type 1) and sealed with sterile closures and overseals.
  • the active ingredient is dissolved in the glycofurol.
  • the benzyl alcohol is then added and dissolved, and water added to 3 ml.
  • the mixture is then filtered through a sterile micropore filter and sealed in sterile 3 ml glass vials (type 1).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

Un tensioactif non ionique, tel qu'un poloxamère, une poloxamine ou du polyéthylène glycol, est utilisé pour stimuler l'activité phagocytaire des macrophages et favoriser par là-même leur rôle anti-infectieux dans le système immunitaire.
PCT/GB1995/002077 1994-09-03 1995-09-04 Composition stimulant les macrophages contenant un tensio-actif non ionique WO1996007420A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU33940/95A AU3394095A (en) 1994-09-03 1995-09-04 Macrophage stimulating composition comprising a non-ionic surfactant

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9417742.5 1994-09-03
GB9417742A GB9417742D0 (en) 1994-09-03 1994-09-03 Macrophage stimulating composition

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WO1996007420A1 true WO1996007420A1 (fr) 1996-03-14

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007123468A1 (fr) * 2006-04-24 2007-11-01 Bruce Medical Ab Agents anticancéreux à base de polymères
EP2572719A4 (fr) * 2010-05-18 2014-04-23 Univ Santiago Compostela Utilisation de poloxamines comme inductrices de la différenciation ostéogénique de cellules mésenchymateuses
CN114259463A (zh) * 2022-02-11 2022-04-01 山东大学 一种靶向补体蛋白发挥抗炎作用的PF-HA-diSE水凝胶及其制备方法与应用

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EP0154316A2 (fr) * 1984-03-06 1985-09-11 Takeda Chemical Industries, Ltd. Lymphokine chimiquement modifiée et son procédé de préparation
US4767763A (en) * 1982-01-29 1988-08-30 Bocquet Roger L E Composition for achieving tumor reversion and its use in cancerology for dogs
EP0283085A1 (fr) * 1987-03-17 1988-09-21 Akzo N.V. Mélange adjuvant
US4902502A (en) * 1989-01-23 1990-02-20 Cetus Corporation Preparation of a polymer/interleukin-2 conjugate
EP0372752A2 (fr) * 1988-11-23 1990-06-13 Genentech, Inc. Dérivés du polypeptide CD4
WO1993015745A1 (fr) * 1992-02-13 1993-08-19 Arch Development Corporation Procede et compositions contenant un polymere (poloxamer) destine a la regeneration des cellules
WO1995013090A1 (fr) * 1993-11-10 1995-05-18 Enzon, Inc. Produits de conjugaison ameliores d'un interferon avec un polymere

Patent Citations (7)

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Publication number Priority date Publication date Assignee Title
US4767763A (en) * 1982-01-29 1988-08-30 Bocquet Roger L E Composition for achieving tumor reversion and its use in cancerology for dogs
EP0154316A2 (fr) * 1984-03-06 1985-09-11 Takeda Chemical Industries, Ltd. Lymphokine chimiquement modifiée et son procédé de préparation
EP0283085A1 (fr) * 1987-03-17 1988-09-21 Akzo N.V. Mélange adjuvant
EP0372752A2 (fr) * 1988-11-23 1990-06-13 Genentech, Inc. Dérivés du polypeptide CD4
US4902502A (en) * 1989-01-23 1990-02-20 Cetus Corporation Preparation of a polymer/interleukin-2 conjugate
WO1993015745A1 (fr) * 1992-02-13 1993-08-19 Arch Development Corporation Procede et compositions contenant un polymere (poloxamer) destine a la regeneration des cellules
WO1995013090A1 (fr) * 1993-11-10 1995-05-18 Enzon, Inc. Produits de conjugaison ameliores d'un interferon avec un polymere

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INGRAM D.A. ET AL: "Phagocytic Activation of Human Neutrophils by the Detergent Component of Fluosol", AM. J. PATHOL. (UNITED STATES), vol. 140, no. 5, pages 1081 - 1087 *
KITA Y. ET AL: "Characterization of a Polyethylene Glycol Conjugate of Recombinant Human Interferon-gamma", DRUG DES. DELIV. (UNITED KINGDOM), vol. 6, no. 3, pages 157 - 167 *
SCHMOLKA I.R.: "Review of Block Polymer Surfactants", J. AM. OIL CHEMISTS' SOCIETY, vol. 54, no. 3, pages 110 - 116 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007123468A1 (fr) * 2006-04-24 2007-11-01 Bruce Medical Ab Agents anticancéreux à base de polymères
AU2007241593B2 (en) * 2006-04-24 2012-01-19 Bruce Medical Ab Polymer-based anti-cancer agents
EP2572719A4 (fr) * 2010-05-18 2014-04-23 Univ Santiago Compostela Utilisation de poloxamines comme inductrices de la différenciation ostéogénique de cellules mésenchymateuses
CN114259463A (zh) * 2022-02-11 2022-04-01 山东大学 一种靶向补体蛋白发挥抗炎作用的PF-HA-diSE水凝胶及其制备方法与应用
CN114259463B (zh) * 2022-02-11 2023-03-28 山东大学 一种靶向补体蛋白发挥抗炎作用的PF-HA-diSE水凝胶及其制备方法与应用

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GB9417742D0 (en) 1994-10-19

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