WO2014122345A1 - Hydrogels de poloxamine et leur utilisation pour la régénération ou la réparation osseuse - Google Patents

Hydrogels de poloxamine et leur utilisation pour la régénération ou la réparation osseuse Download PDF

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Publication number
WO2014122345A1
WO2014122345A1 PCT/ES2014/070070 ES2014070070W WO2014122345A1 WO 2014122345 A1 WO2014122345 A1 WO 2014122345A1 ES 2014070070 W ES2014070070 W ES 2014070070W WO 2014122345 A1 WO2014122345 A1 WO 2014122345A1
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Prior art keywords
poloxamine
hydrogel according
simvastatin
cyclodextrin
hydrogel
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PCT/ES2014/070070
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English (en)
Spanish (es)
Inventor
Ángel CONCHEIRO NINE
Carmen ÁLVAREZ LORENZO
Francisco VEIGA
Susana SIMOES
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Universidade De Santiago De Compostela
Universidade De Coimbra
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Application filed by Universidade De Santiago De Compostela, Universidade De Coimbra filed Critical Universidade De Santiago De Compostela
Publication of WO2014122345A1 publication Critical patent/WO2014122345A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders

Definitions

  • the present invention relates to poloxamine and cyclodextrin hydrogels that can incorporate a statin. These hydrogels promote the differentiation of mesenchymal stem cells to osteoblasts and can be used for the repair, regeneration or increase of bone formation.
  • BMPs bone morphogenic proteins
  • rhBMP-2 and / or rhBMP-7 are used clinically incorporated into collagen sponges for open tibial fractures that do not close and spinal fusions.
  • carriers that can be applied in the critical defect using minimally invasive techniques, and also offer stabilization and slow elimination of BMPs from the place of application.
  • Statins are potent prodrugs of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, which act by blocking the conversion of HMG-CoA mevalonate, a key metabolite in cholesterol biosynthesis.
  • HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A
  • statins particularly simvastatin, promote osteogenesis in murine and human cell lines. Compared to other synthetic osteoinductive agents, statins have the additional advantage of promoting the formation of new blood vessels (angiogenesis) and acting as anti-inflammatory agents.
  • Statins have been shown to induce BMP-2 expression and stimulate bone formation in the cranial vault (calvaria) of mice following daily administration of subcutaneous injections (G. Mundy, Science 1999, 286, 1946).
  • Patent application WO201 1/144785 describes the use of poly (ethylene oxide) -poly (propylene oxide) (PEO-PPO) block copolymers of the poloxamine family (Tetronic ®) for the differentiation of MSCs in osteoblasts.
  • PEO-PPO poly (ethylene oxide) -poly (propylene oxide)
  • Tetronic ® poloxamine family
  • the intrinsic osteoinductive activity of poloxamines offers new perspectives in addressing bone regeneration by allowing minimally invasive procedures; that is, the preparation of low viscosity aqueous systems that can be easily administered using a syringe and that undergo a transition from solution to gel at 37 ° C, becoming osteoinductive viscoelastic supports.
  • the invention is directed to a hydrogel comprising at least one poloxamine, at least one cyclodextrin and at least one statin.
  • the invention relates to the use of the hydrogel of the invention as a vehicle for the administration of an additional biologically active molecule.
  • Another aspect concerns the use of the hydrogel of the invention in the preparation of medicament.
  • Another aspect of the invention relates to the use of the hydrogel of the invention for the preparation of a medicament for inducing or increasing the differentiation of mesenchymal cells to osteoblasts, preferably for the repair, regeneration or increase of bone formation.
  • the invention is directed to a pharmaceutical composition comprising the hydrogel of the invention and a pharmaceutically acceptable excipient.
  • Another aspect relates to an implant comprising the hydrogel or the pharmaceutical composition of the invention.
  • the invention is directed to an in vitro method for inducing differentiation of mesenchymal cells, except human embryonic stem cells, in osteoblasts comprising contacting (a) the hydrogel of the invention, with (b) mesenchymal cells, except human embryonic stem cells, which are found in a culture medium.
  • hydrogel of the invention for use as a medicament and to induce or increase the differentiation of mesenchymal cells to osteoblasts, preferably for use in the repair, regeneration or increase of bone formation.
  • the invention relates to a method for inducing or increasing the differentiation of mesenchymal cells to osteoblasts, preferably for the repair, regeneration or increase of bone formation in a patient, which comprises the administration of the hydrogel of the invention.
  • FIG. 1 Storage modules (full symbols - G ') and loss (empty symbols - G ") of T908-aCD formulations prepared with 1% (squares), 2% (upward triangles), 3% (circles ), 4% (triangles down), 5% (diamonds), 8% (triangles to the left), 13% (stars) and 20% (triangles to the right) of T908, without aCD or with 5% and 9 , 7% aCD at 37 ° C.
  • Figure 2. Viability of osteoblasts in contact with supramolecular gels of T908-aCD.
  • Figure 3. Assignment of simvastatin at 37 ° C from Tetronic 908 formulations at 4% (squares) and 8% (circles), without aCD (empty symbols and solid line), with 5% aCD (black filled symbols and continuous line) and with 9.7% aCD (symbols with black fill and dashed line). 100% assigned would correspond to 0.064 mg / cm 2 .
  • Temporal evolution of mesenchymal stem cell proliferation (determined using the MTT assay) in culture medium (negative control), osteogenic medium (positive control) and culture medium to which 0.08 simvastatin solution was incorporated , 0.85, 8.5 and 42.5 ⁇ , which are represented in the figure with the following symbols: ⁇ negative control; ⁇ I positive control; liil 0.08 ⁇ of simvastatin; 0.85 ⁇ of simvastatin; 8.5 ⁇ of simvastatin; ISS! 42.5 ⁇ of simvastatin.
  • the final drug concentrations in the culture medium were 0.01, 0.1, 1 and 5 ⁇ , respectively.
  • FIG. 5 ALP activity of mesenchymal stem cells in culture medium (negative control), osteogenic medium (positive control) and in culture medium to which simvastatin solution was incorporated at 0.08, 0.85, 8.5 and 42 , 5 ⁇ , which are represented in the figure with the following symbols: M-B negative control; ⁇ 1 positive control; ku 0.08 ⁇ of simvastatin; 3 ⁇ 4S3 ⁇ 4S 0.85 ⁇ of simvastatin; S3 ⁇ 4 8.5 ⁇ of simvastatin; 42.5 ⁇ of simvastatin.
  • the final drug concentrations in the culture medium were 0.01, 0.1, 1 and 5 ⁇ , respectively.
  • Temporal evolution of mesenchymal stem cell proliferation in culture medium (negative control), osteogenic medium (positive control) and culture medium to which the T908 formulations were incorporated without and with aCD and simvastatin, which are represented in the figure with the following symbols: MM negative control; HH positive control; E3 4% T908; E223 4% T908 + 0.08 ⁇ of simvastatin; £ 33 4% T908 + 8.5 ⁇ of simvastatin; B3 ⁇ 43 ⁇ 43 ⁇ 43 ⁇ 4 4% T908 + 5% aCD; ; ⁇ 4% T908 + 5% aCD + 0.08 ⁇ of simvastatin; 4% T908 + 5% aCD + 8.5 ⁇ of simvastatin; 8% T908; H3 ⁇ 4 8% T908 + 0.08 ⁇ of simvastatin; 111 8% T908 + 8.5 ⁇ of simvastatin; H 8% T908 + 0.08 ⁇ of simva
  • the final drug concentrations in the culture medium are those indicated in Table 3.
  • Figure 7 ALP activity of mesenchymal stem cells in culture medium (negative control), osteogenic medium (positive control) and in culture medium to which the T908 formulations were incorporated without and with aCD and simvastatin, which are represented in the figure with the following symbols: ⁇ negative control; ⁇ 1 positive control; 4% T908; 4% T908 + 0.08 ⁇ of simvastatin; E3 4% T908 + 8.5 ⁇ of simvastatin; 1112 4% T908 + 5% aCD; 4% T908 + 5% aCD + 0.08 ⁇ of simvastatin; 4% T908 + 5% aCD + 8.5 ⁇ of simvastatin; ⁇ Hil 8% T908; ü 8% T908 + 0.08 ⁇ of simvastatin; HH 8% T908 + 8.5 ⁇ of simvastatin; S 8% T908 + 5%
  • Figure 8 ALP staining of cells after 12 days in negative control medium (A), osteogenic medium (B), medium with 0.08 or 8.5 ⁇ simvastatin in PBS (C, D), 4% T908 with 0, 0.08 or 8.5 ⁇ simvastatin (E, F, G), 4% T908 - 5% aCD with 0, 0.08 or 8.5 ⁇ simvastatin (H, I, J), 8% T908 with 0, 0.08 or 8.5 ⁇ simvastatin (K, M, N) and 8% T908 - 5% aCD with 0, 0.08 or 8.5 ⁇ simvastatin (O, P, Q).
  • cyclodextrins makes it possible to reduce the concentration of poloxamine necessary to give rise to the formation of gels.
  • cyclodextrins to poloxamines allows the formation of gels at low concentrations of the poloxamine even at room temperature (Table 1). Poloxamine and cyclodextrin are forming an inclusion complex.
  • the use of small amounts of poloxamine and cyclodextrin allows the preparation of hydrogels that have good compatibility with both cells. mesenchymal as with osteoblasts.
  • cyclodextrin favored earlier and prolonged differentiation of mesenchymal cells to osteoblasts.
  • the hydrogels of the invention can be sterilized by moist heat (autoclave) without affecting their rheological properties.
  • the invention relates to a hydrogel comprising at least one poloxamine, at least one cyclodextrin and at least one statin.
  • hydrogel refers to a three-dimensional polymer network that contains water.
  • polystyrene resins means a block copolymer of poly (ethylene oxide) (PEO) and poly (propylene oxide) (PPO) having a star structure with four PEO-PPO arms ending in hydroxyl groups and where the four arms are linked through a central ethylenediamine group.
  • Poloxamines are commercially available in a wide variety of molecular weights and EO / PO molar ratios (marketed by BASF).
  • the poloxamine has the following structural formula
  • a has an average value between 18 and 22 and b has an average value between 1 12 and 116.
  • the poloxamines of the invention have an average molecular weight between 1000 and 35000 Da, preferably between 5000 and 30000 Da, more preferably between 20,000 and 30,000 Da.
  • the poloxamine has an average value of a between 112 and 116, an average value of b between 18 and 22 and an average molecular weight between 20,000 and 30,000 Da.
  • the poloxamines or Tetronic are selected from 304, 701, 901, 904, 908, 1107, 1301, 1304, 1307, 90R4 and 150R1, whose properties are included in the following table
  • the poloxamine is poloxamine (Tetronic) 908.
  • the concentration of poloxamine in the hydrogel is between 1 and 20% w / v, between 2 and 20% w / v, between 2 and 15% w / v between 2 and 10% p / v. In a preferred embodiment, the concentration of poloxamine in the hydrogel is between 3 and 9% w / v, more preferably between 4 and 8% w / v.
  • the od extrins structurally consist of 6, 7 or 8 units of D-glucopyranoside linked by glycosidic bonds to (1 ⁇ 4), denominating ⁇ -, ⁇ - or ⁇ - ci od od extrins, respectively.
  • cyclodextrin includes natural od extrins ( ⁇ -, ⁇ - or ⁇ -cyclodextrins) and their derivatives in which some (s) of the hydroxyl groups are substituted (s) ) such as, for example, hydroxypropylcyclodextrins, carboxymethylcyclodextrins, sulfobutylcyclodextrins, aminocyclodextrins, dimethylcyclodextrins, ci od od extrudes phosphate, hydroxyethylcyclodextrins, acetylcyclodextrins, ethylcyclodextrins, trimethylcyclodextrinasdextrins, cyclodextrindextrinstricyclodextrins, cyclodextrins, cyclodextrins, cyclodextrins, cyclodextrins, trich
  • the cyclodextrin is a-cyclodextrin or a derivative thereof.
  • the cyclodextrin is a-cyclodextrin.
  • Statins are compounds that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.
  • statins that can be employed in the present invention include simvastatin, atorvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, lovastatin, rosuvastatin and fluindostatin.
  • the styline is simvastatin.
  • Simvastatin is a polycyclic compound with a pH-dependent structure and solubility and has low water solubility. Depending on the pH, the predominant form of simvastatin is lactone or the hydroxy acid form. It has been observed (Table 2) that the hydrogels of the invention make it possible to solubilize simvastatin and also stabilize the hydroxy acid form (which is the form to which the osteogenic activity). The incorporation of simvastatin did not alter the gelation process or affect the rheological properties of the gels.
  • the concentration of cyclodextrin in the hydrogel is between 1 and 20% w / v, between 2 and 15% w / v, between 2 and 10% w / v between 3 and 8% p / v. In a preferred embodiment, the concentration of cyclodextrin in the hydrogel is between 4 and 6% w / v, more preferably 5% w / v.
  • the concentration of poloxamine in the hydrogel is between 1 and 20% w / v, or between 3 and 9% w / v. In a particular embodiment, the concentration of poloxamine in the hydrogel is between 1 and 20% w / v, or between 3 and 9% w / v and the concentration of cyclodextrin is between 3 and 8% p / v. In a particular embodiment, the concentration of poloxamine in the hydrogel is between 4 and 8% w / v and the concentration of cyclodextrin is between 4 and 6% w / v.
  • the poloxamine has an average value of a between 112 and 116, an average value of b between 18 and 22 and an average molecular weight between 20,000 and 30,000 Da, and is in a concentration between 3 and 9 % w / v, preferably between 4 and 8% w / v, and the cyclodextrin is ⁇ -cyclodextrin and is in a concentration between 3 and 8% w / v, preferably between 4 and 6% p / v.
  • the hydrogel of the invention further comprises a biologically active molecule.
  • biologically active molecule refers to any substance that is used in the treatment, cure, prevention or diagnosis of a disease or that is used to improve physical or mental well-being.
  • the active molecule is a morphogenic protein, such as, for example, BMP-2, BMP-4, BMP-5, BMP-6, BMP-7 or BMP-8b, or a combination thereof.
  • the invention relates to a process for the preparation of a hydrogel of the invention comprising mixing an aqueous solution of poloxamine at pH between 6.0 and 9.0, preferably 7.4, an aqueous solution of cyclodextrin at pH between 6.0 and 9.0, preferably 7.4 and a statin.
  • Statin is incorporated into the poloxamine solution, or the cyclodextrin solution or an intermediate hydrogel previously formed by the poloxamine and the cyclodextrin.
  • the invention is directed to a hydrogel obtainable by the above procedure.
  • excipient refers to any substance of the pharmaceutical composition other than the active ingredient.
  • excipients may be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, disintegrants, wetting agents , solubilizing agents, antioxidants, preservatives, antimicrobials, tonicity agents, stabilizing or suspending agents, or diluents.
  • pharmaceutically acceptable refers to entities that are physiologically tolerable and do not normally produce allergic reactions or unfavorable reactions such as gastric disorders, dizziness and similar reactions, when administered in humans or animals.
  • pharmaceutically acceptable means that it is approved by a regulatory agency of a state or federal government or is included in the US Pharmacopoeia or other pharmacopoeia generally recognized for use in animals, and more particularly in humans.
  • the formulations can be prepared according to conventional methods such as those described in the Spanish, European or United States Pharmacopoeias, or in similar reference texts, for example "Pharmaceutical Technology", by J.L. Vila Jato, 1997, Editorial S ⁇ ntesis.
  • hydrogels and pharmaceutical compositions of the invention can be administered enterally, topically or parenterally. Preferably, they are for parenteral administration.
  • hydrogels and pharmaceutical compositions of the invention can be administered by injection, for example, intramuscular, subcutaneous, intraosseous or intrathecal injection, or by application in an open cavity during surgery.
  • the hydrogels and pharmaceutical compositions of the invention are administered by injection in the area where it is desired to induce differentiation of mesenchymal cells into osteoblasts.
  • the hydrogels and pharmaceutical compositions of the invention allow controlled or sustained release of the statin.
  • controlled release or "sustained release” refers to the fact that the release of the statin is not immediate, but gradual over a period of time.
  • the rate of statin release can be controlled by adjusting the cyclodextrin content in the hydrogel.
  • Hydrogels and pharmaceutical compositions of the invention may also be useful for promoting or increasing osseointegration of implants.
  • the invention is directed to an implant comprising the hydrogel or pharmaceutical composition of the invention, for example an orthopedic or dental implant.
  • the hydrogel or pharmaceutical composition of the invention is coating the implant.
  • the invention relates to the use of the hydrogel of the invention as a vehicle for the administration of an additional biologically active molecule, preferably a morphogenic protein.
  • the invention relates to the use of the hydrogel, or pharmaceutical composition, of the invention for the preparation of a medicament for the treatment or prevention of a disease or condition selected from osteoporosis, osteoarthritis, osteopenia, Paget's disease , bone fracture, critical defects, pseudoarthrosis, loss of bone reserve, hypocalcaemia, periarticular erosions in rheumatoid arthritis, osteodystrophy, osteomalacia, osteolytic lesions caused by bone metastases, metastatic bone disease.
  • a disease or condition selected from osteoporosis, osteoarthritis, osteopenia, Paget's disease , bone fracture, critical defects, pseudoarthrosis, loss of bone reserve, hypocalcaemia, periarticular erosions in rheumatoid arthritis, osteodystrophy, osteomalacia, osteolytic lesions caused by bone metastases, metastatic bone disease.
  • treatment includes the administration of a hydrogel or composition of the invention to attempt to alleviate or cure the disease or condition or its symptoms or sequelae.
  • treatment also includes the prevention of the disease or condition.
  • hydrogels of the present invention have great advantages over other systems for which osteogenic activity has been described: - have viscoelastic properties suitable for administration, eg by injection, at the desired site. This allows the local administration of simvastatin and poloxamine minimizing systemic side effects;
  • hydrogels can be sterilized by moist heat (autoclave) without affecting their properties;
  • Solutions of T908 and aCD in phosphate buffer (PBS) pH 7.4 were prepared separately. Next, the solutions were mixed in different proportions to cover a wide range of concentrations in both components. The concentration of T908 was always kept below that required by the copolymer only to form gels. Once the solutions were mixed in a vortex, replicates of each of them were kept at 4, 20 and 37 ° C.
  • Fertilized chicken eggs of less than 3 days were incubated for 8 days at 37 ⁇ 0.3 ° C and 60 ⁇ 2.6% relative humidity (Ineltec CCSP0150 Tona, Barcelona, Spain).
  • the ICCVAM protocol for the chorioallantoid membrane (HET-CAM) test was applied.
  • the upper part of the eggshell was removed (corresponding to the air bag) using a circular blade (Dremel 300, Breda, Holland) and the inner membrane of the eggs was wetted with 0.9% solution (w / v ) I was born. After 30 min, that membrane was removed with tweezers.
  • T908-aCD dispersions 300 ⁇ _ at 25 ° C
  • its irritating potential bleeding, vascular lysis and coagulation
  • Negative and positive controls were 0.9% NaCI and 0.1 M NaOH solutions, respectively.
  • the tests were carried out in triplicate.
  • the irritation index was calculated from the time (in seconds) at which the bleeding (H), lysis (L) or coagulation (C) processes begin, as follows:
  • the materials are classified as non-irritants (0-0.9), weakly irritating (1-4.9), moderately irritating (5-8.9) and severely irritating (9-21).
  • SAOS-2 cells (HTB-85, LGD Standards, ATCC, Manassas, VA) were cultured in D-MEM medium supplemented with fetal bovine serum (10% w / v) and gentamicin (0.1 mg / mL). Cells (50,000 per well; 0.5 mL) were seeded in Millicell® 8-well glass EZ slide (Millipore) and 80 of each sample was incorporated.
  • MSCs were cultured in MesenPRO RS medium (Gibco, Invitrogen) supplemented with 1% glutamine and 1% penicillin and streptomycin. They were then seeded (30,000 cells / well, 2.5 ml_) in 6-well plates. 200 ⁇ _ of T908 dispersions (4% or 8%) without and with aCD (5%) and without and with simvastatin (0.08 ⁇ or 8.5 ⁇ , prepared as indicated for the release test) were deposited in the upper compartment of permeable transwell wells. As negative and positive controls, cells were used in culture medium and in osteogenic differentiation medium (10 ⁇ ⁇ -glycerophosphate, 100 nM dexamethasone and 50 ⁇ ascorbic acid), respectively.
  • MSCs were cultured as indicated above and at 3, 7 and 12 days of incubation, the transwell compartments and 1.5 mL of culture medium were removed.
  • 100 ⁇ _ of MTT solution (5 mg / mL in PBS) was incorporated into each well containing 1 mL of remaining culture medium and the plates were incubated 4 h at 37 ° C.
  • 1 mL of MTT solvent (10% SDS in 0.01 M HCI) was added and the plates were incubated overnight at 37 ° C. Media aliquots were processed as indicated in the cell proliferation kit (Roche).

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Abstract

L'invention concerne des hydrogels de poloxamine et leur utilisation pour la régénération ou la réparation osseuse. La présente invention se rapporte à des hydrogels de poloxamine et de cyclodextrine pouvant comporter une statine. La présence de cyclodextrines permet de diminuer la concentration de poloxamine nécessaire pour donner lieu à la formation de gels et augmenter en outre l'activité ostéogénique/ostéoinductrice de la poloxamine. Lesdits hydrogels favorisent la différenciation de cellules mères mésenchymateuses en ostéoblastes et peuvent être utilisés pour la réparation, la régénération ou l'augmentation de la formation osseuse.
PCT/ES2014/070070 2013-02-05 2014-02-03 Hydrogels de poloxamine et leur utilisation pour la régénération ou la réparation osseuse WO2014122345A1 (fr)

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ES201330135A ES2492015B1 (es) 2013-02-05 2013-02-05 Hidrogeles de poloxamina y su uso para la regeneración o reparación ósea

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WO2015035996A1 (fr) * 2013-09-11 2015-03-19 Amphidex A/S Produits de culture cellulaire pour cultures cellulaires adhérentes et leur fabrication

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WO2011144785A1 (fr) * 2010-05-18 2011-11-24 Universidade De Santiago De Compostela Utilisation de poloxamines comme inductrices de la différenciation ostéogénique de cellules mésenchymateuses

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015035996A1 (fr) * 2013-09-11 2015-03-19 Amphidex A/S Produits de culture cellulaire pour cultures cellulaires adhérentes et leur fabrication

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