WO2021121566A1 - Utilisation d'une composition comprenant de la silice organique pour l'amélioration de la qualité de tissus cartilagineux - Google Patents

Utilisation d'une composition comprenant de la silice organique pour l'amélioration de la qualité de tissus cartilagineux Download PDF

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Publication number
WO2021121566A1
WO2021121566A1 PCT/EP2019/085736 EP2019085736W WO2021121566A1 WO 2021121566 A1 WO2021121566 A1 WO 2021121566A1 EP 2019085736 W EP2019085736 W EP 2019085736W WO 2021121566 A1 WO2021121566 A1 WO 2021121566A1
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WO
WIPO (PCT)
Prior art keywords
organic silica
injection
composition
use according
cartilage
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Application number
PCT/EP2019/085736
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English (en)
Inventor
Denis Michel AMMANN
Original Assignee
Aa Healthcare Sàrl
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Priority to PCT/EP2019/085736 priority Critical patent/WO2021121566A1/fr
Publication of WO2021121566A1 publication Critical patent/WO2021121566A1/fr

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Classifications

    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61K31/695—Silicon compounds
    • 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
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • 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
    • 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

Definitions

  • the invention relates to the field of medical treatments of joints disorders such as arthritis, in particular to the field of regenerative treatment of cartilage damages.
  • the invention relates to the utilization of liquid organic silica compositions for restoring joints functionality through improvement of joints cartilage condition or quality.
  • Articular cartilage covers the ends of bones in natural joints in order to distribute the forces of locomotion to underlying bone structures while simultaneously providing low friction articular interfaces. These properties are made possible by an extracellular matrix composed of collagen components and a high concentration of proteoglycan agrecan.
  • the fibriliar collagenous network resists tensile and shear forces while the agrecan substance resists compression and interstitial fluids.
  • the low friction is a result of specific molecular composition of the articular surface and the interstitial fluid.
  • Cartilage disease or damage arrives either due to a physical disrupture or by gradual erosion, such as occurs in many forms of arthritis, which exposes the extremity of the bone to pain in the joints.
  • Articular cartilage has a very limited natural response to damages mainly in the case of adults, which is mainly due to a lack of vascularization or other sources.
  • osteoarthritis The most frequent chronic musculoskeletal disorder and the leading cause of disability in the elderly is osteoarthritis (OA) for which there is no effective treatment option (Ref.l).
  • OA osteoarthritis
  • Both a mechanical and an inflammatory disease reflect part of the mechanisms for the onset and the progression of the disease (Ref.2).
  • OA is now considered as a disease of the whole joint.
  • Subchondral bone (SB), synovium, ligament and supporting neuromuscular apparatus contribute to the onset and the progression of cartilage degradation.
  • the biocomposite formed by the cartilage and the SB is considered as the osteochondral unit and is known to have the capability of transferring loads (Ref. 3). It is therefore natural that structural and/or biochemical alterations of any of the components of this osteochondral unit (leading to its quality impairment) could result in disruption of the joint integrity and loss of function.
  • HA a natural polysaccharide and main component of the synovial fluid and cartilage, ensures optimal joint function and is altered during OA progression.
  • Injection of exogenous HA has beneficial effects within the synovial joint, which include lubrication, shock absorption, chondroprotective properties and proteoglycan synthesis and subchondral protection.
  • Visco-supplementation with hyaluronic acid was proposed to improve the quality of the synovial fluid altered during osteoarthritis restoring an optimal rheology of the joint.
  • Recent study demonstrated that hyaluronic acid diffuses inside the cartilage improving tissue quality and chondrocyte metabolism via modulation of the quality of the tissue material properties.
  • the present invention provides a new and inventive use of an organic silica fluid composition as medical product for the treatment of cartilaginous disorders in bodily joints, comprising intra-articular injection of a determined volume of organic silica fluid composition in injectable form in a bodily joint.
  • the organic silica composition comprises a solvent, said solvent comprising any of the following substances: water, Sodium Chloride, Potassium Sorbate, Sodium Hydroxide, Sodium Benzoate, or a combination thereof.
  • the determined volume of solution injected is comprised between 1ml and 30 ml, preferably between 5 and 25 ml.
  • said injection is reproduced periodically, such as once a month.
  • the concentration of solid organic silica in the composition is comprised between about 0,1% and 1%, preferably between 0,2% and 0, 6%.
  • a particular advantageous implementation of the inventive use comprises intra-articular injection of hyaluronic acid solution beingcarried out before or after injection of the organic silica composition.
  • Said prior injection of hyaluronic acid may in particular be carried out no earlier or no later than 48h after injection of the organic silica composition, preferably no earlier or no later than 24h.
  • injection of hyaluronic acid may also of course be carried simultaneously with the injection of the organic silica composition.
  • organic silica is synergistic with that of hyaluronic acid and in particular helps in prolonging the effects known from hyaluronic acid in the treatment of joint disorders.
  • Figure 1 summarizes in a table a measurement protocol
  • Figure 2 illustrates a bio indentation procedure
  • Figure 4 illustrates micro-ct evaluations performed on distal femur
  • Figure 5 illustrates experimental proof of the surprising effect that the direct exposition of organic silica solution (AA171) to cartilage improves its quality
  • Figure 6 illustrates the effects of organic silica solution (AA171), of Ostenil ® and of the combination of Ostenil ® and organic silica solution combined on cartilage.
  • the present invention relates to a new use of liquid or gel organic silica compositions for the treatment of joint cartilage disorders such as arthritis.
  • This new use consists essentially in the intra-articular injection of an organic silica composition in liquid or gel state to bath an affected joint cartilage and surrounding tissues.
  • organic silica shall be construed as meaning organic silicon, also known chemically as monomethylsilanetriol.
  • organic silica or organic silicon are used equally as synonyms in the medical, pharmaceutical and food industries and literature and shall be understood as identical in the context of the invention.
  • injectable fluid or “injectable composition” shall be understood broadly as encompassing any liquid composition or gel that may be injected in a body by any medical instrument or medical operation dedicated therefor, such as a syringe or a tubing.
  • injected or “injectable” is defined broadly and encompasses also that the product may be introduced in the body by other means such as a medical tubing or by introducing the product during an operation.
  • the medical product of the invention may be comprised in a container that may be for example a polymeric bag introduced in the body and which delivers the medical product inside the body over a certain period of time. Said container may be an implanted container.
  • injectable activated silica (Si) compositions is extremely well tolerated in human tissues and provides a surprising effect for the treatment of cartilage lesions and/or cartilage defects when injected directly in defective joints affected with osteoarthritis in particular.
  • Liquid organic silica compositions have been known as such for long in cosmetic applications and in topical or oral applications and compositions for various purposes. It is known as a product that hydrates cells and as such has been used for example in the treatment of dermatological problems, as described in https://institutebcn.com/fr/classics/organic-silica/.
  • liquid organic silica compositions in various concentrations induce surprising healing effect of osteoarthritis affected cartilage tissues. Without being bound by theory and pending ongoing scientific assessment of the biological mechanisms underlying and supporting such surprising effect, it is anticipated from the results of already conducted experiments that liquid organic silica interacts with collagen and/or proteoglycan in the joint tissues, helping for improved hydration, cartilage quality and inherent improved lubrication in the joint, thus reducing stress on cartilage.
  • the invention thus consists in a new use or organic silica compositions in an injectable form for the treatment of cartilage lesions and/or cartilage defects, whereby said injectable forms essentially comprises a liquid organic silica solution.
  • organic silica means here that an atom of silicon (Si) is linked to at least one carbon (C) preferably linked to at least one radical of CH3.
  • Si is linked to a CH3 group and 3 functional alcohol groups.
  • the radical CH3 provides to the atom Si the ability to penetrate tissues and the alcohol groups provide the ability to provide water solubility.
  • the organic silica composition used for making injectable portions may be a commercially available solution such as Dexsil ® , manufactured by the company B+ Pharma. It may in particular comprise a solvent, which may in turn comprise any of the following substances: water, Sodium Chloride, Potassium Sorbate, Sodium Hydroxide, Sodium Benzoate, or a combination thereof. The solution may also comprise other ingredients such as thickening agents or else to help proper retention or diffusion in bodily joints after injection.
  • the concentration of solid organic silica in the composition is preferably comprised between about 0,1% and 1%, preferably between 0,2% and 0, 6%.
  • each injection of an injectable portion of organic silica may be comprised between 1ml and 30 ml, preferably between 5 ml and 25 ml, still preferably between 1ml and 6 ml, and may be reproduced on a periodical basis, such as every month or less, depending on the severity of the joint affection and the responsiveness of a patient to treatment.
  • the new use of an organic silica fluid composition according to the present invention specifically consists in carrying out intra-articular injections of a determined volume of said organic silica fluid composition in injectable form in a bodily joint.
  • the inventors have confirmed a strong positive effect on osteoarthritis affected osteochondral units of femur bone at the knee joint, with a penetration resistance increase of more than 15% and more than 25% increase in Young’s Modulus of osteochondral units contacted with organic silica solution for 40 hours. These effects were measured in comparison to similar osteochondral units contacted with a standard, neutral, saline solution as reference.
  • the inventors further found out that not only organic silica solution independently has a beneficial effect on the cartilage of a joint but it is compatible and provides a synergistic effect with hyaluronic acid when used in combination.
  • the invention thus provides in a preferred embodiment to inject hyaluronic acid together with organic silica solution in a joint to further improve the treatment of disorders such as osteoarthritis.
  • the intra-articular injection of hyaluronic acid solution may carry out before injection of the organic silica composition, simultaneously or almost simultaneously, or even after intra-articular injection of the organic silica solution.
  • the injection of hyaluronic acid is preferably carried out no earlier than 48h before injection of the organic silica composition, preferably no earlier than 24h.
  • the injection of hyaluronic acid is carried out no later than 48h after injection of the organic silica composition, preferably no later than 24h.
  • hyaluronic acid and organic silica composition are injected simultaneously in a single dosing injection. This allows to avoid multiple injections and limits risks of contamination and pain for patients.
  • hyaluronic acid injection when hyaluronic acid is injected in combination with the organic silica solution according to the new use of the invention, dosage of the hyaluronic acid injection shall be identical to those used in existing treatment protocols comprising only hyaluronic acid injections. Specific details of experiments carried out demonstrating to potential of the invention for the treatment of osteoarthritis in knee joints are presented hereinafter.
  • Figure 1 illustrates the protocol of bio indendation perfomed in a saline neutral solution referred as PBS. Bio-indentation.
  • Cartilage stiffness was assessed by bio-indentation using Bioindenter (Piuma Optics, Netherlands).
  • the distal femoral samples were fully immersed in a PBS solution and glued onto a trapezoidal block, which was positioned in such way that the indented zone was always perpendicular to the axis of the indenter.
  • Two indentation zones (medial condyle) according to joint mechanical loading pattern related to rat ambulation were assessed.
  • Zone 1 is submitted to permanent loading during mobilization and rest, while zone 2 is only loaded by the contact with the patella ( Figure 2).
  • Within each ROI a set of 5 successive cyclic indentations were performed at 200 pm-distant location.
  • a spherical indenter with 50 m m diameter was used.
  • the maximum indentation depth of 25 m m corresponded to 60% of hyaline cartilage thickness.
  • the protocol consisted in a loading period of 30 seconds, followed by a hold period of 10 seconds and finally an unloading period of 30 seconds.
  • Elastic modulus (MPa) and maximal force (N) were recorded (figure 3). Coefficient of variation after repositioning was comprised between 8.8-10.4% for the different parameters measured.
  • Figure 2 illustrates the bio indentation procedure
  • Figure 3 illustrates the Young’s modulus, the maximum force and the indentation depth
  • Cartilage morphology was assessed by ERIOm OT (phase-contrast micro- computed tomography by using contrast agent: Hexabrix). Distal part of the femur including bone metaphyseal and epiphyseal compartments as well as articular cartilage was incubated in a 40% Hexabrix solution. Scans were performed using a m (3T 40 (Scanco Medical, Bassersdorf, Switzerland) at a voxel size of 6 m hi. The resulting transversal cross-sectional slices were then re-sliced horizontally via Scanco Medical software in order to generate a series of sagittal sections.
  • ERIOm OT phase-contrast micro- computed tomography by using contrast agent: Hexabrix
  • Femoral articular cartilage including hyaline and calcified cartilage was semi-automatically segmented by manual contour line. Based on an appropriate threshold according to the histogram of the X-ray attenuation analysis of the cartilage will be performed. Evaluations were performed on the site of indentation (figure 4).
  • Figure 6 illustrates the effects of AA171, of Ostenil and of the combination of Ostenil and AA171.
  • the control group incubated in PBS displayed stable values for all the investigated parameters of cartilage quality as evaluated by bio indentation.
  • the stability of the parameter underlines the absence of deleterious effect of the manipulation on the quality of the cartilage.
  • Ostenil and AA171 could prolong the duration of efficacy of Ostenil.
  • Petrel la RJ, Petrel la M. A prospective, randomized, double-blind, placebo controlled study to evaluate the efficacy of intraarticular hyaluronic acid for osteoarthritis of the knee. The Journal of rheumatology. 2006;33(5):951-6.

Abstract

L'invention concerne une nouvelle utilisation d'une composition fluide de silice organique en tant que produit médical (1) pour le traitement de troubles cartilagineux dans des articulations corporelles, comprenant l'injection intra-articulaire d'un volume déterminé de composition fluide de silice organique sous forme injectable dans une articulation corporelle.
PCT/EP2019/085736 2019-12-17 2019-12-17 Utilisation d'une composition comprenant de la silice organique pour l'amélioration de la qualité de tissus cartilagineux WO2021121566A1 (fr)

Priority Applications (1)

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PCT/EP2019/085736 WO2021121566A1 (fr) 2019-12-17 2019-12-17 Utilisation d'une composition comprenant de la silice organique pour l'amélioration de la qualité de tissus cartilagineux

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Application Number Priority Date Filing Date Title
PCT/EP2019/085736 WO2021121566A1 (fr) 2019-12-17 2019-12-17 Utilisation d'une composition comprenant de la silice organique pour l'amélioration de la qualité de tissus cartilagineux

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107866A2 (fr) * 2010-03-05 2011-09-09 Jasper Llc Dérivés silyliques de polysaccharides
WO2016014408A1 (fr) * 2014-07-21 2016-01-28 Board Of Regents, The University Of Texas System Formulations d'agents pharmaceutiques intraarticulaires et leurs procédés de préparation et d'utilisation
WO2018182436A2 (fr) * 2017-03-20 2018-10-04 Biovico Sp Z O O Composition sous forme de gel

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107866A2 (fr) * 2010-03-05 2011-09-09 Jasper Llc Dérivés silyliques de polysaccharides
WO2016014408A1 (fr) * 2014-07-21 2016-01-28 Board Of Regents, The University Of Texas System Formulations d'agents pharmaceutiques intraarticulaires et leurs procédés de préparation et d'utilisation
WO2018182436A2 (fr) * 2017-03-20 2018-10-04 Biovico Sp Z O O Composition sous forme de gel

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
BALAZS EA.: "Viscosupplementation for treatment of osteoarthritis: from initial discovery to current status and results", SURGICAL TECHNOLOGY INTERNATIONAL, vol. 12, 2004, pages 278 - 89
BANNURU RRSCHMID CHKENT DMVAYSBROT EEWONG JBMCALINDON TE: "Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis", ANNALS OF INTERNAL MEDICINE, vol. 162, no. 1, 2015, pages 46 - 54
BRUYERE 0. ET AL.: "A consensus statement on the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis algorithm for the management of knee osteoarthritis-from evidence-based medicine to the real-life setting", SEMIN. ARTHRITIS RHEUMATOLOGY, vol. 45, no. 4, 2016, pages S3 - 11
CAMPBELL KAERICKSON BJSALTZMAN BMMASCARENHAS RBACH BR, JR.COLE BJ ET AL.: "Is Local Viscosupplementation Injection Clinically Superior to Other Therapies in the Treatment of Osteoarthritis of the Knee: A Systematic Review of Overlapping Meta-analyses", ARTHROSCOPY : THE JOURNAL OF ARTHROSCOPIC & RELATED SURGERY : OFFICIAL PUBLICATION OF THE ARTHROSCOPY ASSOCIATION OF NORTH AMERICA AND THE INTERNATIONAL ARTHROSCOPY ASSOCIATION, vol. 31, no. 10, 2015, pages 2036 - 45 e14
EGLOFF C. ET AL.: "Biomechanics and pathomechanisms of osteoarthritis", SWISS MED. WEEKLY, vol. 142, 2012, pages w13583
GOLDRING SR. ET AL.: "Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage-bone crosstalk.", NATIONAL REVIEW OF RHEUMATOLOGY, vol. 12, no. 11, November 2016 (2016-11-01), pages 632 - 644
LANE NE. ET AL.: "Ostheoarthritis year in review 2016: clinical", OSTHEOARTHRITIS CARTILAGE, 2017, pages 209 - 215
MAGARELLI N.: "Evaluation of magnetic resonance signal modification induced by hyaluronic acid therapy in chondromalacia patellae: a preliminary study", J. BIOL. REGUL. HOMEOST. AGENTS, vol. 22, no. 4, October 2008 (2008-10-01), pages 247 - 52
MAHEU E. ET AL.: "Efficacy and safety of hyaluronic acid in the management of osteoarthritis: Evidence from real-life setting trials and surveys", SEMIN. ARTHRITIS RHEUMATOLOGY, vol. 45, no. 4, 2016, pages S28 - 33
NAVARRO-SARABIA FCORONEL PCOLLANTES ENAVARRO FJDE LA SERNA ARNARANJO A ET AL.: "A 40-month multicentre, randomised placebo-controlled study to assess the efficacy and carry-over effect of repeated intra-articular injections of hyaluronic acid in knee osteoarthritis: the AMELIA project", ANNALS OF THE RHEUMATIC DISEASES, vol. 70, no. 11, 2011, pages 1957 - 62, XP055456713, DOI: 10.1136/ard.2011.152017
PETRELLA RJPETRELLA M: "A prospective, randomized, double-blind, placebo controlled study to evaluate the efficacy of intraarticular hyaluronic acid for osteoarthritis of the knee", THE JOURNAL OF RHEUMATOLOGY, vol. 33, no. 5, 2006, pages 951 - 6
REYNOLDS J E F ET AL: "MARTINDALE, The Extra Pharmacopoeia, 28th edition", 1 January 1982, MARTINDALE - THE EXTRA PHARMACOPOEIA; [MARTINDALE - THE EXTRA PHARMACOPOEIA], LONDON, PHARMACEUTICAL PRESS, GB, PAGE(S) 1068 - 1070, XP002105867 *

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