Login| Sign Up| Help| Contact|

Patent Searching and Data


Title:
UTILIZATION OF A COMPOSITION COMPRISING ORGANIC SILICA FOR THE IMPROVEMENT OF THE QUALITY OF CARTILAGENOUS TISSUES
Document Type and Number:
WIPO Patent Application WO/2021/121566
Kind Code:
A1
Abstract:
The invention relates to a new use of an organic silica fluid composition as medical product (1) 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.

Inventors:
AMMANN DENIS MICHEL (CH)
Application Number:
PCT/EP2019/085736
Publication Date:
June 24, 2021
Filing Date:
December 17, 2019
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
AA HEALTHCARE SARL (CH)
International Classes:
A61K31/695; A61K9/00; A61K31/728; A61P19/02
Domestic Patent References:
WO2018182436A22018-10-04
WO2016014408A12016-01-28
WO2011107866A22011-09-09
Other References:
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
EGLOFF C. ET AL.: "Biomechanics and pathomechanisms of osteoarthritis", SWISS MED. WEEKLY, vol. 142, 2012, pages w13583
LANE NE. ET AL.: "Ostheoarthritis year in review 2016: clinical", OSTHEOARTHRITIS CARTILAGE, 2017, pages 209 - 215
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
BALAZS EA.: "Viscosupplementation for treatment of osteoarthritis: from initial discovery to current status and results", SURGICAL TECHNOLOGY INTERNATIONAL, vol. 12, 2004, pages 278 - 89
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
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
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
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
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
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
Attorney, Agent or Firm:
BLANCHARD, Eugène (CH)
Download PDF:
Claims:
Claims

1. Use of an organic silica fluid composition as medical product (1) 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.

2. The use according to claim 1, wherein 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.

3. The use according to any one of claim 1 or 2, wherein said determined volume is comprised between 1 ml and 30 ml, preferably between 5 and 25 ml, still preferably between 1 and 6 ml.

4. The use according to any one of claims 1 to 3, wherein said injection is reproduced periodically.

5. The use according to claim 4, wherein the period between consecutive injections is at least one month.

6. The use according to any one of claims 1 to 5, wherein the concentration of solid organic silica in the composition is comprised between about 0,1% and 1%, preferably between 0,2% and 0, 6%.

7. The use according to any one of claims 1 to 6, wherein intra-articular injection of hyaluronic acid solution is carried out before injection of the organic silica composition.

8. The use according to claim 7, wherein injection of hyaluronic acid is carried out no earlier than 48h after injection of the organic silica composition, preferably no earlier than 24h.

9. The use according to any one of claims 1 to 6, wherein intra-articular injection of hyaluronic acid solution is carried out after injection of the organic silica composition.

10. The use according to claim 8, wherein injection of hyaluronic acid is carried out no later than 48h after injection of the organic silica composition, preferably no later than 24h.

11. The use according to any one of claims 1 to 6, wherein injection of hyaluronic acid is carried simultaneously with the injection of the organic silica composition.

Description:
UTILIZATION OF A COMPOSITION COMPRISING ORGANIC SILICA FOR THE IMPROVEMENT OF THE QUALITY OF CARTILAGENOUS TISSUES Technical Field

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.

More precisely the invention relates to the utilization of liquid organic silica compositions for restoring joints functionality through improvement of joints cartilage condition or quality.

Background Art

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.

In an adult bone, after the growth process of that bone, a thin layer of articular cartilage remains over the ends of the bones and is maintained by synthesis and regeneration of the extracellular matrix. 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.

Due to the limited natural response to the degeneration of the cartilage leads to portions that can have a local very thin thickness or even portions without any cartilage present.

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). The exact mechanism leading to OA onset and progression remains unknown. Presumably, both a mechanical and an inflammatory disease reflect part of the mechanisms for the onset and the progression of the disease (Ref.2). Importantly, 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.

Visco-supplementation or intra-articular injection of hyaluronic acid (HA), hereinafter referred to as IA-HA, is a symptomatic treatment of osteoarthritis to reduce pain and restore mobility in the affected joint (Refs. 4-7). 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. A systematic review of overlapping meta-analyses comparing IA-HA with other non-operative treatment modalities for knee OA shows that IA-HA is an option for knee OA (Refs. 8, 9). There is also controversy concerning the clinical effect of visco-supplementation. Thus in some consensus, visco-supplementation with HA is recommended as a second-line treatment for knee OA (Refs. 10, 11). However, other reviews doubt the clinical effect of IA-HA (Refs. 8, 11). Despite the fact that a positive effect is observed in the treated patients, the different clinical studies pooled together did not allow to establish a significant effect after visco supplementation as compared to placebo. Therefore, we can argue that the type of patients and inhomogeneity of the investigated population could interfere with the discovery of clear effects. Others argue that only placebo injection could have a positive effect. Regardless of the viscos-supplement product or the number of injections, the long-term effect can be observed; the OA patient can be pain-free for up to 26 weeks (Ref. 8).

In general, there exist no medical oral treatment allowing regeneration of the cartilage. The treatments only are symptomatic decreasing the pain. Surgical treatments for reducing or solving the cartilage defects may be implemented to remove surface irregularities or may consist in drilling into the bone to trigger a natural response to regenerate the cartilage at least partially. Other techniques consist in tissue transplantation or cell transplantation. Joint replacement is the ultimo surgical treatment. While these methods can temporarily improve the cartilage regeneration and/or relieve pain in the joints, none has been able to successfully repair cartilage in the long term, i.e. typically some years.

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.

There is a need of other therapeutic approaches. A huge variety of bio-chemical substance have been proposed to regenerate cartilage damages, but none has been proved successful. Growth factors PRP, parathormone, bisphosphonates, hyaluronic acid, stem cells. Some are expensive in term of synthesis, clinical procedure or leading to allergic reaction avian protein or skin reaction. Globally HA treatments are well positioned but quite expensive, which limits their access to a reduced number of patients suffering from osteoarthritis.

Summary of the invention

Considering the above defects of current therapeutic solutions, 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 inventors indeed surprisingly found out that well-known organic silica compositions could have more than a topical effect as know from their existing external or soluble use and be extremely efficient in injections directly into bodily joints, in particular in arthritis prevention and treatment purposes.

In a prefferend embodiment, 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. In a prefferend embodiment, the determined volume of solution injected is comprised between 1ml and 30 ml, preferably between 5 and 25 ml.

In a preferred embodiment, said injection is reproduced periodically, such as once a month.

In a preferred embodiment, 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.

Alternatively, injection of hyaluronic acid may also of course be carried simultaneously with the injection of the organic silica composition.

It was found in particular that the injection of 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.

Brief description of the drawings

Further details of the invention will appear more clearly upon reading the following description in reference to the appended figures:

Figure 1 summarizes in a table a measurement protocol;

Figure 2 illustrates a bio indentation procedure;

Figure 3 shows experimental typical indentation results;

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. Detailed description and embodiments of the invention

The present invention will now be described in relation to a preferred example of implementation of the invention with reference to the appended drawings, which shall not be construed as a limitation of the scope of the present invention as defined in the claims.

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.

In the context of the present invention, the terms “organic silica” shall be construed as meaning organic silicon, also known chemically as monomethylsilanetriol. The terms “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.

The terms “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. Similarly, the term “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. It is understood that 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.

As explained in the prior art paragraph there is a need for a cheap, not allergenic, and well tolerated active agent for reducing, and possibly treating joints cartilage disorders such as osteoarthritis.

It has been discovered by the inventors that 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/.

The inventors have however discovered and confirmed through ex-vivo testing that 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.

The term 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. In embodiments 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%.

Preferably, according to the invention, 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 tests carried out interestingly demonstrated that the positive effects induced by the organic silica solution on the osteochondral units arise on average after more than 20h after injection, and preferably after 40h.

Most interestingly, 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.

When injected before, 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.

When injected after, the injection of hyaluronic acid is carried out no later than 48h after injection of the organic silica composition, preferably no later than 24h.

Still preferably, 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.

In all cases, 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.

Experimental results

In this paragraph it is explained in detail how it has been discovered how the product of the invention may be used in the treatment of cartilage diseases and especially its surprising effect of healing. The applicant has demonstrated that that organic silica composition (hereafter named as AA171) is able to penetrate in the cartilage and to modulate by a physico-chemical effect the quality of the cartilage. Comparison has been made to the well-known standard HA Ostenil ® and also their potential synergistic effects, i.e. due to the combination of HA Ostenil ® and the product of the invention.

Organic silica solution AA171 effects on cartilage quality

Experimental protocol.

In the experimental protocol, an organic silica composition from commercially available DexSil ® solution, named AA171, in the appended drawings and herein was prepared:

All experimental designs and procedures were approved by the Animal Ethics Committee of the University of Geneva Faculty of Medicine. Distal femurs were collected from twelve 11-month-old Sprague-dawlay female rats (Charles River Laboratories, L’Arbresle, France). Four series of bio-indentations were performed at room temperature before and after an overnight (17 hours) incubation in the different agents PBS (control) AA, Ostenif or Ostenif + AA, as well as after a second overnight in the same incubation solution.

The number of samples tested were 6 in each group. To investigate the persistence of the effect all samples were then tested after an overnight incubation all in PBS at the end of the study. The concentration of AA171 and of Ostenil ® was similar to the solution injected during visco-supplementation in the incubation bath.

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. 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).

For rat studies, analyses were carried out using SPSS Advanced Statistics software and all results were expressed as means ± SEM. Bio-indentation and micro CT parameters were analyzed by an ANOVA. The level of significance was set to p<0.05. Bio-indentation results

A first series of experiments were a proof of concept that AAA 171 can improve cartilage quality. This is illustrated in Figure 5.

After 40 hours exposure to AA 171, the force necessary to induce a given deformation of the cartilage is increased by +17.2% (range 1 in the graph) , the depth of cartilage deformation is reduced by -17.5% ((range 2 in the graph) and the Modulus of the cartilage is increased by +25.7% (range 3 in the graph). Noon of these positive effects was observed after one overnight exposure to AA 171.

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.

Incubation of the distal femur in a solution of AA171 resulted in an increased modulus only after 40 hours incubation and this effect was maintained after a period of wash out. After 20 hours, no effect was observed.

An incubation with Ostenil solution resulted in a highly significant increment of the modulus already after 20 hours incubation. No further increments were observed after a 40 hours exposure. This effect was maintained after a period of wash out. This Ostenil effect was significantly lower than AA171.

The combination of Ostenil and AA171 could prolong the duration of efficacy of Ostenil.

Virtual histology of the distal femur

Virtual histology by EPIC-m OT of the distal femur was performed at the end of the in vitro study, indeed after incubation display no differences between the treated groups.

Conclusions

The experimental results demonstrate that local application of AA171 has a surprising effect on cartilage quality and is able to improve considerably cartilage quality and that this effect is permanent since a washout period does not abolish this effect. Thus, this effect takes more time than HA to modulate quality. We suspect an interaction with collagen and a reorganization of the collagen architecture. The AA171 effect is significantly more pronounced than Ostenil alone. There is a trend of synergistic effect after 40 hours incubation in both agents.

The results obtained with the product and the method of the invention strongly support a potential of improvements of in vivo effect on cartilages after intra articular injection. Furthermore, the previous esthetic of the compound supports our hypothesis and its safety.

References

1. Egloff C. et al., 2012, ‘Biomechanics and pathomechanisms of osteoarthritis’, Swiss Med. Weekly, 142:wl3583;

2. Lane NE. et al., 2017, Ostheoarthritis year in review 2016: clinical’, Ostheoarthritis Cartilage, 209-215;

3. Goldring SR. et al., 2016, 2016, ‘Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage-bone crosstalk.’, National Review of Rheumatology, Nov 12(11) :632-644;

4. Balazs EA., 2004, ‘Viscosupplementation for treatment of osteoarthritis: from initial discovery to current status and results.’, Surgical Technology International, 12:278-89;

5. Navarro-Sarabia F, Coronel P, Collantes E, Navarro FJ, de la Serna AR, Naranjo 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. 2011;70(ll):1957-62.

6. 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.

7. Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Annals of internal medicine. 2015;162(l):46-54.

8. Campbell KA, Erickson BJ, Saltzman BM, Mascarenhas R, Bach 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. 2015;31(10):2036-45 el4. Maheu E. et al., 2016, ‘Efficacy and safety of hyaluronic acid in the management of osteoarthritis: Evidence from real-life setting trials and surveys.’, Semin. Arthritis Rheumatology, 45(4 suppl):S28-33; Bruyere 0. et al., 2016, ‘ 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, 45(4 suppl):S3-ll; Magarelli N., 2008, ‘ Evaluation of magnetic resonance signal modification induced by hyaluronic acid therapy in chondromalacia patellae: a preliminary study’; J. Biol. Regul. Homeost. Agents, Oct-Dec; 22(4):247- 52.