US-12622863-B2 - Injectable composition and use of said composition

US12622863B2US 12622863 B2US12622863 B2US 12622863B2US-12622863-B2

Abstract

Injectable composition in hydrogel form, comprising water, hyaluronic acid, and nicotinamide for inhibiting the action of the hyaluronidase in the injected condition of the composition.

Inventors

Federico Panzieri
Giulia AVIO
Cosimo CELINO

Assignees

INNATE S.R.L.

Dates

Publication Date: 20260512
Application Date: 20211025
Priority Date: 20201026

Claims (7)

1 . An injectable composition in hydrogel form, comprising water and hyaluronic acid, and further comprising nicotinamide for inhibiting action of hyaluronidase in the injected condition of the composition; wherein said hyaluronic acid is of the linear type and comprises between 1000 KDa and 4000 KDa high molecular weight sodium hyaluronate; wherein the hyaluronic acid is provided in weight percentages between 1.0% and 3.0% and the nicotinamide is provided in weight percentages between 0.2% and 5.0%.
2 . The composition according to claim 1 , further comprising sodium chloride.
3 . The composition according to claim 1 , further comprising buffer system comprising sodium phosphate dibasic and sodium phosphate monobasic.
4 . The composition according to claim 3 , wherein said sodium phosphate dibasic is in an anhydrous and/or dihydrate and/or dodecahydrate hydration state and said sodium phosphate monobasic is in an anhydrous and/or dihydrate hydration state.
5 . A method for therapeutic treatment, in a subject in need thereof, the method comprising an intra-articular injection of the composition according to claim 1 , in a joint to increase lubricating capacities of synovial fluid of the joint.
6 . A method for therapeutic treatment, in a subject in need thereof, the method comprising an intradermal injection of the composition according to claim 1 , to correct skin imperfections.
7 . A method for therapeutic treatment, in a subject in need thereof, the method comprising administration of a composition according to claim 1 , in combination with platelet-rich plasma (PRP).

Description

The present invention relates to an injectable composition in hydrogel form, comprising water and hyaluronic acid. Hyaluronic acid is a very biocompatible natural polysaccharide, present in all human tissues, and is one of the fundamental components of connective tissues. It is distributed ubiquitously in animal tissues and fluids, in high concentrations in synovial fluids, in the vitreous humour and in the skin, and is mainly responsible for the viscosity and lubricating activity of synovial fluid. In cartilage, hyaluronic acid acts as a support for the aggregation of proteoglycans and proteins. Hyaluronic acid is a long glycosaminoglycan composed of repeated disaccharides of glucuronic acid and N-acetylglucosamine with high molecular weight and high viscosity. Hyaluronic acid is currently prepared as a gel from a powder in which it is present as a salt (sodium hyaluronate), and in such a gel it forms water micelles thanks to its high affinity with water itself. A crystalline gel is then formed which, when injected, achieves prolonged durability in tissues, as it maintains biocompatibility. Hyaluronic acid is used for example in aesthetic medicine to increase the volume of facial tissues, to correct wrinkles, skin folds, to increase the volume of the lips, and in general to correct skin imperfections. In this case it can be injected inside a scar or at the level of the superficial dermal layer for skin treatments and act as a skin moisturiser or even as a filler and therefore anti-wrinkle substance. This action is made possible thanks to the viscoelastic and hydrating properties of hyaluronic acid, which is naturally present in the extracellular matrix of skin with the function of regulating hydration and elasticity. The intradermal administration of the aid allows to give tissues a good amount of hyaluronic acid to counteract the skin aging process. Alternatively, hyaluronic acid is used for intra-articular administration, in the treatment of osteoarthritis, for example in the knee, where it is naturally found in the synovial fluid, of which it is the main substance responsible for the high lubricating capacities thanks to the viscosity thereof. Hyaluronic acid contributes to lubricating the joint and cushioning mechanical stresses, and therefore has a lubricating function and a cushioning function. It also protects the cartilage from the penetration of inflammatory cells and from the lithic enzymes which degrade it. In intra-articular infiltrations, the preparation generally consists of a sodium salt of a high molecular weight and high purity fraction of hyaluronic acid. The short half-life of this molecule at the joint level means that its effectiveness is not simply linked to the restoration of physiological levels of hyaluronic acid in osteoarthritic joints. The evaluations carried out in patients with osteoarthritis and other arthropathies involving the knee have shown an action which, in principle, exerts an anti-inflammatory activity of the molecule. Microarthroscopy studies and ultrastructural studies on the joint cartilage and synovial membrane have also shown that there is a possible repair of degenerative joint lesions in humans following intra-articular use of the drug. Compositions of this type must address the degradation of the hyaluronic acid over time; in fact, this degradation affects the so-called shelf life, i.e., the duration of the period from production to sale in which the total quality of the product must be maintained intact, and above all the duration of the effect on the body following administration. The duration of hyaluronic acid strongly depends on the type of treatment to which it is subjected and its composition. Two categories can be distinguished: linear hyaluronic acid and cross-linked (or reticulated) hyaluronic acid. Special cross-linking agents such as BDDE (1,4 butanediol diglidyl ether) or DVS (Divinyl Sulfone) are used to switch from linear to cross-linked hyaluronic acid. Currently the compositions exhibiting the longest durability are those comprising cross-linked hyaluronic acid. However, the presence of traces of BDDE or other cross-linking agents at the end of the cross-linking reaction is problematic in several respects, for example because in the immediate term it may trigger intracutaneous reactivity actions and in the long term it may cause the onset of subcutaneous granulomas. A major cause of the degradation of hyaluronic acid is the action of the enzyme hyaluronidase. This enzyme acts very effectively on linear hyaluronic acid, while the three-dimensional structure of the cross-linked hyaluronic acid assumed by virtue of the cross-linking process makes the action of the enzyme difficult. Therefore, in the state of the art, the request for a longer duration of the composition requires the use of cross-linked hyaluronic acid, to the detriment of an increase in risks to the user's health and safety. The use of antioxidants and stabilizers, which act as p