EP-4271428-B1 - INJECTABLE PHOTOCROSSLINKED HYALURONIC ACID HYDROGELS, PRODUCTION METHOD THEREOF AND THEIR USE FOR THE TREATMENT OF OSTEOARTHRITIS

Inventors

• OYTUN, Faruk
• ÇIFTÇI, Mustafa
• KAYA, Busra Gizem

Dates

Publication Date

20260513

Application Date

20211228

Claims (7)

1. A production method of an injectable viscoelastic hydrogel formulation comprising photocrosslinked hyaluronic acid in order to relieve the pain caused by osteoarthritis (OA) and to support synovial fluid which has decreased activity comprising the steps of - Production of acrylated hyaluronic acid monomer, o Dissolving hyaluronic acid (HA) by slowly adding it into deionized water, o Dissolving glycidyl acrylate and triethylamine in dimethylformamide, o Combining these two solutions and mixing thereof for 3 days at room temperature, o Precipitating the mixture in acetone weighing up to 20 times its own weight and filtering it under low pressure, o Removing the impurities of the obtained solid with deionized water, o Drying the mixture by freeze drying method, o Obtaining acrylated HA monomer, - Production of photocrosslinked hyaluronic acid hydrogels, o Dissolving the obtained acrylated HA monomer by slowly adding it into deionized water, o Adding camphorquinone to this HA mixture and mixing it homogeneously, o Illuminating the mixture under visible light and leaving it for crosslinking reaction, o Neutralizing the gel in the buffer solution after the reaction until the pH value becomes stable, o filtering after pH adjustment, and allowing the gel to swell upon adding a new buffer solution, o Then, bringing the obtained gel to a particle size of 50-300 microns, o Adding non-crosslinked HA (Linear HA) into the photocrosslinked HA gel to facilitate its extrusion, o Adjusting the pH of the final mixture to 7 and filling it into the syringes by applying vacuum, o Applying vapor sterilization process to the syringes after filling process.
2. A production method of an injectable viscoelastic hydrogel formulation comprising photocrosslinked hyaluronic acid according to claim 1, wherein 5.0 mmol (2.0 grams) of HA is slowly added into 100 mL of deionized water and dissolved therein within the scope of production of acrylated hyaluronic acid monomer.
3. A production method of an injectable viscoelastic hydrogel formulation comprising photocrosslinked hyaluronic acid according to claim 1, wherein 250 mmol (32.2 grams) of glycidyl acrylate and 250 mmol (25.3 grams) of triethylamine are dissolved in 100 mL of dimethylformamide.
4. A production method of an injectable viscoelastic hydrogel formulation comprising photocrosslinked hyaluronic acid according to claim 1, wherein 5.0 mmol (2.0 g) of acrylated HA monomer is slowly added into 100 ml of deionized water and dissolved therein within the scope of production of photocrosslinked HA hydrogels.
5. A production method of an injectable viscoelastic hydrogel formulation comprising photocrosslinked hyaluronic acid according to claim 1, wherein 0.05-1 % by weight of camphorquinone is added to the HA mixture and mixed homogenously.
6. A production method of an injectable viscoelastic hydrogel formulation comprising photocrosslinked hyaluronic acid according to claim 1, wherein the mixture of camphorquinone and HA is illuminated under visible light for 30-240 minutes at room temperature and left for crosslinking reaction.
7. A production method of an injectable viscoelastic hydrogel formulation comprising photocrosslinked hyaluronic acid according to claim 1, wherein the gel is neutralized after the crosslinking reaction with 0.1 M of hydrochloric acid (HCl) in phosphate buffer solution (PBS) until the pH is 6.8-7.4.

Description

Field of the Invention The present invention relates to the development of an injectable viscoelastic hydrogel formulation comprising photocrosslinked hyaluronic acid in order to relieve pain caused by osteoarthritis (OA), to support synovial fluid which has decreased activity, and to treat osteochondral lesions. Background of the Invention The joint can be defined as the location where two bones come together in movable parts of the body such as arms, legs, feet, wrists, and the ends of these bones are covered with a protective tissue called cartilage. Cartilage is a durable and slippery tissue which allows joint movement to occur almost without friction. Synovial fluid, which provides lubricity between bone ends and cartilage, is comprised of Hyaluronic Acid (HA) that is naturally present in the body. The viscosity, lubrication and shock absorbing properties of the said synovial fluid decrease over time due to mechanical effects and the cartilages begin to rub against each other and break down. As the cartilage wears off and breaks down over time, the friction between the bones increases and a joint disease called Osteoarthritis (OA) begins and progresses with the increase in friction. Osteoarthritis (OA) is the most common, chronic (long-term) joint disease affecting millions of people worldwide. OA is also called degenerative joint disease, degenerative arthritis, and wear and tear arthritis. OA affects the entire joint, as well as cartilage breakdown. It causes changes in the bone structure and the deterioration of the connective tissues that hold the joint together and connect the muscles to the bone; and it also causes inflammation of the joint capsule. Even though OA is usually seen in old ages, it can sometimes be seen in young people. OA symptoms develop over time and they worsen as it progresses. Symptoms of OA include pain, stiffness, tenderness, loss of flexibility, crepitus, osteophyte formation, and swelling. Even though damage of the joints cannot be recovered; exercising, being at a healthy weight and several treatments that are applied can slow the progression of the disease and help relieve pain and improve joint functions. One of the methods that can help relieve OA symptoms, especially pain, is the use of medication. The commonly used drugs and their effects are shown below: Acetaminophen: It is known that acetaminophen (Tylenol and others) helps patients with osteoarthritis suffering from mild to moderate pain. Taking acetaminophen more than the recommended dose may cause liver damage.Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs such as Advil (ibuprofen) and Aleve (naproxen) reduce swelling as well as pain.Duloxetine (Cymbalta): This drug which is generally used as an antidepressant is also used to treat many chronic pains, including osteoarthritis pain. In addition to these, surgical and other procedures that can be used to relieve the symptoms of OA are listed below: Cortisone injections: In corticosteroid drug injections, the area around the joint is checked, and then the drug is injected by inserting a needle into the space in the joint. However, the number of cortisone injections that can be administered annually is generally limited to three or four. This is because the drug worsens joint damage over time.Viscoelastic injections: Injections of HA, which is a component found naturally in the synovial fluid, exhibit a buffering effect on the knee and alleviate the severity of pain.Joint replacement: In joint replacement surgery (arthroplasty), the damaged joint surfaces are replaced with plastic and metal parts. However, this method involves surgical risks related with the infections. In addition, artificial joints can also wear out and loosen over time and may need to be replaced. Today, the most preferred method among the methods of the treatment is to make viscoelastic injections to the problematic area. The most widely used of these injection types is HA injections. People with OA have low amounts of HA in their joint fluid. In the knee with OA, the concentration of HA is approximately half of the normal level. HA is a gel-like substance naturally existing in the synovial fluid surrounding the joints. The said substance provides lubrication and cushioning, acts as a shock absorber, and helps the bones move smoothly by preventing the bones from wearing each other off. Furthermore, it supports the synovial fluid to ensure the healing of intra-articular wounds in pathological conditions. In addition, it improves the physiological environment of the osteoarthritic joint and increases its mobility by regaining its viscoelasticity. Changes in the viscous and elastic properties of HA decrease the joint's ability to withstand tensile and shear forces. HA injections can help recover the normal levels of synovial fluid. These injections not only lubricate the joint, they can also reduce inflammation and protect the cartilage from further wear and tear. The injections are made i