A long-acting sustained-release gel injectable into joint cavity and preparation method thereof

Abstract

The present invention discloses a long-acting sustained-release gel that can be injected into the articular cavity and a preparation method thereof; the gel comprises the following components in mass fraction: 0.05-2.0% of nonsteroidal anti-inflammatory drugs, 1.0-3.0% of gel matrix, 0.1-5.0% of stabilizer, 0.05-1.0% of buffer, 0.5-1.5% of auxiliary materials and the balance of water; the pH of the gel is 7.0±0.5; the method is as follows: S1, dissolving the buffer in water to obtain a buffer solution; S2, dissolving the nonsteroidal anti-inflammatory drugs and stabilizers in the buffer solution to obtain a dissolved solution; S3, adding auxiliary materials and gel matrix to the dissolved solution and stirring until the solution is completely dissolved and in a gel state, and replenishing water; S4, filtering or wet heat sterilization to obtain a long-acting sustained-release gel. Application: The gel is used for the treatment of bone and joint diseases or improvement of joint symptoms. The gel of the present invention can improve the lubrication and protection of bone and joints for a long time while quickly relieving pain, providing an overall therapeutic effect.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical preparations, and in particular to a long-acting sustained-release gel that can be injected into a joint cavity and a preparation method thereof. Background Art

[0002] Ketorolac is a nonsteroidal drug with strong analgesic activity. In order to improve the water solubility of ketorolac, meet the requirements of injection and oral administration, and make ketorolac take effect quickly in body fluids and the gastrointestinal tract, it is usually prepared into ketorolac tromethamine salt, the structure of which is shown in formula (I):

[0003]

[0004] The injection (30 mg / time) and oral preparation (10 mg / time) of ketorolac tromethamine can be used to relieve moderate to severe postoperative pain, swelling pain and pain caused by other inflammations. In addition, it can also relieve acute renal colic, biliary colic, toothache, traumatic pain, cancer visceral pain, and various pains that require morphine or pethidine to relieve. The main pharmacological action of ketorolac is to achieve analgesia, anti-inflammatory, antipyretic and platelet aggregation inhibition by inhibiting the synthesis of prostaglandins.

[0005] At present, the ketorolac preparations marketed in China include tablets, capsules, injections and eye drops. In order to overcome the defect of frequent administration of ketorolac oral preparations, ketorolac is prepared into oral sustained-release microcapsules, osmotic pump tablets, gastric floating tablets, pulse release systems, etc. using a variety of preparation technologies to achieve the long-term analgesic effect of ketorolac. Ketorolac tromethamine oral preparations have gastrointestinal side effects common to non-steroidal drugs and are not targeted in the treatment of local pain. Therefore, a new ketorolac topical preparation with multiple administration routes such as skin, eyes, nasal cavity, oral mucosa, etc. is developed to treat pain in subcutaneous soft tissues, joints, oral cavity, etc. The new ketorolac preparation is developed around the purpose of long-term and local targeted analgesia, so as to meet different clinical analgesic needs.

[0006] Hyaluronic acid (HA) is an anionic non-sulfate glycosaminoglycan, which is composed of N-acetyl-D-glucosamine (GlcNAc) and gluconic acid (GlcA) connected by 1,4-glycosidic bonds to form repeating units, and the repeating units are connected by β-1,3-glycosidic bonds to form a linear main chain. Hyaluronic acid is widely present in mammalian tissues, including connective tissue, epithelial tissue and nervous tissue. Its main biological functions include regulating the viscoelasticity of tissue fluids, such as synovial fluid and vitreous fluid. Due to its good hydrophilicity, biocompatibility and non-immunogenicity, hyaluronic acid has received extensive attention and research in the medical field, such as supplementing synovial fluid to treat arthritis to improve pain and function, using it as a filler in ophthalmic surgery, and applying it to wound dressings, as well as a drug delivery material for targeted drug delivery or drug solubilization. In addition, hyaluronic acid (HA) is also widely used in the fields of food and cosmetics. At present, there are many HA products on the market in China for the treatment of osteoarthritis.

[0007] Chitin's chemical name is poly 1,4-β-N-acetyl-D-glucosamine, which is widely found in the exoskeletons of crustaceans and fungal cell walls. Chitosan is the most important derivative of chitin, which is produced by deacetylation of chitin. Its chemical name is poly 1,4-β-D-glucosamine. Due to the presence of a large number of exposed amino and hydroxyl groups, chitosan easily forms strong hydrogen bonds within or between molecules, which makes it difficult to dissolve in water or conventional organic solvents. N-acylation is a common modification strategy to enhance its water solubility. Medical chitosan (for intra-articular injection) is the only high-molecular polysaccharide currently approved for use in the treatment of osteoarthritis on the market, except for sodium hyaluronate (LIBOXI, National Medical Device Registration No. 20173130026). In addition, polymers such as heparin precursor (Heparosan), pentosan polysulfate (PPS), lubricin or polyvinyl alcohol for the treatment of arthritis are gradually entering the clinical trial stage. Although no products have yet been launched on the market, these are also very promising therapeutic drugs or materials.

[0008] Polyols such as mannitol and sorbitol contain high-density hydroxyl groups in their molecular structures, are soluble in water, have low toxicity, and are often used as food additives. Therefore, polyols are used as moist heat sterilization stabilizers for carboxymethyl chitin preparations. Through the hydrogen bonding effect formed between the two, the molecular structure of carboxymethyl chitin can be stabilized, and the integrity of the molecular chain can be protected to make it resistant to high temperature degradation. Clinical treatment has shown that ketorolac can effectively relieve the pain caused by acute gouty arthritis, and some studies have also confirmed the effectiveness of knee joint injection of ketorolac for the treatment of knee osteoarthritis. The long-acting gel product of ketorolac can play a quick analgesic effect while continuing to maintain a long-term lubricating effect, which is a better choice for the treatment of osteoarthritis, but there is still no such product listed. Summary of the invention

[0009] The purpose of the present invention is to address the problems existing in the above-mentioned background technology and provide a long-acting sustained-release gel that can be injected into the joint cavity and a preparation method thereof.

[0010] The present invention is achieved through the following technical solutions:

[0011] A long-acting sustained-release gel that can be injected into the articular cavity, characterized in that the long-acting sustained-release gel comprises the following components:

[0012] 0.05-2.0wt% of nonsteroidal anti-inflammatory drugs, 1.0-3.0wt% of gel matrix, 0.1-5.0wt% of stabilizer, 0.05-1.0wt% of buffer and the balance of water; the pH of the long-acting sustained-release gel is 7.0±0.5, and the osmotic pressure is 280-380mOsm / kg.

[0013] Specifically, the long-acting sustained-release gel developed by the present invention is suitable for injection into the joint cavity and can be used to treat bone and joint diseases. It can quickly relieve pain while improving the lubrication and protection of the bone and joints for a long time, providing an overall therapeutic effect.

[0014] Furthermore, a long-acting sustained-release gel that can be injected into the articular cavity is characterized in that the non-steroidal anti-inflammatory drug is ketorolac tromethamine.

[0015] Furthermore, a long-acting sustained-release gel that can be injected into the joint cavity is characterized in that the gel matrix is ​​naturally extracted or biologically fermented, or can be chemically synthesized. These gel matrices can be selected from any one of cross-linked sodium hyaluronate, non-cross-linked sodium hyaluronate, medical chitosan, heparin precursor (Heparosan), pentosan polysulfate (PPS), human lubricin or polyvinyl alcohol, or a combination of two or more.

[0016] Furthermore, a long-acting sustained-release gel that can be injected into the joint cavity is characterized in that the molecular weight of the sodium hyaluronate is 100 to 10,000 kD, and the molecular weight of the medical chitosan is 100 to 1,000 kD.

[0017] Furthermore, a long-acting sustained-release gel that can be injected into the articular cavity is characterized in that the stabilizer is selected from sorbitol, mannitol or meglumine. The stabilizer is a polyol stabilizer.

[0018] Furthermore, a long-acting sustained-release gel that can be injected into the articular cavity is characterized in that the buffer is selected from one or a mixture of phosphate, borate or citrate.

[0019] A method for preparing a long-acting sustained-release gel that can be injected into a joint cavity, characterized in that the method is used to prepare the above-mentioned long-acting sustained-release gel that can be injected into a joint cavity, and the method comprises the following specific steps:

[0020] S1, dissolving the buffer in water to obtain a buffer;

[0021] S2, dissolving the nonsteroidal anti-inflammatory drug and the stabilizer in the buffer to obtain a dissolved solution;

[0022] S3, adding the gel matrix to the dissolving solution and stirring until it is completely dissolved and in a gel state, adding water, and adjusting the pH of the system to 7.0±0.5;

[0023] S4. After filtration or wet heat sterilization, a long-acting sustained-release gel that can be injected into the joint cavity is obtained.

[0024] Another method for preparing a long-acting sustained-release gel that can be injected into the articular cavity, characterized in that the method is used to prepare the above-mentioned long-acting sustained-release gel that can be injected into the articular cavity, and the method comprises the following specific steps:

[0025] S1, dissolving the buffer in water to obtain a buffer;

[0026] S2, adding the gel matrix into the buffer and stirring until it is completely dissolved to obtain a gel system;

[0027] S3, adding the nonsteroidal anti-inflammatory drug and the stabilizer to the gel system, replenishing water, and adjusting the pH of the system to 7.0±0.5;

[0028] S4. After filtration or wet heat sterilization, a long-acting sustained-release gel that can be injected into the joint cavity is obtained.

[0029] Uses: The above-mentioned long-acting sustained-release gel that can be injected into the articular cavity can be used to treat bone and joint diseases or to improve joint symptoms. Among them: bone and joint diseases can include joint injuries such as knee joints, hip joints, shoulder joints, ankle joints, and finger joints, osteoarthritis, rheumatoid arthritis, etc.

[0030] Beneficial effects of the present invention:

[0031] (1) The present invention relates to ketorolac tromethamine, which is firstly made into a long-acting sustained-release gel that can be injected into the articular cavity, and is used for the treatment of osteoarthritis; the present invention aims to reduce drug irritation, reduce systemic adverse reactions, increase efficacy and drug safety, and the present invention also has good biocompatibility and in vivo degradability. Wherein: the ketorolac tromethamine used in the present invention is a COX1 / 2 non-steroidal anti-inflammatory drug, which can avoid causing adverse gastrointestinal reactions, liver and kidney toxicity through local administration into the articular cavity. At the same time, the long-acting sustained-release gel provided by the present invention can be injected into the articular cavity, and the articular cavity is a relatively closed space, which is relatively safe after local administration, so the long-acting sustained-release gel of the present invention has high pharmaceutical safety.

[0032] (2) The long-acting sustained-release gel that can be injected into the articular cavity provided by the present invention can not only quickly relieve pain but also improve the lubrication and protection of bone joints for a long time, providing an overall therapeutic effect. Among them, lubrication and protection are mainly due to the viscoelastic supplementation properties of the gel, and as a drug release carrier, it can improve the overall therapeutic effect of arthritis. DETAILED DESCRIPTION

[0033] The technical solution of the present invention will be clearly and completely described below in conjunction with specific embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all of the embodiments. The following description of at least one exemplary embodiment is actually only illustrative and is by no means intended to limit the present invention and its application or use. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] Apparatus: viscotester IQ Air; rotor: P35 / Ti-01150939; temperature: 25°C; shear rate: 0.1-100 / s.

[0035] Example 1

[0036] A long-acting sustained-release gel that can be injected into the articular cavity, characterized in that the long-acting sustained-release gel comprises the following components:

[0037] 0.75wt% nonsteroidal anti-inflammatory drug, 2.0wt% gel matrix, 4.0wt% stabilizer, 0.65wt% buffer and the balance water; the pH of the long-acting sustained-release gel is 6.8-7.4, the osmotic pressure is 280-350mOsm / kg, and the shear viscosity is greater than 3Pas;

[0038] Wherein: the non-steroidal anti-inflammatory drug is ketorolac tromethamine; the gel matrix is ​​a mixture of sodium hyaluronate and medical chitosan in a mass ratio of 1:1; the stabilizer is sorbitol; and the buffer is phosphate.

[0039] The method for preparing the above-mentioned long-acting sustained-release gel that can be injected into the articular cavity comprises the following steps:

[0040] S1. dissolving phosphate in water to obtain phosphate buffer;

[0041] S2, dissolving ketorolac tromethamine and sorbitol in phosphate buffer and stirring at 5 to 50° C. for 1 to 3 hours to obtain a solution;

[0042] S3, add gel matrix (sodium hyaluronate and medical chitosan) to the above solution and stir at 5-50°C for 1-10 hours until it is completely dissolved in a gel state, add water, and adjust the pH of the system to 6.8-7.4;

[0043] S4. After filtration or wet heat sterilization, a long-acting sustained-release gel that can be injected into the joint cavity is obtained.

[0044] The long-acting sustained-release gel can be injected into the joint cavity for the treatment of bone and joint diseases or for improving joint symptoms. Among them, bone and joint diseases may include joint injuries such as knee joints, hip joints, shoulder joints, ankle joints, and finger joints, osteoarthritis, rheumatoid arthritis, etc.

[0045] Example 2

[0046] A long-acting sustained-release gel that can be injected into the articular cavity, characterized in that the long-acting sustained-release gel comprises the following components:

[0047] 1.5wt% nonsteroidal anti-inflammatory drug, 1.5wt% gel matrix, 4.0wt% stabilizer, 0.65wt% buffer and the balance water; the pH of the long-acting sustained-release gel is 7.0±0.5, the osmotic pressure is 280-380mOsm / kg, and the shear viscosity is greater than 3Pas;

[0048] Wherein: the non-steroidal anti-inflammatory drug is ketorolac tromethamine; the gel matrix is ​​a mixture of sodium hyaluronate and medical chitosan in a mass ratio of 1:1; the stabilizer is sorbitol; and the buffer is borate.

[0049] Example 3

[0050] A long-acting sustained-release gel that can be injected into the articular cavity, characterized in that the long-acting sustained-release gel comprises the following components:

[0051] 0.75wt% nonsteroidal anti-inflammatory drug, 1.0wt% gel matrix, 1.0wt% stabilizer, 0.85wt% buffer and the balance water; the pH of the long-acting sustained-release gel is 7.0±0.5, the osmotic pressure is 280-330mOsm / kg, and the shear viscosity is greater than 8Pas;

[0052] Wherein: the non-steroidal anti-inflammatory drug is ketorolac tromethamine; the gel matrix is ​​sodium hyaluronate; the stabilizer is sorbitol; and the buffer is phosphate.

[0053] Example 4

[0054] A long-acting sustained-release gel that can be injected into the articular cavity, characterized in that the long-acting sustained-release gel comprises the following components:

[0055] 0.375wt% nonsteroidal anti-inflammatory drug, 2.0wt% gel matrix, 4.0wt% stabilizer, 0.45wt% buffer and the balance water; the pH of the long-acting sustained-release gel is 7.0±0.5, the osmotic pressure is 280-360mOsm / kg, and the shear viscosity is greater than 0.5Pas;

[0056] Wherein: the non-steroidal anti-inflammatory drug is ketorolac tromethamine; the gel matrix is ​​medical chitosan; the stabilizer is sorbitol; and the buffer is phosphate.

[0057] Example 5

[0058] A long-acting sustained-release gel that can be injected into the articular cavity, characterized in that the long-acting sustained-release gel comprises the following components:

[0059] 0.05wt% nonsteroidal anti-inflammatory drug, 1.0wt% gel matrix, 0.1wt% stabilizer, 0.05wt% buffer and the balance water; the pH of the long-acting sustained-release gel is 7.0±0.5;

[0060] Wherein: the non-steroidal anti-inflammatory drug is ketorolac tromethamine; the gel matrix is ​​non-cross-linked sodium hyaluronate with a molecular weight of 100 to 10,000 kD; the stabilizer is mannitol; and the buffer is a mixture of phosphate and borate.

[0061] The method for preparing the above-mentioned long-acting sustained-release gel that can be injected into the articular cavity comprises the following steps:

[0062] S1. dissolving phosphate and borate in water to obtain a buffer solution;

[0063] S2, adding non-cross-linked sodium hyaluronate to the above buffer and stirring at 5-50° C. for 1-10 hours until it is completely dissolved to obtain a gel system;

[0064] S3, adding ketorolac tromethamine and mannitol to the above gel system, replenishing water, and adjusting the pH of the system to 7.0±0.5;

[0065] S4. After filtration or wet heat sterilization, a long-acting sustained-release gel that can be injected into the joint cavity is obtained.

[0066] Example 6

[0067] A long-acting sustained-release gel that can be injected into the articular cavity, characterized in that the long-acting sustained-release gel comprises the following components:

[0068] 2.0wt% nonsteroidal anti-inflammatory drug, 1.2wt% gel matrix, 5.0wt% stabilizer, 1.0wt% buffer and the balance water; the pH of the long-acting sustained-release gel is 7.0±0.5;

[0069] Wherein: the non-steroidal anti-inflammatory drug is ketorolac tromethamine; the gel matrix is ​​cross-linked sodium hyaluronate; the stabilizer is meglumine; and the buffer is citrate.

[0070] Comparative Example 1

[0071] A long-acting sustained-release gel that can be injected into the articular cavity, characterized in that the long-acting sustained-release gel comprises the following components:

[0072] 0.75wt% nonsteroidal anti-inflammatory drug, 1.0wt% gel matrix, 0.85wt% buffer, and the balance water; the pH of the long-acting sustained-release gel is 7.0±0.5;

[0073] Wherein: the non-steroidal anti-inflammatory drug is ketorolac tromethamine; the gel matrix is ​​sodium hyaluronate; the buffer is phosphate; and the auxiliary material is sodium chloride.

[0074] The difference between Comparative Example 1 and Example 3 is that no sorbitol stabilizer is added in Comparative Example 1, and the rest is the same as Example 3.

[0075] The addition of sorbitol stabilizer in the present invention also has the function of regulating osmotic pressure.

[0076] The above are preferred embodiments of the present invention and are only used to explain the present invention, not to limit the present invention. Any obvious changes or modifications derived from the technical solution of the present invention are still within the protection scope of the present invention.

Claims

1. A long-acting sustained-release gel that can be injected into the articular cavity, characterized in that: The long-acting sustained-release gel comprises the following components: 1.5wt% nonsteroidal anti-inflammatory drug, 1.5wt% gel matrix, 4.0wt% stabilizer, 0.65wt% buffer and the balance water; the pH of the long-acting sustained-release gel is 7.0±0.5, and the osmotic pressure is 280-380mOsm / kg; The nonsteroidal anti-inflammatory drug is ketorolac tromethamine, the gel matrix is ​​a mixture of sodium hyaluronate and medical chitosan in a mass ratio of 1:1, the stabilizer is sorbitol; and the buffer is borate; The molecular weight of the sodium hyaluronate is 100 to 10000 kD, and the molecular weight of the medical chitosan is 100 to 1000 kD.

2. A method for preparing the long-acting sustained-release gel injectable into the articular cavity as claimed in claim 1, characterized in that: The method is used to prepare the long-acting sustained-release gel that can be injected into the articular cavity as claimed in claim 1, and the method comprises the following steps: S1, dissolving the buffer in water to obtain a buffer; S2, dissolving the nonsteroidal anti-inflammatory drug and the stabilizer in the buffer to obtain a dissolved solution; S3, adding the gel matrix to the dissolving solution and stirring until it is completely dissolved and in a gel state, adding water, and adjusting the pH of the system to 7.0±0.5; S4. After filtration or wet heat sterilization, a long-acting sustained-release gel that can be injected into the joint cavity is obtained.

3. A method for preparing the long-acting sustained-release gel injectable into the articular cavity as claimed in claim 1, characterized in that: The method is used to prepare the long-acting sustained-release gel that can be injected into the articular cavity as claimed in claim 1, and the method comprises the following steps: S1, dissolving the buffer in water to obtain a buffer; S2, adding the gel matrix into the buffer and stirring until it is completely dissolved to obtain a gel system; S3, adding the nonsteroidal anti-inflammatory drug and the stabilizer to the gel system, replenishing water, and adjusting the pH of the system to 7.0±0.5; S4. After filtration or wet heat sterilization, a long-acting sustained-release gel that can be injected into the joint cavity is obtained.

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