WO2008014685A1

WO2008014685A1 - Formulation containing trehalose for intraarticular injection

Info

Publication number: WO2008014685A1
Application number: PCT/CN2007/002250
Authority: WO
Inventors: Peixue Ling; Xiaohua Rong
Original assignee: Peixue Ling; Xiaohua Rong
Priority date: 2006-07-24
Filing date: 2007-07-24
Publication date: 2008-02-07
Also published as: CN100571707C; CN101112378A

Abstract

A formulation containing trehalose for intraarticular injection, which can be used to ameliorate and treat rheumatic arthritis, osteoarthritis, synovitis and/or cartilage injure.

Description

0 Intra-articular injection preparation containing trehalose Technical Field:

The present invention relates to an intra-articular injection preparation containing trehalose and the use of trehalose in the preparation of a medicament for intra-articular administration for the treatment and treatment of joint diseases.

Background technique:

Arthritis is one of the most common joint diseases in the clinic and is more common in the elderly. With the prolongation of human life expectancy and the aging society, the incidence of arthritis in the elderly continues to rise, seriously reducing the quality of life of the elderly. Therefore, the treatment of arthritis has become a major problem to be solved.

Arthritis caused by various causes begins with degeneration and injury of articular cartilage, followed by changes in bone mass and synovium, including changes in chondrocytes and stroma. In patients with arthritis, damage to their articular chondrocytes leads to their sensitivity to the environment, especially to changes in temperature. At present, there are various methods for the treatment of arthritis. One of the commonly used methods is to control inflammation by administering glucocorticoids, but it cannot fundamentally improve the ability of cells to resist environmental changes, and glucocorticoids have obvious adverse reactions. Greatly limited its application.

Since the 1980s, viscoelastic supplementation therapy for osteoarthritis has been made, in which osteoarthritis has been treated by intra-articular injection of sodium hyaluronate (also known as sodium hyaluronate), and revolutionary progress has been made. As an important part of joint synovial fluid, sodium hyaluronate is of great significance for maintaining the normal function of synovial fluid, which makes articular cartilage and synovial fluid have good elasticity. In the synovial fluid of patients with osteoarthritis, hyaluronic acid The molecular weight, concentration and viscoelasticity of sodium are significantly reduced. Direct administration of high molecular weight sodium hyaluronate directly into the joint cavity can directly improve joint synovial fluid and gradually repair articular cartilage. The application of this method has resulted in the recovery of many patients with osteoarthritis. However, although sodium hyaluronate alone can directly repair damaged cartilage, it fundamentally treats osteoarthritis, but the repair speed is slower and the required course of treatment is longer. Trehalose is a disaccharide formed by two glucopyranose monomers linked by 1,1 glycosidic bonds. In theory, it has three isomers, namely α, α-form, (3⁄4, 0-form and 0, β-type, in which only α, α-trehalose exists in a free state in nature, that is, commonly known as trehalose, α, β-form and β, β-form is almost absent in nature, but It can be chemically synthesized. The chemical name of α, α-trehalose is α-glucopyranosyl- a-D- than glucopyranosyl-a-/?-gluco-pyranoside, the molecular formula is ( ^ Hn · 2H ₂ 0, the molecular structure is:

a, oc-type trehalose conformation

Trehalose is widely distributed throughout the biological world, including bacteria, fungi, insects, other plants and animals, and has special protective effects on biomolecules. The role of biofilms is stabilized: Trehalose can be protected by lowering the phase transition temperature. The role of biofilms, even at very low temperatures, shows a good protection of biofilms, thereby improving the ability of cells to adapt to the environment. In addition, trehalose has significant antioxidant and anti-free radical action and can fight joints. inflammation. In recent years, studies have found that oral trehalose can improve the symptoms of arthritis, which provides a way for the treatment of arthritis. However, although oral trehalose has a certain effect of improving arthritis and has no adverse reactions, the oral method is slower and it is difficult to obtain a good effect in a short period of time. Based on this, the present inventors conducted related research and provided an intra-articular injection preparation containing trehalose, which can directly act on trehalose to the diseased joint, improve the ability of the cells to adapt to the environment and resist environmental changes, and directly confront Inflammation, while trehalose also provides the required sugar for cartilage repair, thereby improving and treating arthritis, joint damage and/or synovitis symptoms. Summary of the invention:

The present invention provides an intra-articular injection preparation containing trehalose. 5wt度/。 The concentration of trehalose was 0. 5wt ° /. - 50wt°/. , preferably 2wt% - 20wt%, preferred 3wt ― 15wt ₀

The basic composition of the intra-articular injection preparation preparation of the present invention is trehalose and a conventional pharmaceutical auxiliary, wherein the conventional pharmaceutical auxiliary is selected from the group consisting of, but not limited to, a solvent, an osmotic pressure regulator, a pH adjuster, an antioxidant, and a tackifier. And/or a preservative; other active ingredients may be added based on the above basic composition, wherein the other active ingredients are selected from, but not limited to, sodium hyaluronate, chitosan, methyl cellulose, lecithin and/or chondroitin sulfate Among them, it is preferably selected from sodium hyaluronate and/or chondroitin sulfate, and sodium hyaluronate is preferred.

The pH range of the intra-articular injection preparation of the present invention is 5. 5 - 9 , preferably 6. 0 - 8. 0, preferred 6. 5 - 7. 5; osmotic pressure range is 150 - 450 milliosmoles / liter, preferably 220 - 350 亳 per equivalent / liter, preferred 260 - 330 milliosmper equivalent / liter.

The intra-articular injection preparation preparation of the present invention is any dosage form for intra-articular injection, which is selected from the group consisting of, but not limited to, a liquid preparation such as an injectable solution or a gel, such a preparation and its preparation and use method for the field The skilled person is well known or can refer to standard textbooks in the field. Administration of the formulation by intra-articular injection can be used to improve and treat rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, joint damage and/or synovitis.

Accordingly, another object of the present invention is the use of trehalose for the preparation of a medicament for intra-articular administration for the treatment and improvement of joint diseases, preferably intra-articular injection, wherein said joint disease Selected from, but not limited to, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, synovitis, and cartilage damage.

The invention has obvious advantages in improving and treating joint diseases by intra-articular administration of trehalose: 1) can directly act on diseased joints, and the curative effect is faster; 2) can promote cartilage repair, improve the ability of cells to adapt to the environment and resist environmental changes 3) Safety without side effects. Unless otherwise stated, the terms used herein have the meaning as commonly understood in the art. detailed description:

The following examples are now provided to further illustrate the invention, but the scope of the invention is not limited thereto.

The following examples were conducted by taking a, ct-trehalose as an example, but the trehalose used in the present invention may be trehalose of any configuration.

Example 1 : Liquid preparation for intra-articular injection

Composition: Bu

Ingredients preparation 1 preparation 2

Trehalose 28 g 5g

0. 316 g inch 0. 160 g

Disodium phosphate

Sodium chloride 0. 471 g 0. 412 g

Add water to 100ml to 100ml

H 6. 98 7. 38

Osmotic pressure seepage equivalent / liter

325 millimeters 280 milliosmoles per liter

Preparation method: sodium dihydrogen phosphate and disodium hydrogen phosphate are prepared into a buffer system by using water for injection, adding trehalose, stirring and dissolving, adding sodium chloride to dissolve, adding water to the whole amount, aseptic filtration and dispensing.

Example 2: Gel for intra-articular injection

Composition:

Ingredients preparation 3

Trehalose 1. 5 g

Sodium hyaluronate 1. 0 g

Sodium borate decahydrate 1. 166 g

Boric acid

Sodium chloride

Water added to l O Oral

H 7. 09

Osmotic pressure 299 milliequivalent equivalent / liter

Preparation method: Take sodium borate decahydrate and boric acid to prepare a buffer system. After adding sodium chloride to dissolve, take a small amount of trehalose, stir to dissolve, and the other part is added. Sodium Shield, dissolved and mixed with the above trehalose solution, added with water for injection, sterile filtration, and dispensed. Example 3. Liquid formulation preparation for intra-articular injection administration 4 Preparation 5 Preparation 6

Trehalose 10 g 3. 2g 18g

Normal saline to 100ml to 100ml to 100ml

PH 7. 10 7. 11 7. 03

Osmotic pressure 299 milliosmoles equivalent / liter 305 milliosmoles per liter / liter 297 milliosmoles / liter Preparation method: Take trehalose, dissolve in physiological saline, sterile filtration, and dispense. Test Data

1. Therapeutic effect of the preparation of the invention 2 on temporomandibular joint osteoarthritis

Eighteen healthy rabbits were randomly divided into 3 groups (test group-trehalose group, positive control group-prednisolone acetate group, negative control group-saline group), through the bilateral temporomandibular joint upper cavity. A model of temporomandibular joint osteoarthritis was established by injecting papain solution. After the model was established, the test group was injected into the joint cavity of the present invention by 0.2 ml, and the positive control group was intraperitoneally injected with 2.5% of prednisolone acetate 0.2 ml, and the negative control group was injected with normal saline. 2ml, once a week, complete treatment for 4 weeks. After the treatment, the animals were sacrificed and pathological observations were performed to record pathological scores. The lower the score, the lower the degree of joint lesions, and vice versa. The results are shown in Table 1.

Rabbit temporomandibular joint osteoarthritis pathological score table

Group pathological score

Test group 4. 68 ± 1. 12' ^Δ positive control group 7. 45 ± 1. 06'

Negative control group 11. 73 ± 1. 57

*:Compared with the negative control group: Ρ<0. 05; ^Δ : Compared with the positive control group: Ρ<0. 05 It can be seen from the above that both the experimental group and the positive control group can significantly improve the temporomandibular jaw of the rabbit. Articular osteoarthritis, and the test group was also significantly different from the positive control group, indicating that the preparation 2 of the present invention is more effective than the commonly used corticosteroid drug prednisolone acetate.

2. Therapeutic effect of the preparation of the invention 3 on knee osteoarthritis

Twenty healthy rabbits were randomly divided into 4 groups (test group-trehalose group, positive control group-sodium hyaluronate group, negative control group-saline group and oral trehalose group), through bilateral knee joints. A model of knee osteoarthritis was established by injecting papain solution into each of the upper chambers. 2毫升, 1 week, the control group was injected with 1% sodium hyaluronate 0. 2ml, the positive control group was injected with normal saline 0. 2ml, 1 week, 1 The treatment was completed for 4 weeks in a row; the oral trehalose group was intragastrically administered with trehalose 1.5 g/kg, and the treatment was completed for 4 weeks. At the end of the treatment, the animals were sacrificed for pathological observation. According to the Mankin osteoarthrosis group classification method, the cartilage was scored and the scores were recorded. The lower the score, the lower the degree of joint lesions, and vice versa. The results are shown in Table 2.

Rabbit knee osteoarthritis pathological score table

Animal group pathological score test group 4. 43 ± 08Γ ^{ώ Τ}

Positive control group 6. 11 ± 0. 65* ^Δ oral trehalose group 9. 77 + 2. 81 negative control group 11. 23 ± 1. 14

*Compared with the negative control group, P<0.05; compared with the oral trehalose group, Ρ<0. 05; ^τ compared with the positive control group: Ρ<0. 05

It can be seen from the above that both the experimental group and the positive control group can significantly improve the knee osteoarthritis in rabbits, and the experimental group also has significant difference compared with the positive control group, indicating that the preparation of the present invention 3 is more effective than the sodium hyaluronate alone. Significantly, and both were significantly better than the oral trehalose group.

Claims

An intra-articular injection administration preparation containing trehalose.

The intra-articular injection administration preparation according to claim 1, which further comprises a conventional pharmaceutical excipient, for example, selected from the group consisting of a solvent, an osmotic pressure adjusting agent, a pH adjusting agent, an antioxidant, a tackifier, and a preservative.

The intra-articular injection preparation according to claim 1, which further comprises other pharmacologically active ingredients, for example, selected from the group consisting of sodium hyaluronate, chitosan, methyl cellulose, lecithin and chondroitin sulfate, preferably selected From sodium hyaluronate and/or chondroitin sulfate, sodium hyaluronate is preferred.

The intra-articular injection preparation according to any one of claims 1 to 3, which is in the form of a liquid preparation such as a solution or a gel.

5. The intra-articular injection preparation according to any one of claims 1 to 3, wherein the content of trehalose is 0.5 wt% - 50 wt, preferably 2 wt% - 20 wt%, preferably 3 wt ° / o - 15 wt ₀

5 - 7。 The preferred embodiment of the present invention. .

The intra-articular injection preparation according to any one of claims 1 to 3, wherein the preparation has an osmotic pressure in the range of 150 to 450 osmolality per liter, preferably 220 to 350 osmolality per liter, preferably 260 - 330 亳当量 / / liter.

8. Use of trehalose in the manufacture of a medicament for intra-articular administration to improve and treat joint disorders.

9. The use of claim 8, wherein the joint disease is selected from the group consisting of rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, joint damage, and synovitis.

The use according to claim 8 or 9, wherein the drug is an intra-articular injection preparation according to any one of claims 1 to 7.