KR101831168B1 - A composition for treating osteoarthritis comprising hyaluronic acid and magnesium - Google Patents

Abstract

Disclosed is a pharmaceutical composition for treating osteoarthritis including hyaluronic acid or a pharmaceutically acceptable salt thereof or a hydrate thereof and magnesium or a pharmaceutically acceptable salt thereof and a hydrate thereof. Accordingly, the present invention can greatly improve an anti-inflammatory action and an analgesic action against osteoarthritis of hyaluronic acid.

Description

A composition for treating osteoarthritis comprising hyaluronic acid and magnesium.

The present invention relates to a pharmaceutical composition for treating osteoarthritis comprising hyaluronic acid or a pharmaceutically acceptable salt thereof or a hydrate thereof and magnesium or a pharmaceutically acceptable salt thereof or a hydrate thereof.

Osteoarthritis, or degenerative arthritis, is a disease characterized by structural changes in joints and bones, as well as damage to articular cartilage and symptoms or symptoms such as severe pain and arthritis.

Osteoarthritis is a disease that assesses the physiological state of joints, including loss of cartilage loss and changes in bone, through radiography. It is difficult to make a definite definition, but in general, "structural changes of bursa, joints, Confirmed state ". As a result of evaluating the knee joints in patients with degenerative arthritis, it can be confirmed that the cartilage protecting the joints or the bones and ligaments of the joints are irreversibly damaged. These irreversible cartilage injuries can result in loss of joint motor ability, resulting in dysfunction, accompanied by inflammation and pain.

In particular, knee osteoarthritis is a major component of health problems in the elderly, accompanied by pain and physical dysfunction in stair climbing, sitting up, and walking. In addition to the clinical symptoms such as movement disorders of the joint, pain, weakness of the muscles, bending deformation of the joints, and deformation of the joints, the quality of life due to the impairment of the physical function is greatly influenced.

Currently, treatment goals for osteoarthritis patients are to avoid pain as much as possible while avoiding side effects, and to improve function and quality of life. The basic treatment methods of osteoarthritis include non-pharmacological methods and medication. (NSAIDs), acetaminophen or nonsteroidal anti-inflammatory drugs ("NSAIDs") as well as non-drug therapies such as weight loss, lower extremity muscle strengthening, (Eg, intra-articular injection of sodium hyaluronate), and surgical intervention such as arthroplasty (Seo, Jeong-Tak, Clinical Significance and Application of Hyaluronic Acid).

Although hyaluronic acid is a completely biocompatible component present in the joint synovial fluid and has a very low incidence of adverse reactions, the hyaluronic acid injection has a very slow onset of analgesic effect, and because of local pain in the joint, There is a disadvantage in that there is a disadvantage in that the satisfaction is low. According to the clinical test results of a large number of patients with osteoarthritis, improvement of pain index was observed after 4-6 weeks from the first treatment day, compared to the saline treatment group. Due to the delayed onset of this effect, the majority of patients are prescribing oral NSAIDs or steroid injections rather than singly administered hyaluronic acid injections.

Seo, Jeong - Tak, Clinical Significance and Application of Hyaluronic Acid. Journal of Family Medicine, 2002; 23 (9)

The present invention is to provide a pharmaceutical composition which improves the anti-inflammatory action and analgesic action of hyaluronic acid, and its effect is rapidly expressed.

The present inventors can improve anti-inflammatory and analgesic effects against osteoarthritis by combining magnesium or a pharmaceutically acceptable salt thereof or a hydrate thereof with hyaluronic acid or a pharmaceutically acceptable salt thereof or a hydrate thereof in a specific compounding ratio And completed the present invention. The anti-inflammatory and analgesic effects of osteoarthritis of magnesium have not been reported in the past.

According to the composition of the present invention, the anti-inflammatory and analgesic actions against osteoarthritis of hyaluronic acid can be greatly improved and the effect can be rapidly expressed.

Figs. 1 to 7 show experimental results of Experimental Example 1. Fig.
(In the figure, *: P <0.05 compared to the control group (untreated group)
**: P <0.05 compared to the control group (hyaluronic acid alone group)
#: P <0.05 compared to control (magnesium sulfate alone treatment group)
Figs. 8 to 14 show experimental results of Experimental Example 2. Fig.
(In the figure, *: P <0.05 compared to the control group (untreated group)
**: P <0.05 compared to the control group (hyaluronic acid alone group)
#: P <0.05 compared to control (magnesium sulfate alone treatment group)

The present invention relates to hyaluronic acid or a pharmacologically acceptable salt thereof or a hydrate thereof or a mixture thereof; And a pharmaceutical composition for treating osteoarthritis comprising magnesium or a pharmaceutically acceptable salt thereof or a hydrate thereof or a mixture thereof.

In the present invention, pharmaceutically acceptable salts of hyaluronic acid include inorganic salts such as, for example, sodium hyaluronate, magnesium hyaluronate, zinc hyaluronate, cobalt hyaluronate and the like, and organic salts such as tetrabutylammonium hyaluronate And at least two of these salts may be used in combination. Sodium hyaluronate is the most preferred form. The molecular weight of the hyaluronic acid of the present invention is not particularly limited, but is preferably, for example, an average molecular weight of 500,000 to 10,000,000.

In the present invention, hyaluronic acid or a pharmaceutically acceptable salt thereof or a hydrate thereof is preferably contained in an amount of 0.5 to 5.0% by weight, based on the total weight of the composition of the present invention, as hyaluronic acid or a pharmaceutically acceptable salt thereof . If the concentration of hyaluronic acid or its salt is less than 0.5% by weight, the effect of treating osteoarthritis may be insignificant. If it exceeds 5.0% by weight, it may be difficult to fill the pre-field syringe or ampoule container due to an increase in viscosity of the composition. It may cause difficulties in administering the affected part.

In the present invention, the pharmaceutically acceptable salts of magnesium include, for example, magnesium sulfate, magnesium acetate, magnesium aluminum silicate, magnesium aspartate, magnesium carbonate, magnesium Magnesium chloride, magnesium citrate, magnesium hydroxide, magnesium nitrate, magnesium stearate, magnesium oxide, magnesium phosphate, magnesium mono or trisilicate, ), Magnesium tartrate, and the like, and combinations of two or more of these salts may be used. Magnesium sulfate, magnesium hydrochloride, magnesium hydroxide, magnesium acetate or hydrate thereof are the most preferred forms.

Magnesium or a pharmaceutically acceptable salt thereof or a hydrate thereof or a mixture thereof is preferably contained in an amount of 0.2 to 2.0% by weight based on the total weight of the composition of the present invention. For example, in the case of magnesium sulfate, it is preferably used in a content ratio of 1 to 10% by weight. An analgesic effect of less than 0.2% by weight is insignificant and a hypertonic solution of more than 2.0% by weight may cause pain and inflammation when administered intra-articularly.

In the present invention, the weight ratio of magnesium or a pharmaceutically acceptable salt thereof or a hydrate thereof or a mixture thereof, hyaluronic acid or a pharmaceutically acceptable salt thereof or a hydrate thereof or a mixture thereof is 0.25: 1 to 0.75: 1. Outside this ratio, the treatment effect of osteoarthritis is relatively low.

The pharmaceutical composition according to the present invention is preferably formulated as an injectable preparation in the form of a liquid, and is preferably administered by intra-articular injection for the treatment of osteoarthritis.

The present invention can provide an intra-articular administration composition exhibiting excellent therapeutic effect for treatment of osteoarthritis at the same time with excellent therapeutic effect on inflammation and pain.

The present invention relates to an injectable composition comprising a pharmaceutically acceptable salt of magnesium and an hydrate thereof and hyaluronic acid or a pharmaceutically acceptable salt thereof and a hydrate thereof, wherein the salt of magnesium and its hydrate are 0.2 to 2.0% by weight as magnesium, Or a pharmaceutically acceptable salt thereof and 0.5 to 5.0% by weight of hyaluronic acid or a pharmaceutically acceptable salt thereof, wherein the magnesium and hyaluronic acid or a pharmaceutically acceptable salt thereof is contained in an amount of 0.25: 0.75: 1 by weight, based on the total weight of the composition.

The liquid pharmaceutical composition according to the present invention is preferably formulated in an injectable form, and is administered by intraarticular injection to treat osteoarthritis. The pH of the composition of the present invention is preferably 5.5 to 8.5, more preferably 6.0 to 8.0. Hyaluronic acid is unstable at a pH of less than 5.5 or greater than 8.5, and side effects such as pain, swelling, and inflammation through local irritation may occur when the liquid composition is administered to the joints.

In addition, the pharmaceutical composition of the present invention may further comprise at least one selected from the group consisting of an anti-rheumatic agent, a drug, a non-steroidal anti-inflammatory drug (NSAID), an analgesic agent, an anesthetic agent, a local anesthetic agent, a corticosteroid, an anabolic steroid, Drugs, radiopharmaceuticals, and the like.

[Example]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples illustrate the contents of the present invention, and the scope of the present invention is not limited to the following examples, but may be modified into various other forms. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

Example 1 Preparation of Magnesium and Hyaluronic Acid Liquid Composition According to the Present Invention

Histidine equivalent to 10 mM was dissolved in 500 mL of distilled water, and 6.5 g of magnesium sulfate heptahydrate as magnesium sulfate was added and stirred until completely dissolved. Sodium chloride was added thereto to prepare a physiologically appeared solution of 280 to 360 mOsmol. After filtration sterilization with a 0.22 μm syringe filter, 5 g of sodium hyaluronate was slowly added and the mixture was stirred at 30 to 40 ° C for 12 hours using an overhead mixer to prepare a composition.

&Lt; Examples 2 to 6 >

Magnesium sulfate and a hyaluronic acid liquid composition were prepared in the same manner as in Example 1 with the compositions and contents shown in Table 1 below, respectively, and Examples 2 to 6 were prepared.

&Lt; Examples 7 to 8 &

10 mM of histidine was dissolved in 500 mL of distilled water and 6.5 g of magnesium sulfate or 17.7 g of magnesium sulfate heptahydrate was added and stirred until completely dissolved. Sodium chloride was added thereto to prepare a physiologically appeared solution of 280 to 360 mOsmol. After filtration sterilization with a 0.22 μm syringe filter, 5 g of hyaluronic acid was added slowly, and the mixture was stirred at 30 to 40 ° C for 12 hours using an overhead mixer to prepare a composition.

&Lt; Comparative Examples 1 and 2 > Preparation of magnesium sulfate and hyaluronic acid liquid composition according to the present invention

Magnesium sulfate and a hyaluronic acid liquid composition were prepared in the same manner as in Example 1 with the compositions and contents shown in Table 1 below, respectively, and Comparative Examples 1 to 2 were prepared.

<Control 1 to 8> Preparation of magnesium sulfate and hyaluronic acid liquid composition according to the present invention

A magnesium sulfate liquid composition was prepared in the same manner as in Example 1 with the composition and contents shown in [Table 1] below, and each of them was used as a control group 1 to 8 respectively.

&Lt; Control 9 > It is a negative control group not containing magnesium and hyaluronic acid.

The compositions of Examples 1 to 8, Comparative Examples 1 and 2, and Controls 1 to 9 division Magnesium (% by weight) Sodium hyaluronate or hyaluronic acid (HA, wt.%) MS: HA Example 1 0.26 1.0 0.26: 1 Example 2 0.34 1.0 0.34: 1 Example 3 0.40 1.0 0.40: 1 Example 4 0.60 1.0 0.60: 1 Example 5 0.71 1.0 0.71: 1 Example 6 0.60 2.0 0.30: 1 Example 7 0.26 1.0 0.26: 1 Example 8 0.71 1.0 0.71: 1 Comparative Example 1 0.20 1.0 0.20: 1 Comparative Example 2 0.89 1.0 0.89: 1 Control 1 - 1.0 - Control group 2 0.20 - - Control group 3 0.26 - - Control group 4 0.34 - - Control group 5 0.40 - - Control group 6 0.60 - - Control 7 0.70 - - Control group 8 0.89 - - Control 9 - - -

<Experimental Example 1> Evaluation of anti-inflammatory effect in a mono-iodoacetate-induced osteoarthritis model

After purchasing male SD rats of about 8 weeks old, the temperature was 23 ± 2 ° C, relative humidity 40-60%, ventilation frequency 10 times / hour, ammonia concentration 20 ppm or less, average illumination 150-300 lux, noise 60 phon or less , And stabilized for one week in the clean zone where the light and dark intervals of the 12 hour period are maintained. For 10-12 rats per group, 50 μL (60 mg / mL) of mono-iodoacetate (MIA) was once treated to induce osteoarthritis on the right leg. The diameter of the joints was measured 3 days after MIA treatment. After the measurement, 50 μL of each test preparation in Table 1 was administered in a single dose in a syringe with a syringe.

Swelling due to inflammation in the joint tissue was measured as an index to assess the severity of inflammation. Digimatic calipers (Mitutoyo, Japan) were used for measuring the diameter of the joints, and the test results were expressed in terms of the decrease in the right-hand diameter (mm) of the following equation (1).

[Equation 1]

(Mm) = (diameter of right arm after drug treatment - right leg diameter after 3 days of MIA treatment)

The results of measuring the diameter of the joints after treatment 1, 3, and 7 are shown in Table 2 below and shown in FIGS. 1 to 7.

Anti-inflammatory efficacy assessment (measurement of joint diameter) Amount of change in right-hand joint diameter (mm) division Drug treatment 1st day Drug Treatment Day 3 Medication Day 7 Example 1 Reduced by 0.62 0.91 reduction 1.23 reduction Example 2 0.60 reduction 1.17 reduction 1.35 reduction Example 3 0.55 reduction 1.13 reduction 1.35 reduction Example 4 0.76 reduction 1.23 reduction 1.38 reduction Example 5 0.65 reduction 0.97 reduction 1.26 reduction Comparative Example 1 0.33 reduction 0.66 reduction 0.97 reduction Comparative Example 2 0.49 increase Reduced by 0.38 1.03 reduction Control 1 0.25 reduction 0.74 reduction 0.84 reduction Control group 2 0.31 reduction 0.46 reduction 0.80 reduction Control group 3 0.25 reduction 0.43 reduction 0.75 reduction Control group 4 0.24 reduction Reduced by 0.62 0.89 reduction Control group 5 0.23 reduction 0.77 reduction 1.09 reduction Control group 6 0.35 reduction 0.85 reduction 1.10 reduction Control 7 0.32 reduction 0.78 reduction 1.19 reduction Control group 8 0.45 reduction 0.93 reduction 1.18 reduction Control 9 0.05 decrease 0.24 reduction 0.43 reduction

As can be seen from Table 2 and Figs. 1 to 4, Comparative Example 1 and Comparative Example 2 did not show significant anti-inflammatory effects as compared with the single component, the control 1, 2, and 8, respectively. Rather, antagonistic results were observed in Comparative Example 2.

On the other hand, all of Examples 1 to 5 according to the present invention showed significant anti-inflammatory action compared to the same amount of magnesium sulfate treatment group and hyaluronic acid treatment group. Especially, 1 day after the drug treatment, it showed the effect of reducing edema compared with the treatment of each single agent. Thus, it can be seen that the pharmaceutical composition of the present invention can rapidly express the anti-inflammatory action.

<Experimental Example 2> Evaluation of analgesic effect in a monoiodoacetate-induced osteoarthritis model

After purchasing male SD rats of about 8 weeks old, the temperature was 23 ± 2 ° C, relative humidity 40-60%, ventilation frequency 10 times / hour, ammonia concentration 20 ppm or less, average illumination 150-300 lux, noise 60 phon or less , And stabilized for one week in the clean zone where the light and dark intervals of the 12 hour period are maintained. For 10-12 rats per group, MIA was treated with 50 μL (60 mg / mL) for right knee osteoarthritis. Three days after the MIA treatment, the pain of the right leg was evaluated by measuring the weight balance.

After the measurement, 50 uL of each test preparation in Table 1 was administered in a single dose through a syringe.

The degree of pain of the joints after treatment 1, 3, and 7 days was evaluated, and is shown in Table 3 and Figs. 5 to 8.

The pain scale was measured on the right leg weight load ratio (%) and the weight load recovery rate (%) was calculated based on this. The weight-bearing ratio was determined using a Incapacitance meter tester at a 60-degree slope in a plastic chamber, and the intensity applied to each hind paw was averaged over 10 seconds. The weight-bearing ratio and the weight-bearing-load recovery rate are respectively represented by the following equations (2) and (3)

&Quot; (2) &quot;

 Weight load ratio (%) = 100 × right leg weight load ratio / (right leg load ratio + left leg weight load ratio)

&Quot; (3) &quot;

Weight recovery rate (%) = 100 × (right leg weight load ratio after drug treatment - right leg weight load ratio after 3 days of MIA treatment) / right leg weight load ratio after 3 days of MIA treatment

Analgesic efficacy assessment result Recovery rate of right leg weight load (%) division Drug treatment 1st day Drug Treatment Day 3 Medication Day 7 Example 1 34 52 65 Example 2 41 53 68 Example 3 44 57 70 Example 4 43 68 81 Example 5 43 64 87 Comparative Example 1 8 28 32 Comparative Example 2 -8 (decrease) 27 40 Control 1 11 26 42 Control group 2 8 22 28 Control group 3 10 24 36 Control group 4 12 33 50 Control group 5 15 26 54 Control group 6 17 36 56 Control 7 18 41 60 Control group 8 30 39 42 Control 9 9 19 26

As can be seen from Table 3 and Figs. 8 to 14, Comparative Example 1 and Comparative Example 2 did not show any significant improvement compared with the single component, Control 1, 2, and 8, respectively.

On the other hand, in Examples 1 to 5 according to the present invention, the anti-inflammatory action was significantly improved as compared with the same amount of the magnesium sulfate treatment group and the hyaluronic acid treatment group. Particularly, as a result of evaluation 1 day after the drug treatment, the pain reduction effect was improved compared with each single treatment. Thus, it can be seen that the analgesic action of the pharmaceutical composition of the present invention can be rapidly expressed.

The pharmaceutical composition according to the present invention can improve the anti-inflammatory action and the analgesic action of hyaluronic acid and can rapidly express the effect.

Claims (9)

Hyaluronic acid or a pharmaceutically acceptable salt thereof or a hydrate thereof or a mixture thereof; And a pharmaceutical composition for the treatment of osteoarthritis comprising magnesium or a pharmaceutically acceptable salt thereof or a hydrate thereof or a mixture thereof,
The hyaluronic acid or a pharmaceutically acceptable salt thereof or a hydrate thereof or a mixture thereof is contained in an amount of 0.5 to 5.0% by weight based on the total weight of the pharmaceutical composition as hyaluronic acid or a pharmaceutically acceptable salt thereof,
Wherein the magnesium or a pharmaceutically acceptable salt thereof or a hydrate thereof or a mixture thereof is contained in an amount of 0.2 to 2.0% by weight based on the total weight of the pharmaceutical composition,
Wherein the weight ratio of the magnesium or a pharmaceutically acceptable salt or a hydrate thereof or a mixture thereof, hyaluronic acid or a pharmaceutically acceptable salt thereof or a hydrate thereof or a mixture thereof is 0.25: 1 to 0.75 as magnesium and hyaluronic acid or a salt thereof : 1. A pharmaceutical composition for treating osteoarthritis. delete delete delete The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of hyaluronic acid is at least one selected from the group consisting of sodium hyaluronate, magnesium hyaluronate, zinc hyaluronate, cobalt hyaluronate, and tetrabutylammonium hyaluronate &Lt; / RTI &gt; The pharmaceutical composition according to claim 1, wherein the hyaluronic acid has an average molecular weight of 500,000 to 10,000,000. The composition of claim 1, wherein the pharmaceutically acceptable salt of magnesium is selected from the group consisting of magnesium sulfate, magnesium acetate, magnesium aluminum silicate, magnesium aspartate, magnesium carbonate, magnesium hydrochloride, magnesium citrate, magnesium hydroxide, magnesium nitrate, magnesium stearate, Wherein the compound is at least one selected from the group consisting of magnesium oxide, magnesium phosphate, magnesium mono or trisilicate, and magnesium stannate. 2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is an injection formulation. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further contains no polymer except for the hyaluronic acid.

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