KR20180128121A - Pharmaceutical composition comprising hyaluronic acid and non-steroidal anti-inflammatory drug and preparation method thereof - Google Patents

Abstract

The present invention relates to a combination agent comprising hyaluronic acid and ketorolac as active ingredients. Specifically, the present invention relates to a medicine which improved the stability of each drug when mixing two different medicines of the hyaluronic acid and ketorolac into a single medicine.

Description

[0001] PHARMACEUTICAL COMPOSITION COMPRISING HYALURONIC ACID AND NON-STEROIDAL ANTI-INFLAMMATORY DRUG AND PREPARATION METHOD THEREOF [0002] The present invention relates to a pharmaceutical composition containing hyaluronic acid and analgesic anti-

The present invention relates to a preparation of a combination of hyaluronic acid and analgesic anti-inflammatory agent (NSAID).

The present invention relates to analgesic anti-inflammatory agents useful in the treatment of osteoarthritis and the like.

Osteoarthritis is a joint disease that affects cartilage. Osteoarthritis can occur in any joint. It usually occurs in the hands, knees, horns, or vertebrae. Osteoarthritis can be suspected if the joint is stiff after sitting in the bed for a long time, or if there is swelling or tenderness in the joints, or a feeling of breaking or rubbing between the bones.

Cartilage is a tissue that wraps around the tip of a bone in the joint, which helps to absorb the impact of movement of the bone. However, when the upper layer of cartilage is worn out due to osteoarthritis, the lower cartilage bones may come into direct physical contact with each other, resulting in pain, swelling and loss of joint motion. If this symptom persists, the joint may lose its normal shape, and the bony appendix may grow at the joint edge. In particular, bone and cartilage debris can fall off and float within the joint space, all of which leads to great pain and additional joint damage.

Drug therapy for the treatment or prevention of osteoarthritis has mainly focused on pain relief and inflammation treatment. Representative drugs conventionally prescribed include acetaminophen, nonsteroidal anti-inflammatory (NSAID), opioid (OPIOID), or hyaluronic acid.

Acetaminophen is an oral analgesic and has been recommended as a primary drug for mild osteoarthritis. Acetaminophen has been reported to exhibit significant pain relief. However, acetaminophen can cause liver damage, so overdose is prohibited. Therefore, it may be limited to symptoms such as osteoarthritis in which continuous pain treatment is desired.

Nonsteroidal anti-inflammatory drugs are oral drugs that inhibit the function of COX and leukotriene. They have strong pain control effects on arthritis such as hip or knee joints rather than acetaminophen. Nonsteroidal anti-inflammatory drugs are widely used for moderate or severe pain control. In addition, progression of osteoarthritis accompanies cartilage destruction due to synovial inflammation, increase of cytokine or proteolysis, and nonsteroidal antiinflammatory drugs inhibit the synthesis of nitrogen monoxide and superoxide free radicals in systemic and local synovial membrane, It is a drug that is expected to improve the progress of the above diseases. However, non-steroidal anti-inflammatory drugs have been reported to exacerbate osteoarthritis by lowering proteoglycan production during COX-1 inhibition in animal experiments. In addition, it is one of the drugs that can cause serious side effects such as gastrointestinal bleeding or ulcer. Specific examples of non-steroidal anti-inflammatory agents include piroxycam, ibuprofen, and the like.

Nonsteroidal anti-inflammatory drugs are being developed not only for oral administration but also for topical administration. Local topical NSAIDs (topical NSAIDs) are said to have similar efficacy to oral formulations, and because of the use of the skin absorption route, gastrointestinal side effects, etc. can be reduced.

Opioids are oral medications that are used to control pain in moderate arthritis where acetaminophen or NSAIDs are contraindicated, have low response, or require surgical treatment. However, since opioid is a strong narcotic analgesic agent, it may be considered for the treatment of severe osteoarthritis pain, but it is a drug that should be paid attention to in the elderly patient because it causes abuse and causes sleepiness.

Hyaluronic acid has been developed as an injectable injection into the joints. The viscoelasticity of normal joints is maintained by hyaluronic acid. In osteoarthritis, decomposition enzymes expressed by inflammatory reaction promote decomposition of hyaluronic acid and decrease viscoelasticity of synovial fluid. Therefore, injecting hyaluronic acid in the joints can compensate the viscosity and prevent cartilage damage caused by osteoarthritis. The precise pharmacological mechanism has not been elucidated. However, it has been reported that hyaluronic acid injected into the joint also has analgesic effect through sensitization of pain receptors. Hyaluronic acid is known to be a relatively low-risk drug, but it may cause psoriatic arthritis and may be associated with arthritis. There is also controversy about the difference in analgesic effect depending on the molecular weight difference.

The patent literature also suggests a combination of the above drugs. For example, Korean Patent Registration No. 10-1439032 discloses a composite agent prepared by combining hyaluronic acid and PYROXYCAM in a specific compounding ratio, and is reported to be highly effective for anti-inflammatory and anti-inflammatory actions.

Korean Patent Publication No. 10-1439032

Korean Patent Publication No. 10-1439032, as well as the pharmaceutical industry, have suggested a combination of two or more drugs for the treatment and prevention of osteoarthritis. However, the actual developed compound is almost nonexistent. In the case of hyaluronic acid and pyroxycam combination proposed in Korean Patent Publication No. 10-1439032, the product information registered in the Korea Food and Drug Administration is not available. There are many reasons for this, but it is a development value that can be expected to have an effect beyond the effect of each single agent or to overcome the disadvantages of each single agent. In the past, It is highly possible that the synergistic effect of the drug has not been elucidated.

The present inventors have developed an analgesic anti-inflammatory agent which can be more effective in the treatment of osteoarthritis and the like. The present inventors have found that when combined with hyaluronic acid and keto-roll, there is a synergistic effect of cartilage lubrication and a better anti-inflammatory effect in the treatment of arthritis. The present invention relates to a preparation in which a synergistic hyaluronic acid and ketorolac are combined into a single compartment in the treatment of arthritis and administered as a single injection.

The present inventors have found through experimentation the complex synergistic effect of hyaluronic acid and ketorolac, and solved the above-mentioned problems by the following means.

1. A pharmaceutical composition comprising hyaluronic acid or a pharmaceutically acceptable salt thereof and ketorolic acid or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises sodium chloride or a hydrate thereof and sodium phosphate or a hydrate thereof Composition.

2. The pharmaceutical composition according to 1 above, wherein the sodium chloride or its hydrate, sodium phosphate or a hydrate thereof is 89.8 mM to 119.8 mM: 24.7 mM to 10.6 mM based on the compounding molar concentration.

3. The pharmaceutical composition according to 1 or 2, wherein the pH of the composition is 6.3 to 8.3.

4. The pharmaceutical composition according to any one of 1 to 3, wherein the pH of the combination composition is 6.9 to 7.9.

5. The pharmaceutical composition according to any one of 1 to 4 above, wherein the osmotic pressure ratio of the combination composition is 1.0 to 1.2.

6. The pharmaceutical composition according to any one of 1 to 5, wherein the composition has an intrinsic viscosity of 3.0 to 5.0 m ³ / kg.

7. The pharmaceutical composition according to any one of 1 to 6, wherein the weight ratio of hyaluronic acid or a pharmaceutically acceptable salt thereof to keto-rolak or a pharmaceutically acceptable salt thereof is 1: 0.5 to 1.5.

8. The pharmaceutical composition according to any one of 1 to 7, wherein the weight ratio of hyaluronic acid or a pharmaceutically acceptable salt thereof to ketorolic acid or a pharmaceutically acceptable salt thereof is 1: 1-1.5.

9. The pharmaceutical composition according to any one of the above 1 to 8, wherein the pharmaceutical composition is an injection preparation.

10. The pharmaceutical composition according to any one of the above 1 to 9, wherein the pharmaceutical composition is for intraarticular administration.

11. The pharmaceutical composition according to any one of 1 to 10, wherein the hyaluronic acid or its pharmaceutically acceptable salt is sodium hyaluronate and the concentration of sodium hyaluronate is 10 mg / ml.

In the present invention, the stability of the main component satisfies the permissible reference value or more. That is, the present invention is a combined preparation of hyaluronic acid and ketorolic acid with improved stability.

The present invention relates to a combination of hyaluronic acid or a pharmaceutically acceptable salt thereof and ketoallicc or a pharmaceutically acceptable salt thereof. That is, the present invention is a combination agent containing hyaluronic acid and keto-roll as an active ingredient.

In the present specification, hyaluronic acid or keto glutaric acid may be used to include all known main components such as salts thereof.

Hyaluronic acid is a substance represented by Chemical Formula 1, which is a biosynthesized natural polymer discovered by Karl Meye in 1934.

[Chemical Formula 1]

Hyaluronic acid is known to be hydrophilic due to its abundance of hydroxyl groups (-OH), and is known to exist in the vitreous body, joint fluid, cartilage or skin of an animal, and is in a gel state in combination with water. And is characterized by a large viscosity.

Hyaluronic acid is widely used in the treatment of osteoarthritis which can be caused by the decrease of hyaluronic acid component in the cartilage and synovial fluid, and its main ingredient materials registered in Korea Food and Drug Administration are sodium hyaluronate BDDE crosslinked hyaluronic acid sodium gel.

Conventionally, hyaluronic acid has been used for the treatment of pain such as deformity of the knee joint or shoulder joint inflammation, and 20 mg (20 mg / 2 mL) of sodium hyaluronate once a week for 3-5 consecutive weeks in the knee joint or shoulder joint Or the upper biceps tendon hay) and has been prescribed as a method of appropriately increasing or decreasing the number of administration depending on symptoms.

The present inventors have found through experimentation that the analgesic and antiinflammatory effect is enhanced by an unknown action when the hyaluronic acid is combined with ketorolic acid alone, and have completed the present invention.

Ketololac is a substance represented by the formula (2), which is a kind of NSAID and was developed in 1989 by Syntex Corporation.

(2)

Ketololac has been shown to have higher analgesic and antiinflammatory activity than other NSAID drugs, according to published information in the development, including U.S. Pat. No. 4,089,969, which has been shown to be effective for treating arthritis.

Ketorolac as a conventional injectable was administered with 10 mg of intramuscular and intravenous doses of 10 mg as a methotrexate for ketorolac and short-term therapy for moderate to severe acute pain (including postoperative pain) 10 to 30 mg every 4-6 hours.

In summary, it is known that NSAIDs such as Ketololac are administered in order to restore the normal homeostasis of diseased joints and inhibit significant pain caused by osteoarthritis by injecting a viscoelastic solution containing high molecular weight hyaluronic acid into the joints .

However, it has not been found that the combination of hyaluronic acid and ketorolac, which is injected into an articular cavity as an injection, can increase the analgesic and antiinflammatory effect. In other words, the inventor of the present invention first discovered the synergistic effect of hyaluronic acid and Ketololac through experiments.

As described above, in Korean Patent Registration No. 10-1439032, attention has also been paid to the simultaneous administration of hyaluronic acid and other drugs. However, it is difficult to predict the synergistic effect between hyaluronic acid and keto-rolac on the combination of hyaluronic acid such as Korean Patent Registration No. 10-1439032 and piroxycam, which is a kind of NSAID.

Particularly, according to the fact that the present inventors have found through experimentation, hyaluronic acid and ketolol have a particularly preferable compounding ratio indicating analgesic and anti-inflammatory action. For example, Korean Patent Publication No. 10-1439032 discloses that a synergistic effect is exhibited when the blend weight ratio of hyaluronic acid to pyroxicam is 3: 1 to 1: 1, but hyaluronic acid and ketoacrylic are mixed at a ratio of In contrast, when the ratio of hyaluronic acid: ketorolicol was 1: 0.5-1.5, and the proportion of ketorolicol was relatively larger, a synergistic effect was observed. In addition, hyaluronic acid: Ketorollak depending on the proportion of the synergistic effect does not show any tendency, and the exact cause is not known, but unexpectedly in a certain section of the synergistic effect was found by chance through the experiment. For example, the weight ratio of the main component of hyaluronic acid: ketorolic which shows a synergistic effect without a significant tendency was 1: 0.5, 1: 1 or 1: 1.5.

Thus, the present invention is characterized by comprising hyaluronic acid or a pharmaceutically acceptable salt thereof and keto-rolak or a pharmaceutically acceptable salt thereof in a weight ratio of 1: 0.5 to 1.5. It is difficult to expect the therapeutic effect of the additive or synergistic analgesic and antiinflammation at a compounding ratio of less than or equal to that.

In the present invention, it may be particularly preferable to mix sodium hyaluronate and ketolol at concentrations of, for example, 10 mg / 5 mg / mL, 10 mg / 10 mg / mL or 10 mg / 15 mg / mL, respectively.

In the present invention, hyaluronic acid or a pharmaceutically acceptable salt thereof and ketorolac or a pharmaceutically acceptable salt thereof are not limited, and known main components may be arbitrarily adopted. The hyaluronic acid or a pharmaceutically acceptable salt thereof may be formulated by mixing the hyaluronic acid and its pharmaceutically acceptable salt, which are not a single component, if necessary. Preferably, sodium hyaluronate and ketololactam can be mixed as a main component.

In addition, hyaluronic acid may be required to be administered 3-5 times a week for a short duration in the joint cavity. It is recommended to use cross-linked hyaluronic acid to improve the interval of administration Development can also be possible.

The present invention can be developed into various formulations, but preferably it can be developed as an injectable preparation that is administered directly into the joint cavity.

The injectable preparation is prepared by blending the active ingredient showing a pharmacological effect with a solubilizer, a buffer, a stabilizer, a preservative, an emulsifier, a suspending agent, an isotonic agent or a suitable additive. The double buffer is used to prevent chemical degradation or physical degradation of the drug in solution from chemical degradation, and increases the stability or solubility of the drug by controlling the pH. The weak acids commonly used as buffers are citric acid and acetic acid, and the appropriate pH is different for each drug. And the stabilizer is an antioxidant that is formulated to inhibit the oxidation and deterioration of the drug. A chelating agent such as EDTA is mainly used. An isotonic agent is a component that regulates the osmotic pressure of the injectable solution. If injected does not appear in body fluids, pain or tissue irritation may occur when injected into the blood or muscle.

Generally, various additives are used when preparing injections, but buffering agents, stabilizers, and isotonic agents are generally mixed.

Hyaluronic acid may be reduced in molecular size or viscosity due to redox reaction or chain hydrolysis reaction, and decomposition thereof may be accelerated in a strong acid or strong basic aqueous solution. In order to ensure the stability of hyaluronic acid, it is necessary to maintain an appropriate pH. Also, as the viscosity of hyaluronic acid decreases, the pharmacological effect decreases. Therefore, it is also necessary to maintain the viscosity of hyaluronic acid in the final preparation. Normally, when hyaluronic acid is decomposed, its viscosity gradually decreases.

Ketolol can also be stabilized at an appropriate pH.

However, when combining different drugs, pHs suitable for each drug are different from each other, and it is difficult to select a desired pH range. That is, when a pH environment suitable for one drug is established, stability of the other drug may be lowered or precipitation may occur.

The inventors of the present invention have found that the composition of hyaluronic acid, the pH environment, the composition of keto-roll and the pH environment are different from each other, and that the composition of hyaluronic acid is not suitable for keto roll.

Thus, there have been several failures in implementing hyaluronic acid and ketoallol in a single injection, but surprisingly it has been possible to overcome this by mixing sodium chloride or its hydrate with sodium phosphate or its hydrate.

The injectable preparation according to the present invention is characterized in that sodium chloride or its hydrate is combined with sodium phosphate or a hydrate thereof. Here, the hydrate includes all hydrated compounds such as monohydrate, dihydrate and the like.

The combination of sodium chloride or its hydrate and sodium phosphate or its hydrate at a molar concentration of 89.8 mM - 119.8 mM: 24.7 mM - 10.6 mM, preferably 5.25 mg - 7 mg / mL: 3.25 mg - 1.5 mg / It is preferable to improve the stability of keto roll. Wherein the pH of the composition is preferably 6.9 to 7.9. The osmotic pressure ratio of the composition is preferably 1.0 to 1.2, and the intrinsic viscosity of the composition is preferably 3.0 to 5.0 m ³ / kg.

If the pH is out of this range, the physical stability of the keto powder will be lowered to precipitate the precipitate, as well as to give rise to an unknown substance. When the intrinsic viscosity is out of the range, hyaluronic acid is unstable and the viscoelasticity is decreased, so that it can not act as a lubricant for the cartilaginous cartilage. When the liquid composition is administered to the articular cavity, side effects such as pain, inflammation, edema, May appear.

If the osmotic pressure ratio deviates from the range, the range of osmotic pressure ratio similar to blood is required because phlebitis and pain and vascular necrosis are generated at the injection site.

The injectable preparation according to the present invention can be prepared by mixing ketorolac, sodium chloride, sodium phosphate and water for injection, filtering the resulting solution, mixing the sodium hyaluronate therein, and homogenizing and stirring. At this time, stirring is preferably performed at a temperature of 30-40 ° C for 12 hours or more.

Hereinafter, the present invention will be described by way of examples. It should be noted, however, that the present embodiment is merely illustrative of one embodiment of the present invention, and the scope of the present invention is not limited thereto.

Comparative Example 1 - Composition of existing HA single injection

Ketorolak was mixed with the composition of commercially available hyaluronic acid injection.

7.5 g of methotrexate (4.25 g of sodium chloride, 0.28 g of sodium monohydrogenphosphate, 0.02 g of sodium dihydrogenphosphate) and phosphate buffered saline (pH 7.4) are completely dissolved in 500 ml of water for injection for 30 minutes. After sterilization by filtering with sterilization, 5 g of sodium hyaluronate (1% (w / v)) was added thereto, followed by stirring at 30 to 40 ° C for 12 hours using an overhead mixer to prepare a liquid composition.

Comparative Example 2 - Composition of existing KT single injection

Hyaluronic acid was mixed with the composition of a commercially available ketoalcohol injection.

That is, 7.5 g of methanol and 50 g of ethanol and 2.175 g of sodium chloride are added to a total of 500 ml with an injection water and completely dissolved for 30 minutes. After sterilizing by sterilization with filtration, 5 g of sodium hyaluronate was added, followed by stirring at 30 to 40 ° C for 12 hours using an overhead mixer to prepare a liquid composition.

Example 15

Ketolol Lactol 7.5 g of methanine, 2.6.25 g of sodium chloride and 1.75 g of sodium phosphate are added to 500 mL of water for injection and completely dissolved for 30 minutes. After the sterilization by filtration, sterilization was performed, and the standard amount derived from the sodium hyaluronate fixation formula was calculated. After 5 g corresponding to about 1% (w / v) was added, the mixture was stirred at 30-40 ° C for 12 hours, .

ingredient Comparative Example 1
(Molar concentration) Comparative Example 2
(Molar concentration) Example 15
(Molar concentration) Ketol < / RTI > 7.5g 7.5g 7.5g Sodium hyaluronate 5.0g 5.0g 5.0g Buffer Buffer
Furtherance NaCl 4.25 g
(145 mM) 2.175 g
(74 mM) 2.625 g
(90 mM) Na2HPO4 0.28 g
(9.6 mM) - 1.75g
(60 mM) NaH₂PO4 0.02 g
(0.3 mM) - - EtOH - 50g -

For the Comparative Examples 1 and 2 and Example 13, a harsh stability test was conducted at 40 ° C ± 2 ° C.

Comparative Example 1 and Comparative Example 2 prepared by the above method were stored in a stability chamber of 40 ° C ± 2 ° C / 75% ± 5%, which is an accelerated test condition, and then changes in properties, changes in keto- The change in viscosity was evaluated. The viscosity change of the composition was measured by a capillary viscometer of a sodium hyaluronate preparation according to the test method prescribed in EP, and the change of the ketolol lactam-containing substance was evaluated using a high performance liquid chromatography method as specified in USP . The results are shown in Table 2.

division Extreme viscosity difference
(Compared to Example 15) Ketolol lactammetamine gun, the difference in flux generation (compared to Example 15) 0 weeks After 1 week after 2 weeks After 0 weeks After 1 week Comparative Example 1 3.5 m ³ / kg -4.1% -6.1% 1x
(no difference) 1x
(no difference) Comparative Example 2 3.0 m ³ / kg -14.4% -15.1% 2.3 times (↑) 1.9 times (↑)

The total solids content and the non-main constituents were 1.5% or less and the intrinsic viscosity was 3.0 to 5.0 m ³ / kg. In Comparative Example 2, the average of total and flexible materials was 2.42%, which did not satisfy the USP standard. The intrinsic viscosity was 4.1% - 6.1% higher than the comparative example 1 and 14.4 - 15.1% higher than the comparative example 2. In the case of Comparative Example 2, the criteria of the EP standard were not satisfied.

In the following, pH and osmotic ratio were measured with different buffer compositions.

division Keto roll
Tromethamine Sodium hyaluronate Buffer composition
(NaCl: Na2HPO4
Mole concentration ratio)
Buffer pH
buffer
Osmotic pressure ratio PH after KT addition KT
adding
after
Osmotic pressure HA-KT
PH after mixing After HA-KT mixing,
Osmotic pressure ratio Example 1 7.5g 5.0g NaCl 4.25 g
Na2HPO4 0.28g NaH2PO4 0.02g
(145 mM: 3.9 mM: 0.3 mM) 7.4 0.95 7.4 0.95 6.5 1.21 Example 2 7.5g 5.0g NaCl 4.25 g
Na2HPO4 (145 mM: 3.9 mM) 8.5 0.95 8.5 0.95 6.6 1.22 Example 3 7.5g 5.0g NaCl 4.25 g
7.15 g of NaH 2 PO 4
(145 mM: 100.7 mM) 9.0 1.30 9.0 1.30 7.5 1.55 Example 4 7.5g 5.0g 2.125 g of NaCl
7.15 g of NaH2PO4 (72.7 mM: 100.7 mM) 9.1 0.83 9.1 0.83 7.54 1.25 Example 5 7.5g 5.0g 2.125 g of NaCl
3.575g of Na2HPO4
(72.7 mM: 50.4 mM) 8.8 0.64 7.3 0.90 7.4 1.07 Example 6 7.5g 5.0g 2.125 g of NaCl
Na2HPO4 3.265 g
(72.7 mM: 46 mM) 8.8 0.62 7.2 0.87 7.4 1.03 Example 7 7.5g 5.0g 2.125 g of NaCl
Na2HPO4 3g
(72.7 mM: 42.3 mM) 8.8 0.61 7.2 0.88 7.3 1.04 Example 8 7.5g 5.0g 2.125 g of NaCl
Na2HPO4 2.75g
(72.7 mM: 38.7 mM) 8.8 0.61 7.2 0.85 7.3 1.0 Example 9 7.5g 5.0g 2.125 g of NaCl
2.5 g of Na2HPO4
(72.7 mM: 35.2 mM) 8.9 0.59 7.2 0.85 - - Example 10 7.5g 5.0g 2.125 g of NaCl
Na2HPO4 2.25g
(72.7 mM: 31.7 mM) 8.9 0.58 7.1 0.82 - - Example 11 7.5g 5.0g 2.125 g of NaCl
Na2HPO4 2g
(72.7 mM: 28.2 mM) 8.7 0.53 7.1 0.80 7.2 0.96 Example 12 7.5g 5.0g 2.125 g of NaCl
Na2HPO4 1.75g
(72.7 mM: 24.7 mM) 8.7 0.53 7.1 0.79 - - Example 13 7.5g 5.0g 2.125 g of NaCl
Na2HPO4 1.5g
(72.7 mM: 21.1 mM) 8.7 0.52 7.0 0.80 - - Example 14 7.5g 5.0g 2.125 g of NaCl
Na2HPO4 1 g
(72.7 mM: 14.1 mM) 8.7 0.51 6.9 0.77 - - Example 15
High concentration 7.5g 5.0g NaCl 2.625 g Na2HPO4 1.75 g
(89.8 mM: 24.7 mM) 8.9 0.68 7.1 0.96 7.3 1.1 Example 16
Medium concentration 5.0g 5.0g 3.325 g of NaCl
Na2HPO4 1.165 g
(113.8 mM: 16.4 mM) 8.9 0.80 7.1 0.96 7.3 1.1 Example 17
Low concentration 2.5 g 5.0g 3.5 g of NaCl
0.75 g of Na2HPO4
(119.8 mM: 10.6 mM) 8.9 0.82 7.1 0.96 7.3 1.1

When the buffer composition of the conventional hyaluronic acid single agent, which is the composition of Example 1, is applied, The addition of Ketorolac without NaH2PO4 as a buffer in the buffer surprisingly reduced the pH to 6.59 and could not buffer the buffers because the pH could not be controlled by the neutralization reaction by Ketorolac. The osmotic pressure ratio also exceeded the EP reference range

As a result of the intrinsic viscosity analysis of hyaluronic acid, it was lower than that of the hyaluronic acid keto-roll complex, which was developed above, and hydrolysis progressed quickly due to low pH during long-term storage.

COMPARATIVE EXAMPLE 2 The buffer composition of the inketalolactone single agent was close to pH 7.4 due to the buffering effect of ketorolic acid without the presence of sodium phosphate hydrate, but the stability of the injection pressure was below the standard value.

In Example 1 and Example 2, hyaluronic acid was rapidly hydrolyzed to lower the intrinsic viscosity, and unstable soft substances were generated due to destabilization of keto-roll, resulting in lowered stability.

As for the composition of the existing single agent, the molar concentration of Na2HPO4, which acts as a conjugate base, which was very low compared to the conventional HA single agent, was not added to NaH2PO4, which acts as a conjugated acid, Example 1-Example 17 was carried out to adjust the pH and shovel pressure, and since the intrinsic viscosity and pH were maintained as compared with the conventional single agent, generation of a flexible substance was insufficient, and thus the complex agent with stable storage for a long time can be manufactured. .

Thereafter, the pH was adjusted to a stable range by adjusting the amount of Na2HPO4 in order to prepare a composite agent having a weight ratio of 1: 0.5 or 1: 1 by weight of the main ingredient of hyaluronic acid: ketorolic acid. In terms of composition, that is, sodium chloride or its hydrate and sodium phosphate or its hydrate are 89.8 mM: 24.7 mM and 113.8 mM: 16.4 mM and 119.8 mM: 10.6 mM on a molar basis, preferably 5.25 mg: 3.5 mg and 6.65 mg: 2.33 mg, and 7 mg: 1.5 mg, respectively, and the efficacy was evaluated by preparing a model of osteoarthritis-induced rats.

Experimental group Concentration (mg / ml) MIA Treatment 3 day average (%) SD Drug treatment 7 day average (%) SD Vehicle County Saline treatment 26 2.05 28 1.05 HA alone group 5 24 0.9 30 0.9 KL alone treatment group 1.25 24 1.25  31 * 1.12 2.5 23 0.99  32 * 0.85 5 23 0.7  34 * 2.8 7.5 24 2.1  38 * 1.46 10 23 0.79  38 * 1.58 20 25 1.83  38 * 1.63 Combined treatment group (HA / KL) 5.0 / 1.25 (1: 0.25) 25 0.86 33 ** 1.46 5.0 / 2.5 (1: 0.5) 25 0.82   37 ** # 1.13 5.0 / 5.0 (1: 1) 24 1.29   45 ** # 1.34 5.0 / 7.5 (1: 1.5) 25 1.07   45 ** # 0.71 5.0 / 10.0 (1: 2) 22 1.37 41 ** 2.67 5.0 / 20.0 (1: 4) 24 1.85 34 ** 2.33

*: Significance of Vehicle (p <0.05); **: Significance of HA (p <0.05); # KL relative significance (p <0.05)

In Table 4, HA indicates sodium hyaluronate, KL indicates Ketolol, MIA indicates monosodium iodoacetic acid and administered to MIA-induced osteoarthritis model rats. As a result of the potency evaluation, compared with hyaluronic acid and keto-rolled single agent And showed excellent anti-inflammatory and anti-analgesic effects.

Hyaluronic acid / Ketololock combination showed a significant synergistic effect on analgesic effect compared to control group or hyaluronic acid or Ketorolac alone treatment group. In particular, the Ketorolac alone treatment group showed a tendency to increase the effect depending on the concentration of Ketololk, whereas the hyaluronic acid / ketorolic acid combination did not follow the concentration-dependent tendency, in other words, To 1 to 1.5, the most adverse analgesic effect was exhibited, and therefore, Examples 15, 16 and 17 are included.

Claims (6)

Claims 1. A pharmaceutical composition comprising hyaluronic acid or a pharmaceutically acceptable salt thereof and keto-rolak or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 1, which comprises sodium chloride or a hydrate thereof and sodium phosphate or a hydrate thereof. The pharmaceutical composition according to claim 1, wherein the pH of the composition is 6.3 to 8.3. The pharmaceutical composition according to claim 1, wherein the composition has an osmotic pressure ratio of 1.0 to 1.2. The pharmaceutical composition according to claim 1, wherein the composition has an intrinsic viscosity of 3.0 to 5.0 m ³ / kg. The pharmaceutical composition according to claim 1, wherein a molar concentration ratio of sodium chloride or a hydrate thereof to sodium phosphate or a hydrate thereof is 89.8 mM to 119.8 mM: 24.7 mM to 10.6 mM.