CN101756958B - Medicament composition for treating arthritis and preparation method thereof - Google Patents

Abstract

The invention provides an external pharmaceutical composition for treating arthritis, which contains active ingredients of non-steroidal anti-inflammatory drug ketorolac tromethamine and immunosuppressant mycophenolate mofetil. The invention proves that the sodium mycophenolate mofetil and ketorolac trometamol have a good synergistic effect, not only can achieve a good therapeutic effect on the joint pain of arthritis patients, but also can improve the cure rate.

Description

A kind of pharmaceutical composition for treating arthritis and preparation method thereof

Field

The invention belongs to the new technology of medicine, in particular to a pharmaceutical composition for treating arthritis.

Background technique

Arthritis is a common disease, usually caused by one or more joints, mostly knee, ankle, shoulder, elbow, wrist and other joint lesions, mostly due to damage to the cartilage of the joints, causing pain and affecting the to joint activity. When it is severe, it can cause irreversible deformity of the joint, loss of labor and living ability, and once the patient is ill, he is very painful and anxious. It is very important to treat arthritis or delay the progression of the disease. At present, there are more than 80 causes of arthritis, and it is difficult to treat or even cure arthritis. Among them, the most common are rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and gout.

The current treatment methods for arthritis mainly include non-drug treatment, surgical treatment and drug treatment. Non-drug treatment mainly involves changing bad living habits, moderate exercise, and appropriate physical therapy to enhance muscle strength, but these can only relieve symptoms and delay joint degeneration. Surgical treatment is mainly aimed at advanced patients whose joints have been severely damaged, and there are certain surgical risks. Therefore, drug therapy is still the main means of treating arthritis. Generally, there are three types of drugs for the treatment of arthritis.

Non-steroidal anti-inflammatory drugs (NSAIDs), commonly known as "pain relievers." The more commonly used ones are ibuprofen and diclofenac, which can temporarily relieve the symptoms of "redness, swelling, heat, and pain" in the joints.

Drugs that can change the disease include some gold preparations, chloroquine, and immunosuppressants. MTX (methotrexate), tripterygium wilfordii, hydroxychloroquine, sulfasalazine, etc. are commonly used, and the onset of these drugs is slow. Long-term use is required.

Corticosteroids, such as prednisone acetate, have severe side effects when used for a long time and cannot prevent the occurrence of joint deformities. These three types of drugs have different mechanisms of action and different application times, but the disadvantage is that the incidence of adverse reactions of these drugs is relatively high.

In the past, due to the limited development of medical technology and insufficient understanding of arthritis, it was generally treated with "analgesic drugs" alone, and then immunosuppressants or hormones were used when the symptoms could not be controlled or relieved within a short period of time. Although this method avoids many side effects of immunosuppressants or hormones, judging from the treatment results of patients, joint destruction and deformity occur in nearly half of the patients. Studies in recent years have found that using this method in the early stages of the disease often delays the disease. In recent years, a more active treatment method is to use immunosuppressants to control the development of the disease at the early stage of the disease course, and it tends to combine various drugs.

Although non-steroidal anti-inflammatory drugs are still the first choice for the treatment of arthritis, traditional immunosuppressants have a good therapeutic purpose in the treatment of arthritis because they target the etiology. Drugs often have many adverse reactions. Obviously, its therapeutic effect cannot meet the needs of modern treatment, and the current clinical treatment method is more inclined to multi-drug combination treatment of arthritis, so the development of compound drugs with better therapeutic effect is another research direction of arthritis treatment drugs.

Contents of the invention

The invention provides a pharmaceutical composition for treating arthritis, which contains active ingredients of non-steroidal anti-inflammatory drug ketorolac tromethamine and immunosuppressant mycophenolate mofetil.

Ketorolac tromethamine has a powerful analgesic effect and also has a good anti-inflammatory effect, so the present invention can achieve a good therapeutic effect on joint pain of arthritis patients. Sodium mycophenolate mofetil is mainly used in organ transplantation such as kidney and bone marrow and some immune diseases. It has good curative effect on acute rejection, so it is mostly used to treat immune rejection after organ transplantation, and it is clinically proven that sodium mycophenolate mofetil is resistant Good sex, less side effects.

However, according to our research, it is found that mycophenolate sodium also has a good effect on the treatment of systemic immune diseases, so we have further studied and found that the application of mycophenolate mofetil in the treatment of arthritis has achieved good results, and at the same time The creative combination of mycophenolate sodium and non-steroidal anti-inflammatory drug ketorolac tromethamine in the treatment of arthritis, especially rheumatoid arthritis and rheumatoid arthritis, has a significantly enhanced therapeutic effect, which is more effective than single-use drugs. More obvious therapeutic and preventive advantages have shown a good synergistic effect from animal models of acute and chronic arthritis. Through pharmacological and pharmacodynamic tests, the dosage ratio of mycophenolate sodium and ketorolac tromethamine is optimally selected. In the composition provided by the invention, mycophenolate mofetil and ketorolac tromethamine The weight ratio is 0.2-10:1, more preferably 0.5-5:1.

Specifically, the pharmaceutical composition for the treatment of arthritis provided by the present invention achieves the following beneficial effects: 1) adopting topical administration preparations can quickly treat arthritis symptoms such as pain, and play a good therapeutic effect; 2) effectively The etiology of arthritis is treated according to the etiology of arthritis, and most studies believe that the pathogenesis of arthritis is mostly related to autoimmune reactions; 3) The treatment effect is significantly enhanced, and the cure rate is improved; 4) The use of external drug preparations can effectively reduce the risk of systemic adverse reactions incidence.

The invention provides a pharmaceutical composition for treating arthritis, the active ingredients of which include non-steroidal anti-inflammatory drugs and immunosuppressants, specifically, the non-steroidal anti-inflammatory drugs and immunosuppressants of the present invention are respectively ketorolac ammonia Butanetriol and Sodium Mycophenolate Mofetil. The invention provides a compound preparation for treating arthritis, including clinically suitable pharmaceutical dosage forms, specifically including external creams, gels, liniments, transdermal patches, aerosols and other forms of external administration Preparations also include some pharmaceutical excipients suitable for the preparation of pharmaceutical preparations in the specific preparation process of pharmaceutical preparations and their preparation methods.

Detailed ways

The present invention is better explained by the following specific examples, but the following specific examples do not limit the present invention in any form.

Formulation example

The preparation of embodiment 1 compound gel

Ketorolac Tromethamine 10g

Sodium mycophenolate mofetil 30g

Carbomer 10g

Propylene Glycol 50ml

Glycerin 50ml

Triethanolamine Appropriate amount

Add purified water to 1000g

Preparation process: Slowly add carbomer to water with about 50% of the prescription amount, stir while adding until a transparent gel matrix is formed, dissolve ketorolac tromethamine in an appropriate amount of water, pour it into the matrix, and stir Evenly, add the prescribed amount of sodium mycophenolate mofetil into the matrix and stir evenly, add propylene glycol, glycerin, and purified water to the full amount, and adjust the pH value to neutral with triethanolamine, and the product is ready.

The preparation of embodiment 2 compound gel

Ketorolac Tromethamine 5g

Sodium mycophenolate mofetil 1g

Carbomer 10g

Propylene Glycol 50ml

Glycerin 50ml

Ethanol 20ml

Triethanolamine Appropriate amount

Add purified water to 1000g

Preparation process: Slowly add carbomer to water with about 50% of the prescription amount, stir while adding until a transparent gel matrix is formed, dissolve ketorolac tromethamine in an appropriate amount of water, pour it into the matrix, and stir Evenly, add the prescribed amount of sodium mycophenolate mofetil into the matrix and stir evenly, add propylene glycol, glycerin, ethanol, purified water to the full amount, and adjust the pH value to neutral with triethanolamine, and the product is ready.

The preparation of embodiment 3 compound cream

Ketorolac Tromethamine 5g

Sodium mycophenolate mofetil 10g

Glyceryl monostearate 48g

Stearic acid 110g

White Vaseline 100g

Triethanolamine 20g

Ethylparaben 3.5g

Sodium Lauryl Sulfate 12g

Glycerin 15g

Add purified water to 1000g

Preparation process: Take glyceryl monostearate, stearic acid, white petrolatum, and triethanolamine in a water bath and heat until melted according to the prescription, mix well, and use it as the oil phase.

In addition, take an appropriate amount of purified water, and dissolve ketorolac trometamol and sodium mycophenolate mofetil into the water.

Mix glycerin, sodium lauryl sulfate, purified water, and ethylparaben and heat it to about 80°C as the water phase. When the temperature of the oil phase is about 80°C, pour the solution of ketorolac trometamol and sodium mycophenolate mofetil into it under stirring, and keep the temperature at about 80°C.

Slowly add the oil phase that has been stirred evenly into the water phase under slow stirring, then accelerate the stirring for 30 minutes, gradually slow down the stirring speed until it cools down, and stop stirring to obtain a cream (O/W).

The preparation of embodiment 4 compound liniment

Ketorolac Tromethamine 5g

Sodium mycophenolate mofetil 50g

Glycerin 100g

Propylene glycol 30ml

Add purified water to 1000ml

Preparation process: Weigh ketorolac tromethamine and mycophenolate sodium and dissolve them in an appropriate amount of water, then add glycerin and propylene glycol in the prescribed amount, add purified water to the full amount, and stir evenly to obtain the product.

The preparation of embodiment 5 compound transdermal patch

Ketorolac Tromethamine 10g

Sodium mycophenolate mofetil 30g

Propylene glycol 200g

Water 300g

Hydroxypropyl Methyl Cellulose 10g

Preparation process: dissolve the prescribed amount of hydroxypropyl methylcellulose in water, add ketorolac trometamol, sodium mycophenolate mofetil, and propylene glycol and stir evenly; take another acrylic pressure-sensitive adhesive and spread it evenly on the polyester film , dry, apply the drug-containing solution on the above-mentioned film, cover the liner film, heat-press and seal, and die-cut.

Specific examples of pharmacodynamic experiments

Example 6 Anti-inflammatory test of rat adjuvant arthritis model

1. Test material

1.1 A total of 90 Wistar rats, all male, weighing 180±10 g, were provided by the Experimental Animal Center of Shandong New Times Pharmaceutical Industry (animal production license number: SCXK (Lu) 20060019).

1.2 Freund'S complete adjuvant (sigma).

1.3 Mycophenolate sodium ketorolac tromethamine compound gel (self-made), diclofenac sodium gel (self-made).

2. Test method

2.1 Animal modeling

The rats were fed normally for 2 days to adapt to the new environment. Afterwards, the rats were divided into groups. The volume of the right hind paw of each rat was measured and recorded by the volumetric method (unit: ml) on the day before the inflammation was induced. The volume of the hind foot minus the volume of the right hind foot before causing inflammation is the swelling rate method to examine the test results.

Administration was administered 0.5 h before inflammation, and then 0.1 ml of Freund's complete adjuvant was intradermally injected into the right hind paw of each rat to induce inflammation. The volume of the right hind paw of the rats was measured at 18 hours after the inflammation was induced, and the relative index of the primary lesion was obtained;

Measure the right hind foot volume of the rats 24 days after the inflammation, and obtain the secondary lesion-related index;

Detection of arthritis index: observe whether there is "arthritis" summary in the ears, nose, tail, etc. of the rats and score them (the scoring criteria are as follows), and add up the scores of each animal to obtain the arthritis index. Afterwards, the rats were anesthetized, blood was taken to measure the content of lymphocytes, and the rats were bled to death.

Arthritis Index Scoring Criteria:

Ears: no nodules and redness 0

Symptoms of nodules and redness 1

Nose: No connective tissue swelling 0

There is swelling of connective tissue 1

Tail: no tubercle 0

Nodules 1

Front paw: no inflammation 0

Inflammation of at least one joint 1

Hind paw: no inflammation 0

Mild inflammation 1

Moderate inflammation 2

Significant inflammation 3

2.2 Test grouping

Animal group Test drug

1 Blank accessories

2 1% mold + 0.3% ketone compound gel

3 3% mold + 1% ketone compound gel

4 1% diclofenac sodium gel

5 3% mycophenolate sodium gel

6 1% Ketorolac Tromethamine Gel

3. Test results and data analysis

3.1 Test results (see Table 1, Table 2, Table 3 for details)

Table 1 compound on rat arthritis foot swelling rate (primary, secondary lesion index) effect

*Compared with the model control group (Group 1), P<0.05

Table 2 Comparison of arthritis index between each treatment group and model control group

* Compared with the model control group (group 1), P<0.05;

**Compared with the model control group (Group 1), P<0.01.

Table 3 Effects of each treatment group and model control group on lymphocytes

*Compared with model control group (group 1) and drug control group (group 4), P<0.05;

ΔCompared with the drug control group (group 4), P<0.05;

**Compared with the model control group (Group 1), P<0.01.

3.2 Result analysis

From the test data in Table 1 and Table 2, it can be seen that there are significant differences between the compound groups and the model group, showing good drug synergy, although there is no significant difference compared with the drug control group, but from the result data of the test It can be seen that compared with the positive drug control group, the compound group has obvious advantages in treatment and prevention. From the data in Table 3, it is obvious that the compound group not only has a better synergistic therapeutic effect compared with the model control group, but also has statistical significance compared with the positive drug control group (P＜0.05), and the compound high-dose group has more Obvious advantage (P<0.01).

Example 7 Rat Granuloma Anti-inflammatory Experiment

1. Test material

1. A total of 50 SD rats, all female, weighing about 140 g, were provided by Shandong New Times Pharmaceutical Experimental Animal Center (animal production license number: SCXK (Lu) 20060019).

1.2 Mycophenolate sodium ketorolac tromethamine compound gel (self-made), diclofenac sodium gel (self-made).

2. Test method

2.1 Animal modeling

Rats were anesthetized with 3% pentobarbital sodium (45 mg/kg anesthesia dose), and the lower abdomen and groin were shaved and disinfected. In the opening of the abdomen, two 50mg sterilized cotton balls (the weight difference of the cotton balls should be reduced as much as possible, and the weight of each cotton ball should be controlled within the range of 50mg±1, the surface area of the cotton balls has a great influence on the experimental results, so when making For cotton balls, the shape should be as consistent as possible, autoclaved, and dried at 50°C) were implanted into the subcutaneous skin on both sides of the groin of the rat (the implantation site should be the same, in this experiment, the groin was implanted), the incision was sutured and placed on the The incision was disinfected with penicillin solution. On the day of the operation, the drug was administered for 7 consecutive days. On the 8th day, the rats were killed by dislocation, and the cotton balls were taken out (the cotton balls should be peeled off accurately when killing the rats, so as not to affect the weight), placed in an oven at 60°C for 12 hours and weighed Heavy. The weight difference before and after is the net weight of the granuloma.

2.2 Test grouping and administration

Animal Group Test Drugs

1 Blank accessories

2 1% mold + 0.5% ketone compound gel

3 1% mold + 1% ketone compound gel

4 3% mold + 0.5% ketone compound gel

5 3% mold + 1% ketone compound gel

3. Test results and data analysis

3.1 Test results

It has been found through experiments that both food intake and body weight of animals affect the weight of granuloma, so granuloma (mg)/body weight (g) is used as the investigation index in the analysis of test data results.

Each group of table 4 influences on rat granuloma/body weight

**Compared with the model control group (group 1), P<0.01

3.2 Conclusion analysis

Through the compound ratio test of mycophenolate sodium and ketorolac tromethamine in high doses and low doses, it can be seen from the test data that the compound preparations of each group can play a good anti-inflammatory effect, compared with the model group. The extremely significant difference (P<0.01) shows that mycophenolate mofetil and ketorolac trometamol have a good synergistic effect, and the high-dose group (group 5) has a more significant advantage.

Example 8 Xylene Inflammation Experiment in Mice

1. Test material

1.1 Animals: A total of 60 KM mice, half male and half female, weighing 30-55 g, were provided by Shandong New Times Pharmaceutical Experimental Animal Center (animal production license number: SCXK (Lu) 20060019).

1.2 Test drugs: mycophenolate sodium ketorolac tromethamine compound gel (self-made), diclofenac sodium gel (self-made).

2 test method

2.1 Take 20 μl of xylene and apply it to the right ear of each mouse. After 30 minutes, take the test drug and apply it to the right ear of the mouse. After 3.5 hours, kill the mouse. Cut off the two ears along the baseline of the pinna, and use an 8mm punch Ear pieces were punched at the same part of the left and right ears, weighed, and the swelling rate of the ears was calculated by the following formula:

Swelling rate = (right ear weight - left ear weight) / left ear weight * 100%

2.2 Test grouping and administration

Animal group Test drug

1 Blank accessories

2 0.5% mycophenolate mofetil and 1% ketorolac tromethamine gel

3 1% mycophenolate mofetil and 2% ketorolac tromethamine gel

4 1% diclofenac sodium gel

5 1% mycophenolate sodium gel

6 2% Ketorolac Tromethamine Gel

3. Test results and data analysis

3.1 Test results

Each group swelling rate test data of table 5

*Compared with the model control group, P<0.05;

**Compared with the model control group, P<0.01.

3.2 Conclusion analysis

Through the analysis of the mouse anti-inflammatory model, both the high-dose and low-dose compounds of mycophenolate mofetil and ketorolac trometamol had good synergistic anti-inflammatory effects, and there was a significant difference between the high-dose compound group and the model group (P< 0.01), indicating that high-dose mycophenolate mofetil and ketorolac tromethamine have a good synergistic effect, and it can be seen from the data that the high-dose group (group 3) has a more significant advantage.

However, there is no statistical significance in each group of the compound preparation compared with the positive control drug (group 4), but it can be seen from the test data that the compound preparation still has a more obvious advantage than the positive control drug of the fourth group. The reason for the analysis may be that the test caused by too few animals in the

Claims (3)

1. the externally-applied medicinal composition of a treatment of arthritis is characterized in that containing mycophenolate sodium and ketorolac tromethamine, and wherein mycophenolate sodium and ketorolac tromethamine part by weight are 0.2～10:1.

2. compositions as claimed in claim 1 is characterized in that mycophenolate sodium and ketorolac tromethamine part by weight are 0.5～6:1 in the described compositions.

3. compositions as claimed in claim 1 is characterized in that described preparation of compositions becomes ointment, gel, liniment, transdermal patch, aerosol.。