JPH0116A - Arthritis treatment - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION "Industrial Application Field" The present invention relates to a therapeutic agent for arthritis containing a water-soluble magnesium salt as a main component and a sustained release preparation thereof.

"Problems to be solved by the prior art and the invention" Magnesium ions are ions that exist in abundance in living organisms.
It is said to be an indispensable ion for cell structure and homeostasis as well as growth and life. However, while the intake of calcium ions from meals has been increasing recently, the intake of magnesium ions has been decreasing. Also,
Magnesium ion deficiency occurs due to decreased absorption of magnesium ions due to alcohol intake and promotion of magnesium ion excretion due to the use of diuretics, which is said to be a cause of cardiovascular disease. Magnesium oxide powder, an antacid, is used to treat such magnesium deficiency, but it causes soft stools and diarrhea symptoms as one of its side effects. Also, M, Dohert7 and P
A. Dieppe reported that administering magnesium carbonate powder, an antacid, for 6 months to treat arthritis caused by calcium birophosphate deposition was effective, although intermittent diarrhea was observed in some patients. There is. (Ann.

Rheumatic Disease 4L 5u
pp1. , 106 (1983)). These magnesium salts are poorly soluble in water and difficult to absorb into the body, making them unsuitable for treating conditions that require the absorption of magnesium ions.

Diarrhea symptoms caused by antacid powder are painful for patients, and the powder is difficult to take, so Magneji and Ram formulations are suitable for magnesium deficiency and pyrophosphate arthritis, which require long-term magnesium supplementation. is desired.

Enteric-coated magnesium chloride preparations are known for the treatment of arrhythmia, but enteric-coated preparations reach the small intestine and rapidly release magnesium chloride, so they tend to cause diarrhea, similar to when taking antacids. It has the following drawbacks.

Magnesium salts are originally used as laxatives, taking advantage of their property of being difficult to absorb, and are used to treat diseases that require magnesium ion supplementation to prevent the magnesium ion concentration in the digestive tract from increasing rapidly. A sustained release formulation is needed. Furthermore, it is not known whether water-soluble magnesium salts exhibit anti-inflammatory effects and are effective against arthritis, etc., and there was a need to study this as well.

``Means to solve the problem'' As a result of various studies on sustained-release magnesium preparations from the above viewpoints, we found that water-soluble magnesium salt
It has been found that by coating with an H-independent substance, magnesium ions can be eluted over a long period of time without being dependent on pH. At the same time, we investigated whether water-soluble magnesium salts exhibit anti-inflammatory effects and are effective against arthritis.

"Disclosure of the Invention" The present invention relates to an anti-inflammatory agent containing a water-soluble magnesium salt as a main component, and a sustained-release magnesium preparation characterized in that the water-soluble magnesium salt is coated with a pH-independent substance.

Examples of water-soluble magnesium salts include inorganic acid salts such as magnesium chloride, magnesium sulfate, and magnesium phosphate, and organic acid salts such as magnesium gluconate, magnesium lactate, magnesium citrate, and magnesium L-aspartate.

pH-independent coating agents used in sustained-release preparations include hydrocarbons such as paraffin, hydrogenated vegetable oils and other hydrogenated oils, higher alcohols such as stearyl alcohol, higher fatty acids such as stearic acid or their salts, and fatty acids such as beeswax. Examples include ester, lanolin, polyethylene glycol, fatty acid triglyceride, ethyl cellulose, polymethyl methacrylate, polystyrene, and acrylic resin.

The preparation constituting the present invention is an excellent sustained-release preparation that can control the release of magnesium ions without depending on pH, as will be clear in the sustained-release effect section below, and is effective against arthritis, etc. caused by calcium pyrophosphate deposition. Useful in treating magnesium deficiency.

On the other hand, it is not known whether water-soluble magnesium salts are effective against arthritis, and the inventors of the present invention have conducted intensive studies and discovered their excellent effectiveness. Various causes of arthritis are known, but water-soluble magnesium salts are particularly effective against arthritis caused by magnesium deficiency. As an example of evaluating the effect on arthritis, the carrageenan edema suppressing effect was investigated using magnesium chloride. As explained in the pharmacological tests described below, water-soluble magnesium salts showed excellent effects. Furthermore, water-soluble magnesium salts, typified by magnesium chloride, have low toxicity, and when considered in combination with their effects, they are extremely useful as medicines.

The method for producing the sustained release magnesium preparation of the present invention will be briefly explained.

Crystals or powder of water-soluble magnesium salt, sugars such as lactose and mannitol, crystal ses/l10-s,
After adding and mixing excipients such as celluloses such as low-substituted hydroxyglobil cellulose, light silicic anhydride, and surfactants such as borine rupetate and sucrose fatty acid ester, coating is performed using a coating device such as a fluidized bed. Spray a solution of a mixture of coating agent or coating agent and surfactant, or mix the coating agent with a water-soluble magnesium salt (with excipients if necessary) and spray with a solvent that will dissolve the coating agent. By this, sustained release granules are obtained.

The granules thus obtained can be mixed with a lubricant such as magnesium stearate, if necessary, and then compressed into tablets. Furthermore, in order to mask the taste of the water-soluble magnesium salt, the granules or tablets may be coated with a water-soluble coating agent such as hydroxyglobil methylcellulose, and in the case of tablets, they may be sugar-coated.

The present invention also includes preparations in which water-soluble magnesium salt tablets are coated with a coating agent, or water-soluble magnesium salt granules are coacervated with a coating agent, and then microencapsulated and released in a sustained manner.

The dosage of the present sustained release formulation is usually as a water-soluble magnesium salt, once or twice in 18 to 102 days, preferably 1 to 4 days.
It can be administered in divided doses.

Pharmacological Test Magnesium chloride was used as a representative example of a water-soluble magnesium salt, and its effect on arthritis was investigated.

As an example of effect determination, the inhibitory effect on carrageenan edema will be described below. Furthermore, the transfer of 1 magnesium ion into the blood was investigated.

Method Male Wi@tar rats (weight 150 y, group 5
Paw edema was induced by subcutaneously injecting 1ts carrageenin solution 0.11R1 into the right hind limb gland.

The right posterior area was measured by the water displacement method before and after injection of thicalagenin.
Measurements were taken at 0.5.1.2.3.4 and 5 hours after injection.

Magnesium chloride was dissolved in 0.5% gum tragacanth solution and orally administered 1 hour before 1ts tragacanth injection. The results were expressed as an increase rate relative to the constant volume before carrageenin injection.

In addition, 7 hours after administration of magnesium chloride, the rats were given light ether anesthesia, and blood was withdrawn from the abdominal aorta for 5 WI! The serum magnesium ion concentration was measured. That is, the collected blood was left at room temperature for 1 hour, and then heated at 3000 rpm.
m, centrifuged for 10 minutes, and serum was separated and immediately stored frozen. Note that serum magnesium ion concentration was measured using the xylidyl blue method.

Results and Discussion Figure 1 shows the time course of the edema rate. /Kg (P, o, ) showed a dose-dependent carrageenan edema inhibitory effect. Furthermore, the edema-suppressing effect of magnesium chloride was particularly remarkable in the early phase within 1 hour after induction of inflammation.

On the other hand, the serum magnesium ion concentration (g9/dl) 7 hours after administration of magnesium chloride is shown in Table 1, and a dose-dependent increase in serum magnesium ion concentration was observed with the administration of magnesium chloride. The intermediate transferability was demonstrated.

Table 1 Control 2.00 Magnesium chloride 250 2.54 Magnesium chloride 500 2.61 Magnesium chloride 1000 3.17 Examples are shown below.

"Example" Example 1 Prescription A Magnesium sulfate 1000 kg Stearyl alcohol 600 kg total
1600 ■ Production Method 100y of magnesium sulfate passed through 14 meshes is coated with stearyl alcohol using a fluidized bed to obtain sustained release magnesium granules shown in Formulation A.

Example 2 Formulation B Magnesium sulfate 500% Stearyl Alcohol 335% Crystalline Cellulose
45wf total 880■
Manufacturing method 14 Magnesium sulfate passed through a mesh screen,
After mixing stearyl alcohol and crystalline cellulose,
The sustained release granules shown in Formulation B are obtained by the same operation as in Example 1.

Example 3 Prescription C Magnesium chloride 125■ Hardened oil (trade name Loveriwax 101) 65 total
195 ■ Manufacturing method Magnesium chloride 1 passed through a 60 mesh screen
25y is placed in the fluidized bed. Loveriwax 101 for this
Spray the solution and add until the specified weight is reached. Magnesium stearate 5y was added to the obtained punched granules, mixed, and tableted using a rod with a 7rtmφR surface to obtain sustained-release tablets shown in Formulation C.

Tablets having the following formulations DF were obtained in the same manner as in Example 3.

Prescription Magnesium Chloride 125K Hardened Oil
451F glycerin monostearate 10g! 9 Magnesium stearate
5-cho-gumi 185 ki (7m+-R side tablet) Prescription E Magnesium chloride 250 hardened oil
i o o 119 low i Hydroxypropyl cellulose 30 ■ Magnesium stearate 5 towns total 38
5g9 (10flφR-sided tablet) Formula F Magnesium chloride 250■ Hardened oil
50 ■ Polyoxyl stearate 40
2 (1151 talc
5 ■Total 325 kg (1
Example 4 The sustained release tablets of formulation C obtained in Example 3 are placed in a film coating pan. A solution of hydroxypropyl methyl cellulose 2910 (trade name TC-5) is sprayed, and spraying is stopped when each tablet is coated with 10'M9 of TC-5.

Dry thoroughly in the pan to obtain film-coated tablets.

Example 5 Formulation G Magnesium Citrate 250q Paraffin
90119 Lactose
20 Quiborisorbate 80 301
9Magnesium stearate 511IF meter
395119 Process A mixture of magnesium citrate and lactose is placed in a fluidized bed. A solution of paraffin and polysorbate 80 is sprayed using a fluidized bed to obtain coated granules. Magnesium stearate is added to this, mixed, and then tableted on a 10 mIIR surface to obtain sustained-release tablets shown by Formulation G.

Example 6 Formulation H Magnesium chloride 500 ethyl cellulose 200 crystalline cellulose
150 pieces total 850 ■Production method Magnesium chloride is microencapsulated using a conventional method.
Sustained release granules shown in Formulation H are obtained.

Example 7 Recipe Magnesium Ecitrate 250mg Mannitol 100'I9 Polyvinylpyrrolidone-302019 Ethylcellulose 201
19 Magnesium stearate 10g9 total
400 ■ Production method After mixing magnesium citrate and mannitol in a fluidized bed, 130 aqueous solution was added to 5 W/W% polyvinylpyrrolidone and granulated. After adding magnesium stearate and mixing, the mixture is compressed into tablets using a 10m1-R-sided rod. A solution of ethylcellulose is film coated as a spray solution to obtain sustained release tablets as indicated by the formulator.

Example 8 Formulation J Magnesium chloride 100100O paraffin 800ql-menthol
Dosage Needle 1800 Cape Proceed in the same manner as in Example 1 to obtain sustained release granules shown in Formulation J.

Example 9 Magnesium chloride in the recipe 1000q Hydrogenated oil (trade name Loveriwax 101) 750119 Hydroxyglobil methylcellulose 2910 (trade name TC-5)
50m! Total 18
Magnesium chloride 125y passed through a 001960 mesh screen is introduced into the fluidized bed. Spray Love Relax 101 solution onto this and add until the specified weight is reached. Next, TC-5 solution is sprayed to a specified weight to obtain sustained release granules as indicated in the formulation.

"Effect of Sustained Release Preparations" The dissolution of the sustained release magnesium preparations of Formulation B, C, and G was measured using the Japanese Pharmacopoeia's dissolution test rotating basket method 100r, p, and m. The eluate contains Pharmacopoeia 1st solution (pH 1,
2) and Pharmacopoeia 2nd solution (pH 6, 8) were used. Crystals of magnesium sulfate, magnesium chloride, and magnesium citrate were used as controls.

The test results are shown in Figure 2. All three control magnesium salts showed almost 100% elution after 10 minutes. On the other hand, the sustained release magnesium preparation had a dissolution rate of 25 to 70% after 1 hour, 50 to 9096% after 3 hours, and 75% or more after 6 hours, indicating good sustained release properties. Furthermore, even when the pH of the eluate changes from 1.2 to 6.8, there is almost no difference in the dissolution rate, so when this sustained-release preparation is taken, it does not depend on the pH in the body. Magnesium ions can be gradually eluted.

[Brief explanation of the drawing]

FIG. 1 shows the time course of the edema rate (increase rate relative to the paw volume before genin injection) after carrageenin induced inflammation. The vertical axis shows the edema rate ((6), and the horizontal axis shows the elapsed time (hours) after carrageenin injection. The symbols in the figure are shown below. ) Magnesium dichloride administered at 250 W/Kfl per day 1: Magnesium chloride administered at 500 q/Kg --: Magnesium chloride administered at 1000 W/Kfl
Figure 2 shows the elution curve. The vertical axis shows the elution rate (4), and the horizontal axis shows the elapsed time (hours). The symbols in the figure are shown below. One Row: Control magnesium salt crystal eluate
Pharmacopoeia 1st liquid 10-2 Prescription B Eluate Pharmacopoeia 1st liquid---0----: Prescription B Eluate Pharmacopoeia 2nd liquid -2 Prescription C eluate Pharmacopoeia 1st liquid -C: Prescription C eluate Pharmacopoeia 2nd solution -combination-: Prescription G eluate Pharmacopoeia 1st solution

Claims (2)

[Claims] (1) A therapeutic agent for arthritis whose main ingredient is a water-soluble magnesium salt. (2) A sustained-release magnesium preparation characterized by coating a water-soluble magnesium salt with a pH-independent substance.