JPS58162560A - Calcium salt of acidic antiphlogistic and analgesic agent and suppository containing the same - Google Patents

Abstract

PURPOSE:To provide a suppository having excellent absorbability, giving high concentration in blood and little damages to the mucous membrane, by using a calcium salt of an acidic antiphlogistic and anagesic agent as a main component. CONSTITUTION:The calcium salt of an acidic antiphlogistic and analgesic agent such as diclofenac, indomethacin, phenylbutazone, mefenamic acid, flufenamic acid, etc. is prepared in the form of suppository. The amount of the salt in the suppository is 5-20%. It is combined with an oily based such as corn oil, olive oil, vaseline, etc. or their mixture, and if necessary,with a suface active agent, a colorant, a stabilizer, etc. It is used in the form of an anal suppository which is solid at normal temperature and melts by the body heat, or an ointment or liquid enema by mixing with a liquid base.

Description

[Detailed description of the invention] The present invention relates to compositions for rectal administration of acidic anti-inflammatory analgesics.

Acidic anti-inflammatory drugs are usually administered orally. However, since acidic anti-inflammatory analgesics cause severe gastrointestinal disorders when administered orally, other forms of administration are desired. In fact, indomethacin, phenylbutacin, ketoprofen, etc.
Rectal injection has been tested as an alternative to oral administration, and is said to avoid gastrointestinal disorders. However, in the case of rectal administration of acidic anti-inflammatory analgesics by flattening, the area of the rectum is small compared to the gastrointestinal area, and the drug concentration per area of administration is naturally high. Since the drug is administered after being dissolved or suspended, a cloudy substance will be present at a high concentration in some parts of the rectal mucosa, and damage to the mucosa becomes a major problem. In particular, acidic anti-inflammatory, analgesic and antipyretic drugs have been shown to have a strong adverse effect on mucous membranes, as evidenced by the gastrointestinal disorders mentioned above, and are also recognized to be strong on rectal mucosa. For this reason, when administering to the rectum, the base used may affect the reduction of irritation, and attempts have been made to reduce irritation by selecting the base, but there are limits to this. In addition, there are crystal polymorphisms in the compound,
Since the elution from the base, stimulation, and absorption differ depending on the difference, there are attempts to select the one that causes the least irritation, but this also naturally has its limitations.

The present inventors continued their intensive research to solve this problem, and found that by administering a rectal preparation containing a calcium salt of an acidic anti-inflammatory analgesic, it was rapidly absorbed from the rectum and the raw drug was removed. We have completed the present invention by discovering that it shows the same or higher blood concentration, has a tendency to last longer than the original drug, and has an extremely low damaging effect on mucous membranes.

As the acidic anti-inflammatory analgesic used in the present invention, diclof 1 nac, indomethacin, phenylbutacin, mefenamic acid, flufenamic acid, etc. are preferably used, but any of them]
The drug is not limited to those mentioned above, and any other acidic anti-inflammatory analgesic can be used.

When formulating the calcium salt of the acidic anti-inflammatory analgesic drug according to the present invention as a flattened product, the amount of these salts is 5 to 20% per suppository.
It is necessary to contain As the planing base, conventionally used water-based polymer gels and water-soluble polymer-r-compounds can be used, but oil-based bases are particularly preferred because they have less influence on the rectal mucosa. For example, corn oil, olive oil, cocoa butter, liquid paraffin, vaseline, glycerin, chrycerin fatty acids (trade name: Witebusols), etc. are used alone or in combination. In addition, generally known surfactants, colorants, and stabilizers can also be used as necessary. In addition, the dosage forms used for this planing include anal planing that is solid at room temperature and melts at body temperature, ointment-like or complete intestine liquid mixed with a liquid base, such as soft capsules for rectal administration, and injection for rectal administration. Dosage forms that require a container are used.

Example 1 001 mol of diclofenac sodium, an acidic anti-inflammatory analgesic, is dissolved in 50 me of water. A solution prepared by dissolving 0.06 mol of calcium chloride in 10 me of water is added dropwise to this solution. After stirring for 5 minutes after the dropwise addition, the precipitate was collected, washed with water, and dried to obtain diclofenac calcium powder with a yield of 90%. The obtained diclofenac calcium was thoroughly ground and passed through a 100 mesh sieve.
Add Witepsol H15 (trade name) 9y to 40~
The mixture is heated to 45° C. to uniformly dissolve and mix, and a planed shape is formed according to a conventional method to obtain a planed shape of diclofenac calcium.

Examples 2 to 4 Indomethacin sodium, phenylbutacin sodium, and mefenamic acid sodium were each used in an amount of 0.001 mol, and each calcium salt was obtained according to the method shown in Example 1. In addition, by the same formulation method as shown in Example 1, flat pieces of each calcium salt having the formulation shown below are obtained.

Table 1 Test Example 1 A planing product prepared by the method of Examples 1 to 4 (hereinafter referred to as "Finvention Product Planing") was cut into the rectum of a male rabbit with an average body weight of 2.5 Kq that had been fasted for 24 hours. The dose was adjusted and administered.

After casting 5.10.20.30.40,60,90゜12
Blood was collected from the ear vein every minute, and the amount of acidic anti-inflammatory analgesic was determined by high performance liquid chromatography. The area of the blood concentration time curve F was determined from the obtained data and compared with the original product as shown in Table 2. It was found that each calcium salt treatment resulted in approximately the same blood concentration as that of the original drug.

Test Example 2 5omy was administered to the rectum of male SD rats with an average body weight of 250y after being exterminated for 24 hours, and the effect on the rectal mucosa was examined.

After administration of the present invention, the anal area was adhered with Aron Alpha (trade name) (it was confirmed that Aron Alpha (trade name) had no effect on the mucous membranes), and 1 hour later, the head was decapitated and the rectum was collected. After fixation with a 10% polymeric solution, the sections prepared according to a conventional method were stained and examined under a microscope. The microscopic results are shown in Table 6 and Figures 1 to 7. Compared to normal rectal observation results (Table 6, Figure 1), diclofenac sodium 5
When administered with %-containing planing, changes in the mucosa such as -L skin cell shedding, degenerative necrosis, capillary dilation and bleeding, and inflammatory cell infiltration were observed (Table 6, Figure 2). .

On the other hand, no major changes were observed in the mucous membranes due to the suppositories containing 5% diclofenac calcium compared to when the suppositories containing 5% diclofenac sodium were administered (Table 3, Figure 6). The third in which other invention product planing was administered.
As is clear from the results in the table, a reduction in mucosal damage was obtained.

[Brief explanation of the drawing]

Figure 1 is a tissue photograph of a normal rectum, Figure 2 is a tissue photograph after administration of 5% diclofenac sodium by planing, and Figure 2 is a photograph of the tissue after administration of 5% diclofenac calcium by planing. Patent applicant Morishita Pharmaceutical Co., Ltd.

Claims (1)

[Scope of Claims] (1) Calcium salt of an acidic anti-inflammatory analgesic (2) The compound according to claim 1, wherein the acidic anti-inflammatory analgesic is diclofenac, indomethacin, phenylbutacin, mefenamic acid, or flufenamic acid ( 5) Planing mainly composed of a calcium salt of an acidic anti-inflammatory analgesic (4) Planing according to claim 5, wherein the fa anti-inflammatory analgesic is diclofenac, indomethacin, phenylbutacin, or mefenamic acid.