JP4176358B2 - Pharmaceutical composition for hemorrhoids - Google Patents

Description

これらの結果を〔表１〕に示す。
【００２２】
【表１】

表１から明らかなように、実施例のような直腸投与の場合は低濃度においても抗浮腫作用を発揮し、経口投与では高濃度において効果が見られるものの、低濃度になると直腸投与の場合に比して効果が薄れる傾向にある。
【００２３】
試験例２
マグヌス装置を用いた内肛門括約筋収縮抑制作用の検討
方法
ラットを脱血致死後、直腸肛門部を肛門から２ｃｍ摘出し、氷冷下の栄養液中で脂肪を除去しコルク板上に２ｃｍの長さに貼りつけた。歯状線から口側２ｍｍの筋層部（内肛門括約筋）を切り出し、マグヌス装置に懸垂し、１ｇの負荷をかけた。筋条片は９５％O_２−５％Ｃ０_２混合ガス送気下の栄養液２０ｍＬを満たしたマグヌス槽に懸垂し、液温を３７℃に保った。筋条片の張力変化をＦＤピックアップおよび歪圧力アンプを介してレコーダー上に等尺性に記録した。筋張力が一定になるのを確認した後、塩化バリウムを投与し収縮を確認した。塩化バリウムは初回のみ１．５Ｘ１０^−２Ｍ添加し、以後１Ｘ１０^−２Ｍ添加し最大収縮が一定になるまで繰り返した。塩化バリウム収縮確認後は筋条片を３回洗浄し、筋張力が安定するまで１５分間静置し、次の塩化バリウムを添加した。最大収縮安定後、被検物質を投与し、抑制率を算出した。その結果を表２に示した。

【００２４】
【表２】

表２から明らかなように、メロキシカムは内肛門括約筋の収縮を抑制した。
【００２５】
【発明の効果】
本発明の痔疾用医薬組成物は、従来のステロイド系消炎剤および局所麻酔薬配合の痔疾用剤に比して消炎、鎮痛効果に優れ、且つ消化器潰瘍などの副作用も少なく、また痔疾患の悪化要因となる内肛門括約筋の痙攣（異状収縮）を抑制することができる優れた痔疾用剤である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a pharmaceutical composition for hemorrhoids containing meloxicam .
[0002]
[Prior art]
Mange is a disease peculiar to humans that occurs in the human anus or rectum, and can be roughly classified into hemorrhoids, anal fissures, and hemorrhoids, and the symptoms are intractable diseases accompanied by bleeding, pain, swelling, itching and the like. Although the pathophysiology of hemorrhoids has been clarified anatomically, there is still no established theory about the cause and mechanism of the outbreak, and no one that can be decisive for its treatment or prevention has been found. Not in.
So far, anti-manic agents have mainly been provided with steroidal anti-inflammatory agents such as prednisolone and local anesthetics such as lidocaine, and vasoconstrictors, astringents, etc., which are not always satisfactory. No results have been obtained.
A number of non-steroidal anti-inflammatory drugs such as indomethacin have been reported as antipyretic / analgesic agents and are also in practical use. However, many of these cause ulcers in the gastrointestinal tract, and for example, administration of indomethacin to patients with hemorrhoids that develop in the rectum or anus, which are part of the gastrointestinal tract, will exacerbate the condition. Indomethacin is contraindicated in the treatment of hemorrhoids.
Diseases that worsen when the internal anal sphincter is convulsed include anal fissure, thrombotic external hemorrhoids, incarcerated hemorrhoids, anal pain, etc., and these diseases become chronic and refractory.
[0003]
[Problems to be solved by the invention]
Under such circumstances, there is a strong demand for the development of hemorrhoid agents that have more reliable effects than conventional ones and have few side effects such as gastrointestinal disorders.
[0004]
[Means for Solving the Problems]
The present inventors, the conventional anti-inflammatory, analgesic, the number of compounds known as having antipyretic, again the applicability as hemorrhoid agent results discussed individually, main Rokishikamu is exerts a good effect We found that there were almost no side effects. The present invention was completed by further research based on this knowledge.
[0005]
That is, the present invention
(1) A pharmaceutical composition for hemorrhoids comprising meloxicam and a pharmaceutically acceptable carrier,
(2) it is for anal or rectal administration (1) Symbol placement hemorrhoid pharmaceutical composition,
(3) it is for oral administration (1) Symbol placement hemorrhoid pharmaceutical composition, and (4) Further, a local anesthetic, antipruritic, wound healing agents, vitamins, sulfa drugs, disinfectants, vasoconstrictors, antihistamines, The pharmaceutical composition for hemorrhoids according to any one of (1) to (3), comprising one or more of antipruritic / enteric agents,
It is.
[0006]
DETAILED DESCRIPTION OF THE INVENTION
The present invention main Rokishikamu is used. Its single dose to adults of meloxicam 0.1 to 20 mg, preferably, a 1-10 mg, topically to the oral or affected area daily to several times.
[0007]
Examples of the dosage form of the pharmaceutical composition for hemorrhoids of the present invention include topical administration such as anus and rectum and oral administration.
The dosage forms used include tablets, granules, powders, pills, capsules, liquids for internal use, suppositories, ointments, aerosols, liquids for external use, suspensions, emulsions, patches. Any topical preparation such as a poultice, liniment or lotion may be used, but a dosage form such as a suppository or ointment that can be administered accurately to the affected area is more preferred.
[0008]
As a pharmaceutically acceptable carrier, in the case of topical administration, either an oleaginous base or an aqueous base may be used. Examples of the oleaginous base include hard fat derived from cacao butter, lauric fat, beef tallow, or semi-synthetic products, or a coconut oil, palm kernel oil, and camellia oil that are liquid at room temperature. , Olive oil, soybean oil, sesame oil, corn oil, medium chain fatty acid triglyceride, liquid paraffin, white petrolatum, purified lanolin or isopropyl myristate or glyceryl monostearate, polyoxyethylene hydrogenated castor oil, sorbitan fatty acid ester, polyethylene glycol fatty acid ester, One or more combinations of surfactants such as polyoxyethylene sorbitan fatty acid ester, dextrin fatty acid ester and sucrose fatty acid ester and higher alcohols such as stearyl alcohol and cetanol are conceivable, but are not limited thereto. Rather it is sufficient that is acceptable for pharmaceuticals.
[0009]
Examples of the water-soluble base include, but are not limited to, glycerin, polyethylene glycol, sorbitol, 1,3 butylene glycol, propylene glycol, ethanol, purified water, and the like.
Among these, although used for suppositories, a preferred example is hard fat. The ointment is preferably white petrolatum, medium chain fatty acid triglyceride, or liquid paraffin.
In other dosage forms, conventionally known carriers are appropriately used.
[0010]
Examples of pharmaceutically acceptable carriers for internal use include sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectins, tragacanth gum , Gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Such dosage forms also include inert diluents, lubricants such as magnesium stearate, antioxidants such as ascorbic acid, α-tocopherol, cysteine, disintegrants, binders, sweeteners, flavors An imparting agent, a perfume agent or the like can be added. Tablets and pills can also be manufactured with an enteric coating.
[0011]
The pharmaceutical composition for hemorrhoids of the present invention further includes one or more kinds used in local anesthetics, antitussives / wound healing agents, vitamins, sulfa drugs, bactericides, vasoconstrictors, antihistamines, antipruritics / enteric agents. It is possible to formulate drugs.
In addition to the above drugs, additives such as absorption promoters, PH preparation agents, preservatives, dispersants, wetting agents, stabilizers, preservatives, thickeners, surfactants and the like are appropriately blended as necessary. May be.
[0012]
【Example】
Hereinafter, the present invention will be specifically described with reference to examples and test examples.
Example 1
Meloxicam 0.13g
Hard fat 99.87g
After melting the hard fat at 50 ° C., meloxicam was added thereto and dispersed, and then placed in a suppository mold and cooled to produce a suppository (1 piece, 1.75 g).
[0013]
Example 2
Meloxicam 0.013g
Hard fat 99.887g
After melting the hard fat at 50 ° C., meloxicam was added thereto and dispersed, and then placed in a suppository mold and cooled to produce a suppository (1.75 g).
[0014]
Example 3
Meloxicam 0.0065g
Hard fat 99.9935g
After melting the hard fat at 50 ° C., meloxicam was added thereto and dispersed, and then placed in a suppository mold and cooled to produce a suppository (1.75 g).
[0015]
Example 4
Meloxicam 0.0013g
Hard fat 99.99987g
After melting the hard fat at 50 ° C., meloxicam was added thereto and dispersed, and then placed in a suppository mold and cooled to produce a suppository (1.75 g).
[0016]
Example 5
Meloxicam 0.26g
Lidocaine 3g
Tocopherol acetate 3g
Hard fat 93.74g
After melting the hard fat at 60 ° C., dissolve tocopherol acetate lidocainet, add meloxicam and disperse, then place in a suppository mold and cool to produce a suppository (1.75 g per piece). did.
[0017]
Example 6
Meloxicam 0.13g
10g medium chain fatty acid triglyceride
White petrolatum 89.87g
Medium chain fatty acid triglyceride and white petrolatum were heated and mixed at 60 ° C., and meloxicam was dispersed to prepare 100 g of an ointment.
[0018]
Example 7
Meloxicam 3g
Crystalline cellulose 31g
Hydroxypropylcellulose 25g
Magnesium stearate 1g
Total amount 60g (300 tablets, 1 tablet 200mg)
Meloxicam, crystalline cellulose, and hydroxypropylcellulose were mixed, and this was coated with magnesium stearate and directly tableted.
[0019]
Example 8
Meloxicam 2g
Corn starch 23.5g
Lactose 53g
Magnesium stearate 1.5g
Total amount 80g (400 tablets, 1 tablet 200mg)
Meloxicam, a part of corn starch and lactose were mixed, and about 1650 ml of a 4% corn starch solution was gradually added thereto and mixed, dried and pulverized to prepare granules. The obtained granules were tableted with magnesium stearate.
[0020]
Example 9
Meloxicam 0.25g
40g xylitol
Soy lecithin 5g
Hard fat 53.75g
Carboxy vinyl polymer 1g
The hard fat was dissolved at 50 ° C., and the remaining components were dissolved or dispersed therein to make it uniform, and then poured into a mold to obtain a chocolate agent. (1 piece about 2g)
[0021]
Test example 1
A cotton swab dipped in a inflammatory agent (distilled water: pyridine: ether: 6% croton oil ether solution = 1: 4: 5: 10) was inserted into the rectum of a male rat fasted for 24 hours after a croton oil mixture-induced hemorrhoid model. Immediately after the inflammation occurred, 150 mg of each sample obtained in Example 1, Example 2, and Example 3 was administered to the rectum, and the anus was closed with a suture.
Moreover, as an example of oral administration, a liquid preparation (Example 10) containing 0.2 mg of meloxicam in 1 mL of purified water and a liquid preparation (Example 11) containing 0.02 mg of meloxicam in 1 mL of purified water were prepared, respectively. 1mg / kg, 0.1mg / kg
Was administered orally with a sonde.
The untreated group did not initiate inflammation and administration of the sample, and the control group did initiate inflammation but did not administer the sample.
After 24 hours of inflammation, the rats were bled, the rectal anus 15 mm was removed, the wet weight was measured, and the rectal anal coefficient (Recto-anus-coefficent, RAC), which is an index of the degree of edema, was determined according to the following equation (a). Calculated. Furthermore, the edema control rate was calculated from RAC according to the following formula (b).

These results are shown in [Table 1].
[0022]
[Table 1]

As is clear from Table 1, the anti-edema action is exerted even at a low concentration in the case of rectal administration as in the examples, and the effect is seen at a high concentration in the oral administration. The effect tends to be less than that.
[0023]
Test example 2
Examination method of inhibitory effect on internal anal sphincter contraction using Magnus device After exsanguination of the rat, the rectal anus was removed 2 cm from the anus, the fat was removed in ice-cold nutrient solution, and the length was 2 cm on the cork plate I pasted it. A muscle layer (inner anal sphincter) 2 mm on the mouth side was cut out from the dentate line, suspended on a Magnus device, and a load of 1 g was applied. The streak piece was suspended in a Magnus tank filled with 20 mL of nutrient solution under 95% O ₂ -5% CO ₂ gas mixture, and the liquid temperature was kept at 37 ° C. The tension change of the stripe was recorded isometrically on a recorder via an FD pickup and a strain pressure amplifier. After confirming that the muscle tension was constant, barium chloride was administered to confirm contraction. Barium chloride was added for the first time only 1.5 × 10 ^-2 M, was repeated until the subsequent 1X10 ^-2 M added maximal contraction is constant. After confirming the contraction of barium chloride, the strips were washed three times, allowed to stand for 15 minutes until the muscle tension was stabilized, and the following barium chloride was added. After the maximum contraction was stabilized, the test substance was administered, and the inhibition rate was calculated. The results are shown in Table 2.

[0024]
[Table 2]

As is apparent from Table 2, meloxicam suppressed the contraction of the internal anal sphincter.
[0025]
【The invention's effect】
The pharmaceutical composition for hemorrhoids of the present invention is superior in anti-inflammatory and analgesic effects as compared with conventional anti-inflammatory agents containing anti-inflammatory agents and local anesthetics, has fewer side effects such as gastrointestinal ulcers, etc. It is an excellent hemorrhoid agent that can suppress convulsions (abnormal contraction) of the internal anal sphincter, which is a cause of deterioration.

Claims (4)

A pharmaceutical composition for hemorrhoids comprising meloxicam and a pharmaceutically acceptable carrier. Hemorrhoids pharmaceutical composition according to claim 1 Symbol placement is for anal or rectal administration. Hemorrhoids pharmaceutical composition according to claim 1 Symbol placement is for oral administration. Furthermore, local anesthetics, antipruritic, wound healing agents, vitamins, sulfa drugs, disinfectants, vasoconstrictors, antihistamines, to any one of claims 1 to 3, comprising one or more of Tome瀉-antiflatulent The pharmaceutical composition for hemorrhoids as described.