JPS6165823A - Drug for rectal application - Google Patents

Abstract

PURPOSE:To provide an agent for rectal application, containing a carbonate and an acid. CONSTITUTION:The objective agent can be prepared by mixing a carbonate (e.g. NaHCO3, Na2CO3, K2CO3, etc.) and an acid (e.g. citric acid, tartaric acid ascorbic acid, dihydrogen sodium phosphate, etc.) at a ratio of 10:(3-30), especially 10:(3-15), adding the mixture to an agent for rectal application in an amount of 1-60wt%, especially 5-40wt%, and adding 0.1-40wt%, preferably 0.5-30wt% pharmacologically active substance (e.g. physiologically active polysaccharide substance such as heparin; enzymatic agent such as trypsin; hormones; nonsteroidal acidic anti-inflammatory agent such as indomethacin; antibiotic substance such as streptomycin; analgesic such as morphine; etc.), mixing the mixture with an oleagenous base, and forming in the form of a solid suppository by using a mold for suppository, or filling the mixture in a soft gelatin capsule, etc. EFFECT:The absorption of the physiologically active component can be improved.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a preparation for rectal administration, and more particularly to a preparation for rectal administration that contains a carbonate and an acid and has excellent rectal absorption of pharmacologically active substances.

[Conventional technology]

Traditionally, pharmacologically active substances that are difficult to absorb through oral administration are
It has generally been administered as an injection.

[Problem that the invention seeks to solve]

However, administration by injection is often accompanied by pain and is not necessarily the optimal administration method.

[Means for solving problems]

The present inventor has conducted extensive research in view of the above circumstances and has found that when a pharmacologically active substance is administered rectally in the presence of carbon dioxide,
The present invention was completed based on the discovery that pharmacologically active substances, which were hardly absorbed in the past, are easily absorbed.

That is, the present invention provides a rectal administration formulation containing carbonate and rRt-M.

Examples of the carbonate used in the present invention include sodium hydrogen carbonate, sodium carbonate, sodium sesquicarbonate, potassium carbonate, potassium hydrogen carbonate, ammonium carbonate, etc. Among them, sodium hydrogen carbonate and sodium carbonate are particularly preferred. preferable.

In addition, examples of acids include citric acid, tartaric acid, ascorbic acid, 6-abatukazolonic acid, kainic acid, cinnamic acid, rubic acid, tannic acid, boric acid, malic acid, malonic acid, pyrrolidone carmenic acid, and succinic acid. , maleic acid, glutazic acid, aspartic acid, glucono delta lactone, gluconic acid, lactic acid, fumaric acid, phosphoric acid, azobic acid,
Examples include sodium citrate, sodium succinate, potassium noydrozoxysuccinic acid, sodium heptimalate, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sulfamic acid, etc. Sodium dihydrogen acid and ascorbic acid are preferred. The acid content is preferably 10 to 300% by weight, particularly 30 to 150% by weight, based on the weight of the carbonate present in the rectal preparation.

The mixture of carbonate and acid is present in the rectal formulation of the present invention.
-60% by weight, preferably 5-40% by weight.

It is preferable to use these carbonates and acids that have been dried in advance. However, even if anhydrides are used as the carbonate and acid, they will react and decompose in the presence of a small amount of moisture, so it is preferable to use them together with a stabilizer. As a stabilizer,
Examples include magnesium oxide, calcium oxide, sodium albinate, and the like. The stabilizer may be present in an amount of 0.5 to 15% by weight, in particular 0.5% by weight, based on the carbonate and acid mixture.
~.

It is preferable to mix it so that it is 10% by weight. If the amount is less than 0.1% by weight, the stabilizing effect will be insufficient. Note that the particle size of the stabilizer is not particularly limited, but is 1000
It is preferably less than μ, particularly preferably less than 500 μ.

The pharmacologically active substances used in the present invention include heno-9 linoid, dextrin sulfate R% bentosan sulfate (heno-9 linoid)
, polysaccharide physiologically active substances such as chondroitin sulfate and its salts; glucoamylase inhibitors; pleomycin, neocarzinostatin, L-as, Q-laginase-like bezotide antitumor substances; trizocin, chymotrypsin, promethin, no-Q No9in, turotenase, no9-oxidase, nagase, factase, seratiopedetitase, seaderose, lysozyme, streptokinase, streptodornase, plasban, urokinase, cytochrome C1 hyaluronidase, fibrinolysin, thrombin, Enzyme agents such as calicin, kallikrein, cilastane, glu;-suoxidase, β-galactosidase, phytin, deoxyribonuclease, cholinester 2-ase, zolonase v/Q encreatin;
Calcitonin, No9latormon, Relaxin, Insulin, Glucagon, Prolactin, Adrenocorticothrobin (Human CT1f) % 41jl [Super hormone, Thyrotropin (TSH), Growth hormone (BGM),
Luteinizing hormone (LH), follicle stimulating hormone (FSH)
), oxytocin, vasozolecin, antidiuretic hormone,
Peptide hormones such as coherin, melanocyte-stimulating hormone (MSH), gastrin, tetragastrin, pentagastrin, secretin, cholecystokinin, substance P1 gonadotropin (1'ICG), and pazozoresin: corticotropin-releasing factor ( ACTH-RH), follicle-stimulating hormone-releasing factor (FSH-RH), growth hormone-releasing factor (GH
-RH), luteinizing hormone releasing factor (LH-RH),
Prolactin-releasing factor (PR-RH), prolactin-inhibiting factor (PR-IH), thyrotropin-releasing factor (
Peptide hormone release inhibitors such as TSH-RH); polyoligonucleotides, complexes of polyinosinic acid and polycytidylic acid, complexes of polyadenylic acid and polyurisolic acid, ? riboxyribonucleotide etc.? linucreote; insulin secretion activating protein CIAP) % pancreatic basic trizocin inhibitor, antinoqine hydrochloride, chymostatin.

Elastatinal, pepstatin A%? Liricin, zliornithine, polyethyleneimine, broken vinylamine, etc.; steroidal anti-inflammatory agents such as rudnisolone, dexamethacin; non-steroidal anti-inflammatory agents such as indomethacin, flufenamic acid, mefenamic acid; triperenaban, incypencyl, chlorphenyline I , cyanine hydramine, zolomethacin and other antihistamines; sulfa drugs such as sulfamonomethoxine and sulfamethizole; -q
Antibiotics such as nigilin, cephalothrin, erythromycin, tetracycline, chloramphenicol, streptomycin; antineoplastic agents such as 5-fluorouracil, cyclophosphamide, busulfan, actinomycin; morphine, codin, nalorufine, bentazocine, aspirin analgesics such as , acetalinide, and aminopyrine; zolostablandin preparations; hypnotics and sedatives such as parbital and thiobental; antipsychotics and antiepileptics such as chlorpromacine, reserpine, and chlorzoazeboxide: chlorzoxazone, Rebotno Q
Anti-Q-kinesia drugs such as; cardiac drugs such as zochitoxin and digoxin; antiarrhythmic drugs such as zolocainamide hydrochloride and zolosilanol hydrochloride; antianginal drugs such as zoviridamol and amyl nitrite; Examples include, but are not limited to, antihypertensive agents. The pharmacologically active substance is present in the rectal preparation of the present invention in an amount of 0.1 to 40% by weight, preferably 0.5 to 3% by weight.
03[amount%] is blended.

The rectal administration preparation of the present invention can be prepared by mixing a carbonate and an acid, or a carbonate, an acid, and a pharmacologically active substance with an oily base and forming a solid layer using a layer mold, or by filling a soft gelatin capsule. Manufactured by. Examples of the oily base include liquid vegetable oils, animal oils, synthetic oils, and solid glycerin esters of fatty acids.

[Effect]

Although the mechanism of action of the rectal preparation of the present invention is not clear,
It is thought that the action of the generated carbon dioxide gas gives mild irritation to the rectum and promotes peripheral blood flow in the same area, thereby increasing the absorption of pharmacologically active substances.

〔Effect of the invention〕

The rectal administration preparation of the present invention has good absorption of pharmacologically active ingredients,
It enables the intestinal absorption of pharmacologically active substances, which were rarely absorbed in the past, and expands the scope of application of rectal preparations.

〔Example〕

Next, the present invention will be explained with reference to Examples.

Example 1 Insulin rectally administered preparation: ■ Sodium bicarbonate 10.09 ■ Citric acid 8.0 ■ Magnesium oxide 5.0 ■ Insulin
250U total 100f ■～■、■ were sufficiently dissolved and mixed at 45℃, allowed to withstand while mixing up to 40℃, and after adding ■ and mixing thoroughly,
Layer mold! The product was formulated for 7zf. This was sealed and packaged with aluminum laminated L7t film, and the temperature was 40°C.
It was stored for 6 months at ℃ and 75% humidity. No abnormalities were observed in this packaged product.

The effectiveness of this layer agent was confirmed using domestic rabbits by the following method. That is, a male domestic rabbit, which had been fasted for 24 hours and had a mental body weight of about 2.5 cm, was fixed in the dorsal position, and the layer agent if was administered rectally. A cannula is inserted into the femoral vein of the hind leg, and approximately 0.0 mm is inserted at regular intervals.
The % disintegration WI value was measured in 2-increments using a Dextrostek tube, and the amount of insulin in plasma was measured by an enzyme immunoassay method. The results are shown in Table 1 and Table wJ2, respectively. As a control, a layer agent was used in which the above-mentioned incacao was added to insulin 2.50 to make IF.

Below is the margin Example 2 Indomesacin suppository: ■ Sodium hydrogen carbonate 12fi% (riascorbic acid 8■ Magnesium oxide 0.1■ Indomesacin
lO■ Input camera (same as Example 1)
Balance meter 100 ■～■ were sufficiently dissolved and mixed at 45°C, and I
Please make sure to prepare the product for f. This was sealed and packaged with a film laminated with aluminum and stored at a temperature of 40° C. and a humidity of 75% for 6 months. No abnormalities were observed in this packaged product.

This herbal medicine was administered into the rectum of a healthy male, samples were taken over time, and the amount of indomethacin in the serum was determined using high performance liquid chromatography. As a control drug, a commercially available indometacin suppository containing indometacin 1001'IF was used. The results are shown in Figure 1.

Example 3 ■ Sodium charcoal 15.0% by weight■
Sodium dihydrogen phosphate 15.0■ Magnesium oxide 0.3■ Aspirin
1O10■ Inca cao (same as fruiting example 1) Balance meter 100 ■~■ were sufficiently melted and mixed at 40°C, and prepared into If by a layer agent foundry. The storage stability of this product was the same as in Example 1.

[Brief explanation of the drawing]

FIG. 1 is a graph showing the time course of the amount of indomethacin in serum absorbed from the rectum. that's all

Claims (1)

[Claims] 1. Rectal preparation containing carbonate and acid.