JPH04164023A - Base for suppository - Google Patents

Abstract

PURPOSE:To obtain a suppository base by adding a water-insoluble water absorbing resin to a fat and oil or water-soluble suppository base to improve drug retention in the rectum and optionally using an alkali metal salt to improve releasability. CONSTITUTION:A fat and oil or water-soluble suppository base is blended with 1-10wt.%, especially 4-6wt.% water-insoluble water absorbing resin, preferably starch acrylate to retain a drug long in the rectum and optionally further 0.1-10wt.%, especially 0.3-1wt.% based on starch acrylate of an alkali metal salt, preferably a halide, sulfate, carbonate or an organic acid salt of sodium, potassium or lithium to give a suppository base for improving releasability of drug, usable for local and whole body purposes.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a base for suppositories that allows a drug to remain in the rectum for a long time and also has good drug release properties.

[Prior Art] Normally, in a layer agent, for example, an oil-based base melts at body temperature and diffuses, so that the active ingredient in the layer agent moves from the insertion portion. For this reason, in the case of topical drugs, such as hemorrhoid drugs, the active ingredient may migrate from the affected area and may not be effective. In order to improve these drawbacks of the layer agent, incorporating a swelling agent (for example, carboxyvinyl polymer) into the layer agent is disclosed in Japanese Patent Application Laid-open No. 163310/1983.
This is known from Japanese Patent Application Laid-Open No. 63-66116. On the other hand, in JP-A-1-143825.

Hydrophilic carboxyvinyl polymer and silicic anhydride are blended into a base mainly composed of fatty acid glyceride, but carboxyvinyl polymer has the disadvantage that it is particularly prone to agglomeration due to its hydrophilic nature.

[Problems to be solved by the invention] Adding a swelling agent to the inhibitor base solved the problem of local persistence, but on the other hand, problems such as easy aggregation and poor release of the active ingredient occurred. There is a point.

Means for Solving Problem E] The present invention improves retention in the rectum by adding starch acrylate, which is a water-insoluble water-absorbing resin, to the adhesive base. . Furthermore, if necessary, by adding an alkali metal salt, the release properties of the drug are improved, and therefore, the active ingredient is not dispersed (this also relates to a base for a drug that efficiently remains in the affected area).

[Function] As the base for the detergent used in the present invention, any base used in ordinary heavy punishments can be used without particular limitation.

For example, lipophilic bases include glycerin esters of fatty acids, such as Uitebusol (manufactured by Dynamite Nobel), SB-base (manufactured by Kanegafuchi Chemical), peanut oil, olive oil, corn oil, castor oil, cacao oil, 0-D
Examples include vegetable oils such as -0 (manufactured by Nisshin Oil Co., Ltd.), mineral oils such as vaseline, and paraffin. Examples of the hydrophilic base include polyethylene glycol and glycerin.

A water-insoluble water-absorbing resin is a water-soluble monomer and/or a monomer that becomes water-soluble by hydrolysis (A), starch and/or cellulose (B), and/or a crosslinking agent (C) as essential components. Examples include polymers obtained by polymerizing as a compound and, if necessary, hydrolyzing it.

(A), (B) and (C) used in the production of the above water absorbent resin
For details, polymer production methods, and specific examples of water-absorbing resins, see
JP-A-52-149910, JP-A-51-125
Those described in JP-A No. 468, JP-A-52-25886, and JP-A-52-59690 can be used.

Water-absorbing resins other than those mentioned above include those obtained by polymerizing (A) and (B); for example, starch-acrylonitrile graft copolymers and their salts, cellulose-acrylic acid copolymers and their salts; (B ) and (C), such as polyacrylamide crosslinked with a divinyl compound (methylenebisacrylamide etc.) and its partial hydrolyzate, crosslinked sulfonated polystyrene, crosslinked poval, JP-A-52-14689 , JP-A-52-2
Examples include saponified crosslinked vinyl ester-unsaturated carboxylic acid copolymer and crosslinked polyethylene oxide described in Japanese Patent No. 7455.

There are no particular limitations on the form in which the water-absorbing resin is used, and it may be used in the form of granules, powder, or a pasty form that absorbs water, mixed with other ingredients, but it may be used as a base material for heavy punishment or other ingredients. Powders are preferred for uniform mixing with the ingredients.

In the present invention, we investigated the aforementioned water-absorbing resins, and found that starch acrylate absorbs water, provides adequate moisture to the drug, stays at the insertion site for a long time, and has good drug release properties.
It was discovered that it remained efficiently in the affected area. The amount of starch acrylate added as a base for a blocking agent is 1 to 10% by weight, more preferably 4 to 6% by weight. This is because if the amount of starch acrylate added is less than 1%, swelling is insufficient.
The retention property at the insertion site is poor. If it exceeds 10%, the viscosity, etc. will increase, which will become an obstacle during the production of heavy-duty drugs.

The present invention improves drug release properties of heavy-duty drugs by further adding an alkali metal salt to starch acrylate, which is a water-insoluble water-absorbing resin. There are no particular restrictions on the alkali metal salt as long as it is physiologically acceptable, but salts of mineral acids such as sodium chloride and potassium chloride, alkali metal salts of carbonic acid such as sodium carbonate and sodium bicarbonate, Examples include alkali metal salts such as sodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium hydrogen phosphate. The amount of these alkali metal salts added is 0.1 to 0.1 to acrylic starch.
The amount is preferably 10% by weight, more preferably 0.3 to 1% by weight.

In addition to the base for heavy-duty drugs, surfactants such as cetyltrimethyl bromide and sodium lauryl sulfate may be added to improve solubility and dispersibility in body fluids. A variety of pigments are used based on aesthetic, psychological, and safety classifications.Antioxidants may also be added.

There are two types of drugs added to the above-mentioned drug bases: those intended for local action and those expected to have a systemic effect by absorbing the herbal medicine from the application site.

For local effects, corticosteroids such as cortisone, hydrocortisone, prednisone, prednisolone, dexamethacin, varamethacin, triamcinolone, haldinonide, anti-inflammatory agents such as lysozyme chloride, granulation promoters such as allantoin, hydrochloric acid Local anesthetics such as dibucaine, ethyl aminobenzoate, lidocaine, and propylene hydrochloride, antihistamines such as diphenhydramine hydrochloride, hemostatic agents such as phenylephrine hydrochloride, and antibacterial agents such as chlorhexidine hydrochloride, dequalinium chloride, and benzalkonium chloride. , blood circulation promoters such as purple root, vitamin preparations such as tocopherol acetate, astringents such as camphor and menthol, etc. are used as anti-hemorrhoid agents. Antibiotics are also used for constipation and intestinal cleaning.

When a systemic effect is intended, when the drug is inserted into the rectum, the drug dissolved in the rectum is relatively quickly absorbed through the rectal mucosa and transported directly into the venous bloodstream. Antipyretic agents have many advantages such as not causing gastrointestinal disorders due to direct contact, not being degraded in the gastrointestinal tract, and not being affected by taste or odor, so they are suitable for children and the elderly. A wide variety of drugs have been developed in this dosage form, including anti-inflammatory analgesics, hypnotics, antibiotics, antitumor agents, cardiovascular agents, and anticonvulsants.

However, some of these drugs, such as antipyretic and antiinflammatory analgesics, may cause a rapid increase in blood concentration and may cause side effects.

By incorporating these drugs into the heavy-duty drug of the present invention, the drug concentration in the blood immediately after administration can be sustained and side effects can be reduced, making it useful as a sustained-release drug.

Drugs used as systemic antidepressants in the present invention include indomethacin, aspirin, acetaminophen, ethenzamide, ketoprofen, thiaramide hydrochloride, diclozenaf sodium, survirin, naproxen, piroxicam, pranoprofen, mefenamic acid, and dimethothiazine mesylate. Antipyretic and anti-inflammatory analgesics such as , mevirozole, flufenamic acid, ibuprofen, pentazocine, trimethoquinol hydrochloride, bromhexine hydrochloride, carbetapentene citrate, tranilast, ketotifen fumarate. Salbutamol sulfate, anti-asthmatic, anti-allergy agents such as theophylline, anti-tumor agents such as tamococifen citrate, tegafur, fluorouracil, ampicillin sodium, cefazolin sodium, cefmetazole sodium, cephalexin, cefoxitin sodium, sulfuric acid. These include antibiotics such as sisomicin, gentamicin sulfate, and piperazine sodium, and corticosteroids such as prednisolone hydrocortisone acetate.

The method of the present invention will be explained in more detail below with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

(1) Topical antiseptic [Example 1] To 890 parts of melted antiseptic base (Witepzol W35 + Witepzol E85), 13.3 parts of tocopherol acetate, 2.7 parts of chlorhexidine hydrochloride, 3.3 parts of allantoin chlorhydroxyaluminum and lidocaine 40
0.7 parts of prednisolone acetate and 50 parts of starch acrylate were mixed and dispersed, and the total amount was mixed to 10 parts.
00 copies.

This was placed in a stop agent container, cooled, and used as a stop agent.

[Example 2] 13.3 parts of tocopherol acetate, 2.7 parts of chlorhexidine hydrochloride, 3.3 parts of allantoin chlorhydroxyaluminum and 40 parts of lidocaine were added to 887 parts of melted suppository base (Witebuzol W35 + Witevzol E85).
0.7 parts of prednisolone acetate, 3 parts of sodium chloride and 50 parts of starch acrylate were mixed and dispersed to make the total amount 1000 parts.

The suspect was placed in a detergent container, cooled, and sentenced to severe punishment.

[Example 3] 13.3 parts of tocopherol acetate, 2.7 parts of chlorhexidine hydrochloride, 3.3 parts of allantoin chlorhydroxyaluminum and 40 parts of lidocaine were added to 880 parts of melted suppository base (Witebuzol W35 + Witevzol E85).
0.7 parts of prednisolone acetate, 10 parts of sodium chloride and 50 parts of starch acrylate were mixed and dispersed to make the total amount 1000 parts.

The suspect was placed in a detergent container, cooled, and sentenced to severe punishment.

[Comparative Example 1] 13.3 parts of tocopherol acetate, 2.7 parts of chlorhexidine hydrochloride, 3.3 parts of allantoin chlorhydroxyaluminum and 40 parts of lidocaine were added to 940 parts of melted suppository base (Witebuzol W35 + Witepzol E85).
0.7 part of prednisolone acetate was mixed and dispersed to make the total amount 1000 parts.

The suspect was placed in a detergent container, cooled, and sentenced to severe punishment.

[Comparative Example 2] To 890 parts of melted suppository base (Witebuzol W35 + Witevzol E85), 13.3 parts of tocopherol acetate, 2.7 parts of chlorhexidine hydrochloride, 3.3 parts of allantoin chlorhydroxyaluminum and 40 parts of lidocaine were added.
0.7 parts of prednisolone acetate and 50 parts of carboxyvinyl polymer were mixed and dispersed to make the total amount 1000 parts.

The suspect was placed in a detergent container, cooled, and sentenced to severe punishment.

Test method (1) Rectal retention due to dye transfer Using three Japanese white male rabbits weighing 2.5 to 2.8 kg that had been fasted for 48 hours, the dye (Brilliant Blue Aluminum Lake) was added to the severe punishment of Example 1. Add 2%,
It was administered intrarectally, and the rectum was removed 1 hour later, and the distance (cm) from the anus to the tip of the intestine colored with the dye was measured.

The results are shown in Table 1.

Table 1 Retention of heavy drugs in the rabbit rectum Number 2 Cm In Example 1, the coloring distance was clearly shorter than in Comparative Example 1.2 (it was clear that the rectal retention of the drug was superior). .

(2) Intrarectal behavior of heavy X-ray punishment Created according to Example 1, Comparative Example 1, and Comparative Example 2 using two Japanese white male rabbits weighing 2.5 to 2.8 kg that were fasted for 48 hours. A hollow stopper containing lead powder was prepared and administered into the rectum. , X-ray photography was performed at 0.5 hours and 1.5 hours after administration. The results are shown in FIGS. 1 to 3.

From the figure, it is clear that Example 1 stays in the lower rectum for a longer time than Comparative Example 1.2.

(3) Release test For the severe punishment of each Example and Comparative Example 2, 10.2
1 after 0.30.40.60.90.120.150 minutes
Samples of 5 ml each were collected, and the concentration of gluedocaine in the entire drug was analyzed by high performance liquid chromatography.

The operation was performed twice for each sample and the average value was determined.

The results are shown in Table 2 and Figure 4.

Table 2 Release rate of lidocaine As is clear from Figure 4 and Table 2, the release rate of lidocaine in Example 1 using starch acrylate as the inhibitor base was higher than that of carboxyvinyl polymer in Test Example 2. It showed a remarkable effect compared to the base material for pharmaceuticals.

In Examples 2 and 3, in which an alkali metal was added to Example 1, the release properties were further improved.

(2) Systemic antiseptic [Example] Antiseptic base melted at 40-50°C (Witebuzol H5
) 157 parts of starch acrylate was added to 1343 parts,
Stir with a homomixer. Add 20 parts of diclozenaf sodium to this, stir thoroughly, then fill the container.
It was molded to obtain an anal suppressant weighing 1 g.

[Comparative Example] 20 parts of diclozenaf sodium was added to 1580 parts of an analgesic base (Witebuzol H5) and treated in the same manner as in the example to prepare an anal analgesic.

The weight-based 2.
One dose (12.5 mg of diclozenaf sodium) was administered rectally to each 15 kg Japanese white male rabbit, and the anus was immediately closed with adhesive.

Approximately 1.5 ml of blood was collected from the auricular vein at 0.25, 0.5, 0.75, 1.2, and 4 hours after administration, and the concentration of diclozenaf sodium was measured using the quantitative method described below. .

Assay method Add 1 ml of 2.5N phosphoric acid solution and 5 ml of hexane-improper tool (9:1) to 0.2 ml of plasma,
After shaking for a minute, it was centrifuged (3000 rpm, 101 minutes). Then, the organic layer was separated and concentrated to dryness under reduced pressure.
Add eluent (methanol/0.1% phosphate buffer 9) to the residue.
:1) 0.2 ml was added to dissolve and measured by high performance liquid chromatography.

The results are shown in FIG. 5 and Table 3.

Table 3 Diclozenaf Sodium Concentration As shown in Figure 5 and Table 3, it is clear that the drug in the Examples is more sustainedly released than in the Comparative Examples, and the drug efficacy lasts for a long time.

[Effects of the Invention] Compared to conventional water-soluble swelling agents, the antiseptic base of the present invention has better rectal retention and drug release (
Therefore, it can be used for both local and systemic purposes.

[Brief explanation of drawings]

FIGS. 1 to 3 are diagrams of time-lapse X-ray photographs of rabbits to which lead powder-containing hollow planings (Example 1, Comparative Example 1, and Comparative Example 2) were administered into the rectum. The stem represents the rabbit's skeleton (spine and pelvis), and its center shows the movement of the antidepressant over time. FIG. 4 shows the measured release rate of glue docaine in the layer agents of each Example and Comparative Example 2. FIG. 5 shows the plasma concentration of the diclofenac sodium-containing layer administered rectally to rabbits. Applicant Wakodo Co., Ltd. Agent Patent Attorney Akio Ohno

Claims (1)

[Scope of Claims] (1) A suppository base characterized by adding a water-insoluble water-absorbing resin to an oleaginous suppository base or a water-soluble suppository base. (2) The suppository base according to claim 1, wherein a water-insoluble water-absorbing resin and further an alkali metal salt are added to the oil-based suppository base or the water-soluble suppository base (3). 3. The suppository base according to claim 1 or 2, wherein the water-insoluble water-absorbing resin is starch acrylate. (4) The base for suppositories according to claim 1, claim 2, or claim 3, wherein the amount of starch acrylate added is 1 to 10% by weight. (5) The alkali metal of the alkali metal salts is sodium, potassium or lithium, and the corresponding salt is a halogen, sulfuric acid, phosphoric acid, carbonic acid or organic acid. Base for suppositories.