JPS6133111A - Pharmaceutical preparation for rectal administration - Google Patents

Abstract

PURPOSE:The titled pharmaceutical preparation useful as an anti-inflammatory analgesic for rectal or anal diseases, etc., retaining selectively and specifically only in rectal tissue, containing ibuprofen piconol well-known as a nonsteroid drug for exodermis as an active ingredient. CONSTITUTION:A pharmaceutical preparation for rectal administration containing ibuprofen piconol {chemical name: 2-pyridylmethyl 2-[P-(2-methylpropyl) phenyl]propionate} shown by the formula as an active ingredient. The compound shown by the formula is rapidly absorbed in a local part such as the rectum, the anus, etc., accumulated and retained specifically in the local part, and shows anti-inflammatory action for a long time. Since the active ingredient is an oily ester, it has neither unpleasant irritation, nor side effects such as injury, etc. of the local part, and the titled preparation has high dispersion ratio during pharmaceutical manufacturing and stable quality.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention uses 2-pyridylmethyl 2-CP as an active ingredient.
-(2-methylpropyl)phenyl] flobionate (
This invention relates to a medical preparation for rectal administration containing ibuprofen piconol (generic name: ibuprofen piconol).

BACKGROUND OF THE INVENTION Conventional rectal preparations containing non-steroidal anti-inflammatory drugs are used in the form of suppositories or ointments, and these are expected to have antipyretic, analgesic, and anti-inflammatory effects. Drugs intended for systemic treatment have only been diverted for rectal administration, and there are almost no known drugs that have specific effects on local sites such as the rectum or anus. Furthermore, most of these drugs have carboxylic acid in their molecules, and for this reason, many of the drugs themselves have unpleasant irritating properties. In addition, conventional rectal administration preparations are rapidly absorbed and the drug concentration in the blood reaches its peak within a short period of time, so they have shortcomings such as a short duration of medicinal efficacy. Furthermore, in combination with the above-mentioned structural problems, they also have drawbacks such as irritation and damage to the rectal mucosa and the development of other side effects.

In addition, although indomethacin, ketoprofen, diclofenac, etc., are known as active ingredients in conventional rectally administered crude drug preparations, the active ingredient ibuprofen piconol of the present invention has not been used as a rectally administered preparation. There are no publicly known materials that suggest this. Furthermore, since all of the above-mentioned known drugs have crystallinity, they have drawbacks in terms of formulation, such as poor dispersion in the base (and precipitation of crystals).

Next, the state of the art of ibuprofen piconol, which is the active ingredient of the present invention, will be described.

The active ingredient ibuprofen piconol is a non-steroidal dermatological drug with analgesic and anti-inflammatory effects.
It is a drug used in the field of dermatology to treat acute eczema, contact dermatitis, atopic dermatitis, chronic eczema, herpes zoster, rosacea-like dermatitis, perioral dermatitis, etc. The active ingredient is a pale yellow oily compound obtained by reacting ibuprofen, which is frequently used as an anti-inflammatory drug, with 2-pyridine methanol, and has the following structural formula.

As is clear from the above structural formula, the active ingredient ibuprofen piconol protects the intramolecular carboxylic acid with 2-pyridine methanol, so it has a low PKa value against sharp compounds and has increased stability. It is also a compound with extremely mild irritant effects.

Problems to be Solved by the Invention As mentioned in the previous section, conventional rectal administration preparations have various problems and are not satisfactory. Therefore, the inventors of the present application conducted intensive research in search of a rectal administration preparation that could overcome the above-mentioned drawbacks, and found that, unexpectedly, when ibuprofen piconol, which is known as a drug for external skin, is administered rectally, it is selectively administered only within the rectal tissue. The present invention was completed by discovering that this substance is stored in a specific and specific manner and utilizing this knowledge.

That is, an object of the present invention is to provide a novel rectal administration preparation containing ibuprofen piconol as an active ingredient and having an anti-inflammatory effect.

More specifically, (11) It has a fast-acting and specific pharmacological action effect on local sites, (2) It has a slow-acting effect on the systemic action and has a long duration of medicinal effect, (3) An active ingredient (4) There is no crystal precipitation of the active ingredient in the base. (5) There is no irritation to the administration site and there are few other side effects, making it highly safe. The object of the present invention is to provide a preparation for rectal administration having excellent chemical and physical properties such as .

Means for Solving the Problems In the present invention, the components, bases, additives, etc. described in detail below are appropriately mixed and formulated to form the intended rectal administration preparation. The dosage form of the rectal administration preparation of the present invention may be any of suppositories, ointments, creams, gels, and gel-like creams, but suppositories are particularly preferred.

First, we will discuss the amount of ibuprofen piconol, the active ingredient. The amount of ibuprofen piconol in the rectal administration formulation is 1 to 40% by weight, preferably 3 to 35% by weight, and more preferably 5 to 30% by weight, so that the desired anti-inflammatory effect can be sufficiently obtained. .

Next, in the rectal administration preparation of the present invention in the above dosage form, additives that may be added as necessary include, for example, a local anesthetic,
Fungicides, antihistamines, topical astringents, sulfa drugs,
Antibiotics, healing agents, surfactants, vitamins, herbal extracts, bile acids, preservatives, excipients (including aluminum oxide), absorption enhancers, amino acids, etc. are used.

In addition, in the case of gel preparations, water or a medium water is used.

Each of the above-mentioned components will be further explained below.

First, let's talk about the base ingredients. The lipophilic base is a medium to higher fatty acid, and particularly preferably a glycerin ester of a saturated fatty acid or an unsaturated fatty acid having 8 to 18 carbon atoms. Specific examples include caprylic acid, capric acid, perabonic acid, undecylic acid, trisosylic acid, lauric acid, myristic acid, palmitic acid, pentadecylic acid, heptadecylic acid, stearic acid, oleic acid, elaidic acid, and linoleic acid. , glycerin esters such as lylunic acid, etc., and usually a mixture of mono-, di-, tri-, and glycerides is used.The amount of lipophilic base added is 2% to the total amount.
It is 5 to 99% by weight, preferably 40 to 99% by weight, more preferably 60 to 99% by weight.

The hydroxyl value of the glyceride used in the present invention is not particularly limited, but is preferably 70 or less. That is, since glycerides having a hydroxyl value of 50 to 70 have a self-emulsifying effect, they have the characteristic that they can be formulated without adding a surfactant. If no surfactant is added, a highly safe formulation with less side effects (e.g. allergy or irritation) can be obtained, and it has the great advantage of being stable and having excellent drug release properties. It is something.

The specification of the hydroxyl value was discovered by the inventor of the present invention through intensive research in the preparation of the present invention, and there is no other example of this. Examples of commercially available lipophilic bases are listed below.

Uitepsol (manufactured by Guinamit Nobel): This is a mixture of mono-, di-, and tri-glycerides of saturated fatty acids having 12 to 18 carbon atoms. In detail, the Uitep H series (for example, Uitebusol H5゜■2. H15, H
19, H32, H35, H37, 1 (39, H42, H
175° old 85, etc.), Witepsol W series (e.g. Witepsol W25, W2CH35, So45, etc.), Witepsol E series (e.g. Witepsol E75, H76, H79, H85, etc.), Witepsol S series (e.g. Witepsol S52.35)
5. S58 etc.).

Saposia (manufactured by Gatefosse): This has 10 to 1 carbon atoms.
It is a mixture of mono-, di-, and tri-glycerides of 8 saturated fatty acids. For details, please contact Sabosaia N, Sabosaia O8I
Sabosaia AS, Sabosaia BS.

Examples include Sabot Saia Shizuka, Sabot Saia BM, and Sabot Saia Mon.

Masaestalinum (manufactured by Guinamit Nobel): This is a mixture of mono-, di-, and tri-glycerides of saturated fatty acids having 10 to 18 carbon atoms. For details, masaestalinum A, AB, B, BB, BC, BCF, C, D
.

E, BD, masaestalinum 299, and the like.

SB (manufactured by Kanebuchi Kagaku Co., Ltd.): This is a mixture of mono-, di-, and tri-glycerides of saturated fatty acids having 12 to 18 carbon atoms. Specific examples include 5B-H, 5B-E, SR-AM, etc.

Miglyol 810 and Miglyol 812 (manufactured by Guinamid Nobel): This is a mixture of triglycerides of saturated fatty acids having 8 to 12 carbon atoms.

When blending the lipophilic base described above, one or more of these may be blended and used as required.

Next, the oily component that may be added to the lipophilic base as needed will be explained. Oil-based ingredients include sesame oil, olive oil, camellia oil, soybean oil, rapeseed oil, cottonseed oil, linseed oil, castor oil, and bran oil.

Corn oil, peanut oil, coconut oil, almond oil, aho curd oil, palm oil, palm kernel oil, kaya oil, kahok oil, kuromoji oil, sasanquan oil, tea oil, eno oil, cacao butter, Japanese oil, lauric fat.

Fats such as beef tallow, pork tallow, wool fat, turdle oil, and squalene, as well as these animal and vegetable oils, are hydrogenated and converted into fatty acids.

Modified fats and oils, vaseline, and white vaseline obtained by chemically changing them through acetylation, single-part extraction, etc.

Liquid paraffin, paraffin, dehydrated lanolin, Isopar, mineral oils such as silicone oil, isopropyl myristate, n-butyl myristate, isoprobilurate,
Cetyl ricinosate, stearyl lysyllate diethyl sebacate, diisopropyl adipate, cetyl alcohol, stearyl alcohol, white beeswax, gay wax.

Examples thereof include higher aliphatic alcohols such as Japanese wax, higher fatty acid esters, waxes, and higher fatty acids such as stearic acid, oleic acid, and valmitic acid, and one or more of these can be used in combination. By adding the oily component, the hardness and feel of the rectally administered formulation can be adjusted, and the release of the drug from the formulation and the stability of the formulation over time can be improved.

The blending amount of the oily component is 0.1 to 50% by weight, preferably 0.5 to 30% by weight based on the lipophilic base.

Next, the water-soluble base will be described. As a water-soluble base,
Examples include polyethylene glycol, propylene glycol, glycerogelatin, carboxyvinyl polymer, polyvinylpyrrolidone, carboxymethyl cellulose, hydroxypropyl cellulose, polyacrylic acid, sodium polyacrylate, etc., and the water-soluble base may be used alone or in combination. They are used as a mixture, and the blending amount is 5% by weight or less based on the total amount.

Finally, the emulsion base will be explained. An emulsion base means a base obtained by adding an emulsifier to a lipophilic base, and one of them that can be used in the present invention contains a w/o type emulsifier and is melted or dissolved to form a w/o emulsifier. / It is a water-in-oil base that becomes an o-type emulsion. Its blending amount is 10% of the total amount.
It is 90% by weight, preferably 30% to 80% by weight, preferably 30% to 80% by weight. It is also possible to use an oil-in-water base that contains an o/w total emulsifier and melts or dissolves to form an o/w emulsion. The blending amount thereof is 1 to 70% by weight, preferably 5 to 60% by weight, and more preferably 10 to 60% by weight based on the total amount.

Next, the surfactants (emulsifiers) used for each of the bases will be explained. Examples of the surfactant include nonionic surfactants, cationic surfactants, anionic surfactants, and amphoteric surfactants. Among these, nonionic surfactants are particularly preferred, such as glycerin fatty acid ester, propylene glycol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene fatty acid alcohol ether, polyoxyethylene alkyl Phenyl ether, polyoxyethylene castor oil, etc. can be used, especially polyoxyethylene fatty acid alcohol ether (
For example, Nilacol BL-25 manufactured by Nikko Chemicals,
Nilacol BC-207X) and polyoxyethylene castor oil (for example, Nilacol HC manufactured by Nikko Chemicals)
Good results can be expected by using sorbitan fatty acid ester (for example, Nilacol 5o-15, manufactured by Nikko Chemicals). In addition, the blending amount of these is 0.1 to 20% by weight, preferably 0.5 to 1% based on the total amount.
It is 0% by weight.

In addition, when the purpose is an aqueous gel preparation, water or a neutralizing agent (for example, commonly used inorganic amines or organic amines) should be added in an amount that can adjust the pH value to 4 to 8. do.

Next, the additives that may be added to the rectal administration preparation of the present invention as necessary will be mentioned. Among the additives, local anesthetics and antihistamines include, for example, brocaine hydrochloride, Schiff hydrochloride, enhydramine, diphenhydramine, meprilcaine hydrochloride, phenylephrine hydrochloride, cetylpyridium hydrochloride, epicaloine hydrochloride, naphazoline hydrochloride, ephedrine hydrochloride, dypcaine hydrochloride, dl- Methylephedrine hydrochloride, ethyl aminobenzoate, lidocaine, carpocaine,
Peppermint oil, camphor, glycyrrhetinic acid, glycyrrhizic acid, chlorpheniramine maleate, etc. can be used as needed. The blending amount thereof is 0.1 to 30% by weight, preferably 0.1 to 15% by weight based on the total amount of the preparation.

Furthermore, bactericidal agents, local astringents, antibiotics, healing agents, sulfa drugs, vitamins, bile acids, crude drug extracts, and the like may be added. Since these can be used without any conditions as long as they are ordinarily blended into rectal administration preparations or can be blended, specific examples will be omitted.

Next, the manufacturing method of the present invention will be described. It is said that a preparation for rectal administration should remain solid at room temperature and melt at body temperature or dissolve and disperse in digestive fluids, so each of the above bases is melted by heating, and ibuprofen piconol is added to it. It can be manufactured by uniformly dissolving it, molding it in a plastic container for suppositories or other suitable method, and cooling and solidifying it.

Also, soft capsules can be produced by dissolving ibuprofen piconol in each base at room temperature and then filling the solution into soft capsules for pharmaceutical preparation.

Furthermore, ibuprofen piconol may be dissolved or dispersed in each of the above-mentioned bases or a known base to form an ointment or cream, which may be administered via a tube or the like. Alternatively, a gel preparation may be made using a water-soluble polymer such as sodium polyacrylate.

Contains ibuprofen piconol as an active ingredient,
In addition, the rectal administration preparation of the present invention, which contains various bases and additives, is quickly absorbed into local areas such as the rectum or anus, and is specifically accumulated and retained in the local area, and has anti-inflammatory properties over a long period of time. It is what makes it work. still,
Since rectal administration preparations are administered after defecation, they cannot be administered as frequently as oral drugs; therefore, the active ingredient is gradually released and the medicinal effect lasts for a long time. This can be said to be a major advantage as a formulation.

In addition, the action of specifically accumulating and retaining in local areas such as the rectum or anus region not only exerts a great effect when said local area is an affected area, but also gradually absorbs into the blood and can be expected to have a systemic effect. Therefore, it can be fully applied to inflammatory diseases of various parts.

The rectal administration preparation of the present invention is used by inserting or applying the active ingredient ibuprofen piconol locally for an adult, usually 10 to 300 cm, preferably 25 to 200 cm, once to several times per day.

Example First, an experimental example of the present invention will be shown.

Experimental Example 1 Example 1.2 to be described later. and 5, and a suppository in which ibuprofen is dispersed in an attribute base, an emulsifying base, or a water-soluble base (product of the present invention) and a suppository in which ibuprofen piconol is dispersed in an oily base, according to the description in Reference Example 1. (Comparative product)
was prepared and administered into the rectum of rabbits, blood was collected over time, and the plasma concentration of ibuprofen was measured.

Administration method: Male rabbits (body weight around 3 mm) fasted for U hours.
The preparation was inserted into the rectum of the patient, and the anal region was closed with surgical adhesive (Aronalpham, Sankyo) to prevent leakage.

Blood collection was performed at 0.25.0.5.1.0.1.5 after administration of the preparation.
．． At 2.0 hours, heparinized blood was taken from the ear vein at 1.
After centrifugation, plasma was obtained. To measure plasma concentration, add 0.4 ml of 2N hydrochloric acid and 5+nl of benzene to 0.2 ml of plasma, extract with shaking, collect 4 ml of the separated benzene layer, evaporate to dryness, methylate with diazomethane, and use as an internal standard. Fluorene (Wako Pure Chemical Industries, Ltd.) was added thereto and gas chromatography was performed.

The results are shown in Table 1.

Table 1 The above table is the average value of 5 cases, and the detection limit is 5J4
/ml. Furthermore, since ibuprofen piconol undergoes rapid hydrolysis in the blood to produce ibuprofen, 2- and lysine methanol, it was decided to measure ibuprofen.

The formulation of the present invention showed extremely low plasma concentrations compared to the control formulation.

Experimental Example 2 The preparation of the present invention prepared in Experimental Example 1 was administered into the rectum of a rabbit, and the concentration in the rectal tissue was measured 0.5 hours later.

Administration method: Male rabbits (weight around 3 pupils) fasted for U hours.
The preparation of the present invention was inserted into the rectum of the patient, and the anus was closed with surgical adhesive (Aron Alpha A Noah) to prevent leakage.

The rectal tissue was anesthetized with bendoparbital one hour after administration of the preparation, immediately removed and collected, and its surface was thoroughly washed with physiological saline.

To measure the concentration in rectal tissue, add IN sodium hydroxide aqueous solution 9I111 to 1 g of tissue, homogenize it,
．． 0.5 ml of 2N hydrochloric acid and 6 ml of benzene in 25 ml
5 ml of the separated benzene layer was collected, evaporated to dryness, methylated with diazomethane, and subjected to gas chromatography with the addition of fluorene (Wako Pure Chemical Industries, Ltd.) as an internal standard.

The results are shown in Table 2.

Table 2 Note that the above table is the average value of two examples.

The rectal tissue concentration was measured as ibuprofen by hydrolyzing ibuprofen piconol with sodium hydroxide. The preparation of the present invention had an extremely high ibuprofen concentration, and exhibited a tissue concentration sufficient to exhibit anti-inflammatory effects.

Experimental Example 3 Although the concentration in the rectal tissue was shown in Experimental Example 2,
In order to prove that ibuprofen piconol exhibits an anti-inflammatory effect, an effect test of ibuprofen piconol on guinea pig platelet aggregation was conducted.

Platelet preparation was carried out by collecting 9 volumes of blood from the carotid artery of a guinea pig so as to mix it with 1 volume of 3.8% sodium citrate aqueous solution, centrifuging it at 11,000 rpm for 10 minutes, and separating the supernatant.

The aggregation inhibition rate was determined by adding three concentrations of ibuprofen piconol to 1 ml of platelet solution and incubating at 37"C for 4 minutes.
Ine-5'-diphosphate (Kanto Chemical) 10 components of physiological saline solution were added, and a platelet meter (Bry
The change in absorbance was recorded and determined using a lithium ion chloride (Ston).

The results are shown in Table 3.

Table 3 In addition, the above table is the average value of 4 examples.

One of the methods for evaluating the efficacy of non-steroidal anti-inflammatory drugs is the platelet aggregation inhibition test, and it was found that ibuprofen piconol had a strong aggregation inhibition effect at concentrations of 297.43-19/ml and ibuprofen at 206.3 g/ml. The effect was shown.

Next, examples and reference examples of the present invention will be shown.

Example 1 Uitebuzol 555 (manufactured by Guinami Soto Nobel)
86.7 g was heated and melted. After adding and dissolving 13.3 g of ibuprofen piconol, the mixture was filled into plastic suppository containers in 1.5 g portions and slowly cooled to obtain 1.5 g of suppositories per container.

Example 2 Witepsol-35 (manufactured by Guinami Soto Nobel)
82.7g and surfactant (Socol) ICO-60)
3.0 g was added and melted by heating. After adding and dissolving 13.3 g of ibuprofen piconol and 1.0 g of lidocaine, 1.5 g of ibuprofen piconol was added and dissolved in an aluminum suppository container.
Each suppository was filled in 1.5 g each and slowly cooled to obtain 1.5 g of each suppository.

Example 3 Witepsol 555 (manufactured by Guinami Soto Nobel)
92.8g was heated and melted. To this were added 6.7 g of ibuprofen piconol, 0.3 g of procaine hydrochloride and 0.2 g of hexachlorophene, mixed and dissolved, and then formulated in a conventional manner to obtain suppositories of 1.5 g each.

Example 4 Witepsol H15 (manufactured by Guinami Soto Nobel)
83.7g and Sokol BC-20TX as surfactant
) was added and dissolved by heating. After adding and dissolving 13.3 g of ibuprofen piconol, it was formulated in a conventional manner to obtain 1.5 g of suppositories per suppository.

Example 5 Polyethylene glycol (Macrogol 4000) 40
．． 0g, polyethylene glycol (macrogol 15
00) 26.0 g, polyethylene glycol (Macrogol 6000) 20.2 g, surfactant (Nincor) IcO-60) 2.0 g and ibuprofen piconol 11.8 g were added and melted by heating, and then the usual method The product was prepared into a formulation to obtain 1.7 g of suppositories per suppository.

Example 6 Polyethylene glycol (Macrogol 4000) 42
．． 7g, polyethylene glycol (Macrogol 600
0) 25.2 g and 25.0 g of polyethylene glycol (Macrogol 1500) were added and melted by heating. After adding and melting 5.9 g of ibuprofen piconol and 1.2 g of ethyl aminobenzoate, the mixture was formulated in a conventional manner to obtain 1.7 g of suppositories per suppository.

Example 7 Miglyol 812 with a hydroxyl value of 1.3 (Guinami Soto Nobel Co., Ltd.) 90 g and ibuprofen piconol 1
Add 0g to dissolve, then add 1g to soft gelatin shell.
Each was filled to obtain soft capsules.

Example 8 Ibuprofen piconol 10 g, white petrolatum 1
1g1 secunol 6.5g stearyl alcohol 4.0
3.5 g of Sokol BL-25) were added to polyoxyethylene lauryl ether and heated to melt at 75°C. Separately, 64.9 g of purified water and 011 g of methyl paraoxybenzoate were taken and heated and melted at 75°C.

A cream was obtained by adding the aqueous phase to the oil phase without stirring in a conventional manner.

Example 9 Ibuprofen piconol 5g, white beeswax 4g,
2g of microcrystalline wax, liquid paraffin (
Light) 8g, white petrolatum 10g, glyceryl monostearate and Sokol MGS-B) 3g1 hexyl laurate 7g1 sorbitan monostearate and Sokol 5
O-15) 5.5 gtl [su] Melted by heating at 75°C. Separately, 55.4 g of purified water and 0.1 g of methyl hydroxybenzoate were taken and dissolved by heating at 75°C. A cream was obtained by adding the aqueous phase to the oil phase without stirring in a conventional manner.

Example 10 Ibuprofen piconol 10g, white petrolatum 76g
1 isopropyl myristate 5 g, glyceryl monostearate (MGS-B) 6 g.

4 g of microcrystalline wax was mixed, heated and melted at 75°C, and mixed well. Thereafter, the mixture was cooled to 30° C. with stirring to obtain an oily ointment.

Example 11 Ibuprofen piconol 5g 1 white petrolatum 40g
Mix 10g of paraffin and 45g of Ji water lanolin for 75
The mixture was melted by heating at ℃ and mixed well. Thereafter, the mixture was cooled to room temperature while stirring to obtain an oily ointment.

Reference example 1 Uitebuzol-35 (manufactured by Guinamift Nobel)
86.7 g was heated and melted. Ibuprofen 13 for this
．． After adding and dissolving 3 g, 1.5 g each was filled into plastic suppository containers and slowly cooled to obtain 1.5 g of suppository per container.

Effects of the Invention The rectal administration preparation of the present invention has significant analgesic and anti-inflammatory effects, and is a useful drug as a therapeutic agent for rectal or anal diseases or diseases in other parts of the body.

Furthermore, since the active ingredient of the rectal administration preparation of the present invention is an oily ester, it has the advantage of being a highly safe drug without side effects such as local unpleasant irritation and damage. In addition, it is quickly absorbed into the local area, exhibits medicinal efficacy, is retained in the local area for a long time, is gradually absorbed into the blood, and the drug concentration does not reach a sudden peak, resulting in a mild action and long-lasting effect. It also has this effect. Furthermore, since the active ingredient is in the form of an oil, it is easy to handle, the dispersion efficiency is increased due to the formulation design, and it can be formulated uniformly, and crystals do not precipitate in the formulation.
It also has the effect of stable quality.

August 27, 1985 Patent Application No. 125700, 1982 2. Name of the invention: Direct swelling administration preparation 3. Patent applicant (contact information: !i! 09428-3-2101 Hideki Yamakawa) 4. Date of amendment order Voluntary action 5. In the specification subject to amendment, "Detailed explanation of the invention" column (1) In the specification, in the "3. Detailed explanation of the invention" column, from the first line to the second from the top of page 4 The line ``The new compound...increases'' is corrected to ``The new compound has a larger distribution coefficient, so the absorption is improved and local J.''

(2) Insert ", 1" next to "thearyl lysylte" in the 11th line from the top of page 10 in the same book.

(3) In the same book, from the 10th line directly above the 13th line to the 1st
In the first line, "water or" is corrected to "gelling agent, water and j.

(4+ In the same book, in the second line from the bottom of No. 16, the word ``ibuprofen'' is corrected to read ``r ibuprofen piconol''.

(5) In the same book, in the first line from the top of page 17, the phrase "ibuprofen piconol" is corrected to "ibuprofen j."

(6) In the same book, the second line from the top of page 24, "The hydroxyl value is 1.3" is deleted.

(7) In the same book, in the 9th line from the bottom of page 26, the phrase ``made by irritation'' is corrected to read r-irritant J.

Claims (1)

[Claims] 1. A rectal administration preparation characterized by containing ibuprofen piconol as an active ingredient.