JPH01190628A - Sustained action suppository - Google Patents

Abstract

PURPOSE:To obtain the title easily producible suppository having sustained action and exhibiting durable releasing property, by emulsifying macrogols which are solid at normal temperature in fats and oils which are solid at normal temperature using a surfactant. CONSTITUTION:Macrogols which are solid at normal temperature are emulsified in fats and oils which are solid at normal temperature (e.g., hard fat, hardened beef tallow or hardened castor oil) in the presence of a surfactant (e.g., nonionic surfactant or polyoxyethylene polyoxyethylene-propylene glycols). The drug to be compounded in the suppository is acetaminophen, aspirin, hydrocortisone, tetracycline, etc., which is dissolved and/or suspended in molten fats and oils and/or macrogols or is added after emulsification.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a long-lasting suppository in which macrogols, which are solid at room temperature, are emulsified using a surfactant in an oil or fat that is solid at room temperature.

(M! Problem to be resolved) The characteristic of skewers is that absorption is rapid (It) Gastrointestinal disorders can be avoided (1) Decomposition or metabolism of the drug can be avoided compared to oral administration (M Pediatrics/Geriatrics) There may be cases where these characteristics are not desirable depending on the area.

For example, because rectal absorption is good, the blood concentration may rise rapidly immediately after administration, which may cause side effects. In addition, in order to maintain an effective blood concentration of drugs that are quickly eliminated from the body (blood), it is necessary to administer them frequently, and similar complications arise when these drugs are applied to skewers. .

To give an example of a drug, indomethacin is currently
It has been applied in various dosage forms as an anti-inflammatory agent and anti-inflammatory analgesic, but many indomethacin skewers are commercially available and used clinically to avoid gastrointestinal disorders during oral administration.

However, most of the commercially available indomethacin skewers release indomethacin too well from the skewers and are quickly absorbed into the rectum, resulting in a rapid increase in blood indomethacin concentration, which often causes headaches, dizziness, and
Side effects such as feeling dizzy may occur.

Antibacterial agents such as ampicillin sodium are effective against Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae, and are commercially available as skewers for children. The effective blood concentration must be maintained by administering the drug. Similar to other dosage forms, such frequent administration may give patients a sense of complication, leading to decreased compliance and decreased therapeutic efficacy.

Efforts to extend the duration of action of drugs have been investigated using various dosage forms. In particular, research into long-acting formulations that can be administered orally is active, and some of them have already been put into practical use. However, it has an orally administrable drug II+jA11.

On the other hand, when sustained absorption is achieved with a skewer, although there is an effect on defecation, the skewer is retained at the absorption site, and by controlling the release from the skewer, it is possible to sustain the blood concentration.

Therefore, there has been a desire for a skewer with a function of controlling the drug release from the skewer, thereby suppressing the blood concentration at the initial stage of administration and prolonging the action time of the drug.

(Conventional method) Conventional long-acting suppositories can be roughly divided into (+1 to 74 molecules added to a skewer that controls drug release by disintegration or swelling);
11) Layered skewers divided into a fast-acting part and a slow-acting part, (1) skewers added with microcapsules that control drug release, etc. Among these, skewers to which polymers have been added may not disintegrate or swell sufficiently or may not be able to achieve sustained release due to differences in the amount of intrarectal body fluid and intrarectal pressure. Furthermore, layered skewers require special manufacturing equipment for preparation, and skewers using microcapsules have problems such as being complicated to manufacture.

(Means for Solving) Therefore, in order to solve these problems, the present inventors conducted intensive studies on long-acting suppositories that are easy to manufacture and exhibit a constant release property, and as a result, they discovered the present invention. I ended up doing it.

That is, the present inventors can easily produce skewers in which macrogols, which are solid at room temperature, are emulsified using a nonionic surfactant in fats and oils that are solid at room temperature and soften at body temperature.
It was discovered that the compound exhibits sustained release, leading to the completion of the present invention. The long-lasting suppository base of the present invention is a water-in-oil type (WO type) emulsifying base, and when administered, the fat and oil in the external phase does not melt at body temperature, but only softens. As fats and oils soften.

Macrogols in the internal phase dissolve after coming into contact with body fluids, and the dissolved area is filled with body fluids. This process is repeated to obtain a constant release.

Drugs are fats and oils (external phase) and/or macrogols (internal phase)
It may be dissolved and/or suspended in any of the following. When a drug is dissolved and/or suspended in macrogol, the drug is released along with the dissolution of macrogol. When a drug is dissolved and/or suspended in fat or oil, the drug is released into body fluids by diffusion in the fat or oil. In either case, release is controlled by softening of fats and oils and dissolution of macrogols, resulting in constant release for a wide range of drugs.

The control of drug release from the sustained suppositories obtained by the present invention varies depending on the type and blending ratio of the fats and oils and macrogol used, and can also be varied by other additives.

In the present invention, fats and oils that are solid at room temperature are those that do not easily melt and soften due to body temperature, such as castor oil, which has a low melting point, and can be used alone or in combination of two or more.

In the present invention, examples of macrogols that are solid at room temperature include those having a molecular fi of 1000 or more, such as macrogol 1000.1540.2000.

4000.6000.10000, etc., and can be used alone or in combination of two or more.

The surfactant used in the present invention may be a nonionic surfactant as long as it can emulsify macrogols, which are solid at room temperature, into fats and oils that are solid at room temperature when melted, such as polyoxyethylene polyoxyethylene propylene glycol. , polyoxyethylene hydrogenated castor oils, sucrose fatty acid esters, sorbitan fatty acid esters, etc., and may be used alone or in combination of two or more.

Specific examples of drugs to be incorporated into the long-acting suppositories of the present invention include:
Acetaminophen, aspirin, flufenamic acid, mefenamic acid, indomethacin, diclofenac sodium, alflozena, ri, ibubrofe? , anti-inflammatory/antipyretic/analgesic drugs such as ketoprofen, flurbiprofen, clofazone, tolmetin sodium, penflucito,
Steroid anti-inflammatory agents such as hydrocortisone, prednisolone, dexamethacin, antihistamines such as chlorpheniramine maleate, diphenhydramine, dichlorhebutadine, local anesthetics such as dibucaine, lidocaine, tetracycline, cephalothin, cephalexin, gentamicin, ampicillin, penicillin, carbenicillin,
amoxicillin, nitrofurantoin, nystatin,
Antibacterial and antifungal agents such as clotrimazole, antihypertensive agents such as hydralazine, antihypertensive diuretics such as theophylline, furosemide, and penflucit, cardiotonic agents such as ubidecarenone and digoxin, and coronary vascular agents such as nitroglycerin, isosorbide nitrate, dipyridamole, and trapidil. Dilators, vasoconstrictors such as dihydroergotamine, antiarrhythmic agents such as pindolol and propranolol, calcium channel blockers such as nifedipine, antiepileptic agents such as nitrazepam, mebropamate, and phenytoin, antivertigo agents such as isoproterenol and scopolamine, and diazepam. tranquilizers such as, hypnotic sedatives such as cyfrobarbital, muscle relaxants such as tolperisone hydrochloride, agents for the autonomic nervous system such as atropine, ephedrine,
Respiratory agents such as dextromethorphan and sodium cromoglycate, hormonal agents such as corticotropin, oxytocin, vasopressin, testosterone, progesterone, estradiol, kallikrein, and insulin, and antitumor agents such as 5-fluorouracil, Krestin, picibanil, and cytarabine. can give.

In the long-lasting suppository of the present invention, the blending ratio of each component can be changed depending on the desired degree of sustaining, and the amount of fats and oils that are solid at room temperature is 10 to 80% by weight, preferably 20 to 70% by weight of the whole.
Within the range of 0% by weight, the amount of macrogols that are solid at room temperature is 10 to 70% by weight, preferably 15 to 60% by weight, and the surfactant is 0.5 to 50% by weight.
%, preferably within the range of 0.5 to 20% by weight.

In addition, if necessary, fats and oils that melt at body temperature, fats and oils that are liquid at room temperature, macrogols that are liquid at room temperature, polyhydric alcohols such as glycerin and propylene glycol, cetanol,
Fatty acid higher alcohols such as stearyl alcohol, fatty acid esters such as beeswax and isopropyl myristate, hydrocarbons such as vaseline and liquid paraffin, water, etc. may be added.

Further, if necessary, usual additives, absorption promoters, stabilizers, crack preventive agents, etc. can be added.

The method for preparing the long-lasting suppository of the present invention involves heating and melting fats and oils that are solid at room temperature and macrogols that are solid at room temperature, melting the surfactant into the macrogol and/or fat, and then emulsifying the mixture using a stirrer. . Fill the emulsified material into a container,
A long-lasting suppository of the present invention is obtained by cooling and solidifying. The drug may be dissolved and/or suspended in pre-melted oil and/or macrogol, or may be added after emulsification. Other additives can also be added in the same manner as drugs.

The melting temperature of each component may be higher than the melting point of each component, but if it is too high, it is not preferable because it may lead to deterioration of the components. The temperature during emulsification should be a temperature at which oils and fats and macrogols do not solidify, and the stirrer may be a propeller, for example.
Ikari blades, homo mixers, etc. are used.

(Experimental Example) A long-lasting suppository of the present invention containing 50 μm of indomethacin obtained in Example 1 described below, oil-based skewer A (containing 50 μm of indomethacin) obtained in Comparative Example 1, and macros obtained in Comparative Example 2. The release properties of indomethacin from gall-based skewer B (containing 50 μl of indomethacin) were compared. The release test was conducted using an artificial membrane (manufactured by Millipore). From the results shown in Figure 1, the release of indomethacin from the long-acting suppository of the present invention (Example 1) was higher than that from the skewers of Comparative Examples 1 and 2. , clearly suppressed.

Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

(Example 1) Indomethacin 86 Tamacrogol 4000 8849 Uitepzol ■ (mentioned above) E-854009 Pluronic ■ (Asahi Kako 1) F-68209 DK Ester ■ (Daiichi Kogyo NM)
SO-1850y glycerin
6 (1 purified water ao
yTitanium oxide 20y65
After indomethacin was dissolved in macrogol 4000 heated and melted at ~75°C, glycerin, ms water, Pluronic ■F-68, and DK ester ■s-olg were mixed. Titanium oxide was dispersed in Lytepsol E-85, which had been heated and melted at 50 to 60'C in advance, and poured into the Macrogol 4000, and heated using an Ikari blade at 60°C.
Emulsification was carried out at °C. The emulsion thus obtained was filled into a plastic container for 1.4 y, and cooled and solidified to obtain a long-lasting suppository of the present invention containing indomethacin 501HI in each suppository.

(Example 2) Ampicillin sodium 818y Macrogol 4000 2225' Macrogol 1540 80S''y A+-) Fural o (R appearance) E-858209DK ester ■ (previously) S-01850y DK ester ■ (previously) F -10
LOy Purified Water 801 Sodium Caprate 25765-75
A mixture of macrogol 4000 and macrogol 1540 heated and melted at ℃, purified water, and DK ester ■S-01
After dissolving DK ester@F-10, ampicillin sodium and sodium caprate were mixed and dispersed. Lytepsol E-85, which had been heated and melted at 50 to 60°C in advance, was put into the macrogol and emulsified at 60°C using a homomixer (autohomixer M type manufactured by Tokushu Kika Kogyo). went. Fill a container with 1.62 ml of the emulsion obtained in this way, cool and solidify it, and
A long-acting suppository of the present invention containing 500 μm of ampicillin sodium in each suppository was obtained.

(Example 8) Nifedipine 80 macrogol 6000 2009 macrogol 15
40 220y Witetsufsol ■ (il
D) E-851809 Litepsol (previously)
E-75'800yDK ester ■ (mentioned above) F-102
0y Titanium oxide 10y Glycerin 90g Macrogol 6000 and Macrogol 1 heated and melted at 5-75℃
After dissolving nifedipine in 540, glycerin, D
K ester ■F-10 was mixed. 50-60 separately in advance
Itepsol E-85 and Lightepsie JL”E heated to ℃.
Titanium oxide was dispersed in -75 and put into the macrogol described above, and emulsification was performed at 60°C using a sharp blade.

The emulsion thus obtained was filled into a container for 1.0y, cooled and solidified, and one container contained nifedipine 30II.
A long-lasting suppository of the present invention containing IP was obtained.

(Example 4) Acetaminophen Tooy Macrogol 4000 270f Macrogol 1540 6 (1 Witepzol ■ (T3Jl Extrusion) E-8580 (1 Witepzol ■ (mentioned above)) W-851507 Sorbitan Monostearate 21 Purified Water
40-glycerin
Sorbitan monostearate is dissolved in Lytepsol ■E-85 and Lightepsol ■W-85 heated and melted at 60y55 to 65°C. Separately, 60~
Macrogol 4000° Macrogol 15401 heated and melted at 70°C Dissolve acetaminophen in purified water and glycerin, and pour into the above-mentioned Lytepsol,
Emulsification was carried out at 55 to 65°C using an Ikari blade. The emulsion thus obtained was filled into a container for 2.0y, cooled and solidified, and each container contained 2.0y of acetaminophen 2001H1.
A long-lasting suppository of the present invention containing the following was obtained.

(Example 5) Aspirin 250 Tamacrogol 1540 200 Tauitepsol ■ (previously) E-8542 (1) Neutral fatty acid triglyceride 80y Polyoxyethylene hardened castor l'Ell (60E, 0.) 20
yPropylene glycol 80y50～
After aspirin was dissolved in macrogol 1540 heated and melted at 60°C, polyoxyethylene hydrogenated castor oil (
60E, 0. ) and propylene glycol were mixed. Separately, medium-chain fatty acid triglyceride was mixed with Lytepsol E-85, which had been heated and melted at 50 to 60°C in advance, and then poured into the macrogol mentioned above, and 5
It was emulsified at 0 to 60°C. A container was filled with 2.0 μm of the emulsion thus obtained, and cooled and solidified to obtain a long-lasting suppository of the present invention containing 500 η of aspirin in each container.

(Example 6) Diazepam 6.82 Macrogol 6000 20 (1 Macrogol 1
540 140y Uitepzol ■ (previously) E-75440yL) K ester ■ (gu out) S
-01g medium chain fatty acid triglyceride 58.
7y concentrated glycerin 609 purified water 50) Macrogol 6000 and Macrogol 1 heated and melted at 65-75°C
After dissolving diazepam in 54o, concentrated glycerin, D
K ester ■S- (Jlg, purified, mixed with water. Separately, medium chain fatty acid triglyceride was mixed with Lytepsol @ E-75, which was heated and melted at 50 to 60'C in advance, and poured into the macrogol. and emulsified at 55 to 65°C using a homomixer (Autohomomixer M type, Special Machinery Industry Division).The emulsion thus obtained was placed in a container.
．． 62 filled, cooled and solidified, each containing 1 part of diazepam.
A long-acting suppository of the present invention containing 0''9 was obtained.

(Example 7) Theophylline 1507 Macrogol 4000 849y Macrogol 40
0 5 (1 hydrogenated castor oil)
100 Tauitepsol ■ (mentioned above) E-8
5880y polyoxyethylene hydrogenated castor oil (60E,
0. ) 2(1 Sodium edetate
0.1y dibutylhydroxytoluene
1yLitepsol ■E heated and melted at 55-65℃
Disperse theophylline in -85 and hydrogenated castor oil.

Macrogol 40, which has been heated and melted at 55-65°C in advance
Polyoxyethylene hydrogenated castor oil (60E, 0), sodium edetate, and dibutyl hydroxytoluene were dissolved in 00 and Macrogol 400, and added to the above-mentioned Lytepsol. ) and emulsified at 55 to 65°C.

A container was filled with 2.0 ml of the emulsion thus obtained to obtain a long-lasting suppository of the present invention containing 800 ml of theophylline in 14 ml.

(Comparative example 1) Skewer A Indomethacin 36 Nodibutylhydroxytoluene 1y Sodium edetate o, ip Witepzol @ (mentioned above) H-12576,99 Witepuzol ■ (mentioned above)
E-85886y Lytepsol 01 (-12 and Lytepsol 0E-s5 heated and melted at 45 to 55°C)
Indomethacin, dibutylhydroxytoluene, and sodium edetate were dispersed in the mixture using a homomixer (Autohomomixer M type manufactured by Tokushu Kika Kogyo).

Fill a container with 1.42 am of this amount, cool and solidify it, and make skewers A containing 50"P of indomethacin in one piece.
I got it.

(Comparative Example 2) Skewer B Indomethacin 86 Tamacrogol 1540 451 Macrogol 400
0 498y dibutylhydroxytoluene 1-purified water
Macrogol 15 heated and melted at 10y60-70℃
Indomethacin and dibutylhydroxytoluene were dissolved in 40 and Macrogol 4000, and purified water was added to U.
It matched. A container was filled with 1.4 ml of this liquid, and cooled and solidified to obtain a skewer B containing 50 μm of indomethacin per skewer.

[Brief explanation of the drawing]

FIG. 1 shows changes over time in the release rate of indomethacin from the skewers of the present invention as experimental examples and the skewers as comparative examples. Patent applicant Sumitomo Pharmaceutical Co., Ltd.

Claims (1)

[Scope of Claims] (1) A long-lasting suppository characterized by emulsifying macrogols that are solid at room temperature using a surfactant in fats and oils that are solid at room temperature. (2) The long-acting suppository according to claim 1, wherein the drug is dissolved and/or suspended in a solid oil or fat at room temperature. (3) The long-acting suppository according to claim 1, wherein the drug is dissolved and/or suspended in macrogols that are solid at room temperature. (4) Claim 1: Fats and oils that are solid at room temperature are difficult to melt at body temperature.
Long-acting suppositories as described. (5) The long-lasting suppository according to claim 1, wherein the fat or oil that is solid at room temperature accounts for 10 to 80% by weight of the total amount. (6) The long-lasting suppository according to claim 1, wherein the macrogol, which is solid at room temperature, accounts for 10 to 70% by weight of the total amount. (7) The long-lasting suppository according to claim 1, wherein the surfactant is capable of emulsifying macrogols, which are solid at room temperature, into fats and oils, which are solid at room temperature, when heated and melted. (8) The long-acting suppository according to claim 1, wherein the surfactant is nonionic. (9) The long-acting suppository according to claim 1, wherein the surfactant is 0.5 to 50% by weight of the total amount.