JP5223307B2 - Suppository - Google Patents

Description

  The present invention relates to a suppository, and more particularly, to a suppository excellent in rest, storage, and fast solubility (disintegration).

  A suppository is one that is melted naturally by body temperature in the rectum after insertion from the anus, and the drug contained therein is absorbed from the rectum and exerts a pharmacological effect. Among these, in particular, suppositories used for treatment of hemorrhoid diseases are desired to stay in the lower rectum and release the drug here.

  In the past, when the applicant held the finger before insertion of the rectum, the applicant did not melt it due to the body temperature of the finger. In addition, suppositories with excellent rest and storage properties have been reported (Patent Documents 1 and 2).

Although these suppositories are excellent in rest and storage properties, in addition, in order to enhance the therapeutic effect, the suppositories required fast solubility (disintegration) in the rectum.
WO99 / 17737 International Publication Pamphlet WO2002 / 024161 International Publication Pamphlet

  Accordingly, an object of the present invention is to provide a suppository that is excellent in all of the resting property, storage property, and fast solubility (disintegrating property) and has a high therapeutic effect.

  As a result of diligent research to solve the above-mentioned problems, the inventors of the present invention blended a specific ester oil with a suppository to maintain fastness and storage while also being excellent in fast solubility (disintegration). And the present invention was completed.

That is, the present invention provides the following components (A) to (D):
(A) a fatty acid triglyceride that is solid at room temperature,
(B) one or more glycerol fatty acid esters having 14 to 18 carbon atoms that are solid at room temperature,
(C) Lower rectal retention base component,
(D) a clear liquid ester oil at room temperature;
It is a suppository characterized by containing.

  When the suppository of the present invention is held with a finger before insertion into the rectum, it does not melt at the body temperature of the finger, and is inserted into the rectum and is prevented from moving to the upper rectum after melting starts. In addition, in addition to these properties, the fast solubility (disintegration) of the suppository is also improved.

  Therefore, the suppository of the present invention can be suitably used for the treatment of epilepsy and the like.

  In the present specification, “solid at normal temperature” means a solid state at 15 ° C. to 25 ° C. Further, “clear liquid at normal temperature” means a clear liquid state with no turbidity at 15 ° C. to 25 ° C., and this may be colored.

  The fatty acid triglyceride (hereinafter sometimes simply referred to as “fatty acid triglyceride”) of the component (A) contained in the suppository of the present invention at normal temperature includes fatty acid triglycerides such as palmitic acid triglyceride. Examples include cocoa butter, lanolin oil, and hard fat. Among these fatty acid triglycerides, hard fat is preferable. Among these, as hard fat, for example, Witepsol W-35, Witepsol E85 (both trade names: manufactured by Sasol Germany GmbH), Isocacao (trade name: manufactured by Kao), Pharmasol (trade name: manufactured by Nippon Oil & Fats), etc. Commercial products may be used. The content of these components (A) in the suppository of the invention is 50 to 90% by mass (hereinafter simply referred to as “%”), preferably 65 to 85%.

  In addition, as the component (B) contained in the suppository of the present invention, a glycerol fatty acid ester having 14 to 18 carbon atoms that is solid at room temperature (hereinafter sometimes simply referred to as “glycerol fatty acid ester”) includes myristic acid monoglyceride. Examples thereof include one or more of (carbon atom number 14), palmitic acid monoglyceride (carbon atom number 16), and stearic acid monoglyceride (carbon atom number 18). Among these glycerin fatty acid esters, palmitic acid monoglyceride or stearic acid monoglyceride is preferable. Commercially available products such as Sunsoft 8000C, (trade name: Taiyo Kagaku Co., Ltd.), NIKKOL MGS-A (manufactured by Nikko Chemicals), and Poem S-100 (manufactured by Riken Vitamin Co., Ltd.) can be used as the glycerin fatty acid ester. . The content of these components (B) in the suppository of the present invention is 5 to 30%, preferably 6.5 to 13%.

  Further, the lower rectal retention base component of component (C) contained in the suppository of the present invention is a base component for rectal administration that can retain the preparation in the lower rectum near the anus of the rectum. It is. Examples of such components include acrylic acid polymers; polygum alkali metal salts; layered silicate minerals; starch acrylates; polyvinyl alcohol; pectin; celluloses such as methylcellulose and carboxymethylcellulose; Examples include mucoadhesive polymers. Among these, one or more of acrylic polymer, polygum alkali metal salt, layered silicate mineral and starch acrylate are preferred, and acrylic polymer is particularly preferred. Among acrylic acid polymers, carboxyvinyl polymer is most preferable. As this carboxyvinyl polymer, commercially available products such as Carbopol 980NF (trade name: manufactured by Noveon Inc.), Carbopol ULTREZ 10 (Nikko Chemicals Co., Ltd.) can be used. The content of these components (C) in the suppository of the present invention is 0.2 to 15%, preferably 1 to 10%.

  Still further, the component (D) contained in the suppository of the present invention, which is a clear liquid ester oil at room temperature (hereinafter sometimes simply referred to as “ester oil”), includes medium-chain fatty acid triglycerides having an ester structure, And higher fatty acid esters. Among these, preferred are medium-chain fatty acid triglycerides mainly composed of triglycerides of saturated fatty acids having 6 to 10 carbon atoms such as caprylic acid and capric acid, and those having 12 to 18 carbon atoms such as isopropyl myristate and isopropyl palmitate. Examples include middle-chain fatty acids or lower alkyl esters of long-chain fatty acids, and more preferred are medium-chain fatty acid triglycerides and isopropyl myristate. Commercially available products such as Panacet 810S (trade name: Nippon Oil & Fats Co., Ltd.) and Triester F-810 (Nikko Chemicals Co., Ltd.) can be used as the medium chain fatty acid triglyceride. One or more of these components (D) can be blended, and the content in the suppository of the present invention is 1.5 to 30%, preferably 3.0 to 27%.

  The suppository of the present invention may further contain a drug as component (E). Here, the drug is usually a drug that can be administered rectally, for example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, ephedrine hydrochloride, and oxymetazoline hydrochloride vasoconstrictor, acetylsalicylic acid, acetaminophen, buprenorphine hydrochloride, ibuprofen , Ketoprofen, piroxicam, morphine hydrochloride, lysozyme chloride and glycyrrhetinic acid anti-inflammatory / antipyretic / analgesic agents, penicillins, cephalosporins, tetracyclines and macrolides antibiotics, 5-fluorouracil and fturafur antitumor agents, Econazole, econazole nitrate, miconazole, miconazole nitrate, clotrimazole, bifonazole, terbinafine hydrochloride, butenafine hydrochloride antifungal agent, hydrocortisone, hydride acetate Cortisone, prednisolone, prednisolone acetate, dexamethasone and dexamethasone acetate steroids, tetracaine, mepivacaine, cloprocaine, bupivacaine, proparacaine, phenacine, cocaine, oxyprocaine, propitocaine, orthocaine, oxesazein, chlorocaine hydrochloride, procaine hydrochloride, procaine hydrochloride , Bupivacaine hydrochloride, proparacaine hydrochloride, phenacaine hydrochloride, cocaine hydrochloride, oxybuprocaine hydrochloride, propitocaine hydrochloride, meprilucaine hydrochloride and mepivacaine local anesthetics, zinc oxide, tannic acid, albumin tannate and potassium aluminum sulfate astringent, diphenhydramine, diphenhydramine hydrochloride And antihistamines of chlorpheniramine maleate, Tontoin and aluminum chlorohydroxy allantoinate wound healing promoters, chlorhexidine hydrochloride, cetrimide, decalinium chloride and benzalkonium chloride bactericides, sulfisomidine, sodium sulfisomidine, homosulfamine and sulfadiazine sulfa drugs, liver oil, ergocalciferol Vitamins of riboflavin, pyridoxine hydrochloride and tocopherol acetate, d-camphor, dl-camphor, 1-menthol, dl-menthol, mint oil and eucalyptus oil, antipermitant of domperidone, bisacodyl defecation promoter, Theophylline bronchodilator and insulin peptide. The content of these drugs in the suppository of the present invention is 0.01 to 6.0%, preferably 0.06 to 3.6%.

  Furthermore, to the suppository of the present invention, fats and oils, surfactants, solubilizers, dispersants, preservatives, antioxidants, fragrances and the like can be added as optional components as long as the effects of the present invention are not impaired. it can. In addition, there is no limitation on the type of these optional components, the amount of addition, and the like.

  As fats and oils, soybean oil, soybean hardened oil, hardened oil, sesame oil, castor oil, cottonseed oil, wheat germ oil, rapeseed oil, peanut oil, olive oil, safflower oil, sunflower oil, phytosterol, kaunauba wax, beeswax, white beeswax, Owl, lanolin, polyethylene lanolin, squalane, squalene, liquid paraffin, paraffin, gelled hydrocarbon, microcrystalline wax, petrolatum, white petrolatum, cetanol / polyoxyethylene cetyl ether mixed wax, cetanol / polyoxyethylene cetyl ether / Sodium lauryl sulfate mixed wax, cetanol / poly sorbate mixed wax, myristyl alcohol, cetanol / polyethylene glycol fatty acid ester mixed wax, cetanol / polyoxy Tylene sorbitan fatty acid ester mixed wax, cholesterol, myristic acid, stearic acid, palmitic acid, behenic acid, isostearic acid, isostearyl palmitate, oleic acid, oleyl alcohol, stearyl alcohol, behenyl alcohol, octyldodecanol, isostearyl alcohol, cetanol, Cetostearyl alcohol, octanediol, hexyldecanol, lauryl alcohol, dextrin palmitate, dimethylpolysiloxane, methylphenylpolysiloxane, dimethylpolysiloxane-methyl (polyoxyethylene) siloxane copolymer, dimethylpolysiloxane-silicon dioxide mixture, silicone oil And crotamiton.

  Surfactants include propylene glycol fatty acid esters, polyethylene glycol fatty acid esters, sucrose fatty acid esters, fatty acid polyoxyls such as stearic acid polyoxyl, coconut oil fatty acid, coconut oil fatty acid diethanolamide, fatty acid diethanolamide, lecithin, sorbitan sesquioleate, etc. Sorbitan fatty acid ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene fatty acid ether, polyoxyethylene behenyl ether, polyoxyethylene polyoxypropylene glycol, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene Palm oil fatty acid glyceryl, polyoxyethylene sorbitan fatty acid ester (polysorbate), polyoxyethylene alkyl Ether (cetomacrogol), sodium polyoxyethylene alkyl ether phosphate, polyoxyethylene octylphenyl ether, polyoxyethylene oleylamine, polyoxyethylene sorbid beeswax, polyoxyethylene lanolin, polyoxyethylene aralkyl ether / stearyl alcohol mixture, Polyoxyethylene polycyclic phenyl ether ammonium sulfate, sodium lauryl sulfate, lauric acid diethanolamide, sodium lauroyl sarcosine, polyoxyethylene oleyl ether phosphate, sodium polyoxyethylene lauryl ether phosphate, alkylallyl polyether alcohol, higher alcohol sulfate N-cocoyl-L-arginine ethyl ester DL-pyrrolidone carboxylate, N-cocoy Sodium N-methylaminoethyl sulfonate, polyethylene glycol N-methyl-2-pyrrolidone monostearate, sodium N-acyl-L-glutamate, allyl glycidyl ether, alkyldiaminoethyl glycine hydrochloride, alkylbenzene sulfonate, alkylbenzene Sulfonate / alkylnaphthalenesulfonate mixed emulsifier, sodium dodecylbenzenesulfonate, ammonium nonylphenoxypolyoxyethylene ethane sulfate, phospholipid, ethylene glycol monomethyl ether, diethylene glycol monobutyl ether, dioctyl sodium sulfosuccinate, dibutate sodium , Methyl acrylate / acrylic acid-2-ethylhexyl copolymer resin emulsion, silicone resin emulsion, pentae Still citric acid higher fatty acid ester, beeswax, nonionic emulsifier mixture, and the like.

  Examples of solubilizers include purified water, ethanol, butanol, propanol, isopropanol, isobutanol, propylene glycol, 1,3-butylene glycol, dipropylene glycol, ethylene glycol, polyethylene glycol, fructose, glucose, sucrose, lactose, xylitol, Examples thereof include mannitol, sorbitol, trehalose, cyclodextrin and derivatives thereof.

  Examples of the dispersant include light anhydrous silicic acid, hydrophobic light anhydrous silicic acid, light aluminum oxide and the like.

  Examples of preservatives include parabens, phenoxyethanol, sodium benzoate, sodium dehydroacetate, hinokitiol, and benzyl alcohol.

  Antioxidants include sodium nitrite, sodium bisulfite, sodium sulfite, sodium pyrosulfite, ascorbic acid and salts or derivatives thereof, alpha thioglycerin, erythorbic acid, cysteine hydrochloride, citric acid, tocopherol and salts or derivatives thereof, Potassium isosinurate, dibutylhydroxytoluene, butylhydroxyanisole, soy lecithin, sodium thioglycolate, sodium thiomalate, 1,3-butylene glycol, benzotriazole, pentaerythrityl-tetrakis [3- (3,5- Di-t-butyl-4-hydroxyphenyl) propionate], propyl gallate, 2-mercaptobenzimidazole and the like.

  Perfumes include menthol, camphor, bergamot, lavender, pine, rose otto, winter green, citronella, tea tree, peppermint, lemon, lemongrass, lemon eucalyptus, rosemary camphor, clove, geranium bourbon, marjoram sweet, lavandin, Rosewood, Palmarosa, Petit Goren, Cypress, Cinnamon, Juniper, Orange Sweet, Spike Lavender, Time Timor, Time Linalor, Basil, Hyssop, Helichrysum, Mandarin, Eucalyptus Davis, European Red Pine, Labansara Aromatica, Lemon Verbena, Lemon Balm, Roman Chamomile, Ylang Ylang, Chamomile German, Chamomile Roman, Cayupute, Clarisage, Grape Roots, Sandalwood, Cedarwood Atlas, Cedarwood Virginia, Jasmine Absolute, Spearmint, Time Tsuyanol, Niauri Cineol, Neroli, Basil Sweet, Patchouli, Palmarosa, Fennel Sweet, Petit Glen, Frankincense, Eucalyptus Globulus, Eucalyptus Radiata, Lavansara, chamomile oil, cinnamon oil, cinnamaldehyde, clove oil, mint oil, piperonal, eucalyptus oil, rosin, rose water, roman chamomile oil, orange oil, turpentine oil and the like.

  The suppository of the present invention is not particularly limited and can be produced according to a conventional method. Examples of the preferred method include, for example, a suppository base that has been heated and melted (50 ° C. to 70 ° C.) and other suppository bases. A method may be mentioned in which the ingredients are dissolved or dispersed in order while being stirred, cooled to about 50 ° C., filled into a suppository container, further cooled and molded to obtain a suppository.

  The thus obtained suppository of the present invention is excellent in resting property, storage property and fast solubility (disintegrating property), so that the suppository of the lower rectal retention type, that is, inserted into the rectum and started to melt. It is preferable to use it as a suppository that does not move to the upper rectum, but stays in the mandibular lesion in the lower rectum and effectively releases the active ingredient.

  EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Example 1
Production of suppositories (1):
100 suppositories each having the formulation shown in Table 1 were produced according to the production method described below.

<Manufacturing method>
Among the components (A) shown in Table 1, a part of witepsol W-35 and the total amount of witepsol E-85, the total amount of component (C), the total amount of component (D) or liquid oil and dispersant are added to 70 ° C. Warm and stir to dissolve. In addition to this maintained at 55 to 65 ° C., separately add component (E) and a part of component (A) witepsol W-35 to 55 to 65 ° C., stir and dissolve did. Furthermore, what maintained this at 50-55 degreeC, separately heated the remainder of the component (A) witepsol W-35 and component (B) at 70-80 degreeC, and stir-dissolved it. Added. Finally, the lysate was filled in a resin container while maintaining the temperature at 50 ° C., and cooled to produce a suppository.

Test example 1
Melting point measurement:
About each suppository manufactured in Example 1 (n = 3), the melting temperature was measured in accordance with the following method. The results are shown in Table 2.

<Measuring method of melting temperature>
The melting temperature was measured according to the second method of the Japanese Pharmacopoeia melting point measurement method.

<Result>
Examples 1 and 2 both had a melting temperature of 40 ° C. or higher. From these results, it was found that the products 1 and 2 had a high melting temperature and excellent storage properties.

Test example 2
Release test (1):
For each suppository produced in Example 1 (n = 3), a release test of hydrocortisone acetate contained in the suppository was performed according to the following method and conditions. The results of the release test of hydrocortisone acetate are shown in FIG.

<Release test method>
Using a suppository dissolution tester (manufactured by Miyamoto Riken Kogyo Co., Ltd.) equipped with a tube for encapsulating suppositories, vertical dialysis membrane method (Katsu Yamazaki, Soichi Ito, Kazuhisa Tabe, “Comparison of suppository dissolution test methods” ”, Pharmaceutical Research, 28, 232 (1997)). Specific measurement conditions are as follows.

<Measurement conditions for release test>
Release solution: Phosphate buffer solution (pH 7.2) ^{* 1}
Release liquid set temperature: 37 ° C
Measurement tube: Cellulose tube ^{* 2} (approx. 15cm) with stainless steel closer
Stop using a suppository that has been weighed in advance from the top of the tube.
It was sealed with a closer to prevent air from entering.
Number of vertical movements: 30 times / minute Sampling: 1 mL was sampled from the container after a certain time. After sampling
The same amount of release solution was replenished.
Drug release: measured by HPLC method * 1: Preparation of phosphate buffer
0.2N sodium hydroxide in 50mL of 0.2M potassium dihydrogen phosphate reagent for buffer
The sample solution 34.7 mL and water were added to make 200 mL.
* 2: Wako Pure Chemical Industries: Dialysis Membrene, Size36 Viskase Sales Corporation

<HPLC measurement conditions>
・ Quantification conditions for hydrocortisone acetate Column: TSK-ODS 80Ts 4.6 × 150mm
Temperature: 50 ° C
Flow rate: 1.0 mL / min Wavelength: 240 nm
Injection volume: 20 μL
Mobile phase: water / methanol / phosphoric acid = 450/550/1
Standard solution: Hydrocortisone acetate solution ^{* 3}
* 3: Accurately weigh 0.05g of hydrocortisone acetate and accurately 200 with methanol.
mL. Weigh exactly 2 mL of this solution and accurately add 100 mL with methanol.
This was used as a standard solution.

<Result>
As shown in FIG. 1, in the products 1 and 2, the release property of hydrocortisone acetate was remarkably improved as compared with the comparative product 1 in which the component (D) was not blended. In addition, the product 1 and the product 2 were improved in release as compared with the comparative products 2 to 4 in which liquid oil not contained in the component (D) was blended. In particular, when isopropyl myristate was used as component (D), the releasability was improved by about 2.0 times compared with Comparative Product 1. From this result, it was found that Example Product 1 and Example Product 2 were excellent in drug release.

Test example 3
Retention test:
Of the suppositories produced in Example 1, Example 1, Example 2, and Comparative Example 1 (each n = 3) were subjected to a retention test in the rabbit rectum. The retention was evaluated by laparotomy 30 minutes after inserting the suppository into the anus of the rabbit and observing the position of the suppository with the naked eye. The reach of the suppository in the rabbit rectum is shown in FIG.

<Result>
As shown in FIG. 2, Example 1 and Example 2 also contain rectal retention base components, but have the same rectal movement distance that is not significantly different from Comparative Product 1 that does not contain component (D). Met. From this result, it was found that the implementation product 1 and the implementation product 2 are also excellent in staticity.

Example 2
Suppository production (2):
In the formulation shown in Table 1 of Example 1, the content of panacet 810S of component (D) was changed from 300 mg / piece (Example 1) to 150 mg / piece (Example 3), 400 mg / piece (Example 4) and 500 mg. A suppository was produced in the same manner as in Example 1, except that it was replaced with / piece (Example 5).

Test example 4
Release test (2):
Each suppository produced in Example 2 (n = 3) was subjected to a hydrocortisone acetate release test in the same manner as in Test Example 2. The results of the release test of hydrocortisone acetate are shown in FIG.

<Result>
From the results of the release test, it was found that the release rate was improved by increasing the amount of panacet 810S.

Test example 5
Hardness measurement:
The hardness of each suppository (n = 3) produced in Example 2 was measured according to the following method. The results of the suppository hardness measurement are shown in Table 3 and FIG.

<Hardness measurement method>
The load when cutting the suppository was measured to evaluate the hardness of the suppository. Specifically, the suppository is fixed, the load is gradually applied with a knife-like metal plate (material: iron) with a blade thickness of 5 mm, and the load (kg) when the suppository breaks is measured. Was defined as hardness.

<Result>
As a result of the hardness measurement, it was found that the hardness of the suppository decreased with an increase in the amount of panacet 810S. From the viewpoint of production suitability, it was considered that the amount of Panacet 810S was 500 mg / piece or less.

  The suppository of the present invention is excellent in all of stationary properties, storage properties, and fast solubility (disintegrating property).

  Therefore, the suppository of the present invention can be suitably used for the treatment of hemorrhoid diseases and the like.

It is drawing which shows the result of the release test of hydrocortisone acetate. It is drawing which shows the reach distance in the rabbit rectum of a suppository. It is drawing which shows the result of the release test of hydrocortisone acetate. It is drawing which shows the result of the hardness measurement of a suppository. that's all

Claims (4)

Next components (A) to (D)
(A) a fatty acid triglyceride that is solid at room temperature,
(B) one or more glycerol fatty acid esters having 14 to 18 carbon atoms that are solid at room temperature,
(C) Lower rectal retention base component,
(D) a clear liquid ester oil at room temperature;
A suppository characterized by containing.   The suppository according to claim 1, wherein the ester oil of component (D) that is clear at room temperature is one or more ester oils selected from medium-chain fatty acid triglycerides and isopropyl myristate.   Furthermore, the suppository of Claim 1 or 2 which contains a drug as a component (E). The suppository according to any one of claims 1 to 3, which is a lower rectal retention type.

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