JP5279343B2 - Suppository formulation composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a suppository, particularly a suppository preparation composition for treating hemorrhoidal diseases which mitigates the pain on its insertion and solves the problem (defecation pain and defecation fear) on defecation. <P>SOLUTION: The suppository has two layers of a layer which moves in the upper part of the rectum and a layer which stays in the lower part of the rectum, and the layer which moves in the upper part of the rectum is made quickly soluble and the layer which stays in the lower part of the rectum is made slowly soluble and/or swelling. <P>COPYRIGHT: (C)2009,JPO&amp;INPIT

Description

  The present invention relates to a suppository in which pain at the time of inserting a suppository is reduced and pain at the time of defecation is reduced, and particularly relates to a suppository suitable for a manic disease.

  A suppository is a solid external preparation that is mixed with a drug and a base, molded into a torpedo or spindle shape, inserted into the anus, dissolved by body temperature or dissolved by water (secretory fluid) present in the rectum, Its features are that there is little degradation of the drug by the liver like internal medicine, there is no degradation in the gastrointestinal tract and there is no gastrointestinal damage due to the drug, but on the other hand it is painful at the time of insertion and it melts at body temperature There is also the problem that cold storage is necessary.

In particular, pain during insertion is a serious problem in suppositories for hemorrhoids, and the following have been disclosed as techniques for reducing pain during insertion.
1) A preparation in which a semi-solid substance having a viscosity that does not run off during insertion is attached to or blended with the tip of a suppository (see Patent Document 1).
2) The melting point of the suppository tip is lowered to make the tip melt easily and lubricate during insertion, and the base is made into a normal suppository melting temperature and does not melt or deform due to finger temperature during insertion. Suppository (Patent Document 2).
JP 62-175420 A JP-A-62-192320

  Apart from the above-mentioned pain relief technology when inserting a suppository, especially for patients with hemorrhoids, the size and hardness of the stool not only affects the pain during defecation but also has an adverse effect on the treatment of the affected area. The present inventor has paid attention to the problem that stool is also a serious problem, and repetition of stool during defecation leads to hatred of manic diseases.

  Furthermore, for the first time, it has been noticed that there is no formulation technology to solve this problem.

  That is, the problem to be solved by the present invention is a suppository that reduces the pain at the time of insertion and also solves the problems during defecation (defecation pain and feeling of fear of defecation). It is to provide a pharmaceutical preparation composition.

  As a result of intensive studies to solve the above problems, the present inventor found that the suppository was a suppository having two layers of an upper rectal mobile layer and a lower rectal retention layer, and the upper rectal mobile layer was It has been found that the problem can be solved by making it rapidly soluble and making the lower rectal retention layer slowly soluble and / or swellable.

  More specifically, it should be a two-layer suppository where the upper rectal mobile layer covers the lower rectal retentive layer, or the suppository head is the upper rectal mobile layer and the bottom is the lower rectal retentive layer. Thus, the present invention has been completed. More preferably, it has been found that the problem can be solved by using a three-layer suppository having a lubricant layer on the tip of the suppository head or the surface of the suppository head.

That is, the present invention is as follows.
(1) A suppository comprising an upper rectal mobile layer and a lower rectal retention layer.
(2) The suppository according to (1), wherein the upper rectal mobile layer is rapidly soluble and the lower rectal retention layer is slowly soluble and / or swellable.
(3) The suppository according to (1), wherein the suppository core is a lower rectal retention layer and the outer shell is an upper rectal mobile layer.
(4) The suppository according to (1), wherein the suppository has an upper rectal mobile layer and the suppository has a lower rectal retention layer.
(5) The suppository according to any one of (1) to (4), wherein the suppository head has a lubricant layer on the tip of the suppository head or on the surface of the suppository head.
(6) The suppository according to (5), wherein the lubricant layer comprises a base having a melting point lower than that of the upper rectal mobile layer, or a lubricant.
(7) The suppository according to any one of (1) to (6), wherein the upper rectal mobile layer contains a surfactant component.
(8) The suppository according to (7), wherein the surfactant component is dioctylsodium sulfosuccinate.
(9) The suppository according to any one of (1) to (8), wherein the lower rectal retention layer contains a medicinal component for hemorrhoids.
(10) Medicinal ingredients for hemorrhoids include local anesthetics, funnel extract, vasoconstrictor, corticosteroids, astringents, fungicides, sulfa drugs, antihistamines, crotamiton, anti-inflammatory drugs, hemorrhoids, vitamins, camphor, menthol (9) The suppository which consists of 1 type (s) or 2 or more types chosen from an almond and eucalyptus oil.
(11) The suppository according to any one of (1) to (10) for removing pain or defecation fear at the time of defecation as well as acupuncture treatment for persons with hemorrhoids.

  In the suppository of the present invention, fast solubility means that it dissolves quickly after insertion, and slow solubility means that it dissolves gradually. The base contained in such a suppository is not particularly limited as long as it is a base that achieves the object, but specifically, if a base having a melting point temperature lower than the rectal temperature is used, it becomes rapidly soluble, Conversely, if a base with a melting point temperature close to the rectal temperature is used, it gradually dissolves and becomes slowly soluble. Moreover, fast solubility and slow solubility can also be achieved by adjusting the absorption rate of rectal water (secretory fluid).

  In the present invention, the “upper rectal mobile layer” refers to a portion containing a portion that reaches the upper rectum and further reaches the large intestine by dissolving after insertion of the suppository. Therefore, it is preferable that the upper rectal mobile layer dissolves more quickly depending on rectal temperature. In addition, since the components contained in the upper rectal mobile layer reach the upper rectum and further into the large intestine after elution, the component contained in the upper rectal mobile layer reduces the surface tension of the stool and absorbs water into the stool. A component having a surfactant activity that softens the stool and makes the stool slip easily on the wall of the intestine, and a foaming component that promotes defecation by generating carbon dioxide in the intestine and enhancing peristalsis . As a component contained in the rectal upper mobile layer in the present invention, it is particularly preferable to contain a component having a surface active action. Examples of the component having a surface activity include dioctyl sodium sulfosuccinate, and examples of the foamable component include a combination of sodium hydrogen carbonate and anhydrous sodium dihydrogen phosphate. As a component contained in the upper rectal mobile layer in the present invention, dioctyl sodium sulfosuccinate is suitable.

  In the present invention, the “lubricant layer” refers to a part that causes the action of the lubricant when the suppository contacts the anus. The component contained in the lubricant layer is not particularly limited as long as it brings about the above-mentioned action, but it is a lubricant such as petrolatum, plastibase, olive oil or glycerin that does not sag at room temperature, or the upper rectal mobile layer. A base having a melting point lower than the melting point, preferably a base having a melting point of 1 to 4 ° C. lower than the melting point of the upper rectal mobile layer. As a base having a melting point lower than that of the upper rectal mobile layer, macrogol or hard fat having a melting point lower than that of the upper rectal mobile layer can be used. Preferably, the upper rectal mobile layer is used. A macrogol or hard fat having a melting point 1 to 4 ° C. lower than the melting point of can be used. The presence of the lubricant layer allows the suppository to be inserted easily and without pain.

  In the present invention, the “lower rectal retention layer” refers to a portion that tends to stay in the affected area after the suppository is inserted. Accordingly, the lower rectal retention layer has a property of gradually melting and / or swelling with rectal temperature. The lower rectal retention layer contains a component that has a medicinal effect on hemorrhoid diseases because the eluted component stays in the affected area. Medicinal components for hemorrhoids contained in the lower rectal retention layer include local anesthetics, funnel extracts, vasoconstrictors, corticosteroids, astringents, bactericides, sulfa drugs, antihistamines, crotamiton, anti-inflammatory drugs, and hemorrhoids , Vitamins, camphor, menthol, and eucalyptus oil are preferably used.

  In the present invention, the term “local anesthetic” refers to ethyl aminobenzoate, dibucaine hydrochloride, diethylaminoethyl parabutylaminobenzoate, procaine hydrochloride, meprilucaine hydrochloride, lidocaine hydrochloride, oxypolyethoxydodecane, dibucaine, mepivacaine, lidocaine or funnel. Examples include extracts.

  In the present invention, examples of the “vasoconstrictor” include epinephrine, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, and the like.

  In the present invention, “corticosteroid” includes hydrocortisone acetate, prednisolone acetate, hydrocortisone, prednisolone, and the like.

  In the present invention, examples of the “convergence agent” include zinc oxide and tannic acid.

  In the present invention, the “bactericidal agent” includes acrinol, alkylpolyaminoethylglycine, isopropylmethylphenol, cetylpyridinium chloride, decalinium chloride, berberine chloride, benzalkonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, cetrimide or resorcinol. It is done.

  In the present invention, “sulfa drugs” include sulfadiazine, sulfisomidine, sodium sulfisomidine, homosulfamine, and the like.

  In the present invention, examples of the “antihistamine” include diphenylpyraline hydrochloride, diphenhydramine hydrochloride, diphenhydramine, chlorpheniramine maleate, and the like.

  In the present invention, the “anti-inflammatory agent” includes allantoin, aluminum chlorohydroxy allantoinate, ictamol, lysozyme chloride, dry potassium aluminum sulfate, glycyrrhetinic acid, dimethylisopropylazulene, purified egg yolk lecithin, egg yolk oil, or aluminum potassium sulfate. Can be mentioned.

  In the present invention, examples of the “herbal remedy” include sicon, horse chestnut seed, hamamelis, or processed disan.

  In the present invention, “vitamins” include liver oil, strong liver oil, retinol palmitate, vitamin A oil, tocopherol acetate or tocopherol.

  In the present invention, “camphor” includes d-camphor or dl-camphor.

  In the present invention, “menthols” include mint oil, 1-menthol or dl-menthol.

  In the present invention, “for hemorrhoids” means to be used for hemorrhoid diseases, and hemorrhoid diseases are broadly divided into hemorrhoids, anal fissures, and hemorrhoids.

  The suppository of the present invention having two layers of the upper rectal migratory layer and the lower rectal retention layer dissolves the upper rectal migratory layer quickly and moves to the upper rectum and the large intestine, so that the foaming component and the surface activity By making the stool soft with the active ingredient and making the stool slippery from the intestinal tract, the stool becomes soft and easy to go out, reducing pain during defecation (defecation pain and fear of defecation) and Prevents deterioration. In addition, since the lower rectal retention layer gradually melts and swells, the medicinal component for hemorrhoid disease stays in the affected area for a long time, thereby enabling effective treatment of hemorrhoid disease. Furthermore, with a three-layer suppository having a lubricant layer on the tip of the suppository head or on the surface of the suppository head, pain during insertion of the suppository can be reduced.

  The suppository is a suppository having an upper rectal mobile layer and a lower rectal retention layer. More specifically, the lower rectal retention layer is a suppository core, and the upper rectal mobile layer is used as its outer shell. Or a two-layer suppository where the top of the suppository is the upper rectal mobile layer and the bottom is the lower rectal retentive layer.

  More preferably, the suppository head tip or the suppository head surface is a three-layer suppository in which a lubricant is applied as a lubricant layer.

  The upper rectal migratory layer comprises a known base that dissolves quickly by rectal temperature or rectal secretion, and a known surfactant and / or a known foaming component. It consists of a known base that dissolves gradually, a known base that swells, and a known medicinal component for hemorrhoids.

  The base in the present invention is not particularly limited as long as it meets the above-mentioned purpose, but hard fat (hereinafter also referred to as witepsol) as a suppository base having various melting points is dissolved by absorption of moisture. Polyvinyl alcohol, pectin or the like is selected as the material to be used.

  For example, in the upper rectal mobile layer of the present invention, a hard fat is preferably used as a base, and an effective amount of a surfactant component or a foaming component is contained therein. As the hard fat, one kind may be used, or two or more kinds having different melting points may be used in combination. The melting point of the upper rectal mobile layer can be adjusted to a desired temperature by combining one or more hard fats. However, since the upper rectal mobile layer becomes rapidly soluble, the upper rectal mobile layer It is preferable to blend hard fats in combination of one or more kinds so that the melting point of them becomes the rectal temperature or lower. Further, the upper rectal mobile layer can be further combined with a base other than hard fat if desired.

  In addition, when the surfactant is dioctyl sodium sulfosuccinate, the mixing ratio of the surfactant when the surfactant component is mixed in the upper rectal mobile layer is the total weight of the components contained in the upper rectal mobile layer. 0.2-1% is preferable and 0.4-0.8% is more preferable.

  In the lower rectal retention layer in the present invention, hard fat (Witepsol) is preferably used as a base, and further contains a swellable base and an effective amount of a medicinal component for hemorrhoids. preferable. One type of hard fat contained in the rectal retention layer may be used, or two or more types having different melting points may be used in combination. The melting point of the lower rectal retention layer can be adjusted to a desired temperature by combining one or more hard fats. However, if the lower rectal retention layer is slowly soluble, It is preferable to use one hard fat or a combination of two or more hard fats so that the melting point is higher than the melting point of the upper rectal mobile layer. In this case, the difference between the melting point of the upper rectal mobile layer and the melting point of the lower rectal retention layer is preferably 0.1 ° C. or more.

  The lower rectal retention layer according to the present invention may further contain polyvinyl alcohol, pectin or the like as a base. The blending ratio when polyvinyl alcohol is blended with the rectal lower retention layer is preferably 0.2 to 14%, more preferably 1 to 7% of the total weight of the components contained in the lower rectal retention layer. The blending ratio when pectin is blended in the lower rectal retention layer is preferably 2 to 26% of the total weight of the components contained in the lower rectal retention layer, and more preferably 4 to 13%.

  Examples of the swellable base contained in the lower rectal retention layer include acrylic acid polymers, polygum alkali metal salts, layered silicate minerals, starch acrylates, and the like. Is preferred. The acrylic acid polymer is polyacrylic acid, polyacrylic acid salt, polyacrylic acid partial neutralized product or a salt thereof, and preferably a carboxyvinyl polymer. The mixing ratio of the swellable base in the lower rectal retention layer is preferably 1 to 15% of the total weight of the components contained in the lower rectal retention layer when the swellable base is a carboxyvinyl polymer. 8% is more preferable.

Moreover, it is also possible to mix | blend another base with a lower rectal retention layer further if desired.
The surface active component dioctylsodium sulfosuccinate is listed in the Japanese Pharmacopoeia Standards for Pharmaceuticals 2002 and the Pharmaceutical Additives Dictionary 2005.

  Bases such as hard fat and swellable bases such as carboxyvinyl polymer are listed in the Pharmaceutical Additives Dictionary 2005.

  In addition, many of the known medicinal ingredients for hemorrhoids are listed in the 15th revised Japanese Pharmacopoeia and can be easily obtained.

  Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.

Example 1
● Upper rectal mobile layer 1000mg (mg)
------------------------
Dioctylsodium sulfosuccinate 5
Witepsol H12 995

● Lower rectal retention layer 1000mg (mg)
------------------------
Phenylephrine hydrochloride 5
Dibucaine 10
Hydrocortisone acetate 5
Zinc oxide 100
Light anhydrous silicic acid 30
Carboxyvinyl polymer 150
Withepzol H15 700

(Manufacturing method)
Disperse each of the above ingredients and amounts in a suppository base (Witepsol) that has been heated and melted (50 ° C. to 70 ° C.) with stirring, and then sit down according to the 15th revised Japanese Pharmacopoeia Formulation “Suppository” section. The agent was made.

(Example 2)
● Upper rectal mobile layer 1000mg (mg)
------------------------
Dioctyl sodium sulfosuccinate 10
Witepsol W35 990

● Lower rectal retention layer 1000mg (mg)
------------------------
Tetrahydrozoline hydrochloride 1
Lidocaine 60
Hydrocortisone acetate 5
Allantoin 20
Tocopherol acetate 60
Light anhydrous silicic acid 20
Carboxyvinyl polymer 75
Withepzol E75 759

(Manufacturing method)
It was produced in the same manner as in Example 1.

(Example 3)
● Upper rectal mobile layer 1000mg (mg)
------------------------
Dioctyl sodium sulfosuccinate 40
Withepzol H12 960

● Lower rectal retention layer 1000mg (mg)
------------------------
Diphenhydramine hydrochloride 10
Lidocaine 60
Hydrocortisone acetate 5
Allantoin 10
Tocopherol acetate 50
l-Menthol 9
Chlorhexidine hydrochloride 5
Light anhydrous silicic acid 20
Carboxyvinyl polymer 75
Witepsol W35 756

(Manufacturing method)
It was produced in the same manner as in Example 1.

Example 4
● Upper rectal mobile layer 1000mg (mg)
------------------------
Dioctyl sodium sulfosuccinate 20
Witepsol H12 980
● Lower rectal retention layer 1000mg (mg)
------------------------
Diphenhydramine hydrochloride 10
Lidocaine 60
Hydrocortisone acetate 5
Allantoin 10
Tocopherol acetate 50
l-Menthol 9
Chlorhexidine hydrochloride 5
Light anhydrous silicic acid 20
Carboxyvinyl polymer 75
Witepsol W35 756
Lubricant layer -------------------------
White glycerin

(Manufacturing method)
It was produced in the same manner as in Example 1.

(Test Example 1) Effect test (1) Test substance Examples 1 and 2 were used as test substances. The test substance produced this time was manufactured such that the upper rectal mobile layer was located in the upper half (head) of the suppository and the lower rectal retention layer was located in the lower half (bottom) of the suppository.

(2) Test method Two healthy volunteers were administered twice at different dates, and the evaluation scores in Tables 5-6 were marked during defecation.

(Table 5)
How was the stool hardness when using the suppository of the present invention compared to when not using the suppository?
1. It became hard 2. A little harder 3. No change A little softer 5. Softened

(Table 6)
How was the stool's ease of use (the degree of itching) when using the suppository of the present invention compared to when not using the suppository?
1. It became difficult to put it out (a strong spirit was necessary)
2. Slightly difficult to put out (a somewhat strong spirit was necessary)
3. No change Slightly easier to put out (I have a little less energy)
5. It became softer (I don't have much temper)

(4) Test results The results of the obtained tests were 4 in all cases, and the effect of improving the hardness of the stool and the ease of taking out the stool was expressed.

(Example 5)
● Upper rectal mobile layer 600mg (mg)
------------------------
Dioctyl sodium sulfosuccinate 2.5
Witepsol W35 478.0
Witepsol E85 119.5

● Lower rectal retention layer 1000mg (mg)
------------------------
Carboxyvinyl polymer 65.0
Witepsol W35 748.0
Witepsol E85 187.0

(Manufacturing method)
Disperse each of the above ingredients and amounts in a suppository base (Witepsol) that has been heated and melted (50 ° C. to 70 ° C.) with stirring, and then sit down according to the 15th revised Japanese Pharmacopoeia Formulation “Suppository” section. The agent was made.

(Example 6)
● Upper rectal mobile layer 600mg (mg)
------------------------
Dioctyl sodium sulfosuccinate 5.0
Witepsol W35 476.0
Witepsol E85 119.0

● Lower rectal retention layer 1000mg (mg)
------------------------
Carboxyvinyl polymer 65.0
Witepsol W35 748.0
Witepsol E85 187.0

(Manufacturing method)
It was produced in the same manner as in Example 5.

(Example 7)
● Upper rectal mobile layer 600mg (mg)
------------------------
Dioctyl sodium sulfosuccinate 2.5
Witepsol W35 478.0
Witepsol E85 119.5

● Lower rectal retention layer 1000mg (mg)
------------------------
Prednisolone acetate 1.0
Lidocaine 8.0
Chlorpheniramine maleate 1.6
Tocopherol acetate 4.8
Western cypress seed extract 25.0 (equivalent to 150 mg of crude drug)
Carboxyvinyl polymer 65.0
Witepsol W35 715.7
Witepsol E85 178.9

(Manufacturing method)
It was produced in the same manner as in Example 5.

(Test Example 2) Effect test (1) Test substance Examples 5 to 7 were used as test substances. The test substance produced this time was manufactured such that the upper rectal mobile layer was located in the upper half (head) of the suppository and the lower rectal retention layer was located in the lower half (bottom) of the suppository.

(2) Test method and test result 1
Nine healthy volunteers were asked to mark the same evaluation score (Tables 5 to 6) as in Test Example 1. The obtained test results are shown in Table 7 (the numerical values in the table are average values of 9 people).

表７の結果より、本発明の坐剤（実施例５）は、便の硬さ、及び、便の出しやすさの改善効果が発現することが判った。

From the results in Table 7, it was found that the suppository of the present invention (Example 5) exhibited an effect of improving the hardness of stool and the ease of taking out stool.

(3) Test method and test result 2
Of the 9 healthy volunteers administered Example 5, the results of administering Example 5 again in Table 8 are shown in Table 8 for 4 persons with a stool hardness score of 4 or more (hereinafter referred to as the improvement group). Show.
Table 9 shows the results of administration of Example 6 for 5 persons whose stool hardness score is 3 or less (hereinafter referred to as the non-improved group).

表８の結果より、本発明の坐剤（実施例５）の繰り返し投与においても、便の硬さ、及び、便の出しやすさの改善効果は概ね不変であることが判った。

From the results shown in Table 8, it was found that even when the suppository of the present invention (Example 5) was repeatedly administered, the effect of improving the hardness of the stool and the ease of taking out the stool was almost unchanged.

表９の結果より、実施例５の投与で便の硬さに改善がみられない場合、直腸上部移動性層中の界面活性成分の増量によって、便の硬さ、及び、便の出しやすさが改善されることが判った。

From the results of Table 9, when no improvement is observed in the stool hardness by the administration of Example 5, the hardness of the stool and the ease of giving out the stool are increased by increasing the amount of the surfactant component in the upper rectal mobile layer. Was found to be improved.

(4) Test method and test result 3
Table 9 shows the results of administration of Example 7 on 8 healthy volunteers to whom Example 5 was administered, except for one who was hypersensitive to steroids.

表１０の結果より、痔疾治療成分を含有した製剤（実施例７）と含有しない製剤（実施例５）とで大きな相違は見られず、いずれの場合も便の硬さ、及び、便の出しやすさが改善していることが判った。

From the results of Table 10, there is no significant difference between the preparation containing the hemorrhoid treatment component (Example 7) and the preparation not containing it (Example 5). In either case, the hardness of stool and the appearance of stool It was found that the ease was improved.

The suppository of the present invention having two layers of the upper rectal mobile layer and the lower rectal retention layer dissolves quickly in the upper rectal mobile layer and moves to the upper rectum and the large intestine to soften the stool by the medicinal component. Moreover, it is useful to improve the slippage of the stool from the intestinal tract because the stool becomes soft and easy to come out, and it is possible to reduce the pain at the time of defecation and to prevent exacerbation of hemorrhoids. Furthermore, a three-layer suppository having a lubricating layer on the tip of the suppository head or on the surface of the suppository head is useful because pain during insertion of the suppository is reduced. In addition, since the lower rectal retention layer gradually dissolves and swells, the medicinal remedy for hemorrhoids stays in the affected area for a long time, thereby enabling effective treatment of hemorrhoids.

Claims (4)

A two-layer suppository having an upper rectal mobile layer located at the head of the suppository and a lower rectal retention layer located at the bottom of the suppository;
Head containing dioctyl sodium sulfosuccinate and hard fat suppository, and carboxyvinyl polymer consists fast rectal upper mobility layer of soluble not containing, suppositories bottom carboxyvinyl polymers and hard fat containing and, and non-ionic surfactants suppository you, comprising the rectum lower retention layer of slow-dissolving containing no. Suppositories according to claim 1, rectum lower retention layer of suppository base is characterized by containing a medicinal ingredient for hemorrhoids. The medicinal ingredients for hemorrhoids are local anesthetics, funnel extract, vasoconstrictor, corticosteroids, astringents, fungicides, sulfa drugs, antihistamines, crotamiton, anti-inflammatory drugs, herbal medicines, vitamins, camphor, menthols and eucalyptus The suppository according to claim 2 , comprising one or more selected from oils. The suppository according to any one of claims 1 to 3 , which is used for removing a pain or a feeling of fear of defecation along with acupuncture treatment for a person with hemorrhoids.