JP3638299B2 - Sustained release suppository and method for producing the same - Google Patents
Sustained release suppository and method for producing the same Download PDFInfo
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- JP3638299B2 JP3638299B2 JP31128493A JP31128493A JP3638299B2 JP 3638299 B2 JP3638299 B2 JP 3638299B2 JP 31128493 A JP31128493 A JP 31128493A JP 31128493 A JP31128493 A JP 31128493A JP 3638299 B2 JP3638299 B2 JP 3638299B2
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- JP
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- Prior art keywords
- suppository
- fatty acid
- acid ester
- sucrose fatty
- sustained release
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Description
【0001】
【産業上の利用分野】
本発明は医薬製剤、特に徐放性坐剤の分野に関する。
【0002】
【従来の技術および発明が解決しようとする課題】
坐剤は、その投与経路からして生体内での薬物の分解率が低く、しかも食事の影響を受けないこと、および小児や老人のみならず経口投与が困難な患者にも比較的容易に投与できること、等の理由により頻繁に利用されている。しかし、一方では、薬物を直腸投与するとき、急激な血漿中濃度の立ち上がりによる副作用発現の危険性や日に何回も投与することの困難性といった欠点が指摘されている。このような欠点は坐剤を徐放化することにより解決されるとして、従来から種々の試みがなされている。
【0003】
例えば、特開平2−73010号明細書には、ショ糖脂肪酸エステル30〜40重量%および油成分を配合した坐剤が開示され、また、特開昭64−63512号明細書にはショ糖脂肪酸エステル55〜85重量%および油相成分を配合した坐剤が開示されている。更に、特開平1ー110618号明細書にはショ糖脂肪酸エステル50〜90重量%および水溶性基剤を配合した徐放性坐剤が開示されている。
【0004】
しかし、これらの坐剤におけるショ糖脂肪酸エステルの配合量が20%を切ると徐放効果はみられない、とされている。
【0005】
望まれる徐放化の程度は、薬物の種類に応じて異なる。従って、徐放化の程度を調節する手段が豊富であれば、主薬選定の幅が、より広がり有利である。
【0006】
従来技術においても、ショ糖脂肪酸エステルの配合量を変化せしめることにより徐放化の程度を調節することができたが、その配合量が20%を切ると徐放化効果そのものが期待できなくなる。
【0007】
本発明者らは、ショ糖脂肪酸エステルの配合量が、たとえ20%以下であっても確実な徐放効果があり、ひいては徐放化の程度の調節が可能であり、加えて、ショ糖脂肪酸エステルの配合量の増減のみに頼らなくとも徐放化の程度の調節が可能な坐剤を開発すべく種々検討し、本発明を完成した。
【0008】
【課題を解決するための手段】
本発明は、ショ糖脂肪酸エステル中に薬物を分散した粒状剤を坐剤基剤に配合してなる徐放性坐剤およびその製造方法に関する。なお、従来の坐剤におけるショ糖脂肪酸エステルは、最初から坐剤基剤と混合融合されており、粒状剤の形を経ることはない。
【0009】
本発明におけるショ糖脂肪酸エステルとしては、HLBが5以下のものならばいずれでもよいが、好ましくは3以下、特に好ましくは1〜2のものが使用される。ショ糖脂肪酸エステルの量は、最終坐剤の2重量%以上、好ましくは2〜60重量%、特に好ましくは3〜20重量%の範囲から選ばれる。ショ糖脂肪酸エステルのHLB値が高い場合やその配合量を減らす場合においては徐放効果が減少し、逆の条件を選択すると徐放効果が増大する。即ち、条件を選択することにより、薬物の坐剤からの放出速度を調節することができる。ショ糖脂肪酸エステルは、例えば三菱化成株式会社から市販されているリヨ−ト−シュガーエステルS−170(HLB;1)や同270(HLB;2)、同370(HLB;3)などが有利に使用される。
【0010】
薬物は、水可溶性、水難溶性、そのほかいずれの性質を有するものでもよく、その種類は特に限定されない。
【0011】
また、坐剤基剤の種類も、薬物と同様に特に限定されず、従来から使用されているものがいずれも使用可能であるが、40℃以下で溶融するものが好適である。例えば、高級脂肪酸エステルトリグリセリド〔例えば各種のウィテプゾール(ヒュルツ社)、各種のノバタ(ヘンケル社)、各種のファーマゾール(日本油脂)、イソカカオ(花王)〕や中鎖脂肪酸エステルトリグリセライド〔例えば、ミグリオール(ダイナマイトノーベル社)〕、グリセリン脂肪酸エステル、ポリグリセリン脂肪酸エステル、カカオ脂、硬化油、トウモロコシ油、流動パラフィン、ワセリン等の油性基剤およびマクロゴール(=ポリエチレングリコール)やグリセロゼラチンの如き水性基剤が挙げられる。これらの坐剤基剤は単独もしくは混合物の形で用いられる。
【0012】
このほか酸化防止剤、吸収促進剤、粘膜保護剤などの補助成分が必要に応じて配合される。
【0013】
本発明の坐剤は、ショ糖脂肪酸エステルを約70〜90℃に加熱溶融し、これに薬物を分散し、冷却固化し、粉砕し、篩過整粒した粒状剤を、予め加熱溶融した坐剤基剤中に分散し、コンテナに充填し、冷却することにより製造できる。粒状剤を坐剤基剤中に分散せしめる際、アエロジルの如き分散剤を用いるのが、より有利である。
【0014】
すでに説明したように徐放化の程度は、ショ糖脂肪酸エステルの配合量やそのHLB値により調節できるが、粒状剤の粒径を変化せしめることによっても調節できる。粒径を大きくすれば、徐放効果は増大する。
【0015】
従って、ショ糖脂肪酸エステルの配合量、ショ糖脂肪酸エステルのHLB値および粒状剤の粒径を適度に選択すれば、徐放化の程度は自由に変えることができる。例えば、ショ糖脂肪酸エステルの配合量を減し、粒径を大きくするとか、HLB値が小さいショ糖脂肪酸エステルを用い、粒径を小さくするとか、により調節ができる。
【0016】
【発明の効果】
かくして得られる本発明の坐剤は優れた徐放効果を有する。また、徐放化の程度は、ショ糖脂肪酸エステルの配合量を変えてみたり、目的に応じたHLB値を有するショ糖脂肪酸エステルを採用したり、粒状剤の粒径を変化させたりすることにより、自由に調節できる。従って、本発明の坐剤に配合されるべき薬物の種類は、より広い範囲から選択できる。
【0017】
【実施例】
以下に実施例、比較例および試験例をあげて本発明を更に詳細に説明する。
なお、以下の実施例ならびに比較例では薬物の代表例として、酸性薬物たるジクロフェナックナトリウムおよび塩基性薬物たる塩酸モルヒネを用いた。
【0018】
実施例 1:
処方−;
【0019】
【0020】
なお、本処方におけるショ糖脂肪酸エステルの配合量は坐剤の9.4 重量%を占める。
【0021】
製法−;
シュガーエステルS−170を70〜90℃で溶融し、これにジクロフェナックナトリムを分散する。次いで、冷却固化し粉砕する。32メッシュの篩で篩過し、これを予め37℃で溶融しておいたウィテプゾール(アエロジル200を2%含有)に同温度で均一に分散後、坐剤用コンテナに充填し、冷却して坐剤を得た。
【0022】
比較例 1:
処方−;(実施例1と同一処方)
【0023】
【0024】
製法−(粒状剤としない点において実施例1と相違する);
シュガーエステルS−170およびウィテプゾール(アエロジル200を2%含有)の混合物を70〜90℃で溶融後37℃まで冷却した。これに主薬を均一に分散後、坐剤用コンテナに充填し、冷却して坐剤を得た。
【0025】
試験例 1(溶出試験):
実施例1ならびに比較例1の坐剤からの主薬の放出試験をPTSW型坐剤溶出試験器(回転セル法)を用いて行った。溶出溶液は0.02Mリン酸緩衝液(pH7.4)を900ml用い、セルの回転速度は25rpmに、そして温度は37℃に設定した。その結果を表1に示す。
【0026】
【表1】
【0027】
表1に示すように、実施例1の坐剤は優れた徐放性を示した。これに対して比較例1の坐剤は、そのショ糖脂肪酸エステル含量が実施例1の場合と同一であるのに徐放効果はほとんど認められなかった。
【0028】
実施例 2:
処方−;
【0029】
【0030】
なお、本処方におけるショ糖脂肪酸エステルの配合量は坐剤の3.1 重量%を占める。
【0031】
製法−;
実施例1と同様にして本発明の坐剤を得た。:
【0032】
比較例 2:
処方−;(実施例2と同一処方)
【0033】
【0034】
製法−;(粒状剤としない点において実施例2とは異なる。)
比較例1と同様にして坐剤を得た。
【0035】
試験例 2(溶出試験):
実施例2および比較例2の坐剤について、試験例1と同様な溶出試験を行い表2の結果を得た。
【0036】
【表2】
【0037】
表2に示すように、実施例2の坐剤は優れた徐放性を示した。一方、比較例2の坐剤は、そのショ糖脂肪酸エステル含量が実施例2の場合と同一であるのに徐放効果はみられなかった。
【0038】
実施例 3:
処方−;
【0039】
【0040】
なお、本処方におけるショ糖脂肪酸エステルの配合量は坐剤の9.4 重量%を占める。
【0041】
製法−;
実施例1と同様にして本発明の坐剤を得た。
【0042】
実施例 4:
処方−;
【0043】
【0044】
なお、本処方におけるショ糖脂肪酸エステルの配合量は坐剤の9.4 重量%を占める。
【0045】
製法−;
実施例1と同様にして本発明の坐剤を得た。
【0046】
実施例 5:
処方−;
【0047】
【0048】
なお、本処方におけるショ糖脂肪酸エステルの配合量は坐剤の9.4 重量%を占める。
【0049】
製法−;
実施例1と同様にして本発明の坐剤を得た。
【0050】
試験例 3(溶出試験):
実施例3、4および5の坐剤について、試験例1と同様な溶出試験を行い表3の結果を得た。
【0051】
【表3】
【0052】
表3に示すように、HLBの値が大になるにつれて、徐放化の程度が低くなる。ジクロフェナックナトリウムを主薬とし、ショ糖脂肪酸エステルの配合量が9重量%前後である場合には、HLB値が1のショ糖脂肪酸エステルを用いるのが適当である。
【0053】
実施例 6−9:
処方−;
【0054】
【0055】
製法−;
実施例1と同様にして本発明の坐剤を得た。
【0056】
試験例 4(溶出試験):
実施例6−9の各坐剤について、試験例1と同様な溶出試験を行い表4の結果を得た。
【0057】
【表4】
【0058】
表4は、ショ糖脂肪酸エステルの配合量が増加するにつれて徐放効果が大となることを示している。主薬がジクロフェナックナトリウムであるとき、HLB値が1のショ糖脂肪酸エステルの配合量は、10−20重量%が適当である。
【0059】
実施例 10−12:
処方−;
【0060】
【0061】
なお、本処方におけるショ糖脂肪酸エステルの配合量は坐剤の9.4 重量%を占める。
【0062】
製法−;
粒状剤の粒径を変化させるほかは実施例1と同様にして本発明の坐剤を得た。
【0063】
試験例 5(溶出試験):
実施例10−12の各坐剤について、試験例1と同様な溶出試験を行い表5の結果を得た。
【0064】
【表5】
【0065】
表5に示すように粒子剤の粒径が大なるほど徐放効果も増大する。主薬がジクロフェナックであり、HLBが1であるショ糖脂肪酸エステルを約9重量%配合する場合の粒状剤の粒径は、150μmから600μmが適当である。
【0066】
実施例 13:
処方−;
【0067】
【0068】
なお、本処方におけるショ糖脂肪酸エステルの配合量は坐剤の60重量%を占める。
【0069】
製法−;
実施例1と同様にして本発明の坐剤を得た。
【0070】
試験例 6(溶出試験):
実施例13の坐剤について、試験例1と同様な溶出試験を行い表6の結果を得た。
【0071】
【表6】
[0001]
[Industrial application fields]
The present invention relates to the field of pharmaceutical formulations, particularly sustained release suppositories.
[0002]
[Background Art and Problems to be Solved by the Invention]
Suppositories are relatively easy to administer to patients who have a low rate of drug degradation in vivo by the route of administration, are not affected by diet, and are difficult to administer orally as well as children and the elderly. It is frequently used for reasons such as what it can do. However, on the other hand, when a drug is administered rectally, there are drawbacks such as the risk of side effects due to a sudden rise in plasma concentration and the difficulty of administering it several times a day. Various attempts have been made in the past as such drawbacks can be solved by slow release of the suppository.
[0003]
For example, JP-A-2-73010 discloses a suppository containing 30 to 40% by weight of a sucrose fatty acid ester and an oil component, and JP-A 64-63512 discloses a sucrose fatty acid. A suppository containing 55 to 85% by weight of an ester and an oil phase component is disclosed. Further, JP-A-1-110618 discloses a sustained-release suppository containing 50 to 90% by weight of a sucrose fatty acid ester and a water-soluble base.
[0004]
However, it is said that the sustained-release effect is not seen when the amount of sucrose fatty acid ester in these suppositories is less than 20%.
[0005]
The desired degree of sustained release varies depending on the type of drug. Accordingly, if there are abundant means for adjusting the degree of sustained release, the range of selection of the active ingredient is more widened and advantageous.
[0006]
Also in the prior art, the degree of sustained release could be adjusted by changing the blending amount of sucrose fatty acid ester, but if the blending amount is less than 20%, the sustained release effect itself cannot be expected.
[0007]
The present inventors have a reliable sustained release effect even if the blending amount of sucrose fatty acid ester is 20% or less, and thus the degree of sustained release can be adjusted. Various studies were conducted to develop a suppository capable of adjusting the degree of sustained release without relying only on the increase or decrease in the amount of the ester, and the present invention was completed.
[0008]
[Means for Solving the Problems]
The present invention relates to a sustained release suppository comprising a suppository base containing a granular agent in which a drug is dispersed in a sucrose fatty acid ester, and a method for producing the same. In addition, the sucrose fatty acid ester in the conventional suppository is mixed and fused with the suppository base from the beginning, and does not go through the form of a granule.
[0009]
The sucrose fatty acid ester in the present invention may be any as long as the HLB is 5 or less, but preferably 3 or less, particularly preferably 1-2. The amount of sucrose fatty acid ester is selected from the range of 2% by weight or more of the final suppository, preferably 2 to 60% by weight, particularly preferably 3 to 20% by weight. When the HLB value of the sucrose fatty acid ester is high or when the blending amount is reduced, the sustained release effect decreases, and when the reverse condition is selected, the sustained release effect increases. That is, by selecting the conditions, the release rate of the drug from the suppository can be adjusted. As the sucrose fatty acid ester, for example, lyo-sugar ester S-170 (HLB; 1), 270 (HLB; 2), and 370 (HLB; 3) commercially available from Mitsubishi Kasei Co., Ltd. are advantageous. used.
[0010]
The drug may be water-soluble, poorly water-soluble, or any other property, and the type is not particularly limited.
[0011]
Also, the type of suppository base is not particularly limited, as is the case with drugs, and any conventionally used one can be used, but those that melt at 40 ° C. or less are preferred. For example, higher fatty acid ester triglycerides [for example, various witepsol (Hurtz), various novatas (Henkel), various pharmasols (Japanese fats and oils), isocacao (Kao)] and medium chain fatty acid ester triglycerides [for example, miglyol (dynamite) Nobel))], glycerin fatty acid esters, polyglycerin fatty acid esters, cacao butter, hydrogenated oil, corn oil, liquid paraffin, petroleum jelly and other aqueous bases such as macrogol (= polyethylene glycol) and glycero gelatin It is done. These suppository bases are used alone or in the form of a mixture.
[0012]
In addition, auxiliary components such as antioxidants, absorption promoters and mucosal protective agents are blended as necessary.
[0013]
In the suppository of the present invention, a sucrose fatty acid ester is heated and melted at about 70 to 90 ° C., a drug is dispersed therein, cooled and solidified, pulverized, and sieved granulated granules are preheated and melted. It can be produced by dispersing in a base agent, filling a container, and cooling. It is more advantageous to use a dispersing agent such as Aerosil when dispersing the granulate into the suppository base.
[0014]
As already described, the degree of sustained release can be adjusted by the blending amount of sucrose fatty acid ester and its HLB value, but can also be adjusted by changing the particle size of the granule. Increasing the particle size increases the sustained release effect.
[0015]
Therefore, if the blending amount of the sucrose fatty acid ester, the HLB value of the sucrose fatty acid ester, and the particle size of the granule are appropriately selected, the degree of sustained release can be freely changed. For example, the amount can be adjusted by reducing the amount of sucrose fatty acid ester and increasing the particle size, or by using a sucrose fatty acid ester having a small HLB value and decreasing the particle size.
[0016]
【The invention's effect】
The suppository of the present invention thus obtained has an excellent sustained release effect. Also, the degree of sustained release can be changed by changing the amount of sucrose fatty acid ester, adopting a sucrose fatty acid ester having an HLB value according to the purpose, or changing the particle size of the granule. Can be adjusted freely. Therefore, the kind of the drug to be blended in the suppository of the present invention can be selected from a wider range.
[0017]
【Example】
Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples.
In the following Examples and Comparative Examples, diclofenac sodium as an acidic drug and morphine hydrochloride as a basic drug were used as representative examples of drugs.
[0018]
Example 1 :
Formula-
[0019]
[0020]
The amount of sucrose fatty acid ester in this formulation accounts for 9.4% by weight of the suppository.
[0021]
Manufacturing method;
Sugar ester S-170 is melted at 70 to 90 ° C., and diclofenac nutrim is dispersed therein. Next, it is cooled and solidified and pulverized. After sieving with a 32 mesh sieve, this was uniformly dispersed in witepsol (containing 2% Aerosil 200) previously melted at 37 ° C. at the same temperature, then filled into a suppository container and cooled to sit down. An agent was obtained.
[0022]
Comparative Example 1 :
Formula-; (same formulation as Example 1)
[0023]
[0024]
Manufacturing method-(different from Example 1 in that it is not a granulating agent);
A mixture of sugar ester S-170 and witepsol (containing 2% Aerosil 200) was melted at 70 to 90 ° C and then cooled to 37 ° C. The main drug was uniformly dispersed in this, then filled into a suppository container and cooled to obtain a suppository.
[0025]
Test example 1 (dissolution test):
The main agent release test from the suppositories of Example 1 and Comparative Example 1 was performed using a PTSW suppository dissolution tester (rotary cell method). The elution solution used 900 ml of 0.02M phosphate buffer (pH 7.4), the cell rotation speed was set to 25 rpm, and the temperature was set to 37 ° C. The results are shown in Table 1.
[0026]
[Table 1]
[0027]
As shown in Table 1, the suppository of Example 1 exhibited excellent sustained release properties. In contrast, the suppository of Comparative Example 1 had almost the same sustained release effect although the sucrose fatty acid ester content was the same as in Example 1.
[0028]
Example 2 :
Formula-
[0029]
[0030]
The amount of sucrose fatty acid ester in this formulation accounts for 3.1% by weight of the suppository.
[0031]
Manufacturing method;
A suppository of the present invention was obtained in the same manner as in Example 1. :
[0032]
Comparative Example 2 :
Formula-; (same formulation as Example 2)
[0033]
[0034]
Production method-; (different from Example 2 in that it is not a granule)
A suppository was obtained in the same manner as in Comparative Example 1.
[0035]
Test Example 2 (Dissolution test):
The suppositories of Example 2 and Comparative Example 2 were subjected to the same dissolution test as in Test Example 1 and the results shown in Table 2 were obtained.
[0036]
[Table 2]
[0037]
As shown in Table 2, the suppository of Example 2 showed excellent sustained release properties. On the other hand, although the suppository of Comparative Example 2 had the same sucrose fatty acid ester content as in Example 2, no sustained release effect was observed.
[0038]
Example 3
Formula-
[0039]
[0040]
The amount of sucrose fatty acid ester in this formulation accounts for 9.4% by weight of the suppository.
[0041]
Manufacturing method;
A suppository of the present invention was obtained in the same manner as in Example 1.
[0042]
Example 4 :
Formula-
[0043]
[0044]
The amount of sucrose fatty acid ester in this formulation accounts for 9.4% by weight of the suppository.
[0045]
Manufacturing method;
A suppository of the present invention was obtained in the same manner as in Example 1.
[0046]
Example 5 :
Formula-
[0047]
[0048]
The amount of sucrose fatty acid ester in this formulation accounts for 9.4% by weight of the suppository.
[0049]
Manufacturing method;
A suppository of the present invention was obtained in the same manner as in Example 1.
[0050]
Test Example 3 (Dissolution test):
For the suppositories of Examples 3, 4 and 5, the same dissolution test as in Test Example 1 was performed, and the results in Table 3 were obtained.
[0051]
[Table 3]
[0052]
As shown in Table 3, as the HLB value increases, the degree of sustained release decreases. When diclofenac sodium is the main drug and the amount of sucrose fatty acid ester is about 9% by weight, it is appropriate to use a sucrose fatty acid ester having an HLB value of 1.
[0053]
Example 6-9 :
Formula-
[0054]
[0055]
Manufacturing method;
A suppository of the present invention was obtained in the same manner as in Example 1.
[0056]
Test Example 4 (Dissolution test):
About each suppository of Example 6-9, the elution test similar to Test Example 1 was performed, and the result of Table 4 was obtained.
[0057]
[Table 4]
[0058]
Table 4 shows that the sustained release effect increases as the blending amount of sucrose fatty acid ester increases. When the main drug is diclofenac sodium, the blending amount of the sucrose fatty acid ester having an HLB value of 1 is suitably 10-20% by weight.
[0059]
Example 10-12 :
Formula-
[0060]
[0061]
The amount of sucrose fatty acid ester in this formulation accounts for 9.4% by weight of the suppository.
[0062]
Manufacturing method;
A suppository of the present invention was obtained in the same manner as in Example 1 except that the particle size of the granule was changed.
[0063]
Test Example 5 (Dissolution test):
About each suppository of Examples 10-12, the elution test similar to Test Example 1 was performed, and the result of Table 5 was obtained.
[0064]
[Table 5]
[0065]
As shown in Table 5, the sustained release effect increases as the particle size of the particle increases. The appropriate particle size of the granule is 150 μm to 600 μm when the main drug is diclofenac and about 9% by weight of a sucrose fatty acid ester having an HLB of 1 is blended.
[0066]
Example 13 :
Formula-
[0067]
[0068]
In addition, the compounding quantity of the sucrose fatty acid ester in this prescription occupies 60 weight% of a suppository.
[0069]
Manufacturing method;
A suppository of the present invention was obtained in the same manner as in Example 1.
[0070]
Test Example 6 (Dissolution test):
The suppository of Example 13 was subjected to the same dissolution test as in Test Example 1 and the results shown in Table 6 were obtained.
[0071]
[Table 6]
Claims (4)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP31128493A JP3638299B2 (en) | 1993-11-16 | 1993-11-16 | Sustained release suppository and method for producing the same |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP31128493A JP3638299B2 (en) | 1993-11-16 | 1993-11-16 | Sustained release suppository and method for producing the same |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH07138149A JPH07138149A (en) | 1995-05-30 |
JP3638299B2 true JP3638299B2 (en) | 2005-04-13 |
Family
ID=18015288
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JP31128493A Expired - Fee Related JP3638299B2 (en) | 1993-11-16 | 1993-11-16 | Sustained release suppository and method for producing the same |
Country Status (1)
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JP (1) | JP3638299B2 (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4866518B2 (en) * | 2001-09-21 | 2012-02-01 | 天藤製薬株式会社 | Suppository manufacturing method |
JP2003095923A (en) * | 2001-09-26 | 2003-04-03 | Tendou Seiyaku Kk | Method for producing oil and fat formed material |
JPWO2003059344A1 (en) * | 2002-01-15 | 2005-05-19 | 日本新薬株式会社 | Suppository containing indole derivative |
-
1993
- 1993-11-16 JP JP31128493A patent/JP3638299B2/en not_active Expired - Fee Related
Also Published As
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JPH07138149A (en) | 1995-05-30 |
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