JPH01190631A - Remedy for bronchial asthma - Google Patents

Remedy for bronchial asthma

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Publication number
JPH01190631A
JPH01190631A JP1358388A JP1358388A JPH01190631A JP H01190631 A JPH01190631 A JP H01190631A JP 1358388 A JP1358388 A JP 1358388A JP 1358388 A JP1358388 A JP 1358388A JP H01190631 A JPH01190631 A JP H01190631A
Authority
JP
Japan
Prior art keywords
bronchial asthma
theophylline
remedy
present
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
JP1358388A
Other languages
Japanese (ja)
Inventor
Yasuo Ito
伊藤 安夫
Hideo Kato
日出男 加藤
Eiichi Ecchu
越中 栄一
Koji Morikawa
宏二 森川
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Japan Co Ltd
Original Assignee
Hokuriku Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hokuriku Pharmaceutical Co Ltd filed Critical Hokuriku Pharmaceutical Co Ltd
Priority to JP1358388A priority Critical patent/JPH01190631A/en
Publication of JPH01190631A publication Critical patent/JPH01190631A/en
Pending legal-status Critical Current

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Abstract

PURPOSE:To obtain a remedy for bronchial asthma having highly selective excellent bronchodilating action and high safety, by using a specific xanthine derivative as an active component. CONSTITUTION:The objective drug contains, as an active component, pentoxifylline of formula which is known to be effective in ameliorating the subjective symptom, mental symptom and memorization activity caused by cerebrovascular disorder. The compound exhibits nearly the same bronchodilation action to respiratory tract as that of theophylline of formula II known as a xanthine-type remedy for bronchial asthma. It exhibits the activity even by duodenal administration and necessitates higher dose than theophylline for the development of the central excitation, diuretic and cardiac excitation actions. Accordingly, it is a drug having separated main effect and side effect and having high safety compared with theophylline and is extremely useful for ameliorating the symptom of bronchial asthma and the reversible bronchospasm caused by chronic bronchitis and pulmonary emphysema.

Description

【発明の詳細な説明】 −つの1 ノ 本発明は、次式(I)で示されるキサンチン誘導体を有
効成分とする気管支喘息治療剤に関するものであり、医
療の分野において有用である。
DETAILED DESCRIPTION OF THE INVENTION - Part 1 The present invention relates to a therapeutic agent for bronchial asthma containing a xanthine derivative represented by the following formula (I) as an active ingredient, and is useful in the medical field.

1迷1」ulCH3 気管支喘息治療剤として、気管支拡張剤をはしめとして
種々の薬剤が広く臨床に供されている。
1.1 ulCH3 Various drugs, including bronchodilators, are widely used clinically as therapeutic agents for bronchial asthma.

それらの中で、キサンチン系化合物も気管支喘息の治療
剤として使用されており、テオフィリン(Theoph
yl l lne ニー船名; The Merck 
Index l 0版、 9114;式(■))は市販
されている代表的なH3 一方、本発明に係る前記式(1)で示されるキサンチン
誘導体は、ペントキシフィリン(pentoxifyl
line ニー船名;  The Merck 1nd
exl 0版、7002)と称する化合物で、従来より
脳血管障害による自覚症状、精神症状、記銘力に対し有
効性が認められ、微小循環改善剤として広く臨床に供さ
れている。しかしながら、ペントキシフィリンの気管支
喘息治療剤としての適用についてその可能性はないもの
とされていた(応用薬理、 15,153(1978)
)。
Among them, xanthine compounds are also used as therapeutic agents for bronchial asthma, and theophylline (Theophylline)
yl l lne Ship name; The Merck
Index l 0 edition, 9114; Formula (■)) is a commercially available representative H3. On the other hand, the xanthine derivative represented by the formula (1) according to the present invention is
line ship name; The Merck 1nd
exl 0 edition, 7002), has been recognized to be effective against subjective symptoms, mental symptoms, and memory ability due to cerebrovascular disorders, and is widely used clinically as a microcirculation improving agent. However, it was thought that there was no possibility of pentoxifylline being used as a treatment for bronchial asthma (Applied Pharmacology, 15, 153 (1978).
).

−1(゛ よ′  。■ しかしながら、前記式(■)で示されるテオフィリンは
、主作用と副作用の分離が小さ(、副作用として中枢神
経興奮、利尿、心臓興奮、胃液分泌昂進等が発現しやす
く、又、有効血中−度域が非常に狭い為薬物1度モニタ
リングの必要があり、更に他剤との併用による相互作用
に注意する必要もある等、使用に際しては種々留意すべ
き点が多く、臨床使用上問題点が多かった。
-1 (゛ YO'.■ However, theophylline represented by the above formula (■) has a small separation between the main action and side effects (and tends to cause side effects such as central nervous excitement, diuresis, cardiac excitement, and increased gastric juice secretion). Furthermore, since the effective blood concentration range is very narrow, it is necessary to monitor the drug once, and there are also many points to keep in mind when using it, such as the need to be careful about interactions when used in combination with other drugs. However, there were many problems in clinical use.

本発明は、テオフィリンのこれらの欠点を改善し、副作
用が少なく安全域の広い、かつ他剤との相互作用の少な
い薬剤の開発を目的としている。
The present invention aims to improve these drawbacks of theophylline and develop a drug that has fewer side effects, a wide safety margin, and fewer interactions with other drugs.

I   −の 本発明者らは、テオフィリンの欠点をしのぐ薬剤として
のキサンチン系化合物につき、前述の事情に鑑み鋭意研
究した結果、これまで微小循環改善作用しか知られてい
なかった前記式(I)で示されるペントキシフィリンが
、全く予期しえぬ気管支拡張作用を有し、しかも、中枢
神経興奮、利尿、心臓興奮等の副作用が非常に弱t〜こ
とを見い出し、本発明を完成するに至った。
In view of the above-mentioned circumstances, the present inventors of the present invention conducted extensive research into xanthine compounds as drugs that overcome the drawbacks of theophylline. The present inventors have discovered that pentoxifylline has a completely unexpected bronchodilatory effect, and has very low side effects such as central nervous stimulation, diuresis, and cardiac stimulation, and has completed the present invention. .

本発明の前記式(I)で示されるキサンチン誘導体(以
下、本発明化合物)を有効成分として含打する気管支喘
息治療剤は、経口、非経口のいずれにおいても投与でき
る。経口投与剤の剤型としては、例えば、錠剤、カプセ
ル剤、散剤、細粒剤。
The therapeutic agent for bronchial asthma containing the xanthine derivative represented by the formula (I) (hereinafter referred to as the compound of the present invention) of the present invention as an active ingredient can be administered either orally or parenterally. Examples of dosage forms for oral administration include tablets, capsules, powders, and fine granules.

顆粒剤及びシロップ剤等が挙げられ、非経口投与剤の剤
型としては、例えば、注射剤、串刺、吸入剤、軟膏剤及
び貼付剤等が挙げられる。これらの製剤の1裂には、薬
理学的、製剤学的に許容しうる添加物を加えることがで
き、賦形剤、崩壊剤ないし崩壊補助剤、結合剤、滑沢剤
、コーティング剤9色素、希釈剤、基剤、溶解剤ないし
溶解補助剤9等張化剤+ pl調節剤、安定化剤等が用
いられる。
Examples include granules and syrups, and examples of dosage forms for parenteral administration include injections, skewers, inhalants, ointments, and patches. Pharmacologically and pharmaceutically acceptable additives can be added to one part of these preparations, including excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, pigments, etc. , a diluent, a base, a solubilizing agent or a solubilizing agent, 9 an isotonizing agent, a PL adjuster, a stabilizer, etc. are used.

経口剤及び粘膜投与剤においては、賦形剤として、ブド
ウ糖、乳糖、D−マンニトール、でんぷん。
In oral formulations and mucosal administration formulations, excipients include glucose, lactose, D-mannitol, and starch.

結晶セルロース等が、崩壊剤、崩壊補助剤として、カル
ボキシメチルセルロース、でんぷん、カルボキシメチル
セルロースカルシウム等が、結合剤として、ヒドロキン
プロピルセルロース、ヒドロキシプロピルメチルセルロ
ース、ポリビニルピロリドン、ゼラチン等が、滑沢剤と
して、ステアリン酸マグネシウム、タルク等が、コーテ
ィング剤として、ヒドロキシプロピルメチルセルロース
、オイドラギフト、セルロースアセテートフタレート。
Microcrystalline cellulose, etc. are used as disintegrants and disintegration aids, carboxymethylcellulose, starch, carboxymethylcellulose calcium, etc. are used as binders, hydroquinepropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, etc. are used as lubricants, and stearin is used as a lubricant. Magnesium acid, talc, etc., as a coating agent, hydroxypropyl methylcellulose, Eudragift, cellulose acetate phthalate.

ヒドロキシプロピルメチルセルロースフタレート。Hydroxypropyl methylcellulose phthalate.

グリセリン脂肪酸エステル、白糖、酸化チタン等が、基
剤として、ポリエチレングリコール、ハードファツト等
が、分散剤としてソルビタントリオレエート等が使用さ
れ、又、経皮投与剤においては、基剤として、ワセリン
、流動パラフィン、ポリエチレングリコール等が、粘着
剤として、ポリアクリル酸ナトリウム、ポリビニルアル
コール。
Glycerin fatty acid ester, sucrose, titanium oxide, etc. are used as the base, polyethylene glycol, hard fat, etc. are used, and sorbitan trioleate, etc. are used as the dispersant.In addition, for transdermal preparations, petrolatum, liquid paraffin, etc. are used as the base. , polyethylene glycol, etc., as adhesives, sodium polyacrylate, polyvinyl alcohol.

メチルセルロース、ポリブテン等が、基布として、木綿
布などの製剤用成分が、又、注射剤においては水性ある
いは用時溶解型注射剤を構成しうる溶解剤ないし溶解補
助剤として、注射用蒸留水、生理食塩水、プロピレング
リフール等が、等張化剤として、ブドウ糖、塩化ナトリ
ウム、D−マンニトール、グリセリン等がN pu調節
剤として、無機酸。
Methylcellulose, polybutene, etc. as a base fabric, formulation components such as cotton fabric, and in the case of injections, distilled water for injections, as a solubilizing agent or solubilizing agent that can constitute an aqueous or ready-to-dissolve injection. Physiological saline, propylene glycol, etc. as tonicity agents, glucose, sodium chloride, D-mannitol, glycerin, etc. as N pu regulators, inorganic acids.

有機酸又は無機塩基等の製剤用成分が使用される。Formulative ingredients such as organic acids or inorganic bases are used.

本発明化合物の治療患者への投与量は、経口投与で通常
成人の場合、−日100−1200+gであるが、年齢
、症状等により適宜増減することができる。
The dose of the compound of the present invention to be administered orally to a patient is usually 100-1200+g per -day for adults, but it can be adjusted as appropriate depending on age, symptoms, etc.

作1− 以下、本発明化合物の優れた作用を試験例により説明す
る。その際、比較薬としてはテオフィリンを用いた。統
計学的検定は5tudentのt検定により行なった。
Example 1 - The excellent effects of the compounds of the present invention will be explained below using test examples. At that time, theophylline was used as a comparison drug. Statistical tests were performed using a 5student's t-test.

試験例1 [摘出モルモット気管弛緩作用コ バートレー系雄性モルモット(体重400g前後)から
気管を摘出し、気管切片鎖状標本を作成した。標本は9
5%02及び5%CO2の混合ガスで通気したロンクー
リンガ−液槽中(37℃)に懸垂し、静止時緊張を等偏
性に測定した。薬物は液槽中に累積適用し、イソプロテ
レノール10Mによる弛緩を100%として表した。結
果を表1に示す。
Test Example 1 [Extracted Guinea Pig Tracheal Relaxation Effect] The trachea was removed from a Covertley male guinea pig (weighing around 400 g), and a tracheal section chain specimen was prepared. There are 9 specimens
The specimen was suspended in a Ronkulinger liquid bath (37°C) aerated with a mixed gas of 5% CO2 and 5% CO2, and the resting tension was measured isotropically. Drugs were applied cumulatively in the bath and relaxation by isoproterenol 10M was expressed as 100%. The results are shown in Table 1.

表  1 N、S、:有意水準5%において薬物間に差がない。Table 1 N, S: There is no difference between drugs at the 5% significance level.

試験例2 [モルモットのアセチルコリンによる気道1[の増加に
対する抑制作用コ バートレー系雄性モルモット(体fE400g前後)を
ウレタン(1、5g/kg、+、p、)で麻酔したのち
、気管及び頚動脈にカニユーレを挿入し、それぞれ気道
抵抗及び血圧を測定した。気道抵抗はKonzett−
R6ssler法[Archiv fur Exper
lmentellePathologle  und 
 Pharmakologle、  195ニア1(1
940)]の変法により、流量の変化として測定した。
Test Example 2 [Suppressive effect of acetylcholine in guinea pigs on the increase in airway 1] A male Covertley guinea pig (body fE around 400 g) was anesthetized with urethane (1.5 g/kg, +, p,), and then a cannula was inserted into the trachea and carotid artery. were inserted, and airway resistance and blood pressure were measured. Airway resistance is Konzett-
R6ssler method [Archive fur Expert
lmentelle Pathologle und
Pharmakologie, 195 Near 1 (1
940)] was measured as a change in flow rate.

アセチルコリン(40μg/kg)は10分間隔で頚静
脈内に投与し、薬物はアセチルコリンの投与1分前に頚
静脈内に投与した。
Acetylcholine (40 μg/kg) was administered into the jugular vein at 10 minute intervals, and the drug was administered into the jugular vein 1 minute before administration of acetylcholine.

また、本発明化合物の消化管内投与に対する作用を併せ
て検討した。この場合、アセチルコリン(40μg/k
g)は15分間隔で頚静脈内に投与し、本発明化合物は
アセチルコリンの投与5分前に十二指腸内に投与した。
In addition, the effects of the compounds of the present invention on administration into the gastrointestinal tract were also investigated. In this case, acetylcholine (40 μg/k
g) was administered into the jugular vein at 15 minute intervals, and the compound of the present invention was administered into the duodenum 5 minutes before administration of acetylcholine.

薬物の作用は、薬物投与前後のアセチルコリンによる気
道抵抗増加の変化率を抑制率(%)として表した。結果
を表2及び表3に示す。
The effect of the drug was expressed as the rate of change in airway resistance increase due to acetylcholine before and after drug administration as an inhibition rate (%). The results are shown in Tables 2 and 3.

# :薬物は頚静脈内に投与した。#: The drug was administered into the jugular vein.

N、Sパ有意水準5%において薬物間に差がない。N, S: There is no difference between drugs at the 5% significance level.

表     3 # :薬物は十二指腸内に投与した。Table 3 #: The drug was administered into the duodenum.

X :膏意水準5%において対照と差がある。X: There is a difference from the control at a mean level of 5%.

東京:有意水準1%において対照と差がある。Tokyo: There is a difference from the control at a significance level of 1%.

試験例3 [マウス自発運動量に対する作用] −一夜絶食たddy系雄性マウス(体重22g前後)に
薬物を経口投与し、60分間の自発運動量をアニメノク
ス(Ty9eS、Farad Electronics
)を用いてA11l定した。結果を表4に示す。
Test Example 3 [Effect on mouse locomotor activity] - The drug was orally administered to DDY male mice (body weight around 22 g) that had been fasted overnight, and the locomotor activity for 60 minutes was measured using Animonox (Ty9eS, Farad Electronics).
) was used to determine A11l. The results are shown in Table 4.

表    4 0:有意水準1%において対照と差がある。Table 4 0: There is a difference from the control at a significance level of 1%.

試験例4 [ラット尿排泄に対する作用] 一夜絶食したウィスター系雄性う、ト(体重200g前
後)を実験開始3時間前に給水した。薬物を経口投与(
2,5■l/kg)したのち、5時間目までの排尿量−
をd−1定した。/III定値はラット100g体重当
たりに換算して表した。結果を表5に示す。
Test Example 4 [Effect on rat urine excretion] Male Wistar rats (weighing around 200 g) that had been fasted overnight were watered 3 hours before the start of the experiment. Oral administration of drugs (
2.5■l/kg), the amount of urine urinated until the 5th hour -
was determined as d-1. /III constant value was expressed in terms of weight per 100 g of rat. The results are shown in Table 5.

表     5 本x:有意水準1%において対照と差がある。Table 5 Book x: There is a difference from the control at a significance level of 1%.

試験例5 [摘出モルモット心房に対する作用コ バートレー系雄性モルモット(体!400g 前後)か
ら心臓を摘出し、左心房標本を作成した。
Test Example 5 [Effect on isolated guinea pig atrium] The heart was extracted from a Covertley male guinea pig (body weight: approximately 400 g), and a left atrium specimen was prepared.

標本は95%02及び5%CO2の混合ガスで通気した
クレブス−・\ンゼライト[J中(30°C)に懸垂し
、双極白金電極を通して短形波IHz、1m5ec、 
 3−5 Vの電気刺激を与え、生じる収縮を等尺性に
測定した。薬物は液槽中に累積適用し、薬物投与前後の
電気刺激による収縮力の変化を増加率(%)として表し
た。結果を表6に示す。
The specimens were suspended in Krebs-Nzerite [J] (30°C) aerated with a gas mixture of 95% CO2 and 5% CO2, and were heated with a rectangular wave IHz, 1 m5ec, through a bipolar platinum electrode.
Electrical stimulation of 3-5 V was applied and the resulting contractions were measured isometrically. The drug was applied cumulatively into the liquid bath, and the change in contractile force due to electrical stimulation before and after drug administration was expressed as an increase rate (%). The results are shown in Table 6.

以上の試験例の結果、本発明化合物は気道系に対してテ
オフィリンとほぼ同等の気管支拡張作用を示し、また十
二指腸内投与でも作用を示すことか明らかにされた。一
方、本発明化合物の中枢興酊、利尿及び心1a其a作用
の発現にはテオフィリンよりも高用量を必要とすること
から、本発明化合物はテオフィリンと比較して主作用と
副作用とが分離された安全性の高い薬剤であることが明
らかとなった。
As a result of the above test examples, it was revealed that the compound of the present invention exhibits a bronchodilatory effect on the respiratory system almost equivalent to that of theophylline, and also exhibits an effect when administered into the duodenum. On the other hand, since the compound of the present invention requires a higher dose than theophylline to exhibit its central arousal, diuretic, and cardiac 1a-a effects, the compound of the present invention has separate main effects and side effects compared to theophylline. It was revealed that this drug is highly safe.

このことから本発明化合物は、気管支喘息治療剤として
のa用件が期待される。
From this, the compound of the present invention is expected to have a use as a therapeutic agent for bronchial asthma.

尚、本発明化合物の急性す外傾は、マウスに経口投与し
て、1225.1500mg/kg  (雌、雄)であ
り、ラットに経口投与して、2100.2380 mg
/kg  (雌、雄)である。
In addition, the acute ectropion of the compound of the present invention is 1225.1500 mg/kg (female, male) when orally administered to mice, and 2100.2380 mg/kg when orally administered to rats.
/kg (female, male).

1駁■ 以下、本発明化合物の製剤例を実施例によって説明する
が、本発明はこれらの実施例の特定の細部に限定される
ものではない。
1. Formulation examples of the compounds of the present invention will be explained below with reference to Examples, but the present invention is not limited to the specific details of these Examples.

実施例1 下記の方法により、錠剤を作成する。Example 1 Tablets are prepared by the following method.

本発明化合物          100鵬g乳糖  
             適 量トウモロコシデンプ
ン        10mgステアリン酸マグネシウム
      1醜gヒドロキシプロピルメチルセルロー
ス フタレート71g ポリエチレングリコール8000 0.5mg実施例2 下記の方法により、カプセル剤を作成する。
Compound of the present invention 100g lactose
Appropriate amount Corn starch 10 mg Magnesium stearate 1 g Hydroxypropyl methyl cellulose phthalate 71 g Polyethylene glycol 8000 0.5 mg Example 2 Capsules are prepared by the following method.

本発明化合物           50−g乳糖  
             適 量カルボキシメチルセ
ルロースカルシウム15霞g ヒドロキシプロピルセルロース    2醜gステアI
ン マグ シウム       鵬20mg 以上を常法により混合し、硬カプセルに充填する。
Compound of the present invention 50-g lactose
Appropriate amount Carboxymethylcellulose calcium 15g Hydroxypropyl cellulose 2ugly Stair I
20mg or more of Magnesium Peng is mixed in a conventional manner and filled into hard capsules.

実施例3 下記の方法により、顆粒剤を作成する。Example 3 Granules are prepared by the following method.

本発明化合物          200mg乳糖  
             適 量結晶セルロース  
        100mgヒドロキシプロピルメチル セルロースフタレート 90■g グリセリン脂肪酸エステル      8a+g実施例
4 下記の方法により、注射剤を作成する。
Compound of the present invention 200mg lactose
Appropriate amount of crystalline cellulose
100 mg Hydroxypropyl methylcellulose phthalate 90 g Glycerin fatty acid ester 8a+g Example 4 An injection is prepared by the following method.

本発明化合物          100醜g塩化ナト
リウム          35−gml 実施例S 下記の方法により、串刺を作成する。
Compound of the present invention 100g Sodium chloride 35gml Example S A skewer is prepared by the following method.

本発明化合物          100mg実施例6 下記の方法により、パップ剤を作成する。Compound of the present invention 100mg Example 6 A poultice is prepared by the following method.

本発明化合物          100+gゼラチン
            1100mgポリビニルアル
コール メチルセルロース         100□2グリセ
リン         1500mgカオリン    
         850mgポリアクリル酸ナトリウ
ム     50−gポリブテン          
  150麿gリ                 
                         
    15000mg 光J[1文じ【 本発明により、キサンチン誂導体を有効成分とする気管
支喘息治療剤が提供される。
Compound of the present invention 100+g gelatin 1100mg polyvinyl alcohol methyl cellulose 100□2 glycerin 1500mg kaolin
850mg sodium polyacrylate 50-g polybutene
150 grams

15000mg Hikari J [1 text] The present invention provides a therapeutic agent for bronchial asthma containing a xanthine conductor as an active ingredient.

即ち、本発明化合物は選択性の高い優れた気管支拡張作
用を有し、かつ安全性が高いので、気管支喘息症状の緩
和,慢性気管支炎及び肺気腫に伴う可逆的気管支痙掌の
緩和に極めて有用である。
In other words, the compound of the present invention has an excellent bronchodilation effect with high selectivity and is highly safe, so it is extremely useful for alleviating bronchial asthma symptoms and reversible bronchospasm associated with chronic bronchitis and emphysema. be.

Claims (1)

【特許請求の範囲】 式 ▲数式、化学式、表等があります▼ で示されるキサンチン誘導体を有効成分とする気管支喘
息治療剤。
[Scope of Claims] A therapeutic agent for bronchial asthma containing a xanthine derivative represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼ as an active ingredient.
JP1358388A 1988-01-26 1988-01-26 Remedy for bronchial asthma Pending JPH01190631A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP1358388A JPH01190631A (en) 1988-01-26 1988-01-26 Remedy for bronchial asthma

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP1358388A JPH01190631A (en) 1988-01-26 1988-01-26 Remedy for bronchial asthma

Publications (1)

Publication Number Publication Date
JPH01190631A true JPH01190631A (en) 1989-07-31

Family

ID=11837202

Family Applications (1)

Application Number Title Priority Date Filing Date
JP1358388A Pending JPH01190631A (en) 1988-01-26 1988-01-26 Remedy for bronchial asthma

Country Status (1)

Country Link
JP (1) JPH01190631A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995019174A1 (en) * 1994-01-18 1995-07-20 Alza Corporation Pentoxifylline dosage form

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995019174A1 (en) * 1994-01-18 1995-07-20 Alza Corporation Pentoxifylline dosage form

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