• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Pharmaceutical composition for administration primarily to the respiratory tract when treating and controlling anti-inflammatory conditions comprising liposomes in combination with a compound of the formula wherein Q is and R1 is a saturated or unsaturated, straight or branched alkyl group with 11-19 carbon atoms and R is H, -COCH3, -COC2H5, -CO(CH2)2CH3 or -CO(CH2)3CH3. The invention also refers to the compounds of the formula I per se processes for preparation of these compounds and to a method for the treatment of inflammatory conditions.
    公开号:SU1493111A3
    申请号:SU853929451
    申请日:1985-07-25
    公开日:1989-07-07
    发明作者:Ингемар Аксельссон Бенгт；Леннарт Браттсанд Ральф；Магнус Олоф Дальбек Карл；Арне Келлстрем Лейф；Вильям Трофаст Ян
    申请人:Актиеболагет Драко (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of novel corticosteroid derivatives, namely steroid esters of the general formula
    Q - O - C - R I / O
    (I)
    MO
    ;WITH
    rj
    and
     W: n2sn s11z
     CM
    where Q - means the residue of the formula
    or
    BUT
    or
    but
    or
    or
    CHi
    .
    0
    or
    SNG ss
    .OSPN2SIe-C1b
    Where
    R, - saturated or unsaturated,
    straight or branched Cc-J j-alkyl group; R is a hydrogen atom, or
    pines) jCH group with valuable pharmacological properties.
    The purpose of the invention is to obtain new steroid esters with anti-inflammatory and anti-allergic properties and a more prolonged effect in
    1A93111
    five
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    Compared with the well-known ones, which are similar to similar data.
    The mass spectrum (spectral data was obtained by chemical ionization mass spectrometry (methane - gas) analysis, all of which are consistent with the molecular weights of the compounds. The purity of each compound is determined using a high-resolution liquid chromatography system). using a micro-Bondapak C | (ZOOx X 3.9 mm - inner diameter) column with a flow rate of 1.0 ml / min and ethanol / water mixture in ratios from 70:30 to 90:10 as the mobile phase.
    Example 1. Budeson-21-palmitate.
    1 mmol of budesonide is dissolved in 20 MP of pyridine. 2 mmol of palmitoyl chloride is added to the solution and then incubated overnight at room temperature. With cooling, a mixture of 2M hydrochloric acid is added to the ice slots until an acidic reaction occurs. Next, the mixture is subjected to extraction treatment with three pores - {{50 MP chloroform each. The organic phase is successively shaken with 5% sodium bicarbonate and water, dried over sodium sulfate and evaporated. Cbipoit material was purified by preparative thin layer chromatographic treatment (silica gel; 3% tanol and 97% chloroform). Vyuod AO. The degree of purity is 95.5%. ; imic ionization mass spectrometric analysis (M1 – MS, methane), M +29 697.
    Example 2. Gududeson-21- - liquid.
    In a rosultl reaction of 0.5 mmol of judesocide with 0.25 ml x of legal lauryl in 3 ml of pyridine according to example i, after preparative thin-layer chromatographic treatment (silica gel; 3% ethanol and 97% chloroform), the indicated compound is obtained. Exit 47%. CI-MS (methane).
    Example 3. Budesonide-21-myristat.
    Mlrystryl chloride is synthesized by boiling at reflux 7.0 g of myristic acid and 9 ml of tuityl chloride in 100 ppm of trichlorethylene for 3 hours. Then the solvent is evaporated.
    2 mmol of budeso-iide and 2.4 mmol of myristoyl chloride in 40 ml of methylene chloride are treated by extracting together with 2.4 mmol of triethylamine in 10 ml of methylene chloride for 2 hours at room temperature. Methylene chloride is then added to the mixture and the organic phase is successively treated with 1 M hydrochloric acid and three portions of 100 ml each of water. Chromatographic processing (Sephadex LH20, chloroform) after drying over sodium sulfate and evaporation of the solvent to achieve a 65% yield, the title compound is obtained. The degree of purity is 98.2%. CI-MS (methane): MH 641, -.
    Example 4. Budeson-21-myrista (method A).
    1 mmol of budesonide, 1 mmol of myristic acid and 5 mg of p-toluene sulfonic acid are refluxed in 30 ml of benzene for 5 hours. The organic phase is successively shaken together with 5% sodium bicarbonate and water, dried over sodium sulfate and evaporate. As a result of the purification by preparative thin layer chromatography, the compounds obtained are identical to those obtained in Example 1.
    Example 5. Budezonid-21-sterat.
    The reaction of 1 mmol of budesonide with 1.0 ml of stearoyl chloride in 6 MP of pyridine in accordance with the description of Example 4 after preparative thin-layer chromatographic treatment (silica gel} 3% ethanol and 97% chloroform) gives this compound. Yield 74%. CI-MS (methane): MH, 697; M + 29 725.
    Example 6. Budeson-21-oleate.
    As a result of the reaction, 1.16 mmol of budesonide and 1.4 mmol of chloride chloride were mixed in 50 ml of methylene chloride with 1.4 mmol of triethylamine in 5 ml of methylene chloride for 2 hours at room temperature after treatment according to Example 3 and chromatographic treatment (silica gel hexane mixture with acetone in co
    Q 5 0
    5 Q
    five
    0
    five
    0
    five
    relation 40; 20) with the achievement of 22% yield, the indicated compound is obtained. The degree of purity is 98.7%. EM-MS (methane): MP 695, M + 9 723.
    Example 7. Betamethasone-21- -laurate.
    As a result of the reaction, 2 mmol of betamethasone and 2.4 mmol of laurine chloride in 20 ml of dimethylformamide with 2.4 mmol of triethylamine in 5 ml of dimethylformamide for 2 hours at room temperature after evaporation of dimethylformamide, following the procedure described in example 3 and chromatographic processing ( silica gel; a mixture of hexane and acetone in the ratio of 60:40; with the achievement of a 22% yield, the indicated compound is obtained. Degree of purity 92.7% IC-MS (methane): MH 575; 29 603.
    Example 8. Betamethasone-21-myristate.
    As a result of the reaction of 2 mmol of betamethasone and 2.4 mmol of myristoyl chloride in 40 ml of methylene chloride and 5 ml of dimethylformamide with 2.4 mmol of triethylamine in 10 mp of methylene chloride for 2 hours at room temperature after the preparation of dimethylformamide. described in example 3, and chromatographic processing (silica gel; a mixture of hexane and acetone in the ratio of 70:30) with the achievement of a 29% yield to obtain the specified connection. The degree of purity of 97%. EM-MS (methane) 603-, M + + 9,631.
    Example 9. Betamethasone-21-palmitate.
    Reaction of 0.5 mmol of betamethasone with 1.0 mmol of palmitoyl chloride in 10 ml of pyridine according to example 1 after preparative thin-layer chromatography (silica gel; 3% ethanol and 97% chloroform) gives the indicated compound. Yield 33%. EM-MS (methane):: MH 631, + 29 659.
    Example 10. Betamethasone-21-oleate,
    As a result of the reaction of 2 mmol of betamethasone and 3 mmol of oleoyl chloride in 20 ml of dimethylformade 1 d with 3 mmol of triethylamine in 5 ml of dimethylformamide for 2 hours at a commatum temperature after evaporation of dimethylformamide, the procedure described in example 3 and chromatographic processing (Sephadex LH20; chloroform) receive the indicated compound. The degree of purity is 96.7%. EM-MS (methane):: MH 657; M - - - +9 685.
    Example 11. Betametaeon-21- -laurat-17-valerate.
    As a result of the reaction of 2 mmol of betamethasone-17-valerate and 2.4 mmol of lauroyl chloride in 90 ml of methylene chloride with 2.4 mmol of triethylamine in 10 ml of methylene chloride for 2 hours at room temperature after the procedure described in example 3, and chromatographic processing (Sephadex LH20j chloroform) with the achievement of 62% yield get the specified connection. The degree of purity of 97.8%. EM-MS (methane): MH 659, - M + 29 687.
    Example 12. Betamethasone-21-myristate-17-valerate.
    As a result of the reaction, 2 mmol beta methazone-17-valerate and 2.4 mmol of myristoyl chloride in 90 ml of methylene chloride with 2.4 mmol of triethylamine in 10 ml of methylene chloride for 2 hours at room temperature after the procedure described in Example 3, and chromatographic processing (Sephadex LH20j chloroform) to achieve 62% yield, the indicated compound is obtained. The degree of purity is 95.5%. EM-MS (methane): MH 687; And + 29 715.
    Example 13. Betamethasone-21-palmitate-17-valerate.
    As a result of the reaction of 1 mmol beta methazone-17-valerate and 1.2 mmol of mitoyl chloride in 50 ml of methylene chloride with 1.2 mmol of triethylamine in 10 ml of methylene chloride for 2 hours at room temperature after the procedure described in Example 3, and chromatographic processing (Sephadex LH20, chloroform) with the achievement of 63% yield get the specified connection. Degree of purity 95.9%, IC-MS (methane): MH 715; 29,743.
    PRI m e. R. 14, Betametazo-21- -stearate-17-valerate.
    As a result of the reaction, 2 mmol beta methazone-17-valerate and 2.4 mmol of aryl chloride in 90 ml of methylene chloride with 2.4 mmol of triethylamine in 10 m
    ten
    15
    20
    25
    thirty
    35
    40
    45
    50
    55
    methylene chloride for 2 h at a combo temperature after the procedure described in example 3 and chromatographic treatment (Sephadex LH-20; chloroform mixed with heptane and ethanol in a ratio of 20: 20: 1) to achieve 59% yield the specified connection. The degree of purity is 92%. EM-MS (methane):: M 743, - M + 29 771.
    Example 15. Flumetazon-21- -laurate.
    As a result of the reaction 1.0 mmol of flumethasone and 1.5 mmol of lauroyl chloride in 5 ml of dimethylformamide and 40 ml of methylene chloride with 1.5 mmol of triethylamine in methylene chloride for 2 hours at room temperature after evaporation of dimethylformamide by the procedure described in example 3, and chromatographic processing (silica gel; a mixture of hexane and acetone in the ratio of 70:30) with the achievement of 64% yield of the indicated compound. The degree of purity of 97.7%. EM-MS (methane): MH 593; M + 29 621.
    Example 16. Flumetazon-21-palmitate.
    The reaction of 0.5 mmol of flumethasone with 1.0 mmol of palmitoyl chloride B 10 MP pyridine according to example 1 after preparative thin-layer chromatographic treatment (silica gel; 3% ethanol and 97% chloroform) gives the indicated compound. Exit 38%. The degree of purity is 98.5%. EM-MS (methane): MH 649; M -t- 29,677.
    Example 17. Flumetazon-21-β-stearate.
    As a result of the reaction of 1.0 mmol of flumethasone and 1.5 mmol of stearyl chloride in 5 ml of dimethylformamide and 40 ml of methylene chloride with 1.5 mmol of triethylamine in 10 ml of methylene chloride after sharing the dimethylformamide procedure described in example 3 and chromatographic processing ( silica gel mixture of hexane with acetone in the ratio of 70:30) with the achievement of 38% yield, the indicated compound is obtained. The degree of purity of 90%, IC-MS (methane): MH 677.
    Example 18. Flumetazon-21-oleate.
    As a result of the reaction of 1.0 mmol of flumethasone and 1.5 mmol of oleoyl chloride in 5 M.Ch of dimethylformamide and 40 m of methylene chloride with 1.5 mmol of three ethylamine in 10 mg of methylene chloride after evaporation of dimethylformamide by the procedure described in example 3 and chromatographic processing (strength Kagel mixture of hexane with acetone in the ratio of 70:30) with the achievement of 12% yield of the specified connection. The degree of purity of 98.2% IC-MS (methane): MH 675-, H + + 29,703.
    Example 19. Flumetazon-21-laurate-17-propionate.
    As a result of the reaction of 1 mmol of flumetazon-17-propionate and 1.5 mmol of lauroyl chloride in 40 units of methylene chloride with 1.5 mmol of triethylamine in 10 ml of methylene chloride following the procedure described in Example 3 and chromatographic treatment (silica gel mixture hexane with acetone in the ratio of 70:30) with the achievement of a 33% yield get the specified connection. The degree of purity of 94.4%. EM-MS (methane): W 649; M + 29 677.
    Example 20. Flumetazon-21-myristate 17-propionate.
    As a result of the reaction of 1 mmol of flumethasone-17-propionate and 1.7 mmol of myristoyl chloride in 40 mp of methylene chloride with 1.7 mmol of triethylamine in 10 MP of methylene chloride after the procedure described in example 3, and chromatographic processing ( kagel mixture of hexane with acetone in the ratio of 70:30) with the achievement of a 55% yield, the indicated compound is obtained. The degree of purity is 96.7%. EM-MS (methane): M 677.
    Example 21. Flumetazon-21-β-palmitate-1 7-propionate.
    As a result of the reaction, 2.8 mmol of flumethasone-17-propionate and 3.3 mmol of palmitic chloride in 150 mp of methylene chloride with 3.3 mmol of triethylamine in 10 ml of methylene chloride after the procedure described in the 1st in Example 3 and chromatographic processing (Ce - fadex LH20; chloroform) with the achievement of 14% yield get the specified connection. The degree of purity is 98.8%. EM-MS (methane): MH 705; + 29 733.
    Example 22. Flumetazon-17-propionate-21-stearate.
    five
    Q
    0
    five
    0
    five
    As a result, 1.0 mmol of flumethasone-17-propionate and 1.5 mM of stearoyl chloride in 40 mp of methylene chloride with 1.5 mmol of triethylamine in 10 ml of methylene chloride after the procedure described in example 3 and chromatographic treatment ( ; a mixture of hexane with acetone in the ratio of 70:30) with the achievement of a 44% yield get the specified connection. The degree of purity is 95%. EM-MS (methane): MH 733; - 761.
    Example 23. Flunisolid-21- -laurate.
    As a result of the reaction, 0.3 mmol of flunisolide and 0.64 mmol of lauroyl chloride in 20 MP of methylene chloride with 0.64 mmol of triethylamine in 5 ml of methylene chloride after the procedure described in Example 3 and chromatographic treatment (silica gel, hexane / acetone mixture in the ratio of 70:30) with the achievement of 65% yield get the specified connection. The degree of purity is 97.6%. EM-MS (methane):: MH 612; M + 29 645.
    Example 24. Flunisolid-21-myristate.
    As a result of the reaction of 0.5 mmol flunisolid and 0.65 mmol of myristoyl chloride in 20 ml of methylene chloride with 0.65 mmol of triethylamine in 5 ml of methylene chloride after the procedure described in example 3, and chromatographic processing (silica gel; hexane / acetone in a ratio of 60% : 40) with a 54% yield, the indicated compound was obtained. The degree of purity is 98.5%. EM-MS (methane):: MH 645; M + 29 673.
    Example 25. Flunisolid-21-palmitate.
    As a result of the reaction, 433 mg of phpunnzolide, 400 mg of palmitoyl chloride and 500 mg of triethylamine in 8 mp of methylene chloride for 2 hours at room temperature, following the procedure described in example 3, and preparative chromatographic thin layer processing (silica gel, chloroform), the indicated compound is obtained. with a 29% yield. The degree of purity is 98.5%. EM-MS (methane): MH “673j M + 29 701.
    Example 26. Flunisolid-21-β-stearate.
    As a result of the reaction, 0.46 mmol of flunisolide and 0.7 mol of starsaroyl chloride in 40 ml of methylene chloride with 0.7 mmol of triethylamine in 10 ml of methylene chloride after the procedure described in Example 3 and chromatographic treatment (silica gel; hexane mixture with acetone in the ratio of 70: 30) with the achievement of 53% pus output, the indicated compound is obtained. The degree of purity of 92%, IU-MS (methane): MH 701, 29 729.
    Example 27. Beclomethasone-21-β-palmitate-17-propionate.
    As a result of the reaction, 40 ml of beklometazon-17-propionate, 100 mg of palmytoyl chloride and 50 mg of triethylamine in 5 ml of methylene chloride for 2 hours at room temperature after the procedure described in Example 3 and preparative thin-layer chromatography : 3% ethanol and 97% chloroform) with the achievement of 54% yield get the specified connection. EM-MS Sour Cream): MH 703.
    Example 28. Dexamethasone-21-palmitate-17-propionate.
    As a result of the reaction, 4 mmol of dexametazon-17-propionate and 8 mmol of palmitoyl chloride in 100 ml of methylene chloride with 8 mmol of triethylamine in 30 ml of methylene chloride for 2 hours at room temperature after the procedure described in Example 3 and chromatographic processing (Sephadex LH20J a mixture of heptane with chloroform and ethanol in the ratio 20: 20: 1) with the achievement of a 25% yield, the indicated compound is obtained. The purity is 96%. EM-MS (methane): 715.
    Biological testing. Anti-inflammatory effect.
    Intratracheal inspiration of Sephadex globules in rats leads to bronchial as well as alveolar inflammation. This causes interstitial pulmonary edema, which leads to an increase in lung weight, so this inflammation can be classified as an increase in lung weight in comparison with the lungs of animals in the control group subjected to instillation of a saline solution. The formation of pulmonary edema can be prevented by pre-treatment with glucocorticoids, before
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    more respectful than the local introduction into the body by way of pinnopracheal in- ST) CH1E1 AND or inhalation. The ideal anti-inflammatory effect should be achieved only by local glucocorticoid treatment of the lungs, and not of the rest of the body, since such long-term treatment can lead to therapeutic, restrictive systemic side effects.
    The difference between glucocorticoid effects in the treated. zone of the lungs and outside this zone can be set as follows. Sprague-Dawley rats (weighing 225 g each) were lightly anesthetized with diethyl ether, and the glucocorticoid test preparation (in liposomes suspended in saline solution) in an amount of 0.5 MP / kg was injected into the left lobe of the lungs of animals. After 2 hours far above the bifurcation, a suspension of Sephadex globules (5 mg / kg in a volume of 1 mg / kg) was instilled into the trr1 shey, due to which this suspension reached both the left and right dollars of the lungs. After 20 hours, they killed 1; and, they removed the left and right lobes of the lungs and weighed them separately. In addition, after 20 hours, the determination of the weight of the ce, 1 tesenko and body weight. Only the carrier was administered to the control group instead of the glucocorticoid drug, and instead of the suspension of Sephadex balls, saline, which allowed determining the weight of edema caused by Sephadex balls, in the absence of treatment, the normal weight of the lungs, as well as the normal weight of the spleen and the body weight.
    As indicated, the ideal glucocorticoid drug should have a very high glucocortical activity at the site of treatment with a light, but very weak action outside this one. Thus, in the selected model, the optic preparation should, to a greater or lesser extent, block edema in the area of the locally pretreated left lung lobe, but show a significantly weaker effect in the right lung lobe, having only half the amount of inhibitory or not. Something noticeable is generally inhibitory about the effect on the weight of the spleen and on the weight of body weight in cen
    scrap. It is considered more important to search for a high degree of difference between a local action (an example of which is an action in the left lung) and other effects than to achieve a high absolute potency (high activity per milligram of the drug) for the effect on the left lung. During the tests, dosages were selected that lead to more or less complete blockage of edema in the left lung, and at such dosages the degree of activity in other areas was calculated. At the selected dosage, parallel tests were performed on 7-9 rats. The mean values of + s.e.m were calculated and compared with the Student's criterion related to the results of the corresponding control group of animals that were injected with Sephadex balls.
    The results of comparative studies of pulmonary edema caused by Sephadex beads are summarized in Table 1. The pharmacological profile of the proposed compounds was compared with the pharmacological profile of budesonide (selected as normal glucose).
    a co-corticoid with a local effect, as established by skin testing) and pharmacological profiles of budeson-21-valate, dexamethasone-21-palmitate, fluocinolone-cetonide-21-palmitate and hydrocortisone-21-palmitate. Bu-desonide, budesonide-21-valerate and hydrocortieon-21-palmitate do not meet the requirement of very high local activity (only 38% decrease in edema of the left lung). Dexamethasone-21-palmitate and fluocinolone-21-palmitate completely block the edema of the left lung, but this action is combined with high activity in the area of the other lung, which is only half the effect in the left lung, and at the same time with a decrease in weight gain of the body and spleen. Thus, none of the tested drugs have a selective glucocorticoid effect at the site of their treatment of the lung.
    Preparations based on the proposed compounds have a significantly more selective action at the site of their treatment of the lung. They are all in
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    more or less block the edema of the left lung (minimum protection for beclomethasone-21-palmitate-1 7-propionate 87%). This action was completely unexpectedly combined with only a weak or moderate protective effect in another lung (maximum approximately 45% on protection) in the absence of a statistically noticeable decrease in the increase in body weight or spleen.
    The obtained test data of pulmonary edema given in Table 2 show, compared to the control group, the inhibition of pulmonary edema when administered locally to the left lobe comparable to systemic activity in the right lobe of the lung.
    Thus, the proposed compounds have high local activity in blocking edema, for example, the left lobe of the lung and at the same time exhibit low inhibitory activity in another, i.e. in the right lobe, lung.
    In addition, the compounds do not lead to a significant reduction in body weight, which is an advantage with respect to side effects compared with some of the compared compounds.
    The observed effects on the right lobe of the lung, spleen and body weight in comparison with the control are criteria for evaluating side effects on the body. These effects are relatively low for the proposed compounds as compared with the known compounds.
    权利要求:
    Claims (1)
    [1]
    Thus, in comparison with known compounds of similar structure, an unobvious and unexpected indicator of the therapeutic effect of the target compounds is noted. Invention Formula
    The method of producing steroid esters of the general formula
    Q - OS - R,
    II
    Where Q is a residue of the formula:
    55
    BUT
    or
    .... 0-R
    or
    or
    whitefish
    but .i .-- Ov.f, CH3
    go ggt
    I
    F
    Available:
    Be Clometazon-21-Palmitate-17-Propionate
    betamethasone-21-palmitate
    budesonide-21 palms
    tat
    dexamethasone-21-palmitate-17-propionate
    flumetazon-21-palmitate-17-propionate
    Equal: budezoid
    budesonide-21-valerate dexametaz he-21-palmitate
    fluocinolone acetonide -21 palmitate
    or
    sixteen
    CIS
    C-0
    ..-- PSPG, 11,11,
    -t,
    where R is saturated or unsaturated, straight or branched C, 1 -C, 5-alkyl cadaver R is hydrogen, the group
    or WITH (СН), СНз,
    characterized in that the compound of formula
    Q - Z,
    where Q has the indicated values
    Z is a hydroxyl group, is esterified with a compound of the general formula
    ,
    where R, has the indicated meanings; X is a hydroxy group or halogen, followed by isolation of the target products.
    Table 1
    hydrocortisone-21-palmitate335
    (DK) - negligible - not explored
    ,, 0.05, 0.01, 0.001.
    Continuation of table 1
    -13
    -7
    -UH3)
    Table 2
    类似技术:
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    同族专利:
    公开号 | 公开日
    FI852932A0|1985-07-29|
    HK78293A|1993-08-13|
    EP0170642B1|1991-02-27|
    ES8704969A1|1987-04-16|
    NO168042B|1991-09-30|
    DD236535A5|1986-06-11|
    HUT39460A|1986-09-29|
    CS254342B2|1988-01-15|
    HU196827B|1989-01-30|
    FI84914C|1992-02-10|
    FI852932L|1986-01-31|
    KR930000045B1|1993-01-06|
    JPH0459297B2|1992-09-21|
    PT80884A|1985-08-01|
    IS3026A7|1986-01-31|
    AU582173B2|1989-03-16|
    EP0170642A3|1986-10-29|
    IE58074B1|1993-06-30|
    DD248055A5|1987-07-29|
    YU45735B|1992-07-20|
    PL254681A1|1986-11-18|
    SE8403905D0|1984-07-30|
    DK336385D0|1985-07-24|
    NZ212861A|1989-01-27|
    PT80884B|1987-11-30|
    SG69093G|1993-08-06|
    NO852672L|1986-01-31|
    PL145673B1|1988-10-31|
    ES557143A0|1987-05-16|
    EG17462A|1991-03-30|
    ZA855032B|1986-03-26|
    AT60990T|1991-03-15|
    DK164509C|1992-11-23|
    AU4530785A|1986-02-06|
    EP0170642A2|1986-02-05|
    IE851892L|1986-01-30|
    NO168042C|1992-01-08|
    CY1731A|1994-05-06|
    ES545651A0|1987-04-16|
    ES8705895A1|1987-05-16|
    CA1250830A|1989-03-07|
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    YU123885A|1988-02-29|
    IS1515B|1992-11-04|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    SE8403905A|SE8403905D0|1984-07-30|1984-07-30|LIPOSOMES AND STEROID ESTERS|LV930864A| LV5527A3|1984-07-30|1993-06-30|Saturation of steroid esters|
    LTRP951A| LT2257B|1984-07-30|1993-09-06|STEROID ESTER RECEIPT BUDGET|
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