1
`
`EX 1020
`IPR of U.S. Pat. No. 7,829,595
`
`

`
`BIOA VAILABILITY OF SPIRONOLA CTONE
`
`tone improved bioavailability when com-
`pared to that of the standard tablet and to
`determine whether micronization increased
`pharmacologic activity.
`
`Methods
`
`Physical’ Characteristics of Formulations.
`The formidations complied with the B.P.
`monography requirements for spironolac-
`tone. To ensure that the materials in the
`study were as closely related as possible, a
`common batch of the precursor, canrenone,
`was used to manufacture all tablets, the
`proportions and batches of excipients also
`being kept constant. After thioacetylation,
`the resultant spironolactone was washed
`normally, producing standard spironolac-
`tone. Subsequently, half of the standard
`batch was converted to micronized spiron o-
`lactone by means of a fluid energy micron-
`izer. The chemicals were compressed into
`25- and 100-mg tablets by conventional
`manufacturing procedures which were
`
`identical for all tablets. For standard ta-
`blets spccific surface area was 1.37 m2/Gm
`and median particle size was 78.8 ,um, while
`for micronized tablets the values were 6.00
`mg/Gm and 2.2 pm, respectively.
`In Vitro Dissolution'Rate. U.S.P. gastric
`juice, 5 liters, without enzymes was equili-
`brated to 3'/"C in a three-neck, round-
`bottom flask. A Polytef paddle (132 X 24
`mm) was immersed to 2 cm from the bottom
`of the flask and rotated at 100 rpm. The
`I amount of drugin solution from four 25-mg
`tablets or one 100-mg tablet placed on the
`bottom of the flask was determined from
`samples removed at 20, 40, 60, and 120 min-
`utes. After removal, the fluid was filtered
`and the amount of spironolactone was de-
`termined spectrophotometrically with a
`standard solution of spironolactone U.S.P.
`as reference (Fig. 1).
`Outline of Method. Micronized spirono-
`lactone tablets were compared to standard
`tabletsin 24 healthy men, each given single
`
`Percentage
`dissolution
`
`W0
`
`90
`
`80
`
`70
`
`60
`
`
`
`0
`
`T‘
`l
`
`Time in hours
`Fig. 1. In uitro dissolutionprofiles ofthe spironolactone tablets used in the
`study. Micronfzed tablets: (0-—~ol 25 mg; (><~-—x) 100 mg. Standard tablets:
`(o-o) 25 mg; {x—x) I90 mg.
`August-Sept.ember1982
`
`411
`
`J.K.),
`J.K.),
`J.K.},
`B.Sc.
`]ClOi'n
`
`moi
`
`u.»
`
`asma
`activ-
`armo-
`
`ildac-
`Great
`
`ii the
`it bad
`
`if spi-
`eir in
`on of
`l v"*"o
`b.
`78 to
`iolac-
`
`uzology
`
`2
`
`

`
`to 96 1'.
`ble I.
`nary I
`size ai
`tistica
`
`25-mg
`
`August
`
`l t l l l e
`
`Mc1NNES, ASBURY, RAMS/4. Y, ET AL.
`
`200-mg doses of spironolactone on two oc-
`casions separated by an interval of two
`weeks. The order of administration of the
`two formulations was balanced. Tablets
`were prescribed open-label, but all labora-
`tory assays were performed with out knowl-
`edge of the medication taken. Twelve of the
`subjects were givenspironolaetone as 25-
`mg tablets and theiother 12, as 100-mg tab-
`lets. Bioavailability was assessed by mea-
`surement of plasma and urinary canre-
`none levels for 96 hours after treatment.
`Pharmacologic activity was measured by
`urinary electrolyte responses in the 24-hour
`period after drug administration.
`'
`
`Subjects. Twenty-four male subjects,
`judged healthy after medical history, phys-
`ical examination, and biochemical and
`hematologic screening, gave written in-
`formed consent to participate in the studies.
`The groups of subjects taking part in the
`experiments were comparable in age, height,
`and weight. Characteristics of the subjects
`in the treatment groups were as follows:
`25-mg Tablets: age, mean 28.8 i- 4.1 years
`(range 24 to 37 years); height, mean 69.6 i
`2.6 in. (range 65 to 73.5 in.); weight, mean
`153.9 : 16.6 lb (range 133 to 182 lb). 100-mg
`Tablets: age, mean 28.3 i 4.3 years (range 24
`to‘ 37 years); height, mean 69.5 :t: 1.9 in.
`(range 66 to 73 in.); weight, mean 1563 i
`18.1 lb (range 133 to 196 lb). The protocol
`was approved by an independent ethical
`committee.
`
`Procedure. The treatments were taken
`with 300 ml water at 9 A.M. after a 10-hour
`fast, fasting being continued for a further 4
`hours. For 24 hours after medication, the
`subjects, who were ambulatory, followed a
`diet designed to provide mild sodium re-
`striction (calculated sodium content 90'
`mmoles/24 hr), constant during each study
`period. In these Circumstances, the ‘urinary
`electrolyte responses to spironolactone
`differ
`significantly from those after
`placebo.9 Venous blood samples were taken
`at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 8,12, 24, 28, 32, 48,
`72, and 96 hours after treatment. Plasma
`412
`
`was separated immediately and stored at
`—20°C until just before assay. Urine was
`collected at 0-24, 24-48, 48-72, and 7296
`hours after drug administration. After
`measurement of volumes, aliquots were
`stored at -20°C for subsequent assay. The
`subjects abstained from alcohol during
`sampling periods, and all other medica-
`tions were prohibited throughout the study.
`Laboratory. Plasma and urinary canre-
`none concentrations were measured by a
`iluorimetric method,” urinary sodium by
`atomic absorption spectrophotometry, and
`urinary potassium by flame photometry
`with lithium as internal standard. Recov-
`ery of canrenone from plasma averaged
`89.6 per cent (range 80 to 111 per cent), and
`mean recovery ofcanrenone from urine was
`85.9 per cent (80 to 90 per cent).
`
`Statistical. Analysis of variance was
`used to compare the direct treatment effects
`after isolating variability related to sub-
`jects and phases of the studies. The area
`under the plasma canrenone concentration-
`time curve to 96 hours was calculated by the
`trapezoidal rule.
`
`Results
`
`Plasma Canrenone. The plasma canre-
`none concentration—tirne curves for 25- and
`100-mg tablets are shown in Fig. 2. For
`convenience, results for only the first 32
`hours after administration are shown. Be-
`tween 32 and 96 hours, there were no signif-
`icantdifferences between standard and mi-
`cronized tablets of either size. Overall, the
`micronized preparation gave significantly
`greater peak canrenone concentration (55.2
`i 3.0 pg/I00 ml against 43.1 i: 2.3 pg/100
`ml, P < 0.001) and area under the plasma
`concentration—time curve (A UC) (757.8 i
`38.9 ,::g/100 ml - hr against 661.5 :i: 33.6
`pg/100 ml - hr, P< 0.001). The times to peak
`concentrations (2.9 i 0.1 and 3.1 i 0.2
`hours, respectively) were not significantly
`different.
`
`Urinary Canrenone Excretion. The ex-
`cretion of canrenone in urine for periods up
`
`The Journal of Clinical Pharmacology
`
`3
`
`

`
`BIOA VA ILABJLITY OF SPIRONOLA CTONE
`Mean Plasma Canrenone
`Concentration
`
`50 Hg/300ml
`
`25 mg tablets
`
`Mean Plasma Canrenona
`Concentration
`
`60
`
`ug/100ml
`
`Ll
`1‘
`
`_
`
`100mg tablets
`~
`
`
`
`
`to 96 hours after treatment is shown in Ta-
`ble I. Micronization produced higher uri-
`nary canrenone excretion for each tablet
`size and overall, but the difference was sta-
`tistically significant (P < 0.025) only for
`251mg tablets in the first 24 hours.
`August-September 1982
`
`Relative Bioavazihbiliiy. Table ll ShOWS
`the observed ratio of micronized tablets:
`standard tablets for mean 96-hour AUC
`and 96-hour urinary canrenone excretion
`with 95 per cent confidence limits for the-true
`ratio. Overall, the bioavailability ofthe mi-
`413
`
`
`
`‘3\..
`
`
`
`atry
`:ov-
`
`ged
`and
`was
`
`was
`
`acts
`;ub—
`IE?
`
`Lhe
`
`are-
`
`For
`
`ntly
`55.2
`‘100
`mm
`
`8 :l:
`33.6
`ea};
`0 2
`
`utly
`
`ex-
`
`-113
`
`-logy
`
`4
`
`

`
`McINNES, ASBUIEY, RAMSA Y, ETAL. '
`
`Table I
`
`Mean :1: S.E.M. Urinary Canrenone Excretion After Oral
`Administration of 200-mg Single Doses of Spironolactone
`as Eight 25-mg Tablets or Two 100-mg Tablets
`
`
`Time after
`drug
`admini.-stratipn (hr) -
`
`Urinary canrenonc excretion (mg)
`25—mg Tablets (N : 12) 100-mg Tablets (N = 12}
`.j.flé____1.
`Micronized
`Standard Micronized
`Standard
`
`0 - 24
`24 — 48
`48 — 72
`72 — 96
`0 — 96
`
`,
`
`8.42 :1: 0.90‘
`1.14 I 0.15
`0.35 :1: 0.05
`0.16 :1: 0.03
`10.08 i 1.04
`
`7.07 d: 0.48
`1.40 i 0.23
`0.37 :l:_CI.03
`70.1’? i 0.06
`9.01 t 0.63
`
`613-: 0.42
`0.9’? :1: 0.13
`0.42 :t.' 0.06
`0.2} i 0.03
`7.74 i 0.57
`
`6.01 3: 0.37
`1.02 :t: 0.13
`0.39 ;t 0.05
`0.21 :l: 0.04
`7.63 :1: 0.47
`
`‘ Statistical significance of difference between means: P< 0.05.
`
`cronized formulation relative to standard
`spironolactone was 114.6 per cent (95 per
`cent confidence limits 108.0 and 121.6 per
`cent) for 96-hour AUC and 107.0 per cent
`(98.1 and 116.8 per cent) for 96-hour urinary
`canrenone excretion. The increase in rela-
`tive bioavailability was particularly marked
`for 25-mg tablets: 118.3 per cent (108.0 and
`129.7 per cent) and 111.8 per cent (99.6 and
`125.8 per cent) for 95-hour A UC and 96-hour
`urinary canrenone excretion, respectively.
`
`Bios um'labi1.'ity Related to In Vitro Disso-
`lution Cha.racteristz'cs. Micronization lead
`to more rapid dissolution, and this was par-
`ticularly marked for the 25-mg tablets. At
`
`40 minutes, for 25—mg tablets, 91 per cent of
`micronized drug was in solution, in con-
`trast to 71 per cent of the standard tablet
`(Fig. 1). Per cent dissolutions for the 100-mg
`tablets were 80.7 and 73 per cent, respec-
`tively. Figure 3 demonstrates the relation-
`ship of 96-hour AUC for canrenone with
`percentage dissolution at 40 minutes. The
`relationships for 25- and 100-mg tablets
`were similar, indicating that in vivo differ-
`ences are consistent with in vitro dif-
`ferences.
`
`Phormacologic Responses. The urinary
`electrolyte responses, increased sodium ex-
`cretion, and reduced potassium excretion in
`
`TABLE 11
`
`Per Cent Bioavailability of Micronized Relative to
`Standard Spironolactone Tab1ets*
`
`Preparation
`
`25-mg Tablets
`100~mg Tablets
`
`Overall
`
`By 96- hr A UCT
`
`113.3 (108.0 — 129.7)
`111.1 (101.8 — 121.5)
`
`114.6 (103.0 - 121.6)
`
`Bioavailability (912)
`
`By 96-hr urinary canrennne excretion“
`
`111.8 (99.5 e 125.8)
`101.4 (87.2 - 117.9)
`107.0 (98.1 — 115.3)
`
`Mean 96?
`lug /100m
`750
`
`?00
`
`6.5
`
`60
`
`Fig. 3. 1
`crmreno
`minutes.
`ized (0)::
`
`the 24 l
`
`ently gr
`
`lactone
`the mo:
`ralocorr
`III. The
`
`highly .
`
`Discus
`
`Com;
`microni
`
`* Figures in parentheses are 95 per cent confidence limits.
`________i___;__;___ X 100.
`1 Canrenonc A US after micmnized tablets
`Canrenone A UC after standard tablets
`
`** Urinary canrenone excretion after micronized tablets
`Urinary canrenone excretion after standard tablets
`414
`
`X 100.
`
`The Journal of Clinical Pharmacology
`
`
`
`August-E
`
`5
`
`

`
`t of
`on-
`
`Jlet
`mg
`Jee-
`on-
`
`ilogy
`
`rith
`[‘h-V
`ts
`‘fer-
`dif-
`
`flTy
`. ex-
`
`n in
`
`Menn96hrAUC
`[pg/300ml X hr]
`750
`
`700
`
`«S50
`
`600
`
`BIOA VA ILA BILITY OF SPIRONOLA CTO-‘NE
`
`.
`
`ment in the bioavailability of spironolac-
`tone; and, for plasma canrenone variables,
`the differences were statistically signifi-
`cant. Urinary canrenone excretion was’
`also greater following micronized spirono-
`lactone. Although representing only a small
`fraction of the total drug dose, there is evi-
`dence that urinary canrenone excretion
`may provide bioavailability information
`similar to that obtained from plasma data.fl
`Urinary canrenone may be particularly
`relevant since the renal activity of spirono-
`lactoneis related more closely to the level of
`canrenone in distal tubular fluid than to
`that in plasma."
`The greater bioavailability of the micron-
`ized formulation reflected differences in the
`dissolution profiles of the spironolactone
`preparations, the correlation between dis-
`solution characteristics in vitro and bio-
`availability of spironolactone tablets being
`consistent with previous observations.” In
`turn,
`this may be attributed to particle
`size—the median particle sizes of micron-
`ized and standard spironolactone tablets
`were 2.21 and 78.8 ,u.II'l, respectively. Reduc-
`tion iniparticle size improves the bioavaila-
`bility of other drugs with poor solubility in
`water,” presumably by increasing dissolu-
`tion rate.” Our findings support sugges-
`tions ofa similar advantage for micronized
`spironolactone.” However, the results of
`this study relate directly only to the particu-
`lar chemical batch from which the tablets
`were made; moreover, the improvement in
`bioavailability attributed to micronization
`depends partly on the performance of the
`I
`
`T:"’f'
`70
`B0
`90
`Z Dissolution ol 40mins
`
`Fig. 3. Relationship of mean 96-hour AUC for
`canrenone with percentage dissolution at 4'0
`minutes. Mean data for both tablet sizes: micron-
`ized (I) and standard {0} spironolactone tablets.
`
`the 24 hours after treatment were consist-
`ently greater following micronized spirono-'
`lactone; and the results for log“; 10 Na/K,
`the most sensitive index ofrenala1itirnine-
`ralocorticoid activity, are shown in Table
`III. The overall difference was statistically
`7 highly significant (P< 0.01).
`
`Discussion
`
`Compared to the standard preparation,
`micronization clearly lead to an improve-
`
`TABLE III
`
`Mean :l: S.E.M. Urinair
`y logmlfl Na/K Responses in 24-Hour
`Period After Oral Administration of 200-mg Single Doses of
`Spironolactone as Eight 25-mg 'Pablets or Two 100-mg Tablets
` m_;_
`Spironolactone
`Iogm 10 Na/K
`_c_______.c_____.
`preparation
`
`25-mg Tablets
`100-mg Tablets
`Overall
`
`Micronlzed
`
`Standard
`
`1.53 i 0.04
`1.47 1: 0.04‘
`1.50 i 0.03”
`
`1.47 .4: 0.03
`1.411 0.05
`1.44 i 0.03
`
`Statistical significance of difference between means: “ P< 0.05; "" .P< 0.01.
`August-September 1982
`
`415
`
`6
`
`

`
`12.
`
`.
`
`13.
`
`14.
`
`-Mr:INNES, ASB URY, RAMS/1 Y, ET AL.
`
`reference tablets. Since the standard tab-
`lets had relatively good dissolution charac-
`teristics, the benefits of micronization may
`have been underestimated slightly.
`K
`The levels of a drug or its metabolites in
`blood or urine provide prima facie evidence
`of absorption but not proof of pharmaco-
`logic activity. Howfyer, micronizatioli also
`resulted in a significant improvement in
`24-hour urinary logm 10 Na/K, the most
`sensitive single index of renal antimineral-
`
`ocorticoid activity.” This is in keeping with
`animal studies,” where the pharmacologic
`activity of different preparations of spiro-
`nolactone given orally was related posi-_
`tively to the plasma levels of canrenone
`
`achieved. No such relationship was noted
`in one previous study in healthy men,” but
`in that study the urine collecti on period was
`inappropriately short."
`It should be remembered that results
`
`from single-dose studies may not reflect
`clinical practice where spironolactone is
`usually prescribed for long periods and ex-
`hibits cumulative pharmacokinetics” and
`pharmacodynamics.]9 Since spironolactone
`has a shallow dose-response relationship
`and a high therapeutic ratio, itis difficult to
`predict the degree to which the observed
`
`differences in bioavailahility would be ac-
`companied by either increased clinical effi-
`
`' cacy or increased side effects. Nevertheless,
`the significant changes in urinary electro-
`lyte responses associated with microniza-
`ti_on suggest that some improvement in ac-
`tivity should be seen in the clinical situation.
`In more general terms, our results emphas-
`ize the importance of bioavailability in de-
`termining the therapeutic effect of different
`spironolactone preparations. As a ‘conse-
`quence, modifications in the manufacture
`of spironolactone (Aldactone) tablets are
`being considered.
`
`Acknowledgments
`
`The authors gratefully acknowledge the con-
`tributions of Dr. J. K. Butler, Dr. S. A. Murray,
`Dr. R. F.Palmer, Mr. F.St.J. Forbes, and Mrs. M.
`Porteous in the execution of these studies.
`416
`
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`
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`
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`
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`The Journal of Clinical Pharmacology
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`Augi
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`7
`
`

`
`810A VA ILABILITY OF SPIRONOLA CTONE
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`
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`‘.
`
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`
`Address for correspondence: Gordon T. Mclnnes, De-
`partment of Medicine, Gardiner Institute, Western In-
`firmary, Glasgow G11 SNT, United Kingdom.
`
`tion
`gen-
`
`962;
`
`VI. A
`tone
`ll‘. of
`
`-g‘o.
`dac-
`23:
`
`tone
`
`962;
`
`JR,
`Fa c-
`bio-
`niets.
`
`: IR.
`tone
`9rJ
`
`etri c
`
`August—Sepl.embcr 1982
`
`417
`
`8
`
`

`
`J C!!!
`
`Van
`
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`
`am
`
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`
`ergi
`
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`latic
`man
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`tion
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`tion
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`drug
`From
`and l'
`
`Augu
`
`The. Journal
`
`of Clinical
`Pharmacology
`
`(ISSN 00912700)
`
`
`
`AUGUST-SEPTEMBER1982
`
`Vol. 22
`
`Nos. 8 and 9-
`
`PHARMACOLOGY
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`Official Publication of The American College of Clinical
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`Pharmacology
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`9