CA1327009C

CA1327009C - Pharmaceutical composition for oral administration, based on a diphosphonic acid derivative

Info

Publication number: CA1327009C
Application number: CA000595974A
Authority: CA
Inventors: Jean-Pierre Fels; Jean-Claude Gromenil; Bernard Abramovici
Original assignee: Sanofi SA
Current assignee: Sanofi Aventis France
Priority date: 1988-04-07
Filing date: 1989-04-06
Publication date: 1994-02-15
Anticipated expiration: 2011-02-15
Also published as: DE68900994D1; KR0135420B1; IL89868A; IE891103L; OA09415A; FR2629716A1; EP0336851B1; IL89868A0; KR890015738A; JPH026409A; DK166989A; NZ228617A; EP0336851A1; AU3258889A; DK166989D0; FR2629716B1; IE60923B1; PH26647A; JP2602947B2; US4980171A

Abstract

entitled : Pharmaceutical composition for oral administration, based on a diphosphonic acid derivative in the names of : Jean-Pierre FELS
Jean-Claude GROMENIL
Bernard ABRAMOVICI

Assignee : SANOFI

Abstract of disclosure The invention relates to oral pharmaceutical compositions comprising a diphosphonic acid derivative and sodium laurylsulfate in the amount of 1.5 to 6% by weight, relative to the diphosphonic compound.

Description

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The pre~ent invention relate~ to a pharmaceutical compo~ition for oral administration, based on a diphos-phonic acid derivative and containing ~n appropriate amount of ~odium l~urylsulfate. Such a pharmaceutical 05 compo3ition has an excellent bioavailability in human.
In the deqcription and in the claim~ which follow, dipho~phonic acid derivative i~ understood as meaning a compound of the for~ula O R O
D ll H ~I) OH R2 ~

in which R1 represent~ a hydrogen atom, a halogen atom~
hydroxyl, an amino or a dial~yl(Cl-C4)amino, and R2 represents a halogen atom, a linear al~yl ~ontainin~
from 1 to 5 ~arbon ~tom~ which i~ unsub~titut~d or ~ub~
stituted by a chlorine atom9 a hydroxyl, an amino or a dialkyl(C1-C4)amino, or ~z represent~ a phenoxy, a phenyl, a thiol, a phenyl-thio, a chlorophsnylthio~ a pyridyl or a thiomorpholin-: 4-yl, ~nd their 8alt8 with pharmaceutic~lly acceptabl~ mineral or orsanic a~ids.
The~e compound~ are ~no~n. ~h~y ha~ been de~-cribed as drugs which are u~eful i~ the oral treatm~nt o~
bone complaints or articular complaints o~ tha arthritis type~ e8pecially in the ~ollowing patent~: BE 902~08, B~
BB5434, EP 203649, DE 2130794, BE 822930, ~S 4134969, ~P
162510, FR 2525223, EP 39033. US 4578376~ US 4621077, JP
55-98193, ~P 186405~ EP 100718, WO 86/00902, WO 87~03598 1327~9 and FR 2531088.
The following compound~ may be mentioned in par-ticular a~ diphosphonic acid derivative~:
- 1-hydroxyethylidenedipho~phonic acid, who~e inter-05 national common name i9 etidronic acid 7 and its sodlumsalt~;

- 2-(pyridin-2-yl)sthylidenedipho~phonic acid, whose international common name i~ piridronic acid, and it~
~odium 8alt8, - dichloromethylenedipho~phonic acid, whose international COmmOD name i~ clodronic acid, and it~ ~odium salt~;
~ 3-amino-1-hydroxypropylidenedipho~phonic acid, who international common name is pamidronio acid, and it~
sodium ~alt~;
~5 - 4-amino-1-hydroxybutylidenedipho3phonic acid and it~
9alt8;
- 6-amino-1-hydroxyhexylidenediphosphonic acid and it~
salt~;
- phenoxymethylenedipho~phonio acid and ~ t8 8alt~;
- thiomorphollnomethylenediFho~phonic acid and it~ salt~;
and - 4-chlorop~enylthiomethylenediphoaphonic ac~d, called compound A below, and it3 pharmaceutically acceptable ~alt~, especlally the di~odium ~alt of com~ound A.
2~ Compound A and ~ts ~alt~ are ds~cr~bed ln French patent 2 531 088. The~e compound~ have ant~rhe~matic and antiarthritic properties ~nd they al~o inhlbit bone re-80rption. The~e com~ound~ can be u~d ~n the treatment o~
rheumato~d polyarthriti~, Paget'~ disea ~ and 08too-porosi~.
It i~ known that dipho~phonic acid derivative~ are u9c~ul as d ru~ in the oral treatment of bone complaint~
or artioular complaints of the arthriti~ type~ It i~ al80 known that these d~rivative~ are not woll ab~orb~d when 3~ they are ~dminl~tered orally ~nd that, to overcome tht~

1327~9 poor ~bsorption, it is nece~ary to admini~ter high ~Dsages of active principle.
US patent 4 230 700 de~cribe~ a method of treatin~
Paget~ 8 disea~e which comprise~ concurrently admini3tering 05 a d$phosphonate and an antirachitic v~tamin D. It i 8 ~tated in the specification of the said patent (page 9 lines 6 to 10 and line~ 49-50) that:
- the oral mode of admini~tration i8 the prQferred mode;
- high dosage~ of the active principle are required because of the limited oral ab~orption of thë active principle (the diphosphonate); and - the a~orption of hlgh dosages of active principle pro-duces toxic effects and mu~t be avoided.
Example 1 of the ~aid patent describ~ a 15 capsule having the ollowing compo~ition:
disodium salt of 1-hydroxy-~thylidenedipho~phonio acid 350 m~
vitamin D3 3000 IU
~tarch 55.60 mg ~odium lauryl~ulfate 2.90 m~
In this Exampla~ the amount of sodium lauryl-sulfat0 containsd in the capsule is about 0.8% by wei~ht relative to the di~odium salt of l-hydroxy-ethylidenediphosphonic acid and about 1% by weight rela-ti~e to the free acid.
Eu~opean patent appl.ication 88 462 de~cribes apharmaceutical compoait~on comprl ing a p~armacologically active and efecti~e ~mount of ~n orgenopho~phonate and a pharM~cologically active and e~fectiYe amount of ~
3~ steroid, it al~o b~ing pos~ible for thc 3aid compo~ition to contain additlonal constltuent~, conventionally used in pharmaceutical compo~itions7 in cu~tomary proportions.
Sodiu~ l~uryl~ul~ate i8 mentioned among th~e ~08 ibl~
additional constituent~.
The ssid document indicates thBt, on oral adminis-1327~9 tration, only 10% of the organopho~phonate i~ ab~orbed by the inteqtine, the remainder being excreted.
It ha~ now been found that if ~odium lauryl~ul*ate i8 added to the dipho~phonic acid derivative~ in an oral 05 pharmaceutlcal compo~ition, in an amount greater than or equal to 1.~% by weight relative to the diphosphonic derivative, the ab~orption of the ~aid diphosphonic derivative i~ improved.
It ha~ al~o been *ound, surpri~ingly, that this improved ab~orption re~ult~ in an lncrea~e in the amount of product ab~orbed without giving ab~orption peak~
capable of having a toxic effect.
It has been found7 totally surpri~ingly, that the be~t ab~orption of the diphosphonic acid derivative i~
accom~anied by a very di~kinct decrea~e in the absorption variation~ between individual~ and hence by a more homo-geneou~ re~pon~e of the treated population toward the dosage of diphosphonic acid derivat.ive administered.
Finally, lt ha~ been found that this improved bio-availability enable ~ufficient and uniform blood level~to ba achievod with ~maller dosages of diphosphonic acid derivative than the do eæ normally employed in therapy.
Thiæ property i~ all the ~ore ~urpri~ing-if one con~iders that, in the ~wo document~ cited ~bove, sodium lauryl~ulfate i8 ~pecifically mentioned, but either in in~ufficient proportion3 to gi~e an absorption-potentiating effect, a~ in the ca3e of US patent 4 230 700, or ~enerically a~ a ~urface-active excipient, a~ in the ca~a of European patent application 88 462.
Thu~ the present inv~ntion relata3 to ~ pharma-ceutical composit~on bssed on a diphoRphonic aoid derivative I or a pharmaceutically acce~table salt, which comprises from 1~5 to 6~ by weight of sodium laurylsulfate rel~tive to the diphosphonic acid derivative.
Accordlng to the present invention, the pre~erred ` 1327~9 pharmaceutical compositions are those containing a di-phoaphonic acid derivative selected from etidronic acid, piridronic acid, pamidronic acid, clodronic acid, 4-chlorophenylthiomethylenediphosphonic acid, 4-amino-1-05 hydroxybutylidenedipho~phonic acid, 6-amino-1-hydroxy-hexylidenediphoaphonic acid, phenoxymethylenedipho~phonic acid, thiomorpholinomethylenediphosphonic acid or one of their pharmaceutically acceptable ~alt~.
Such a compoaition ha~ an improved bioavailabilitY
in human compared with a composition not comprising sodium lauryl~ulfate.
In particular, ~uch a pharmaceutical composition contain~ compound A or it~ di~odium ~alt a~ the active principle.
Preferably, the p~armaceutical compo~ition com-pri~es between 100 mg and 500 mg of 4-chlorophenylthio-methylenedipho~phonic acid (compound A) or the e~uivalent amount of it~ di~odium ~alt, and the amount of sodium laurylsulfate i~ between 1.7 and 4~ by weight relative to the diphoaphonic acid derivative.
The pharmaceutical compo~ition accor~ing to the invention can be in the form of tablet~, capsules, powder, granule3 or drops or in any other form which can be admini~tered orally. The tablet form i~ a pref~rred form.
The compo~ition according to the inventio~ can al~o contain in~redients customarily used in pharmacy for the preparation of oral form~. Thu~ the composition according to the invention may contain a disintegrating agent, a flowing agent, a lubricant and any suitable bulking ~xcipient.
Lactose, cellulose or starche~ can be u~ed as ths bulking excipient. Stesric acid, magnesium atearate, L-leucine or, for example, ~lyc0rnl tribehenate can be used a8 the lubricant. Sodiu~ carboxymethyl atarch, cro~~

~- 1327~0~

linked sodium ~arboxymethyl cellulose or~ for example, cro~linke~ polyvinylpyrrolidone can be u~ed a~ the dl~-inte~ratin~ agent. Pure ~ilica or colloidal silicon di-oxide can be used a~ the flol~lln~ a~ent.
05 The pre~ent invention furthcr relat~e to instan-taneously di~solving oral form~ and to efferve~cent oral forms obtained by addin~ an efferv~scenk pair of compound~
to the compo3ition accordin~ to the invention. Example~
of effervescent pairs of compound~ whlch can be u3ed are tartaric acid and sodium bicarbonate or citric acid and sodium bicarbonate.
Th~ tablet form is a preferred ~orm according to the inverltion. The invention further relate~ to in~tan taneously di~solving tablets, effer~e~cent tablets and coated table$~.
The pharmaceutical compo~ition~ are describad as ~xample~ and in no ~ay limit the scope of the invention.

EXAMPL~ 1 Divi~ible tablet:
- disodium salt of compound A, corre~-ponding to 200 mg of compound A240 m~
- sodium laurylsulfake 4.5 mg - cros~linked sodium carboxymethyl 2~ callulose 24 mg - microcry~talline laGtose 177 mg - ma~nesium ~tearate 4.5 mg 450 mg ~XAMPLE 2 Divi~ible t~blet:
- dl~odium 3alt of compound A~ corra~-ponding to 200 mg o~ compound A240 mg 3~ - ~odium laurylsul~ate 8 mg 13~7~

.

- cro~slinked ~odium carboxymethyl cellulose 24 mg - microcrystalline lacGo~e ~73,5 mg - magnesium ~tearate 4.5 mg 450 mg A study of bioavailability in human was carried out with the tablet~ prepared accordin~ to Examples 1 and 2.
Thi~ study wa~ carried out on haalthy volu~teer~
by comparing the result~ obtained after oral admini~tra-tion of the composition according to Example 1 of the inv~ntion with the result~ obtained after oral admini~tra~
.
tion of a capsule or a sachet containing the same 8mount o aotive principle, corresponding to 200 mg of compound Ai but not co taining ~odium laury~l~ulfa~e. .
The capsule contains the active principle and an appropr{ate exclpient~ The ~achet~contain the active principle only~
PROTOCOL OF THE CLINICAL TRIAL
: : Twelve healthy volunteer~ of the male 8~X~ a~ed ~etween 20 and 28 years, too~ part in the trial. None Qf the ~ub~ecta had a partieular medical hi~torY. The clinical an~ laboratory eX~minatiOnB were normal. None of the ~ub~ects had received dru~s during the 2 week~ prior to the trial9 or abaorb0d calGlu~ rioh food within the 48 houra immediately prec~din~ the trial.
After overnight ~a~*ing, the 3 formulation : 30 (tablet, capsule~ sachet~ were absorbed with 150 ml of min~ral water with a low calcium content (1.55 m~.
The trial consi~t~ of 3 admin~stration~ ~eparated by intervals of one week. For each of the admini~tra : tions, the do~e corre&pondin~ to 400 mg of compound A 1 ~5 glven in the form of 2 capsules, 2 tablets or 2 - ~327~

sachet~ in a ~ingle admini~tration.
Th~ order in which the formulat~on~ were admini~-tered, corresponding to 6 different ~e~uences 7 waB as follow~:

J Subject no. I Order of admini~tration 1- 1 ., , 1~ 1 ,... i 1,2 I tablet I capsule I ~achet . 1 . I
1 3 9 4 I tablet I sachet I capsule 5,6 I capsule l tablet I ~achet ... I
7, a I capsule I sach~t I t~blet , 1 1 9,10 1 sachet I tablet I capsule 'I I ~ I I
. 1 11,12 1 ~achet I capsule I tablet : : 25 8 ml blood ~am~les wera t~ken at th~ followin~
: ti~e~: before treatment and then 0.~9 1.0~ 1.53 2.09 2 5 3.0, 4~0, ~.0, 8.0, 10.0, 12.0~ 24.0, 36sO and 48.0 hour~
a~ter admini~tration of the pharmacsutical compo~ltion.
~0 The unchanRed activ~ principl~ was determ~ned in the~e di~ferent 8ampl03.

ANALYSIS QF THE SAMPLES
Compound A was determined by hi~h performance 9~ liguid chromatography with W detection.

~327~

The ~electivity, exactne 8 and reproducibility o~
the method were checked. The limit of ~uanti*ication i~
about 0.~5 mg/l.
A calibration curve was establi~hed every day and 05 control samples wera included in all the individual kinetics .

PHARMACOKINETIC INTERP~ETATION
The ~ollowing pharmacokinetic parameters were determined from the plasma concentrations of compound A:
Cmax: maximum plasma concentration observed, Tmax: time re~uired to reach the value Cmax, AUC: area under the curve of pla~ma concentra-tion calculated by the trapezium method between the time~ O and 48 h.
To facilitate comparison~ between the different trial~, the maximum plasma csncentrations and the area~
under the curve were ~tandardized for a body weight of 70 kg by applying the following correction factor 0 individual weight lkg) standardized parameter - mea~ured parameter x PHARMACOKINETIC PARAMETERS
~ xamination of the pla~ma prof~le3 for each sub-~ect ~how~ a very large ~catter of the re3ult~ for some of the sub~ects in the case of the sach~t and capsule forms. Thes2 difference~ are evident to a le~3~r exte~t in the ca~e of the tablet form, althou~h they do not totally di~appear. Tha Cmax and AUC value~ show a ~maller v~riabiliky for the tablot form ~cueffici~nt of variation of the order of 30% ~or the tablet form and greater than 3~ 60% for tha capsule and sachet forms). The ~ ~L3~7~9 re~ult~ are collated in Table 1 below.

05 Mean pharmacokinetic parameter~ obtained after a single admini~tration of 400 mg of active principle in the form of 2 tablet~, 2 capsules or 2 sachets Parameter I Tablet I Capsule I Sachet I T~ax ~h) I 1.25 1 3 15 1 3.13 j (~ SD) I (0.40) 1 (0.87) 1(1.03) Cmax* (mg/l)l 3.00 1 1~06 ¦ 0.37 j (+ SD) I (0.98) 1 (0.92) 1(0.623 1, I AUC 0-4B h* l 20J (mg.h/l) I 30.91 1 11.94 1 12.4a (+ SD) I (9.79) 1 (7.63) 1(7.75) The ~t~ndard devi~tion~ (+ SD) are indicated for 26 each value.
*Parameter ~tandardized for a body weight of 70 ~g.

The time~ taken to r~ach the Rla~ma concentration pe~k (Tmax) are si~nificantly ~horter with the tablet than with the capsule and the sachet (1.25 + 0.40 h *or the tablet, 3.15 * 0.87 h for the capsule and 3.13 i 1.03 h for thc ~achet). The diffarence between aach~t and capsule ls not statistically significant.
The tablot produce~ di~tinckly hi~her max~um ~ 327~9 pla~ma concentration~ (Cmax) with very highly significant difference~ compared with both the capsule and the ~achet (3.00 + O.98 mg/l_for the tablet, 1.06 + O.92 mg/l for the capsule and 0.97 + 0.62 mg/l for the 05 sachet). The difference between ~achet and capsule is not statistically significant.
Comparison of the areaæ under the plasma concen-tration curve (AUC~ at 48 hour~ for the 3 forms ~tudied ~hows that the mean bioavailability of the tablet according to the invention i~ 3 time~ greater than that of the other two form~. The difference~ between the areas under the curves are very highly signifioant between the tablet and the ~achet or between the tablet and the jcapsule. By contrast, no significant difference l noted between the capsule and the sachet.
The ~tudy of bioavailability in human was repeated under the ~ame condition~ with tablet~ prepared accordin~
to Example 2.
The results obtained are collated below:
- T~ax ~ 6 h (+ 1.02) - Cmax* : 2.46 mg/l (~ O.98~
- AUC~ 0-48 hours : 23.94 mg.h/l ~ 5.21) : The 3tandard de~iation~ (+ SD~ are indicated.
*Parameter ~tandardized for a body weight of ~5 70 kg.
The~e re~ults are comparable to tho~e obtained with the tablet~ prepared according to Exampl~ 1.

CONCLU~ION OF THE STUDY
Th~ pharmaceutical compo~ition accordin~ to the invention make~ it po sible to obtain:
- a more rapid absorption of compound A, - a bioava~lability wh~ch i8 about 3 times greater than that of the other two forms, and 3~ - a reduced variabili~y between individuals in 1327~

1~ .

term~ of the pla~ma ooncentrations.
No ~igns of poor tolerance were ob~erved after administratinn of the pharmaceutical compo~ition accor-ding to the invention.

~5 .

~5

Claims

1. A pharmaceutical composition for oral administration, based on a diphosphonic acid derivative of the formula (I) in which R1 represents a hydrogen atom, a halogen atom, a hydroxyl, an amino or a dialkyl(C1-C4) amino, and R2 represents a halogen atom, a linear alkyl con-taining from 1 to 5 carbon atoms which is unsubstituted or substituted by a chlorine atom, a hydroxyl, an amino or a dialkyl(C1-C4)amino, or R2 represents a phenoxy a phenyl, a thiol, a phenylthio, A chlorophenylthio, a pyridyl or a thiomorpholin-4-yl, or one of its pharmaceutically acceptable salts, which comprises from 1.5 to 6% by weight of sodium laurylsulfate relative to the diphosphonic acid derivative.

2. A pharmaceutical composition according to claim 1, wherein the diphosphonic acid derivative is selected from etidronic acid, piridronic acid, clodronic acid, pami-dronic acid, 4-chlorophenylthiomethylenediphosphonic acid, 4-amino-1-hydroxybutylidenediphosphonic acid, 6-amino-1-hydroxyhexylidenediphosphonic acid, phenoxymethylenedi-phosphonic acid, thiomorpholinomethylenediphosphonic acid or one of their pharmaceutically acceptable salts.

3. A pharmaceutical composition according to claim 1, in which the diphosphonic acid derivative is 4-chlorophenyl-thiomethylenediphosphonic acid or its disodium salt.

4. A pharmaceutical composition according to any one of claims 1, 2 or 3, comprising from 100 to 500 mg of 4-chlorophenylthiomethylenediphosphonic acid or the equiva-lent amount of its disodium salt, and from 1.7 to 4% by weight of sodium laurylsulfate.