Document FPl
`
`'
`
`PCT
`
`lntematlonal Bureau
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 6 i
`A61
`9/20
`K
`
`(11) International Publication Number:
`(43) International Publication Date:
`
`,WO 98/10753
`19 March 1998 (19.03.98)
`
`EGIS
`(for all designated States except US):
`(7]) Applicant
`GYOGYSZERGYAR RT. [HU/HU]; Kereszttiri
`lit 30-38.
`H-l l06 Budapest (HU).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): FEKETE. Ptil [HU/HU];
`Arany .l. u. 15. H-1051 Budapest (HU). PALFI. Zoltanné
`[HU/HU];’ Erdem u.
`24. H-l172 Budapest
`(HU).
`KRISZTIAN, Maria [HU/HU]; Matild u.
`l3. H-116I
`Budapest (HU). GORA. Laszlone [HU/HU]; Nagy S. u. 42.
`H-21l7 Isaszeg (HU). LADY. Blanka IHU/HU]; Dagaly u.
`6. H-l l38 Budapest (HU). SZENTGROTI. Pélne [HU/HU];
`Damjanich u. 35. H-l07l Budapest (HU).
`
`(74) Agent: ADVOPA’I’ENT; Office of Patent and Trademark
`Attorneys. PO. Box ll. H-l251 Budapest (HU).
`
`(54) Title: CAP’I‘OPRIL TABLETS
`
`(57) Abstract
`
`The invention relates to captopril tablets comprising a filler and binding agent, a disintegrating agent. a lubricant and a glidant agent
`wherein the filler and binding agent is a l.5:l - l:l weight ratio mixture of lactose and microcrystalline cellulose and the total amount of
`said mixture is 60-80 % by weight of the totalweight of the tablet. The captopril tablets of the present invention are highly stable. can be
`readily manufactured and the standard deviation of the active ingredient content of the individual tablets and also of the pans of tablets
`
`(21) International Application Number:
`
`PCT/HU97/00051
`
`(22) International Filing Date:
`
`10 September I997 ( 10.09.97)
`
`(30) Priority Data:
`P 96 02470
`
`I0 September I996 (10.09.96)
`
`HU
`
`(81) Designated States: AL. AM. AT, AU. AZ. BB. BG. BR. BY.
`CA. CH. CN, CZ, DE, DK. EE, ES. Fl. GB. GE. IL. IS. JP.
`KE. KG. KP. KR, KZ. LK, LR, LS. LT, LU. LV, MD.
`MG. MK. MN. MW, MX. NO. NZ. PL, PT, RO. RU.
`SD, SE. 50, SI, SK. TJ. TM, TR, TT, UA. UG, US. UZ,
`VN, ARIPO patent (CH. KE. LS. MW, SD. 52. U6, ZW),
`Eurasian patent (AM. AZ, BY, KG. KZ. MD, RU, TI, TM),
`European patent (AT, BE. CH. DE, DK. ES. FI, FR, GB,
`GR, IE, IT, LU. MC, NL, PT. SE), OAPI patent (BF. B],
`CF. CG. CI, CM. GA. GN. ML, MR. NE. SN. TD. TG).
`
`Published
`With international search report.
`Before the expiration of the time limit for amending the
`claim: and to be republished in the event of the receipt of
`amendments.
`
`split into two or four pans is very low.
`
`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Zimbabwe
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`8!
`Slovenia
`l3
`Lesotho
`ES
`Albania
`SK
`Slovakia
`Lithuania
`Fl
`LT
`Armenia
`SN
`LU
`Aualria
`Fll
`Senegal
`Luxembourg
`81
`Swaziland
`Latvia
`LV
`Australia
`GA
`Monaco
`TD
`Chad
`MC
`GB
`Azerbaijan
`T6
`MD
`Togo
`Republic of Moldova
`Bosnia and Herzegovina
`MG
`TJ
`Barbados
`Madagascar
`Tajikiatan
`TM
`MK
`Turkmenistan
`The former Yugoslav
`Belgium
`TR
`Burkina Paso
`Turkey
`Republic of Macedonia
`'l'l‘
`Mali
`Trinidad and Tobago
`Bulgaria
`UA
`Ukraine
`Benin
`Mongolia
`UG
`Mauritania
`Brazil
`Uganda
`United States of America
`Malawi
`US
`Belarus
`UZ
`Uzbekistan
`Mexico
`Canada
`VN
`Viet Nam
`Niger
`Central African Republic
`YU
`Netherlands
`Yugoslavia
`Congo
`ZW
`Switzerland
`Notway
`New Zealand
`Cu: d‘lvoire
`Poland
`Cameroon
`China
`Portugal
`Romania
`Cuba
`Russian Federation
`Czech Republic
`Sudan
`Germany
`Sweden
`Denmark
`Estonia
`Singapore
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`
`PL
`PT
`R0
`RU
`SD
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Rewblic of Korea
`Kaulutan
`Saint Lucia
`Liechtenstein
`Sri Lama
`Liberia
`
`GR
`GN
`GR
`HU
`IE
`IL
`15
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`Ll
`LK
`LR
`
`

`

`WO 98110753
`
`PCT/HU97100051
`
`Captopril tablets
`
`Background of the invention
`
`This invention relates to tablets containing captopril as
`
`active ingredient and a process for the preparation thereof.
`
`it
`
`is known
`
`that
`
`(S)-1—(3-mercapto-2-methyl-1-oxo-
`
`propyl)-L-proline (International Non-propriatory Name.
`
`lNN,
`
`"captopril") is a competitive ACE inhibitor. decreases arterial
`
`and venal vascular tone.
`
`the complete periferial vascular
`
`resistance, the cardial pre- and post-loading and increases the
`
`minute-volume. Preparation of captopril
`
`is disclosed in
`
`Hungarian patent No. 181,965. The active ingredient content
`
`of captopril tablets used in therapeutical practice amounts to
`
`625-100 mg and the daily dosage is 625-300 mg. Captopril is
`
`highly sensitive to oxidation and captopril disulfide is formed
`
`on the thiol group in a free radical oxidation process. In solid
`
`pharmaceutical compositions the velocity of decomposition is
`increased during the drying step of the manufacturing process
`
`and also by the moisture content of the composition.
`
`In the
`
`preparation of captopril compositions particular care is to be
`
`taken to select
`
`a
`
`suitable auxiliary agent
`
`system and
`
`manufacturing
`
`process.
`
`respectively.
`
`which
`
`induces
`
`decomposition and oxidation of the active ingredient to the
`smallest extent.
`
`It
`
`is well-known to the skilled art worker dealing with
`
`formulation that captopril
`
`is susceptible to decomposition.
`
`Several patent specifications are directed to this problem.
`
`According to Japanese patent N9 86 36,127 the stability of
`
`

`

`WO 98/10753
`
`PC'l‘ll-IU97/00051
`
`active ingredients comprising a thio group - including captopril
`
`- may be improved by using ascorbic acid, sodium ascorbate.
`
`erithorbinic acid or the sodium salt thereof, sodium bisulfite,
`
`sodium sulfite and/or sodium metabisulfite. According to
`
`Japanese patent N9 82 112,367 in injectabie solutions the
`
`stability of captopril may be augmented with the aid of amino
`
`acids and salts thereof. Japanese patent N9 94 32,776 relates
`
`to the use of antioxidants as well. According to US patent N9
`
`5,158,777 the simultaneous use of disodium edetate and
`
`ascorbic acid is suggested. However.
`
`the use of the above
`
`antioxidants - with the exception of ascorbic acid
`
`-
`
`is
`
`accompanied by sanitary risks because said substances may
`
`often cause allergic symptoms. However according to the
`
`disclosure of US patent N9 5,158,777 ascorbic acid failed to
`
`exhibit satisfactory stabilising effect when used per 5;.
`
`Another problem emerging in the therapeutical use of
`
`captopril compositions is
`
`that
`
`the individual dose of
`
`the
`
`compositions varies to a large extent and that
`
`in chronical
`
`treatment the applicable dose can only be adjusted by gradual
`
`increase of the dosage. in order to provide flexible dosage of
`
`pharmaceutical compositions containing captopril which can
`
`be readily adjusted in view of the individual requirements of
`
`the patients. there is a strong need for tablets which have a
`
`variable active ingredient content within wide limits one the
`
`one hand and can be broken to two parts (halved) on the
`
`other. Constant
`
`active
`
`ingredient delivery requires
`
`that
`
`compositions having different active ingredient content should
`
`be made available with identical percentual composition on the
`
`

`

`WO 98/10753
`
`PCT/HU97/00051
`
`one hand. and that when splitting the composition the active
`
`ingredient content should be substantially the same in each
`
`part of the tablet on the other.
`
`It
`
`is very important that the
`
`manufacturing process should ensure high homogenity of the
`
`active ingredient and the auxiliary agents in the composition.
`
`The
`
`known
`
`processes
`
`for
`
`the manufacture
`
`pharmaceutical
`
`compositions
`
`containing captopril
`
`fail
`
`of
`
`to
`
`comply completely with the above requirements.
`
`In European
`
`patent publication EPA N9 288,732 captopril containing pellets
`
`filled
`
`into
`
`capsules
`
`and
`
`prepared
`
`by
`
`extrusion
`
`and
`
`spheronization are disclosed. Such pellets contain 3-60 “/0 of
`
`the active ingredient and 5-50 % of a carboxylic acid facilitating
`
`pellet formation.
`
`The preparation of oral osmotic
`
`compositions
`
`is
`
`disclosed in PCT WO 91/01.130. This composition is a two-
`
`layered tablet coated,with a semipermeable layer. One layer
`
`contains the active ingredient and the other layer comprises a
`
`water-swellable polymer. while a bore is drilled into the layer
`
`containing the active ingredient
`
`through which the active
`
`ingredient is delivered into the organism.
`
`The preparation of zero order sustained release coated
`
`tablets is disclosed in US patent specification N9 4 756 911.
`
`The tablet core contains at least 70 % of active ingredient and
`
`5-15 % of a hydrocolloidal gel
`
`forming auxiliary agent.
`
`particularly hydroxypropyl methyl cellulose, and the coating of
`
`the tablet consists of a 4:1 - 1:4 mixture of at
`
`least one
`
`hydrophlic polymer and at least one hydrophobic polymer.
`
`

`

`W0 98110753
`
`PCT/111197100051
`
`The preparation of compositions comprising gel forming
`
`auxiliary agents (eg. a polymer comprising a lactame group
`
`and a polymer comprising a carboxy group) and a gas forming
`
`auxiliary agent (eg. sodium hydrogen carbonate) is disclosed
`
`in European patent publication N9 EPA 669.129.
`
`Sustained release capsules comprising a
`
`semisolid
`
`filling, which consists of at least one fatty acid glyceride and/or
`
`polyethylene glycol ester. are disclosed in US patent N9
`
`5,433,951.
`
`Summary of the invention
`
`it
`
`is the object of
`
`the present
`
`invention to provide
`
`captopril
`
`tablets which are highly stable and show a high
`
`homogenity of the active ingredient and the auxiliary agents.
`
`The above object is achieved by selecting a special
`
`filler/binding agent combination and a specific ratio of filler and
`
`binding agent.
`
`According to the present invention there are provided
`
`captopril
`
`tablets comprising a filler and binding agent.
`
`a
`
`disintegrating agent, a lubricant and a glidant agent wherein
`
`the filler and binding agent is a 1.521 - 1:1 weight ratio mixture
`
`of lactose and microcrystalline cellulose and the total amount
`
`of said mixture is 60-80 % by weight of the total weight of the
`
`tablet.
`
`According to the present
`
`invention there is also
`
`provided a process for the preparation of captopril
`
`tablets
`
`containing a filler and binding agent. a disintegrating agent, a
`
`lubricant and a glidant agent which comprises using as filler
`
`and binding agent a 1.521 -1:1 mixture of
`
`lactose and
`
`

`

`W0 98/ 10753
`
`PCT/HU97100051
`
`microcrystalline cellulose. the amount of said mixture being
`
`60-80% by weight related to the total weight of the tablets.
`
`Detailed description of the invention
`
`The present invention is based on the recognition that
`
`captopril
`
`tablets having high stability can be prepared by
`
`adjusting the ratio of lactose and microcrystalline cellulose in
`
`the tablets to a value between 1.5:1 and 1:1.
`
`The above recognition is so much the more surprising
`
`as on the basis of the state of the art
`
`it could have been
`
`expected that high stability of captopril can be achieved by
`
`using a system of auxiliary agents which has the lowest
`
`moisture content and the smallest moisture~uptake
`
`It can be seen from the comparative experiments
`
`disclosed in the present patent specification that on increasing
`
`the amount of the microcrystalline cellulose having a high
`
`moisture-uptake. also the moisture-uptake of
`
`the tablets
`
`increases.
`It has been found, however,
`in an unforeseen
`manner.
`that when using a relatively narrow interval of
`
`lactose/microcrystalline cellulose ratio,
`
`the amount of
`
`the
`
`captopril disulfide formed in the captopril
`
`tablets shows a
`
`minimum and tablets of high stability are obtained.
`
`The total lactose and microcrystalline cellulose content
`
`of the captopril tablets of the present invention is 60-80 % by
`
`weight, preferably 65-75 % by weight, particularly 70% by
`
`weight, related to the total weight of the composition.
`
`The active ingredient content of the tablets according to
`
`the present invention is preferably 5-150 mg. The particle size
`
`of 90 % of the active ingredient is preferably 3-80 pm and the
`
`

`

`WO 98/10753
`
`PCT/HU97/00051
`
`starting captopril disulfide content is preferably below 0.3 % by
`
`weight.
`
`Lactose is used preferably in the form of
`
`lactose
`
`monohydrate. The amounts and % values used in the present
`
`patent specification are expressed in lactose monohydrate.
`
`It is preferred to use lactose monohydrate prepared by
`
`spray-drying and having an average particle size of 50-200
`
`pm. particularly 80-160 pm.
`
`The particle size of 90 °/o the microcrystalline cellulose
`
`used in the compositions of the present invention is 20—150
`
`pm, particularly 50-100 pm.
`
`The compositions of the present invention may contain
`
`as disintegrating agent preferably corn starch. carboxymethyl
`
`starch. partially hydrolized starch. carbomethyl cellulose or
`
`cross—linked
`
`polyvinyl
`
`pyrrolidone. The
`
`amount
`
`of
`
`said
`
`disintegrating agent is preferably 1-20 % by weight, particularly
`5-15 % by weight,
`related to the “ total weight of
`the
`composition.
`~
`
`The compositions of the present invention contain as
`
`lubricant preferably stearine, magnesium stearate. calcium
`
`stearate, sodium stearine fumarate or hydrogenated castor oil.
`
`The amount of
`
`the glidant agent
`
`is 0.2-3 % by weight,
`
`preferably 0.5-2 % by weight. related to the total weight of the
`
`composition.
`
`The compositions of
`
`the present
`
`invention contain
`
`preferably silica as glidant agent . The amount of this auxiliary
`
`agent is 0.2-1 % by weight. preferably 0.4-0.6 % by weight.
`
`

`

`WO 98/10753
`
`PCT/HU97/00051
`
`The auxiliary agents - disintegrating agents. glidant
`
`agents and lubricants meet
`
`the criteria disclosed in the
`
`Pharmacopoeia
`
`(e.g.
`
`USP
`
`23
`
`or
`
`Vll.
`
`Hungarian
`
`Pharmacopoeia).
`
`The tablets according to the present invention may be
`
`prepared preferably by the so-called direct compression
`
`technology which has the advantage that the drying step is
`
`eliminated. According to this process prior to the tabletting
`
`step the powder of the active ingredient is homogenized in
`
`solid
`
`state with
`
`auxiliary agents which ensure suitable
`
`compressibility of the composition.
`
`The stability of the captopril
`
`tablets of the present
`
`invention is very good. If broken one into two or four parts. the
`
`standard deviation of the active ingredient content of the parts
`
`thus obtained is better than the corresponding values of
`
`known compositions.
`
`Further details of the present invention are to be found
`
`in
`
`the following Examples without
`
`limiting the scope of
`
`protection to the Examples.
`
`in comparative Example 1
`
`the effect of the ratio of
`
`lactose monohydrate and microcrystalline cellulose on the
`
`compressibility of
`
`the powder blends
`
`is examined. The
`
`measured data are in conformity with the teaching of the state
`
`of
`
`the art and show that on increasing the amount of
`
`microcrystalline cellulose used as dry binder,
`
`the powder
`
`mixture can be more easily pressed i.e. on using identical
`
`pressing force the breaking strength of the tablets becomes
`
`higher and the friability gets lower.
`
`

`

`WO 98/10753
`
`PCT/HU97/00051
`
`in comparative Example 2 the effect of the ratio of
`
`lactose and microcrystalline cellulose on the moistureuptake
`
`of the tablets is examined. The results are in conformity with
`
`the teaching of prior art and show that when stored under a
`
`relative humidity of 75 % the increase of the amount of the
`
`microcrystalline cellulose having a higher moisture—uptake
`
`(higher equilibrum moisture content) results in an increase of
`
`the moisture-uptake of the tablets.
`
`ln comparative Examples 3 and 4 the effect of the ratio
`
`of lactose and microcrystalline cellulose on the stability of the
`
`active ingredient content of the tablets is examined. In view of
`
`the state of the art the results are surprising and show in an
`
`unforeseen manner that when storing the tablets under 75 %
`
`relative humidity, oxidation of captopril
`
`-
`
`i.e.
`
`the captopril
`
`disulfide content of the tablets - shows a minimum at a lactose
`
`monohydrate : microcrystalline cellulose ratio interval of
`
`1.5-1: 1-1. On the basis of prior art
`
`it could have been
`
`expected that
`
`tablets containing the lowest amount of
`
`microcrystalline cellulose would be the most stable. The series
`
`of experiments show, however,
`
`that
`
`if the ratio of lactose
`
`monohydrate and microcrystalline cellulose is adjusted to a
`
`relatively narrow interval,
`
`the amount of captopril disulfide
`
`formed in the tablets is reduced to a minimum and this value is
`
`below the captopril disulfide content of captopril
`
`tablets
`
`allowed by Pharmacopoeia (e.g. USP 23).
`
`In Examples 5-8 the preparation of captopril tablets of
`
`varying composition according to the present
`
`invention is
`
`descnbed.
`
`

`

`WO 98110753
`
`PCT/HU97/00051
`
`,
`
`In comparative Example 9 the standard deviation of the
`
`individual active ingredient content of tablets manufactured on
`
`industrial scale and the standard deviation of the individual
`
`active ingredient content of parts of tablets split in two or four
`
`parts, respectively is disclosed. The experimental results show
`
`that if the captopril tablets of the invention are split in two or
`
`four parts, respectively, the standard deviation of the active
`
`ingredient content of said tablet parts is very favourable.
`
`Accordingly the pharmaceutical composition of the present
`
`invention can be preferably used because such compositions
`
`meet the special requirements of captopril therapy i.e. when
`
`on adjusting the individual dosage required by a patient the
`
`dose is to be increased, the tablets according to the present
`
`invention can be reliably split in two or four parts due to the
`
`low standard deviation of the active ingredient content of the
`
`tablet parts.
`
`in comparative Example 10 the disulfide content of
`samples subjected to loaded stability test
`is determined.
`
`Tablets containing 12.5 mg of captopril are packed into blisters
`
`formed from a PVC/PVDC plastic foil and closed by an
`
`aluminium foil. The tablets of
`
`the present
`
`invention are
`
`compared to tablets which have a lactose/microcrystalline
`
`cellulose ratio outside the scope of the present invention but
`
`are otherwise of identical composition. The blistered tablets
`
`are stored at 40°C under a relative humidity of 75 % for 3
`
`months. After this storing period the captopril disulfide content
`
`of the invention tablets increases from the initial value of
`
`

`

`WO 98110753
`
`PCT/HU97/00051
`
`10
`
`0.31 % to 3.32 %. while in the reference tablets the captopril
`
`disulfide content augments from 0.30 % to 5.04 %.
`
`Example 11 shows that captopril tablets of the present
`
`invention have a very high stability in moisture-proof "cold
`
`blister" packaging.
`
`

`

`W0 98/10753
`
`PCT/HU97/00051
`
`11
`
`Examgle 1
`
`(comparative Example)
`
`(Effect
`
`of
`
`the
`
`ratio
`
`of
`
`lactose monohydrate
`
`and
`
`microcrystalline cellulose on the compressibility of the powder
`
`blends)
`
`Composition (mg/tablet)
`
`(g/5000 tablets)
`
`
`
`N9 of experiment
`
`
`
`
`
`
`
`
`
`
`50.0 250.0
`
`25.0 125.0
`
`40.0 200.0
`
`
`
`
`
`22.0 110.0
`
`22.0 110.0
`
`22.0 110.0
`
`160.0 800.0 160.0 800.0 160.0 800.0
`
`Lactosezmicrocrystalline
`cellulose ratio
`
`3.4:1
`
`1.75:1
`
`1.2:1
`
`The components are sieved through a 0.5 mm sieve
`
`and thereafter homogenized in a Lc'idige 5M type high speed
`
`mixer under stirring for 5 minutes. The homogenized powder
`
`mixture is pressed to tablets on a Fette E Xl type eccentric
`
`tabletting machine by using flat rimmed tabletting punches
`
`under a pressing force of 5 kN. 10 kN and 15 kN, respectively.
`
`The
`
`breaking
`
`strength
`
`(Schleuniger
`
`4M measuring
`
`apparatus), friability (Roche-type friability measuring device,
`
`100 r.p. 4minutes) and the disintegration time at 37°C in
`
`

`

`WO 98/10753
`
`PCT/HU97/00051
`
`12
`
`distilled water (Erweka disintegration measuring apparatus) of
`the tablets is determined.
`
`The results are summarized in Table 1.
`
`
`Table 1
`
`Results of tests carried out on the tablets
`
`
`
`N9 of experiment
`
`
`
`
`
`
`
`
`
`Breaking
`strength
`
`(average of
`
`10tablets,N
`Friability
`
`(average of
`10 tablets. %
`
`
`
`Dismtegration
`
`time
`
`
`(average of
`6 tablets, s
`
`11
`
`35
`
`15
`
`41
`
`51
`
`19
`
`59
`
`
`
`‘
`
`6.3
`
`0.4
`
`14
`
`1.2
`
`
`
`The above data show that on changing the ratio of
`
`in
`cellulose
`and microcrystalline
`lactose
`microcrystalline cellulose the pressability of
`
`favour . of
`the powder
`
`mixture improves (the breaking strength values corresponding
`
`to identical pressing force increase and the friability decrease)
`
`and the disintegration time of the tablets is very good (shorter
`
`than
`
`1 minute).
`
`If
`
`the mixture
`
`contains
`
`lactose
`
`and
`
`microcrystalline cellulose in approximately identical amounts.
`(Experiment N9 1/3) the friability is below 0.5 % and this is a
`
`

`

`W0 98/10753
`
`PCI‘IHU97/0005]
`
`13
`
`characteristic feature of tablets having excellent mechanical
`
`strength.
`
`in the above Experiment N9 1/3 corresponds to the
`
`composition of the present invention.
`
`Example 2
`
`(comparative Example)
`
`and
`lactose monohydrate
`of
`ratio
`the
`of
`(Effect
`microcrystalline cellulose on the moisture-uptake of tablets)
`Composition (mg/tablet)
`(9/1000 tablets)
`
`
`
`
`
`N9 of composition
`
`Captopril
`
`
`
`
`—&
`
`-—L o
`
`O
`
`n—I oo o
`
`—l o o o
`
`
`
`
`
`—l0'2or»O
`mo0.000
`..O
`. --m
`3
`Lactose monohydrate
`-m120.0 180.0 240.0-
`
`
`_mmmmm
`
`
`
`
`
`
`
`
`
`
`
`
`oo o
`
`.N ono
`
`to oo o
`
`N ono
`
`.N 00 o
`
`Remarks:
`
`i
`
`1*
`
`= hydrogenated castor oil
`
`= colloidal silica
`
`The tablets are prepared by using the method and
`
`equipment disclosed in Example 1; batch size: 1000 tablets,
`
`The tablets are pressed by using tabletting punches and dye
`
`

`

`W0 98/10753
`
`PCT[HUM/00051
`
`14
`
`having a diameter of 12 mm and under a pressing force of 20
`
`kN.
`
`Moisture-uptake is determined by storing the tablets in
`
`an air-conditioner (LABORMIM. LP~23) at 40°C and a relative
`
`humidity content of 75 %. (The relative humidity content of 75
`
`°/o is provided by a saturated solution of ammonium sulfate;
`
`the fluctuation of temperature and humidity is controlled by a
`
`thermometer—hygrometer
`
`-
`
`"LOMBIK
`
`HOMERO
`
`és
`
`UVEGlPARI MUSZERGYARTO
`
`SZOVETKEZET"
`
`type
`
`06912). During
`
`the
`
`storing period
`
`of
`
`two weeks
`
`the
`
`temperature fluctuated between 397°C and 404°C, while the
`
`humidity varied between 73 % and 88 %.
`
`Moisture-uptake of the tablets is measured after a
`
`storing period of 1, 2, 4. 8 and 14 days,
`
`respectively.
`
`Moisture-uptake is determined on the basis of the weight
`
`increase of
`
`the tablets (SARTORIUS A 200 S analytic
`
`balance) and calculated with the aid of the following equation:
`
`Moisture-uptake w/w % = ---------------------------- x 100
`mi
`
`wherein
`
`m2 - m1
`
`m = weight of the sample before storage
`
`m2 = weight of the sample after storage
`
`Not only the tablets. but also the components used for
`
`the preparation thereof were placed in the air conditioner and
`
`moisture-uptake of the captopril (active ingredient) and the
`
`auxiliary agents was measured at the points of time indicated.
`
`The results are summarized in Tables 2 and 3.
`
`

`

`WO 98/10753
`
`PCT/HU97100051
`
`15
`
`Table 2
`
`Moisture-uptake of tablets w/w %
`
`Storing period (days)
`
`2
`
`4
`
`m2/5
`
`2/2
`
`_033 -605 _00.437
`
`
`Table 3
`
`Moisture-uptake of the active ingredient and the auxiliag
`
`agents (w/w %)
`
`
`
`0.01
`1.15
`
`0.02
`1.O7
`
`1.24
`
`
`
`
`
`Lactose monohydratem"<001 <0.01
`Microcrystalline m09
`
`A
`
`—A N m
`
`
`cellulose
`
`
`
`—m 144 ----
`_mmmmmm
`
`
`—-m-m
`
`
`
`-m----
`
`

`

`WO 98/10753
`
`PCTlHU97/00051
`
`16
`
`The above data show that on augmenting the amount
`
`of microcrystalline cellulose in the tablets the moisture-uptake
`
`of the tablet increases and this is in conformity with the finding
`
`that during storage lactose monohydrate does not take up
`
`moisture while
`
`the moisture-uptake
`
`of microcrystalline
`
`cellulose is above 1 w/w %. Since the high moisture-uptake of
`
`microcrystalline
`
`cellulose
`
`is known from prior
`
`art.
`
`the
`
`moisture-uptake of
`
`the tablets is
`
`in conformity with the
`
`expected results.
`
`In
`
`the
`
`above Experiment
`
`composition
`
`N9
`
`2/3
`
`corresponds to the present invention.
`
`Examgle3
`
`(comparative Example)
`
`(Effect
`
`of
`
`the
`
`ratio
`
`of
`
`lactose monohydrate
`
`and
`
`microcrystalline cellulose on the stability of captopril)
`
`In
`
`this experiment
`
`the captopril active
`
`ingredient
`
`content of the tablets is characterized by determining the
`
`captopril disulfide content of
`
`the tablets before and after
`
`storing (the conditions of storing are those disclosed in
`
`Example 2). The amount of captopril disulfide in the tablets is
`
`determined according to the HPLC methods described in USP
`
`23. To the measurement VARIAN MODEL 5000 Liquid
`
`Chromatograph type apparatus. PYE UNICAM LC-3 UV
`
`detector and HEWLETT-PACKARD HP 3394A integrator is
`
`used. The disulfide content of the tablets is expressed in the
`
`% by weight of the nominal captopril content of the tablets.
`
`The results are summarized in Table 4.
`
`

`

`W0 98/10753
`
`PCT/HU97/00051
`
`17
`
`
`Table 4
`
`Amount of cagtogril disulfide in the tablets exgressed in % by
`
`weight of the nominal cagtogril content of the tablets (w/w %)
`
`Storing time (days)
`
`0
`
`1
`
`2
`
`4
`
`8
`
`0.28
`
`0.73
`
`
`0.95
`
`2.13
`
`14
`
`5.15
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`mm
`
`It appears from the above data that on increasing the
`
`microcrystalline
`
`cellulose
`
`content
`
`of
`
`the
`
`tablets
`
`(Le.
`
`decreasing the lactose content)
`
`the amount of captopril
`
`disulfide formed in the tablets passes a minimum value i.e.
`
`decomposition of the composition (disulfide formation) is the
`
`lowest at a well-defined ratio of lactose monohydrate and
`
`microcrystalline
`
`cellulose.
`
`This
`
`experimental
`
`result
`
`is
`
`surprising because according to the teaching of prior art a
`
`greater rate of oxidation of captopril - la the formation of a
`
`higher amount of captopril disulfide - could have been
`
`expected in a system having higher moisture content, i.e. at a
`
`higher microcrystalline cellulose content.
`
`

`

`W0 98/10753
`
`PCTlHU97I00051
`
`18
`
`Example 4
`
`(comparative Example)
`
`(Effect
`
`of
`
`the
`
`ratio
`
`of
`
`lactose monohydrate
`
`and
`
`microcrystalline cellulose on the stability of captopril)
`
`In order to determine more precisely the optimal ratio,
`
`in this series of experiments the stability of the captopril
`
`content
`
`of
`
`the
`
`tablets
`
`is
`
`determined
`
`by
`
`using
`
`lactose/microcrystalline ratios near to those found to be
`
`advantageous
`
`according to Examples
`
`2
`
`and
`
`3. The
`
`composition of the tablets is adjusted to values between the
`
`compositions 2/2 and 2/4. The compositions used are
`
`disclosed in Table 5. Stability is determined before and after a
`
`storing period of 2 weeks and 4 weeks,
`
`respectively. by
`
`measuring the captopril disulfide content of
`
`the tablets
`
`according to the HPLC method disclosed in Chapter
`
`"Captopril Tablets" of USP 23. To the measurements a
`
`VARIAN MODEL 5000 Liquid Chromatograph type apparatus,
`
`a PYE UNlCAM LC-3 UV detector and a HEWLETT
`
`PACKARD HP 3394A integrator
`
`is used. The amount of
`
`disulfide measured in the tablets is expressed as % weight of
`
`the nominal captopril content of the tablets. The results are
`
`summarized in Table 5.
`
`

`

`W0 98/10753
`
`PCT/HU97/00051
`
`Table 5
`
`Composition (mg/tablet)
`
`(9/1000 tablets)
`
`
`
`
`4/1
`
`2:1
`
`N9 of composition
`
`4/3
`
`1 6:1
`
`1.25:1
`
`4/4
`
`1:1
`
`4/5
`
`0,721
`
`Lactose: microcrystalline
`cellulose ratio
`
`Captopril
`
`oo o
`
`1
`
`.3 o o o
`.
`
`A o.0 o
`
`—I oo o
`.
`
`_L oo o
`.
`
`
`
`
`Lactose monohydrate
`
`260.0
`
`234.0
`
`217.0
`
`195.0
`
`160.0
`
`Microcrystalline cellulose
`
`130 0
`
`146.0
`
`173.0
`
`195.0
`
`230.0
`
`
`
`
`
`
`
`
`
`560.0
`560.0
`560.0
`560.0
`560.0
`Average weight
`
`
`
`
`
`
`
`
`
`
`
`
`S” a)o
`
`m 0) o
`
`01 ono
`
`u: a)o
`
`Aerosil 200"
`
`2.80
`
`2.80
`
`2.80
`
`2.80
`
`2.80
`
`Magnesium-stearate
`
`O
`
`1 6
`
`—l 0')O
`.
`
`—-l 0') O
`.
`
`.1 O) O
`.
`
`Remarks:
`
`t
`
`it
`
`= hydrogenated castor oil
`
`= colloidal silica
`
`The tablets are prepared by using the method and
`
`apparatus described in Example 1; batch size 1000 tablets.
`
`On pressing the tablets with tabletting punches and dye
`
`having a diameter of 12 mm and a pressing force of 12 kN is
`used.
`
`Moisture uptake is carried out by storing the tablets in
`
`an air conditioner (LABORMIM, LP-23) at 40°C and a relative
`
`

`

`WO 98110753
`
`PCT/HU97/00051
`
`20
`
`humidity of 75 %. (The relative humidity content of 75 % is
`
`provided by a saturated solution of ammonium sulfate:
`
`the
`
`fluctuation of temperature and humidity is controlled by a
`
`thermometer-hygrometer -
`
`"LOMBIK HOMERO es UVEG—
`
`IPARI MUSZERGYARTO SZOVETKEZET"
`
`type 06912).
`
`During the storing period of
`
`two weeks the temperature
`
`fluctuated between 396°C and 405°C, while the humidity
`varied between 72 % and 78 %.
`
`Moisture-uptake is determined after a storing period of
`
`4 weeks. Moisture-uptake is determined on the basis of the
`
`weight
`
`increase of
`
`the tablets
`
`(SARTORIUS A 200 S
`
`analytical balance) and calculated with the aid of the following
`
`equation:
`
`Moisture-uptake w/w % = ---------------------------- x 100
`m1
`
`wherein
`
`m2 - m1
`
`m = weight of the sample before storage
`
`m2 = weight of the sample after storage
`
`The results are summarized in Table 6.
`
`

`

`W0 98/10753
`
`PCT/HU97/00051
`
`21
`
`
`Table 6
`
`
`
`Ratio of lactose and
`
`Storing for 2 weeks
`
`captopril disulfide (%)
`
`Storing for 4 weeks
`
`captopril disulfide (%) I.“
`
`
`
`Moisture uptake (%)
`
`
`
`
`
`
`
`
`
`
`
`
`The results of this experiment fully confirm the data
`
`obtained according to Example 3. Thus on increasing the
`
`microcrystalline
`
`cellulose
`
`content
`
`of
`
`the
`
`tablets
`
`(i.e.
`
`decreasing the lactose content)
`the amount of captopril
`disulfide formed in the tablets on storing reaches a minimum
`
`value
`
`and
`
`at
`
`a
`
`specified
`
`lactose monohydrate
`
`microcrystalline cellulose ratio the decomposition of the tablet
`
`(disulfide formation) shows a minimum. The results of these
`
`two series of experiments are surprising and unforeseen
`
`because on the basis of prior art one could expect an
`
`oxidation of higher extent of captopril (i.e. the formation of a
`
`larger amount of captopril disulfide) in a system of higher
`
`moisture content. One could expect
`
`that
`
`the higher
`
`the
`
`microcrystalline cellulose content.
`
`the larger degree of
`
`captopril decomposition would take place and the higher
`
`amount of captopril disulfide would be formed. However if the
`
`

`

`WO 98/10753
`
`PCT/HU97I00051
`
`22
`
`ratio of lactose and microcrystalline cellulose is between 1.521
`
`and 1:1 a surprising surplus effect takes place.
`
`Example 5
`
`Tablets having an active ingredient content of 12.5 mg
`
`Batch size: 2 million tablets (140 kg)
`
`Substances used:
`
`Component
`
`Amount kg
`
`Captopril (particle size: 90 % between 3.5
`
`25.00
`
`and 46.9 um)
`
`Lactose monohydrate
`
`Microcrystalline cellulose
`
`Corn starch
`
`Hydrogenated castor oil
`
`Colloidal silica
`
`Magnesium stearate
`
`52.50
`
`45.00
`
`15.00
`
`1.40
`
`0.70
`
`0.40
`
`The
`
`above
`
`substances
`
`- with
`
`the exception of
`
`magnesium stearate - are stirred in a 450 l mixer for 20
`
`minutes. whereupon the magnesium stearate is added and
`
`stirring is continued for further 2 minutes. Tabletting is carried
`
`out with a Fette Perfecta 2000 type tabletting machine (43
`
`pressing sites) by using flat rimmed split punches at 40 rpm.
`
`The breaking strength of
`
`the tablets
`
`is 35-45 N,
`
`the
`
`disintegration time amounts
`
`to 2-3 minutes,
`
`the active
`
`ingredient is dissolved within 5 minutes at a rate of 100 % and
`
`the relative standard deviation (RSD) of the individual active
`
`ingredient content
`
`is 3.7 %. On storing the tablets for 3
`
`months
`
`at 40°C in
`
`a glass
`
`container
`
`closed with
`
`a
`
`

`

`WO 98/10753
`
`PCT/HU97/00051
`
`23
`
`polyethylene cap the amount of captopril disulfide formed is
`
`1.6 %, while the .breaking strength. disintegration time and the
`
`velocity of active ingredient dissolution remained substantially
`
`unchanged. On the basis of the above data the captopril
`
`containing tablets prepared according to this Example fully
`
`meet
`
`the requirements of
`
`the Pharmacopoeia (USP 23,
`
`CaptOprii Tablets).
`
`In the tablets the ratio of lactose and microcrystalline
`
`cellulose amounts to 1.16:1.
`
`mm
`
`Tablets having an active ingredient content of 25 mg
`
`Batch size: 100,000 tablets (14 kg)
`
`Substances used:
`
`Comgonent
`
`Amount kg
`
`Captopril (particle size: 90 % between 5.5
`
`2.50
`
`and 69.6 um)
`
`Lactose monohydrate
`
`Microcrystalline cellulose
`
`Corn starch
`
`Hydrogenated castor oil
`
`Colloidal silica
`
`Magnesium stearate
`
`4.90
`
`4.90
`
`1.50
`
`0.10
`
`0.06
`
`0_o4
`
`The
`
`above
`
`substances
`
`- with
`
`the
`
`exception of
`
`magnesium stearate — are stirred in a 50 | mixer for 20
`
`minutes. whereupon the magnesium stearate is added and
`
`stirring is continued. Tabletting is carried out on a Manesty
`
`BBB type tabletting machine having 16 pressing sites. by
`
`

`

`W0 98/l 0753
`
`PCTIHU97/0005]
`
`24
`
`using flat rimmed twice split press punches at 30 rpm. The
`
`breaking strength of the tablets amounts to 4055 N.
`
`the
`
`disintegration time amounts to 2—3 minutes, the dissolution of
`
`the active ingredient is 100 % within 10 minutes. The relative
`
`standard deviation (RSD) of the individual tablets is 1.9 %. On
`
`storing the tablets
`
`in a glass container closed with a
`
`polyethylene cap at 40°C