.4'
`
`
`
`W02004/064809A1|||||||I|||||l||||||||||||||||||||||||||||||Il||||||||||||l|||||||||||||||||||||||||||||||l||||
`
`Document FPS
`
`Appl. No.: 11/273,575
`
`;_J
`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
` ||l|||IlllllllllIlllll|||l|||||||||l||||i|||IllIlllllllll|l|ll||||||||||||||lllllillllllllllll
`
`(10) International Publication Number
`(43) International Publication Date
`PCT
`5 August 2004 (05.08.2004)
`WO 2004/064809 A1
`
`(51) International Patent Classificationl:
`
`A61K 9/20
`
`(74)
`
`(21) International Application Number:
`PCT/EP2004/000456
`
`(81)
`
`(22) International Filing Date: 21 January 2004 (21.01.2004)
`
`(25) Fillng Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`03014719
`103 54 862.9
`1024899
`
`GB
`22 January 2003 (22.01.2003)
`24 November 2003 (24.11.2003) DE
`27 November 2003 (27.11.2003) NL
`
`(34)
`
`(71) Applicant (forall designated States except US): SANDOZ
`GMBH [AT/AT]; Biochemiestrasse 10, A-6250 Kundl
`(AT).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): BHARATRA-
`JAN, Ramaswaml [IN/IN]; 86—B/l2 Vrindavan Society,
`Thane (West) 400 601 (IN). ZEISL, Erich [AT/AT];
`Wiesing 74b, A-6200 Wiesing (AT). KOFLER, Niklaus
`[AT/AT]; Feldweg 44, 6134 Vomp (AT). PATIL, Man-
`isha, Rajesh [IN/IN]; B2-602, Vikas Complex, Castlemill
`compound, LBSMarg, Thane (West) 400 601 (IN). SA-
`HASRABUDHE, Parfulla, S. [IN/IN]; 13, Pradnya, G.K.,
`Gokhalc Road, Mulund (East), Mumbai, 400 081 (IN).
`
`Agent: GRUBB, Philip; Novartis AG, Corporate Intellec-
`tual Property, CH—4002 Basel (CH).
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`MG, MK, MN, MW, MX, MZ, NA. NI, NO, NZ, OM, PG,
`PH, PL, PI, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
`ZW.
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), Euro-
`pean (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR,
`GB, GR, HU, IE, IT. LU. MC, NL, PT, RO, SE, SI, SK,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`ML, MR, NE, SN, TD, TG).
`
`Published:
`with international search report
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes andAbbreviatians" appearing at the begin-
`ning ofeach regular issue of the PCT Gazette.
`
`
`
`(54) Title: SOLID PHARMACEUTICAL COMPOSITION COMPRISING RAMIPRIL
`
`(57) Abstract: The present invention relates to solid pharmaceutical compositions comprising ramipril with a suitably low water
`content, and processes for preparing said compositions.
`
`

`

`WO 2004/064809
`
`PCT/EP2004/000456
`
`SOLID PHARMACEUTICAL COMPOSITION COMPRISING RAMIPRIL
`
`Organic Compounds
`
`The present invention relates to solid pharmaceutical compositions comprising ramipril with a
`suitably low water content, and processes for preparing said compositions.
`
`Description of the invention
`
`The present invention relates to the discovery of stable pharmaceutical compositions
`
`containing ramipril and to methods for making such compositions.
`
`Ramipril (1) corresponds to (28,3aS,SaS)-1—{(S)-N-([(S)-1—carboxy-3—
`phenylpropyl]alanyl}octahydro-cyclopenta[b]pyrrole-Z-carboxylic acid 1-ethyl ester and is
`used for the treatment of i.a. hypertension, heart failure, and nephropathia.
`
`5
`CH, 3
`‘
`N
`“JR/“(swifir
`0
`H
`O HO
`
`s
`s
`
`0
`
`(1)
`
`The preparation of ramipril has been described in EP 0 079 022 A2.
`Stability is an important aspect of a pharmaceutical composition. The degradation of
`ramipril occurs mainly via two pathways: the hydrolysis to ramipril diacid [(2); impurity E
`. described in the European Pharmacopoeia] and the cyclization to ramipril diketopiperazide
`
`[(3): Impurity D described in European Pharmacopoeia].
`
`2
`
`CH3
`
`Horn/km?“
`
`o
`
`O
`
`HO
`
`O
`
`(2)
`
`H,cvo\n/\N/Kfo
`
`3
`
`CH,
`
`N
`
`0
`
`O
`
`(3)
`
`Information published in EP 0 317 878 A1. data generated on stress stability testing of
`commercial ramipril formulations (e. g. Delix®) and data generated internally during
`development of own formulations reveal that the major instability arises from the formation of
`the diketopiperazide. Table 1 shows the level of ramipril diketopiperazide and ramipril diacid
`after storage of Delix® 1.25mg (batch number C—423; originating from the German market) for
`
`8 weeks at 40° C/75% relative humidity (RH).
`
`

`

`WO 2004/064809
`
`PCT/EP2004/000456
`
`Table 1:
`
`
`
`
`
`ramipril diketopiperazide [%]
`
`
`
`
`
`ramipril diacid [%]
`
`
`
`
`
`If not specified othentvise, assay values of ramipril (1). ramipril diacid (2) and ramipril
`
`diketopiperazide (3) in % are generated with suitable HPLC methods, eg. as described in
`
`the European Pharmacopoeia 2001, monograph ‘Ramipril'.
`
`The European Pharmacopoeia states and encourages a limit of 0.5% for diketopiperazide.
`
`Preferably the stability of a commercial composition is such that, after 3 months, preferably 6
`
`months storage in a controlled environment of 40° C/75% RH, the loss of the active principle
`
`is less than 5% and the increase of impurities is preferably less than double the amount
`
`stated in the relevant Pharmacopoeia, in the case of ramipril the European Pharmacopoeia
`
`for the relevant impurity in the active principle. In the particular case of ramipril the level of
`
`ramipril diketopiperazide should preferably not exceed 1.0% after storage at 40° C/75% RH
`
`for 3 months, preferably 6 months.
`
`According to EP 0 317 878 A1 it is well documented that ramipril formulations manufactured
`
`by standard technologies show a considerable degree of instability. Hoechst did manage to
`
`overcome the stability problem by applying a commercially expensive and technically
`
`complicated technology (coating of ramipril with a polymer prior to compression). It was
`
`surprisingly found that these prior art stability problems can be overcome applying
`
`pharmaceutical standard technologies when properly controlling/limiting water content in the
`
`final formulation. It was found that stability with the proposed formulations and processes is
`
`even improved over the currently marketed commercial formulations of ramipril. it was
`
`surprisingly found that other prior art approaches for stabilisation of ACE inhibitors
`
`(formulations with acid-donors, formulations with sodium bicarbonate) did not reveal a
`
`sufficiently stable formulation except when water content was properly controlled
`
`concurrently. In addition it was surprisingly found that testing formulations with controlled
`
`water content not applying prior art approaches prove sufficiently stable as well. Whereas the
`
`focus of the trials was put on tablet formulations, the principle could be demonstrated to be
`
`as well suitable for capsules and is considered to be suitable for sachets as well.
`
`

`

`WO 2004/064809
`
`PCT/EP2004/000456
`
`The cyclization of ramipril to the ramipril diketopiperazide seems to be directly linked to the
`
`presence of moisture in the formulation.
`
`Therefore the invention covers a solid pharmaceutical composition containing
`(a) ramipril and/or a pharmaceutical acceptable salt thereof and
`
`(b) one or more pharmaceutical excipients,
`
`wherein the composition has a suitably low water content.
`
`Solid pharmaceutical compositions according to the invention include tablets, capsules,
`capsulets and sachets. Tablets may be suitably coated (film coated tablets, pills). Capsule
`
`formulations may cover both soft and hard capsules.
`
`The form of the ramipril and/or a pharmaceutical acceptable salt thereof is not particularly
`
`limited and includes all pharmaceutically acceptable anhydrates, solvates. hydrates,
`
`crystalline and amorphous forms. The amount of ramipril in the solid pharmaceutical
`composition is not particularly limited and comprises any amount that is pharmaceutically
`effective.
`
`Low water content can be achieved by a combination of suitable excipients showing low
`
`water content, process parameters that prohibit uptake of moisture during manufacture and
`proper packaging material that prohibits uptake of moisture during storage of the finished
`dosage form over shelf life. Suitable excipients with low water content are most preferably
`special grades of microcrystaliine cellulose (e. g. Avicel PH 112), starch (e. 9. Starch 1500
`LM), silicon dioxide (e. g. Syloid AL-1 FP), calcium hydrogen phosphate (e. g. Dicafos A) but
`should not be limited to the excipients mentioned herein but extended to all declared low
`
`water content excipients including diluents, binders lubricants, disintegrants colorants, etc.
`
`In another embodiment of the invention, one or more of the excipients can be dried prior to
`
`use or throughout the manufacturing process to achieve the required level of water content.
`Even when applying excipients with low levels of water the blend and final formulation is
`susceptible to take up moisture during manufacture and during storage. Accumulation of
`humidity during processing can be properly limited by performing the manufacture under
`controlled environmental conditions. Preferred is the manufacture in an environment of equal
`
`

`

`WO 2004/064809
`
`PCT/EP2004/000456
`
`-4-
`
`or less than 35% RH at ambient temperature, preferably in an environment of equal or less
`
`than 35% RH at equal or less than 30°C.
`Accumulation of moisture during storage can be properly avoided by using packaging
`
`materials known to be suitably tight against penetration of humidity. Preferred packaging
`materials are containers including lid composed of polyethylene and/or polypropylene and/or
`
`glass, and blisters or strips composed of aluminium or high density polyethylene.
`Therefore, other embodiments of the inventions are packages comprising compositions of a
`suitably low water content packaged with packaging materials which are suitably tight against
`penetration of humidity, preferably packaging materials as mentioned above.
`
`The water content in the composition can, for example, be determined by loss-on-drying
`(LOD) and/or Karl-Fischer (KF)-analysis as it is understood by workers skilled in the art. For
`the determination of all the data cited the below mentioned methods were used. Out of these
`two methods, KF is known to be more reproducible and specific. Thus KF is the preferred
`
`method to assess water content in pharmaceutical formulations.
`
`LOD: For tablet formulations, tablets are crushed to powder in a mortar with a pestle. For
`capsule or sachet formulations, the content of the capsule or sachet is emptied. The loss on
`drying is determined on a moisture balance e.g. Mettler LP 16 using approximately 1.0 g of
`the sample. The mixture is evenly spread on the weighing plate of the moisture balance. The
`weighing plate is preheated to 80°C and the mixture is then dried for 15 minutes at 80° C.
`
`KF: For tablet formulations tablets are crushed to powder in a mortar with a pestle. For
`capsule or sachet formulations the content of the capsule or sachet is emptied out. The water
`content is determined with an automated KF apparatus e. g. Metrohm 784 KFP Titrino using
`
`conventional Karl Fischer reagent using 0.1 g of the sample.
`
`Manufacturing the product with conventional excipients results in a considerably high
`decrease of ramipril and increase in ramipril diketopiperazide on storage. In EP 0 317 878
`A1. the increase of ramipril diketopiperazide up to 22.8% after 6 months at 40° C/70% RH
`and the decrease of ramipril down to 20% after 6 months at 40° C was attributed to
`mechanical stress,, and therefore the active principle was coated in order to protect it from
`
`mechanical stress.
`
`

`

`WO 2004/064809
`
`PCT/EP2004/000456
`
`Commercial formulations of Ramipril can be taken as reference for formulations
`
`manufactured with conventional excipients and showing normal levels of water content.
`
`Results on commercial formulations of Ramipril achieved with LCD and KF are presented in
`
`Tables 2 and 3.
`
`Strength
`
`Formulation
`
`.
`
`Table 2: Water content of originator formulation as determined by KF
`
`
`Product Name Batch No
`
`
`
`
`
`Water content
`weioht-%
`
`
`
`
`
`W—
`
`
`
`
`
`Product Name Batch No.
`
`40A428
`40A475
`
`
`
`
`
`
`
`
`
`
`
`2.5m
`.
`'
`Tablets
`6.11%
`.
`
`
`
`.—
`
`6.70%
`
`This type of formulation is only stable when ramipril is separated by a polymeric barrier from
`
`the water —containing excipients. The effect of the barrier was attributed by EP 0 317 878 A1
`
`to reduced mechanical stress during compression, but according to our surprising findings
`
`might as well be attributable to minimising the contact of ramipril with water on storage over
`the shelf life.
`
`Stability results generated on Examples 3 and 4 demonstrate the superior stability of
`
`formulations with low water contents (Table 4).
`
`Table 4: Stability of ramipril in tablets as a function of water content
`Assa of rami-ril %
`Example 3 (water content by
`LOD: 2.71 wei-ht-%
`101.11
`102.23
`
`99.90
`
`Example 4 (water content by
`LOD: 6.60 wei- ht-%
`97.85
`90.73
`
`

`

`WO 2004/064809
`
`PCT/EP2004/000456
`
`Besides choosing excipients with low water content, performing the manufacture in an
`
`environment of sufficiently low relative humidity is essential as demonstrated in enclosed
`
`example. A blend manufactured according to Example 1 was exposed to well defined
`environmental conditions of relative humidity at ambient temperature for up to 6 hours. Only
`
`when maintaining the relative humidity at approximately 30% the initial load with moisture
`could be maintained. At ambient humidity levels (50 — 60%) the blend has significantly taken
`
`up moisture already after 2 hours (Table 5). Considering that normal processing times for
`pharmaceutical products range from 8 hour up to one week control of this parameter
`becomes essential.
`
`
`
`
`
`Table 5: Water uptake in tablets as a function of relative humidity during production
`I
`
`
`
`30% RH
`'
`
`LOD
`wei . ht-%
`
`KF
`wei . ht-%
`
`50-60% RH
`LOD
`wei . ht—%
`
`KF
`wei - ht-%
`
`70% RH
`
`LOD
`wei . ht—%
`
`KF
`wei . ht-%_
`
`
`
`
`
`
`
`
`-_
`
`
`
`
`
`
`
`
`
`
`
`
`The third factor to control humidity in the final product is to prevent uptake of moisture during
`
`storage. It is well established that storing products in the containers including lid made of
`polypropylene and/or polyethylene and/or glass or in blisters and/or strips composed of
`aluminium or high density polyethylene prevents them from taking up moisture during
`
`storage over shelf life. Table 6 shows the uptake of moisture of tablets manufactured
`according to Example 1 and stored at 40° C/75% RH in various packaging materials.
`
`Whereas trilaminate (PVC/PE/PVDC 250p/25p/90 gsm and aluminium foil 20 pm) blister
`
`packs reach a level of saturation already after 1 month, polypropylene containers with
`polyethylene lid and Alu/Alu strips show no increase in water content over up to 6 months.
`
`Table 6: Water content as a function of packaging material
`
`LOD [weight-%]
`
`
`
`
`PVC/PE/PVDC
`250p/25u/90 gsm and
`aluminium foil 20 pm
`
`Alu/Alu 40 gm strip pack
`
`
`
`
`Polypropylene container
`with polyethylene lid
`
`

`

`WO 2004/064809
`
`PCT/EP2004/000456
`
`
`
`Application of the above mentioned principles reliably yields compositions with a suitably low
`water content, preferably less than 4.0 weight-%, most preferably less than 3.0 weight-% as
`determined by LOD, or less than 5.5 weight-%, most preferably less than 4.5 weight-% as
`determined by KF. By applying adequate packaging technologies the moisture content in the
`
`formulation can be maintained adequately low.
`
`it was surprisingly observed that these pharmaceutical compositions only prove sufficiently
`stable under accelerated testing conditions when water content is low. Concurrently with
`
`increase of moisture, degradation to diketopiperazide occurs.
`
`Working Examples:
`
`Example 1:
`During the manufacturing process environmental conditions of 30% RH/ 30°C are kept.
`Milled glycine hydrochloride (0.300kg) is dry-mixed with ramipril (0.125kg), microcrystalline
`cellulose (Avicel PH112; 7.125kg), precipitated silicon dioxide (Syloid AL-1-FP; 0.800kg) and
`pregelatinised starch (Starch 1500 LM; 0.450kg), and the resulting mixture is dry-mixed with
`glycerol dibehenate (Compritol ATO 888; 0.200kg) and compressed to yield 100,000 tablets
`
`containing 1.25mg Ramipril each.
`
`For enclosed stability investigation the tablets are immediately packaged into PVC/PE/PVDC
`
`250ul25p/90 gsm and aluminium foil 20 um blister packs and Alu/Alu 40 pm strips. The
`samples are subjected to stability testing at 40° C/75% RH. The LOD of the tablets after
`
`manufacture is 3.19 weight—%.
`
`Table 7: Stability and water content as a function of packaging material
`
`Alu/Alu 40 pm strip pack
`
`
`
`PVC/PE/PVDC 250p/25p/90 gsm and
`aluminium foil 20 m blister ack
`
`
`
`
`
`
`
`
`e%
`%
`wei-ht-%
`e%
`%
`wei-ht-%
`months
`um
`
`
`
`
`
`
`
`
`
`
`

`

`WO 2004/064809
`
`PCT/EP2004/000456
`
`-3-
`
`Example 1 demonstrates that pharmaceutical compositions prepared with glycine
`hydrochloride prove sufficiently stable under accelerated testing conditions when water
`content is low but prove unstable when water content increases to normal levels of moisture
`
`within pharmaceutical formulations.
`
`Example 2:
`During the manufacturing process environmental conditions of 30% RH/ 30°C are kept.
`Milled glycine hydrochloride (0.300kg) is dry-mixed with Ramipril (0.500kg), microcrystalline
`cellulose (Avicel PH112; 29.36kg), precipitated silicon dioxide (Syloid AL-1FP; 3.200kg),
`pregelatinised starch (Starch 1500 LM; 1.800kg), and Iron Oxide Red (0.040kg) and the
`resulting mixture is dry-mixed with glycerol dibehenate (Compritol ATO 888; 0.800kg) and
`compressed to yield 100,000 tablets containing 5mg ramipril each, which are immediately
`packaged into PVC/PE/PVDC 250p/25u/90 gsm and aluminium foil 20 um blister packs.
`Alu/Alu 40 um strips and polypropylene container with polyethylene lid. The LCD of the
`
`tablets after manufacture is 3.19 weight-%.
`
`Table 8: Stability of ramipril (1), generation of ramipril diketopiperazide (3) and water content
`
`as a function of packaging material
`Packag
`PVC/PE/PVDC
`e
`250u/25u/90 gsm and
`aluminium foil 20 um blister
`
`LCD
`Time
`[weight
`[month
`%
`s]
`n .
`
`(1)
`[%]
`
`Alu/Alu 40 um strip pack
`
`Polypropylene container
`with polyethylene lid
`
`.
`
`Example 2 supports the findings of example 1. In particular example 2 demonstrates that low
`humidity compositions maintain levels of diketopiperazide far below the limit of 0.5% as
`stated in the European Pharmacopoeia and far below the results obtained for commercial
`ramipril formulation (Delix® 1.25mg batch number C-423; originating from the German
`
`market; 2.16% diketopiperazide).
`
`Example 3:
`
`

`

`WO 2004/064809
`
`PCT/EP2004/000456
`
`In analogy to example 1 aluminium strips containing tablets with the following composition
`
`are prepared: ramipril (1 .25mg), microcrystalline cellulose (Avicel PH112; 50.32mg),
`
`precipitated silicon dioxide (Syloid AL—1-FP; 4.6mg), lactose (Lactose DCL-21; 37mg),
`
`glycerol dibehenate (Compritol ATO 888; 1.83mg) at laboratory scale at ambient
`
`environmental conditions. The tablets are packaged into Alu/Alu 40 um strips and put on
`
`stability at 40° 0/75% RH. The LCD of the tablets after manufacture is 2.71 weight-%.
`
`Table 9: Stability at low water content
`
`
`—_I_
`
`
`
`
`
`
`
`
`
`
`
`
`
`Example 3 demonstrates that pharmaceutical compositions prepared with suitable excipients
`
`and not containing prior art stabilising agents do not show any significant degradation over 4
`
`weeks when stored under accelerated testing conditions.
`
`Example 4:
`
`In analogy to example 1 aluminium strips containing tablets with the following composition
`
`are prepared: ramipril (1.25mg), starch (Starch 1500; 20.32mg), silicon dioxide (Aerosil 200;
`
`1.00mg), lactose (Lactose DCL—21; 78.00mg), Ac-Di-Sol (4.00mg) and Sterotex (1.80mg)‘ at
`
`laboratory scale at ambient environmental conditions. The tablets are packaged into Alu/Alu
`
`40 pm strips and put on stability at 40° C/75% RH. The LCD of the tablets after manufacture
`
`is 6.60 weight-%.
`
`Table 10: Stability at high water content
`
`
`__.-
`
`
`
`
`
`—_
`
`
`_—
`
`
`
`Example 4 demonstrates that pharmaceutical compositions prepared with conventional
`
`excipients and not containing prior art stabilising agents do not prove stable when stored
`
`under accelerated testing conditions. Already after one week of storage the content of
`
`ramipril has decreased by more than 5%.
`
`

`

`WO 2004/064809
`
`PCT/EP2004/000456
`
`-10-
`
`Example 5:
`
`At laboratory scale at ambient environmental conditions capsules containing ramipril
`
`(1.25mg) and starch (Starch 1500; 138.75mg) are prepared by dry-mixing of ramipril and
`Starch 1500 and filling the blend into conventional hard gelatine capsules. The capsules are
`
`packaged into Alu/Alu 40 um strips and put on stability at 40° C/75% RH. The LCD of the
`
`capsules is 8.27 weight-%.
`
`Table 11: Stability at high water content
`
`
` 4 weeks
`
`Diketo - i oeraZIde [%
`
`3.93
`
`
`
`
`
`Example 5 demonstrates that capsule formulations showing a conventional level of water
`content do not prove stable when stored under accelerated testing conditions. After 6 weeks
`
`of storage at accelerated testing conditions the content of diketopiperazide has increased up
`to 4%.
`
`Example 6:
`
`In analogy to example 5 aluminium strips containing capsules with the following composition
`are prepared: ramipril (1.25mg), starch (Starch 1500 LM; 37.00mg) and perlitol (148.75mg)
`
`are mixed and the blend is filled into conventional capsules at laboratory scale at ambient
`
`environmental conditions. The capsules are packaged into Alu/Alu 40 um strips and put on
`
`stability at 40° C/75% RH. The LCD of the capsules 5.79 weight-%.
`
`Table 12: Stability at high water content
`
`DiketOui oerazide _°.
`
`

`

`WO 2004/064809
`
`PCT/EP2004/000456
`
`-11-
`
`Example 6 support the findings of example 5. A LOD above 5 weight-% does not allow a
`
`sufficiently stable formulation. A significant trend toward stabilisation with decreased
`
`moisture load is obvious.
`
`Example 7:
`
`In analogy to example 5 aluminium strips containing capsules with the following composition
`
`are prepared: ramipril (1.25mg), microcrystalline cellulose (Avicel PH 101; 71.48mg). starch
`
`(Starch 1500; 20.47mg), and arginine (1.80mg) are mixed and the blend is filled into
`
`conventional capsules at laboratory scale at ambient environmental conditions. The capsules
`
`are packaged into Alu/Alu 40 um strips and put on stability at 40° CI75% RH. The LCD of the
`
`capsules 3.24 weight-%.
`
`Table 13: Stability at low water content
`
`
`
`_—
`
`
`
`
`
`
`
`
`
`Diketo-i nerazide _%]
`
`Example 7 demonstrates that capsule formulations showing a low level of water content
`
`prove considerably stable towards cyclization of the active principle to diketopiperazide when
`
`storage at accelerated testing conditions. Example 5, 6 and 7 demonstrate that the principle
`
`of stabilising ramipril formulations by excluding moisture in the formulation applies for
`
`capsule formulations as well. The assay of ramipril as well remains above 95%.
`
`

`

`WO 2004/064809
`
`PCT/EP2004/000456
`
`-12-
`
`Claims
`
`1.
`
`Solid pharmaceutical composition comprising
`
`(a) an effective amount of ramipril and/or a pharmaceutical acceptable salt thereof and
`
`(b) one or more pharmaceutically acceptable excipients,
`
`wherein the composition has a suitably low water content.
`
`Composition according to claim 1, wherein the water content is less than about 5.5
`
`weight-% measured by Karl-Fischer-analysis.
`
`Composition according to claim 1, wherein the water content is less than about 4.5
`
`weight-% measured by Karl-Fischer-analysis.
`
`Composition according to any of the preceding claims, wherein ramipril and/or a
`
`pharmaceutical acceptable salt thereof is in form of pharmaceutically acceptable
`
`anhydrate, solvate and/or, hydrate and/or in crystalline and amorphous form.
`
`Composition according to any of the preceding claims, wherein the pharmaceutical
`
`composition is a tablet.
`
`Composition according to claim 5, wherein the tablet is suitably coated to generate a
`
`filmcoated tablet and/or a pill.
`
`Composition according to claim 1 —4, wherein the pharmaceutical composition is a
`
`capsule.
`
`Composition according to claim 1 — 4, wherein the pharmaceutical composition is a
`sachet
`
`Composition according to any of the preceding claims, wherein the excipients have a
`
`suitably low water content.
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`Composition according to claim 9, wherein one of said excipients is microcrystalline
`cellulose.
`
`Composition according to claim 1 — 9, wherein one of said excipients is Avicel PH 112.
`
`Composition according to claim 9, wherein one of said excipients is starch.
`
`Composition according to claim 1 - 9, wherein one of said excipients is Starch 1500
`LM.
`
`Composition according to claim 9, wherein one of said excipients is silicon dioxide.
`
`Composition according to claim 1 - 9, wherein one of said excipients is Syloid AL-1
`FP.
`
`Composition according to claim 9, wherein one of said excipients is calcium hydrogen
`
`phosphate.
`
`

`

`WO 2004/064809
`
`PCT/EP2004/000456
`
`-13-
`
`17.
`
`18.
`
`19.
`
`20.
`
`21.
`
`22.
`
`23.
`
`24.
`
`25.
`
`26.
`
`27.
`
`28.
`
`29.
`
`30.
`
`31.
`
`32.
`
`Composition according to claim 1 — 9, wherein one of said excipients is Dicafos A orA
`
`Tab or Anhydrous Emcompress.
`
`Composition according to claim 9, wherein one of said excipients is lactose.
`
`Composition according to claim 1 - 9, wherein one of said excipients is Pharmatose
`DCL 21.
`
`Composition according to claim 9, wherein one of said excipients is mannitol.
`
`Composition according to claim 1 - 9, wherein one of said excipients is Perlitol.
`
`Composition according to claim 9, wherein one of said excipients is calcium sulphate.
`
`Composition according to claim 1 - 9, wherein one of said excipients is Destab or
`
`Drierlte.
`
`Composition according to any of the preceding claims where one or more excipients
`
`are dried prior to use or throughout the manufacturing process to achieve the
`
`required level of water content.
`
`Process for the preparation of a composition according to any of the preceding
`
`claims, wherein environmental conditions during manufacture are maintained at a
`
`relative humidity equal or less than 35% at ambient temperature.
`
`Process for the preparation of a composition according to claim 1 - 23, wherein
`
`environmental conditions during manufacture are maintained at a relative humidity
`
`equal or less than 35% at equal or less than 30° C.
`
`Process according to any of the preceding claims, wherein the pharmaceutical
`
`composition is packaged into a packaging material suitably tight against penetration
`
`of humidity.
`
`‘
`
`Process according to claim 27, wherein the packaging material is a container
`
`including lid composed of polyethylene and/or polypropylene and/or glass.
`
`Process according to claim 27, wherein the packaging material is a strip or blister
`
`pack composed of aluminium which might be suitably coated or high density
`
`polyethylene.
`
`Package comprising a composition according to claims 1 - 23 packaged with
`
`packaging material suitably tight against penetration of humidity.
`
`Package according to claim 30, wherein the packaging material is a container
`
`including lid composed of polyethylene and/or polypropylene and/or glass.
`
`Package according to claim 30, wherein the packaging material is a strip or blister
`
`pack composed of aluminium which might be suitably coated or high density
`
`polyethylene.
`
`

`

`l'iFRNAHONALSEARCHREPORT
`it
`
`
`in.tlonal Application No
`PCT/EP2004/000456
`
`A. CLASSIFICATION OF UBJECT MATTER
`IPC 7
`A61K9 20
`
`According to International Patent Classification (IPC) or to both national classification and IPC
`B. FIELDS SEARCHED
`Minimum documentation seardted (classification system followed by classification symbols)
`IPC 7
`A61K
`
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
`
`Electronic data base consulted during the International search (name at data base and. where practical. search terms used)
`
`EPO-Internai, NPI Data, PAJ, BIOSIS, EMBASE, CHEM ABS Data
`
`0. DOCUMENTS COt‘SlDEFtED TO BE RELEVANT
`
`Category ‘
`
`Citation of document. with Indication. where appropriate, at the relevant passages
`
`Relevant to claim No.
`
`
`
`US 5 442 008 A (FUELBERTH WERNER
`15 August 1995 (1995—08-15)
`column 1,
`line 60 — column 2,
`
`line 64
`
`ET AL)
`
`DE 44 20 102 A (ASTA MEDICA AG)
`14 December 1995 (1995—12—14)
`example 8
`
`EP 0 317 878 A (HOECHST AG)
`31 May 1989 (1989—05-31)
`cited in the application
`examples 6,7
`
`m Furtherdocumente are listed In the continuation of box 0.
`° Special categories at cited documents:
`
`‘A' document defining the general state of the art which is not
`mnsidered to be of particular relevance
`'E' ear-Her document but published on or atterthe intemallonel
`filing date
`
`which Is cited to e
`blish the publica ion date of another
`'L' comment which ma throw doubts on priority olalm(s) or
`citation or other special reason (as specified)
`'0' document reierrlng to an oral disclosure. use. exhibition or
`other means
`'P' document published prior to the lntemationat tiling date but
`later than the priority date claimed
`Date of the actual completion of the international search
`
`14 May 2004
`Name and mailing address at the lSA
`European Patent Ottloe. PB 5818 Patentiaan 2
`NL — 2280 HV Fillswiik
`Tel. (+31—70) 340-2040. Tx. 31 651 epo ni.
`Fax: (+31—70) 340-3016
`
`Form PCT/ISN210 (socmd shoot) (January 2004)
`
`'T'
`
`Patent tamlly members are listed in annex.
`later document published after the lntematlonal filing date
`or priority date and not In conflict with the application but
`vent on
`fitter“? understand the principle or theory underlying the
`'X' document at particular relevance; the claimed invention
`cannot be considered novel or cannot be considered to
`involve an inventive step when the document is taken alone
`'Y' document at particular relevance; the claimed invention
`cannot be considered to involve an lnventtle step when the
`document is combined with one or more other such docu~
`e
`.
`metrntshiuch combination being obvious to a person skilled
`'5' document member at the same patent family
`Date of mailing or the intematlcnal search report
`
`26/05/2004
`Authorized officer
`
`VON EGGELKRAUT, S
`
`page 1 of 2
`
`

`

`‘
`
`I‘ERNATIONAL SEARCH REPORT
`
`
`c.(Conunuauon) DOCUMENTS CONSIDERED TO as RELEVANT
`
`
`Category °
`
`Citalion of document, with indlmllon, where appropriaie. o! the relavam passages
`
`ll'.tlonal Applicaflon No
`PCT/EP2004/000456
`
`Relevant to claim No.
`
`
`
`
`
`
`
`
`NO 99/03453 A (LEK TOVARNA FARMACEVTSKIH ;
`REBIC LJUBOMIRA BARBARA (SI); KOFLER
`BOJAN) 28 January 1999 (1999—01—28)
`page 4, paragraph 3
`page 7, paragraph 2
`
`
`
`
`
`
`
`
`
`
`Faun PCT/ISAI21 D (mmhualbon 01 second #106!) (January 2904)
`
`page 2 of 2-
`
`

`

`I
`
`[BNATIONAL SEARCH REPORT
`Inlormation on patent family members
`
`
`In
`
`none! Appllmtlon No
`
`
`PCT/EP2004/000456
`
`
`
`A
`
`Publlcation
`date
`
`Patent family
`member(s)y
`
`Publication
`date
`
`15--08-1995
`
`3739690 A1
`08-06-1989
`74513 T
`15--04-1992
`2581888 A
`25-05-1989
`1338344 C
`21-05-1996
`13-06-1990
`1042917 A ,B
`3869919 D1
`14-05-1992
`653688 A
`25-05-1989
`31—05-1989
`0317878 A1
`2033400 T3
`16-03-1993
`25-05-1989
`885398 A ,3,
`3004925 T3
`28-04-1993
`
`28-06-1989
`48455 AZ
`05-10-1994
`61173 81
`
`29-06-1989
`1165596 A
`10-05-1996
`2049604 0
`
`7068140 8
`26-07-1995
`9704908 Bl
`08-04-1997
`
`25-05—1989
`885213 A ,3,
`227032 A
`28—05-1991
`
`21-06-1993
`27416 A
`01-12-1988
`89061 A ,3
`
`29-09—1992
`5151433 A
`
`8808734 A
`26-07— 1989
`
`
`
`Patent document
`cited in search report
`
`
`
`US 5442008
`
`
`
`
`
`
`
`
`
`
`
`A
`
` EP 0317878
` 08-06-1989
` 3739690 A1
`31~05~1989
`15-04-1992
`74513 T
`
`2581888 A
`25-05-1989
`
`21-05—1996
`1338344 0
`13-06-1990
`1042917 A ,8
`
`3869919 01
`14-05-1992
`653688 A
`25-05-1989
`
`31-05-1989
`0317878 A1
`2033400 T3
`16-03-1993
`
`25-05—1989
`885398 A ,8,
`3004925 T3
`28—04-1993
`
`48455 AZ
`28-06-1989
`
`61173 Bl
`05-10~1994
`
`29-06-1989
`1165596 A
`2049604 C
`10-05-1996
`
`26-07-1995
`7068140 8
`9704908 Bl
`08-04-1997
`
`25-05-1989
`885213 A ,3,
`
`227032 A
`28-05-1991
`
`21-06-1993
`27416 A
`01-12-1988
`89061 A ,8
`
`15-08-1995
`5442008 A
`
`
`5151433 A
`29-09-1992
`
`26—07-1989
`8808734 A
`
`
`
`
` NO 9903453
`28-02-1999
`A
`28-01—1999
`9700186 A
`
`
`756884 82
`23-01-2003
`8252398 A
`10-02-1999
`
`1003487 A1
`31-05—2000
`25-09-2000
`338010 A1
`
`9903453 A1
`28-01—1999
`
`18“09~2003
`2003175348 A1
`
`
`
`Form PCT/Isuzu] (patent (amlty emu) (January 2cm)
`
`page 1 of 2
`
`

`

`ISERNATIONAL SEARCH REPORT
`
`Infotmatlon on patent famlly membnrs
`
`In
`
`Hana! Application No
`
`PCT/EP2004/000456
`
`.
`
`
`
`Form PCT