(12) INTERNATIONAL APPLl
`
`Doc Ref. szo
`Appl. No. 11/273,575
`
`I
`
`THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`|l||||IlllllllllllllllllllllllllllllllllllllllllllllIIIIIIIIIIIIIIIIIIIIIIHlllllflllllllllIlll
`
`13 January 2005 (13.01.2005)
`
`(43) International Publication Date
`
`(10) International Publication Number
`WO 2005/002548 A1
`
`
`(51) International Patent Classification":
`9/ 16, 31/403
`
`A61K 9/26,
`
`(74) Agent: BRAINARD, Charles, R.; Kenyon & Kenyon,
`One Broadway, New York, NY 10004-1050 (US).
`
`.
`_
`(21) International Application Number:
`PCT/U32004/020434
`
`(22) International Filing Date:
`
`24 June 2004 (24.06.2004)
`
`(81) Designated States (unless otherwise indicated, for every
`kind ofnational 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, Fl,
`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,
`
`English _
`
`English
`
`MG, MK, MN, MW, MX, MZ, NA, NI, No, NZ, OM, PG,
`PH, PL, PT, 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.
`
`(84) Designated States (unless otherwise indicated, for every
`kind ofregtonal protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT BE BG CH CY CZ DE DK EE ES FI
`FR, GB, GR, HU, IE, IT, LU, MC, NL, PL, PT, RO, SE, SI,
`
`GW, ML, MR, NE, SN, TD, T6).
`.
`P““1511“:
`— 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 "Guidr
`ance Notes on Codes and Abbreviations " appearing at the begin-
`ning of each regular issue of the PCT Gazette.
`
`(25) Filing Language,
`
`(26) Publication Language:
`
`(30) Priority Data:
`60/482,518
`
`26 June 2003 (26.062003)
`
`US
`
`(71) Applicant (forall designatedSmtesexceptBB, US):TEVA
`PHARMACEUTICAL INDUSTRIES LTD. [IIJIL]; 5
`
`(71) Applicant (for BB only): TEVA PHARMACEUTICALS
`USA, mc. [US/US]; 1090 Horsham Road, PO. Box 1090,
`North Wales, PA 19454_1090 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): HRAKOVSKY,
`Julia [IL/IL]; 6/4Mivza Uvda StreeL 48057 Rosh-Ha-Ayin
`(IL). TENENGAUZER, Ruth [II/IL]; 9/4 Ben Gamla
`Street, 45322 Hod Hasharon (IL).
`
`
`
`002548A1l|||||||ll||||ll||||||lllllllllllllllllllllllll||l||||||||||||||||||l||||l|l|||l|l||||l||||||l|
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`(54) Title: STABLE PHARMACEUTICAL COMPOSITIONS OF 2-AZA-BICYCLO[3.3.0]-OCTANE-3-CARBOXYLIC ACID
`\ DERIVATIVES
`05
`c (57) Abstract: A stable composition of a 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivative and a method for its preparation
`are described. The stable composition includes an intimate admixture of the derivative and a stabilizing effective amount of a lubri-
`cant. The stable composition further includes an external excipient. A method of preparing the stable composition includes forming
`an intimate admixture of the derivative and a lubricant and then blending the intimate admixture with at least one excipient. Prefer—
`g ably the final blend is transformed into solid unit dosage form.
`
`

`

`WO 2005/002548
`
`PCT/U82004/020484
`
`STABLE PHARMACEUTICAL COMPOSITIONS OF 2-AZA-BICYCLO [3.3.0]-
`OCTANE-3-CARBOXYLIC ACID DERIVATIVES
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`This application claims the benefit ofprovisional application Serial Number
`
`60/482,518, filed June 26, 2003, which is incorporated herein'by reference in its entirety.
`
`FIELD OF THE INVENTION
`
`This invention relates to stabilized compositions of 2-aza—bicyclo[3.3.0]-octane-3—
`
`carboxylic acid derivatives and methods for preparing them.
`
`BACKGROUND OF THE INVENTION
`
`Ramipril, quinapril, moexipril, fosinopril, enalapn'l, perindopril, and trandolapril
`
`are examples of 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid derivatives used in
`
`pharmaceutical formulations. Ramipril, which has the chemical name (ZS, 3aS, 6aS)-
`
`1[(S)-N-[(S)-1-carboxy-3-pheny1—propyl] a1anyl]octa hydrocyclopenta [b]pyrrole-2-
`
`carboxylic acid, l-ethyl ester, is a pro-drug of ramiprilat, the active form of this
`
`angiotensin—converting enzyme (ACE) inhibitor.
`
`Ramipril and certain other ACE inhibitors are reported to be effective
`
`antihypertensive drugs, but they are often susceptible to degradation. Ramipril is
`
`believed to degrade into two main products: diketopiperazine (DKP) and ramiprilat.
`
`Decomposition during manufacture and storage may adversely affect the effectiveness of
`
`the drug product or may cause the drug product to deviate from regulatory purity or
`
`potency requirements. It is therefore desirable to increase the stability of 2-aza-
`
`bicyclo[3.3.0]-octane—3-carboxy1ic acid derivative formulations.
`
`The following chemical structures are some examples of 2-aza-bicyclo[3.3.0]-
`octane-3—carboxylic acid derivatives and their corresponding active form degradants.
`
`

`

`WO 2005/002548
`
`PCT/U82004l020484
`
`Ramipril
`
`Ramiprilat
`
`M583
`
`Quinapril
`
`Quinaprilat
`
`v “Ln”
`
`HYa
`
`O
`
`CH
`
`Fosinopril
`
`Fosinoprilat
`
`’9
`W HO
`
`Enalapnl
`
`Enalaprilat
`
`

`

`WO 2005/002548
`
`PCT/US2004/020484
`
`Perindopril
`
`Perindoprilat
`
`0H
`
`NH
`
`EP 280,999 B1 (Jan. 7, 1993) describes stabilized pharmaceutical compositions
`
`that contain ACE inhibitors, an alkali or alkaline earth metal carbonate, and a saccharide.
`
`EP 317,878 B1 (April 8, 1992) is directed towards stabilized compressed
`
`pharmaceutical formulations that may contain ramipril.
`
`U.S. Patent No. 6,417,] 96 is directed to ACE inhibitor-containing compositions
`
`stabilized by the presence of magnesium oxide.
`
`U.S. Patent No. 4,830,853 is directed towards the oxidation- and color-stability of
`
`certain ACE inhibitors.
`
`U.S. Patent No. 4,793,998 is directed towards minimizing cyclization and
`
`hydrolysis of certain ACE inhibitors.
`
`SUMMARY OF THE INVENTION
`
`In one embodiment, the present invention provides a stable pharmaceutical
`
`composition comprising an intimate admixture including a 2-aza-bicyclo[3.3.0]-octane-3-
`
`carboxylic acid derivative and an effective amount of a lubricant to stabilize the
`
`composition, and at least one external excipient. In a preferred embodiment, the external
`
`excipient is in powder form.
`
`

`

`WO 2005/002548
`
`PCT/U82004/020484
`
`In another embodiment, the present invention provides a method for preparing a
`
`stable pharmaceutical composition comprising forming an intimate admixture including
`
`an 2-aza-bicyclo[3.3.0]-octane-3—carboxylic acid derivative and an effective amount of a
`
`lubricant. The method further comprises blending the intimate admixture with an
`
`external excipient.
`
`Definitions
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`As used herein, the term “stable pharmaceutical composition” refers to a
`
`pharmaceutical composition according to the invention that is less susceptible to
`
`degradation than a similar composition not having an intimate admixture of a derivative
`
`and a stabilizing effective amount of lubricant.
`
`The term “effective amount” refers to possible weight percentages that will
`
`produce the intended effect of stabilizing the composition.
`
`The term “by weight,” unless otherwise specified, means by weight of the total
`composition.
`.
`
`The term “by weight ofthe derivative” means by weight of the 2-aza-
`
`bicyclo[3.3.0]-octane-3 -carboxylic acid derivative before degradation of the derivative. _
`
`The term “intimate admixture” refers to a mixture of closely-packed components,
`
`such as those exemplified herein, as opposed to a simple blend. An intimate admixture
`
`can be obtained, for example, by co-precipitation, co-milling, compression, granulation,
`
`or the like.
`
`The term “external excipien ” refers to an excipient or combination of excipients
`that have not been intimately admixed with a derivative.
`'
`
`The term “derivative” refers to a 2-aza-bicyclo[3.3.0]-octane-3-carboxylic acid
`
`derivative. 2—aza-bicyclo[3.3.0]-octane—3-carboxy1ic acid derivatives include, for
`
`example, ramipril, quinapril, moexipril, fosinopril, enalapril, perindopril, and
`
`trandolapril.
`
`The term “principal degradant” refers to the single degradant from a 2-aza-
`
`bicyclo[3.3 .O]—octane-3-carboxylic acid derivative with the highest percentage by weight.
`
`For example, the principal degradant of ramipril is usually diketopiperazine.
`
`

`

`WO 2005/002548
`
`PCT/U82004/020484
`
`The term “active form degradan ” refers to the active compound that 2-aza-
`
`bicyclo[3.3.0]-octane-3-carboxy1ic acid derivatives degrade into. For example, the active
`
`form degradant of ramipril is ramiprilat.
`
`The term “DKP” refers to diketopiperazine.
`
`In one embodiment, the present invention provides a stable pharmaceutical
`
`composition comprising (a) an intimate admixture including a 2-aza-bicyclo[3.3.0]-
`
`octane-3-carboxylic acid derivative and an effective amount of a lubricant to stabilize the
`
`composition, and (b) at least one excipient.
`
`With respect to the intimate admixture of the stable pharmaceutical composition
`
`_ of the present invention, the derivative ofthe intimate admixture is preferably selected
`
`from the group consisting of ramipril, quinapril, moexipril, fosinopril, enalapri],
`
`perindopril, and trandolapril. The amount of the derivative is preferably from about 0.3%
`
`to about 6% by weight. More preferably, the derivative is present in the amount of from
`
`about 0.8% to about 5% by weight, and most preferably from about 0.8% to about 4.2%
`
`by weight.
`
`The lubricant of the intimate admixture can be selected from the group consisting
`
`of magnesium stearate,ta1c, stearic acid, glycerylbehenate, polyethylene glycol, ethylene
`
`oxide polymers, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium
`
`stearyl fiimarate, DL-leucine, and others known in the art. Preferably, the lubricant is
`
`sodium stearyl furnarate. The effective amount of lubricant in the intimate admixture is
`
`preferably from about 0.3% to about 60% by weight, more preferably fiom about 0.8% to
`
`about 50% by weight, more preferably from about 1% to about 40% by weight, and more
`
`preferably from about 2% to about 10% by weight of the intimate admixture.
`
`The intimate admixture can also include processing agents or other excipients that
`
`do not significantly adversely affect the stability of the composition. Thus, it is desirable
`
`to minimize the number and quantity of these additional excipients in the intimate
`
`admixture. In one embodiment, the intimate admixture further comprises one non-
`
`lubricant excipient. Preferably, the non-lubricant excipient is in the amount of about 95%
`
`by weight of the intimate admixture, or less, preferably less than about 50%.
`
`

`

`WO 2005/002548
`
`PCT/U82004l020484
`
`Examples of possible excipients are spray-dried monohydrate lactose or
`
`anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch, pregelatinized starch (e.g.
`
`starch 1500), cellulose (e.g. microcrystalline cellulose; Avicel), dihydrated or anhydrous
`
`dibasic calcium phosphate (available commercially under the registered trademark
`
`Emcompress from Mendel] or A-Tab and Di-Tab from Rhone-Poulenc, Inc., Monmouth
`
`Junction, N.J.), calcium carbonate, calcium sulfate, and others as known in the art. To
`
`improve flowability, a preferred excipient is microcrystalline cellulose, preferably in the
`
`amountof about 30% or less by weight of the total composition.
`
`The intimate admixture can also include disintegrants, binders, coloring agents,
`
`buffering agents, and other commonly employed pharmaceutically acceptable agents,
`
`provided they do not cause substantial degradation of the derivative, which is believed to
`
`be particularly sensitive to acidic agents.
`
`With respect to the external excipient of the stable pharmaceutical composition of
`
`the present invention, the external excipient may include one or more excipients, such as
`
`processing agents. A preferred processing agent is microcrystalline cellulose.
`
`Preferably, the external excipient is in the amount of from about 20% to about 99% by
`
`weight, more preferably from about 40% to about 98% by weight, and more preferably
`
`from about 50% to about 90% by weight.
`
`.
`
`The external excipient may include, for example, a lubricant, such as those
`
`described herein. A preferred lubricant is sodium stearyl fumarate or magnesium
`
`hydroxide. Preferably, the amount of lubricant in the external excipient, if any, is in the
`
`amount of from about 0.3% to about 10% by weight, more preferably from about 0.5% to
`
`about 3% by weight, and more preferably fiom about 0.8% to about 2% by weight.
`
`Alternatively or additionally, the external excipient may also include
`
`disintegrants, binders, coloring agents, buffering agents, and/or other commonly
`
`employed pharmaceutically acceptable agents.
`
`-
`
`Examples of suitable disintegrants are starch, pregelatinized starch, sodium starch
`
`glycolate, sodium carboxymethylcellulose, crosslinked sodium carboxymethylcellulose
`
`(e.g., sodium croscarmellose; crosslinked starch available under the registered trademark
`
`Ac-Di-Sol from FMC Corp., Philadelphia, Pa), clays (e.g., magnesium aluminum
`
`silicate), microcrystalline cellulose (such as those available under the registered
`
`

`

`WO 2005/002548
`
`PCT/USZOO4/020484
`
`trademark Avicel from FMC Corp. or the registered trademark Emcocel from Mendell
`
`Corp., Carmel, N.Y.), alginates, gums, surfactants, effervescent mixtures, hydrous
`
`aluminum silicate, cross-linked polyvinylpyrrolidone (available commercially under the
`
`registered trademark PVP-XL from International Specialty Products, Inc.), and others as
`
`known in the art.
`
`Examples of suitable binders include, e.g., acacia, cellulose derivatives (such as
`
`methylcellulose and carboxymethylcellulose, hydroxypropylmethylcellulose,
`
`hydroxypropylcellulose, hydroxyethylcellulose), gelatin, glucose, dextrose, xylitol,
`
`polymethacrylates, polyvinylpyrrolidone, starch paste, sucrose, sorbitol, pregelatinized
`
`starch, gum tragacanth, alginic acids and salts thereof such as sodium alginate,
`
`magnesium aluminum silicate, polyethylene glycol, guar gum, bentonites, and the like.
`
`Coloring agents may include titanium dioxide and/or dyes suitable for food such
`
`as those known as FD & C dyes and natural coloring agents such as grape skin extract,
`
`beet red powder, beta carotene, annato, carmine, turmeric, paprika, and so forth.
`
`Examples of possible bufi‘ering agents include tn'basic sodium phosphate,
`
`anhydrous sodium carbonate, glycine, magnesium hydroxide, and the like.
`
`In another embodiment, the stable pharmaceutical composition further includes a
`
`diuretic agent. Acceptable diuretic agents include high-ceiling diuretics, furosemide,
`
`bumetanide, ethacrynic acid, torsemide, muzolimide, azosemide, piretanide, tripamide,
`
`-
`
`chlorothiazide, hydrochlorothiazide, chlorthalidone, indapamide, metozalone,
`
`cyclopenthiazide, xipamide, mefi'uside, dorzolamide, acetazolamide, methazolamide,
`
`‘ ethoxzolamide, cyclothiazide, clopamide, dichlorphenamide, hydroflumethiazide,
`
`trichlormethiazide, polythiazide and benzothiazide. A preferred diuretic agent is
`
`hydrochlorothiazide. The preferred amount of the diuretic agent, when present, is from
`
`about 0.5% to about 40% by weight, more preferably from about 1% to about 30% by
`
`weight, and more preferably from about 2% to about 15% by weight.
`
`Preferably, the stable pharmaceutical composition of the present invention resists
`
`degradation when stored under high stress conditions. For example, when stored at 55°C
`
`for 48 hours, preferably (1) the total amount of the principal degradant and the active
`
`form degradant is about 3.3% by weight of the derivative, or less, more preferably about
`
`1% by weight of the derivative, or less; (2) the amount of the principal degradant present
`
`

`

`WO 2005/002548
`
`PCT/U52004/020484
`
`is about 3% by weight of the derivative, or less, more preferably about 1% by weight of
`
`the derivative, or less; and/or (3) the amount of the active form degradant present is about
`
`0.3% by weight of the derivative, or less, more preferably about 0.2% by weight of the
`
`derivative, or less.
`
`For example, for the derivative ramipril, when stored at 55°C for 48 hours, (1) the
`
`total amount ofDKP and ramiprilat is preferably about 3.3% by weight of the ramipril, or
`
`less, more preferably about 1% by weight of the ramipril, or less; (2) the amount of DKP
`
`present is preferably about 3% by weight of the ramipril, or less, more preferably about
`
`1% by weight of the ramipril, or less; and/or (3) the amount of ramiprilat present is
`
`preferably about 0.3% by weight of the ramipril, or less, more preferably about 0.2% by
`
`weight of the ramipril, or less.
`
`A stable pharmaceutical composition of the derivatives can be prepared by, first,
`
`forming an intimate admixture comprising a derivative and a lubricant. Second, the
`
`intimate admixture can be blended with an external excipient to form a final blend that is
`
`preferably transformed into solid unit dosage form, such as a tablet or capsule.
`
`Preferably, the intimate admixture is in granular form. Granules can be formed,
`
`for example, by dry granulation or wet granulation. Wet granulation techniques are
`
`known in the art and involve mixing the ingredients with a solvent, such as ethanol or
`
`isopropyl alcohol, and drying the mixture to obtain granules. Dry granulation can be
`
`performed, for example, by compaction or slugging. Compaction techniques are well
`
`known in the art and typically include the use of a roller compactor. Slugging is a
`common technique in the field and involves the use ofa tableting machine to produce
`
`slugs and passing the slugs through a mill or an oscillating granulator to form granules.
`
`Typical screen aperture sizes are, for example, 0.5 mm, 0.8 mm, or 1.0 mm.
`
`The stable pharmaceutical composition of the present invention is preferably in
`
`solid unit dosage form, more preferably in tablet or capsule form. Conventional tableting
`
`processes can be employed, e.g., by forming a tablet from a desired mixture of
`
`ingredients into the appropriate shape using a conventional tablet press. Tablet
`
`formulation and processing techniques are generally known in the field. Capsule
`
`formulation methods are also commonly known in the art.
`
`

`

`WO 2005/002548
`
`PCT/U82004/020484
`
`The functions and advantages of these and other embodiments of the present
`
`invention will be more fully understood from the examples below. The following
`
`examples are intended to illustrate the benefits of the present invention, but do not
`
`exemplify the full scope of the invention.
`
`W E
`
`xamples 1-2: m Granulation
`
`The following tablets were prepared by dry granulation. The ingredients of Part I
`
`of Table l were blended, and initial compression was carried out using a rotary tableting
`
`machine. The compressed material was milled through an oscillating granulator to
`
`produce granules having an average diameter of about 0.8 mm. The external excipient
`
`was added (Part E) and the final blend was then compressed to form tablets.
`
`
`Table 1
`
`Ingredient
`
`Example 2
`
`mg/tablet
`
`
`
` Example 1
` mg/tablet
`
`
`Microcrystalline Cellulose
`Sodium Stearyl Furnarate
`
`
`Microcrystalhne cellulose
`-
`--
`I.
`Maddedum Hydroxide
`_m
`
`
`Sodium Stead/d dumarde
`
`
`
`.
`
`
`

`

`WO 2005/002548
`
`PCT/U52004/020484
`
`Comparative Examples 3-5: Direct Compression
`
`The ingredients in Table 2 were blended and compressed into tablets.
`
`Table 2
`
`
`
`Example 3
`
`Example 4
`
`Example 5
`
`
`
`
`
`
`
`Colorant
`
`Crospovidone
`
`Sodium Stearyl Fumarate
`
`
`
`
`
`—_mm
`Microcrystalline Cellulose
`115.3
`112.75
`100.75
`
`Methocel E—5
`V
`
`Povidone (PVP K-30)
`
`Magnesium Hydroxide
`
`
`
`3 0
`
`1 3 0
`
`Comparative Examples 6-7: Wet Granulation
`
`The ingredients of Part I of Table 3 were granulated using isopropyl alcohol as a
`
`granulation liquid. The granulate was dried, milled and blended with ingredients from
`
`Part II. The final blend was compressed into tablets.
`
`10
`
`

`

`WO 2005/002548
`
`PCT/U82004/020484
`
`Table 3
`
`
`$0.; - ~-, 3-mi- 13:: ' §£.;7-!—::—,
`
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`-. 1
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`-‘='r47fi-_-
`3
`953:}
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`-
`Fri.
`.-
`1’3..-
`:
`
`”1;"? .
`..-_ -
`-
`i’k'f‘“ 1,; ”3.33.
`_
`I,
`-3 .1."
`-
`‘:
`gm“
`—.3:-~ - "er: mar,
`
`k
`
`_
`
`..n-
`
`_-
`~ 31:2,}.
`_ 7
`~:"
`.9;
`_
`.‘=l
`‘
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`
`~
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`
`
`
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`.
`
`.
`
`.
`
`.
`
`
`Results
`
`A stability test was performed on each sample by packing the tablets in plastic
`
`containers and storing them in the oven at 55°C with added water. After 48-hour storage
`
`9
`
`the amount of ramiprilat and DKP present were measured. High performance liquid
`
`chromatography (HPLC) was employed with the following parameters:
`
`Column: Zorbax SB C-8, 5pm, 250 x 4.6 mm
`Mobile Phase: Buffer adjusted to pH 2.00 with acetonitrile (65:35 V/V)
`Flow Rate: 1.0 mL / min
`
`Detection: UV, 9» = 215 nm
`
`Column Temp.: 60°C
`Sample Temp.: 4°C
`Injection Volume: 50 pl
`
`11
`
`

`

`WO 2005/002548
`
`PCT/U82004/020484
`
`A stability test was also conducted for the marketed product Tritace® 1.25 mg,
`
`which is reported to contain ramipril, starch, microcrystalline cellulose, sodium stearyl
`
`filmamte, hypromellose, and colorant.
`
`The results are shown in Table 4.
`
`'
`
`
`Table 4
`
`
`
`
`
`Total % of DKP and "
`
`Ramiprilat
`
`3.18
`
`8.49
`
`18.73
`
`15.51
`
`11.94
`
`14.88
`
`1.42
`
`
`
`
`
`
`
`
`
`Example
`
`Ramiprilat (%)
`
`DKP (%) after
`
`No.
`
`l
`
`Tritace®
`
`after 48h at 55°C
`
`48h at 55°C
`
`0.26
`
`0.08
`
`0.13
`
`0.08
`
`0.80
`
`18.65
`
`15.45
`
`11.81
`
`14.80
`
`1.36
`
`
`
`12
`
`

`

`WO 2005/002548
`
`PCT/U82004/020484
`
`What is claimed is:
`
`1.
`
`A stable pharmaceutical composition comprising:
`
`an intimate admixture including a 2—aza-bicyclo[3.3.0]-octane-3-
`
`carboxylic acid derivative and an effective amount of a lubricant to stabilize the
`
`composition; and
`
`an external excipient.-
`
`2.
`
`The composition according to Claim 1, wherein the intimate admixture is in
`
`granular form.
`
`3.
`
`The composition according to Claim 1, wherein the effective amount of the
`
`lubricant ranges from about 0.3 % to about 60% by weight of the intimate admixture.
`
`4.
`
`The composition according to Claim 1, wherein the effective amount of the
`
`lubricant ranges from about 0.8 % to about 50 % by weight of the intimate admixture.
`
`5.
`
`The composition according to Claim 1, wherein the effective amount of the
`
`lubricant ranges from about 1 % to about 40 % by weight of the intimate admixture.
`
`6.
`
`The composition according to Claim 1, wherein the effective amount of the
`
`lubricant ranges from about 2 % to about 10 % by weight of the intimate admixture.
`
`7.
`
`The composition according to Claim 1, wherein the lubricant is selected from the
`
`group consisting ofmagnesium stearate, talc, stearic acid, glycerylbehenate, polyethylene
`
`glycol, ethylene oxide polymers, sodium lauryl sulfate, magnesium lauryl sulfate, sodium
`
`oleate, DL-leucine, and sodium stearyl fiimarate.
`
`8.
`
`The composition according to Claim 7, wherein the lubricant is sodium stearyl
`
`fumarate.
`
`13
`
`

`

`WO 2005/002548
`
`PCT/U52004/020484
`
`9.
`
`The composition according to Claim 1, wherein the intimate admixture further
`
`comprises one non—lubricant excipient.
`
`10.
`
`The composition according to Claim 9, wherein the non-lubricant excipient is
`
`microcrystalline cellulose.
`
`11.
`
`The composition according to Claim 9, wherein the non-lubricant excipient is in
`
`the amount of about 95% or less by weight of the intimate admixture.
`
`12.
`
`The composition according to Claim 1, further comprising a diuretic agent.
`
`13.
`
`The composition according to Claim 12, wherein the diuretic agent is
`
`hydrochlorothiazide.
`
`14.
`
`The composition according to Claim 1, wherein the derivative is selected from the
`
`group consisting oframipril, quinapril, moexipril, fosinopril, enalapril, perindopril, and
`
`trandolapril.
`
`15.
`
`The composition according to Claim 14, wherein the derivative is ramipril.
`
`16.
`
`The composition according to Claim 1, wherein the derivative is present in an
`
`amount of from about 0.3% to about 6% by weight ofthe total composition.
`
`17.
`
`The composition according to Claim 1, wherein the derivative is present in an
`
`amount of from about 0.8% to about 5% by weight of the total composition.
`
`18.
`
`The composition according to Claim 1, wherein the derivative is present in an
`
`amount of from about 0.8% to about 4.2% by weight ofthe total composition.
`
`19.
`
`The composition according to Claim 1, wherein the composition is in solid unit
`
`dosage form.
`
`14
`
`

`

`WO 2005/002548
`
`PCT/US2004/020484
`
`20.
`
`The composition according to Claim 19, wherein the composition is in tablet
`
`form.
`
`21.
`
`The composition according to Claim 19, wherein the composition is in capsule
`
`form.
`
`22.
`
`The composition according to Claim 1, wherein the amount of a principal
`
`degradant present in the composition after 48 hours at 55 °C is less than 3% by weight of
`
`the derivative.
`
`23.
`
`The composition according to Claim 1, wherein the amount of a principal
`
`degradant present in the composition after 48 hours at 55 °C is less than 1% by weight of
`
`the derivative.
`
`24.
`
`The composition according to Claim 22, wherein the principal degradant is
`
`diketopiperazine and the derivative is rampiril.
`
`25.
`
`The composition according to Claim 23, wherein the principal degradant is
`
`diketopiperazine and the derivative is rampiril.
`
`26.
`
`The composition according to Claim 1, wherein the amount of an active form
`
`degradant present in the composition afier 48 hours at 55°C is less than 0.3% by weight
`
`of the derivative.
`
`27.
`
`The composition according to Claim 1, wherein the amount of an active form
`
`degradant present in the composition afier 48 hours at 55 °C is less than 0.2% by weight
`
`of the derivative.
`
`15
`
`

`

`WO 2005/002548
`
`PCT/U82004/020484
`
`28.
`
`The composition according to Claim 1, wherein the total amount of an active form
`
`degradant and a principal degradant present in the composition after 48 hours at 55 “C is
`
`less than 3.3% by weight of the derivative.
`
`29.
`
`The composition according to Claim 1, wherein the total amount of an active form
`
`degradant and a principal degradant present in the composition after 48 hours at 55 °C is
`
`less than 1% by weight of the derivative.
`
`30.
`
`The composition according to Claim 28, wherein the active form degradant is
`
`ramprilat, the principal degradant is diketopiperazine, and the derivative is rampiril.
`
`31.
`
`The composition according to Claim 29, wherein the active form degradant is
`
`ramprilat, the principal degradant is diketopiperazine, and the derivative is rampiril.
`
`32.
`
`A method for preparing a stable pharmaceutical composition comprising:
`
`forming an intimate admixture including a 2-aza—bicyclo[3.3.0]-octane-3-
`
`carboxylic acid derivative and a lubricant; and
`
`blending the intimate admixture with an external excipient.
`
`33.
`
`The method of Claim 32, further comprising transforming the final blend into
`
`solid unit dosage form.
`
`34.
`
`The method of Claim 33, wherein the composition is in tablet form.
`
`35.
`
`The method of Claim 33, wherein the composition is in capsule form.
`
`36.
`
`The method of Claim 32, wherein the intimate admixture is in granular form.
`
`37.
`
`The method of Claim 32, wherein the intimate admixture is formed by dry
`
`granulation or wet granulation.
`
`16
`
`

`

`WO 2005/002548
`
`PCT/U82004/020484
`
`38.
`
`A 2-aza—bicyclo[3.3.0]-octane-3-carboxy1ic acid derivative composition made by
`
`the process of Claim 32.
`
`17
`
`

`

`CLASSIFICA‘HON 0F UBJECT MATTER
`iPc 7
`A61K9 26
`A61K9/16
`
`A61K31/403
`
`Pcl,iszoo4/020484
`
`According to intemationai Patent Classification (lPC) orto both national classification and lPC
`B. FIELDS SEARCHED
`
`Minimum documentation searched (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 ileids searched
`
`Electronic data base consulted during the international search (name of data base and, where practical. search terms used)
`
`EPO-Internal, WPI Data, PAJ, EMBASE, MEDLINE, BIOSIS
`
`
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Citation of document, with indication. where appropriate. of the relevant passages
`
`Relevant to claim No.
`
`US 5 006 344 A (JERZEwSKI ROBERT L
`9 April 1991 (1991-04—09)
`.column 1,
`line 22 — line 34
`column 3,
`line 11 ~ line 34
`example 1
`
`ET AL)
`
`US 2002/131999 A1 (SHERMAN BERNARD
`CHARLES) 19 September 2002 (2002—09—19)
`paragraph ‘0002! - paragraph ‘0008!
`paragraph ‘0015!
`claim 1
`
`US 4 830 853 A (MURTHY KUCHI S
`16 May 1989 (1989—05—16)
`cited in the application
`column 1,
`line 15 — line 26
`column 4,
`line 3 - line 23
`
`m Further documents are listed in the continuation of box C.
`°
`ciai mte ories of cited docu
`nts:
`me
`9
`Spa
`'A' document defining the general state of the art which is not
`considered to be of particular relevance
`
`'E' earlier document but published on or afterthe international
`filing date
`'L' document which may throw doubts on priority cla|m(s) or
`.
`which is cited to establish the publication date of another
`citation or other special reason (as spectiied)
`'0' document referring to an oral disclosure, use, exhibition or
`other means
`‘P' document published prior to the international filing date but
`later than the priority date claimed
`
`IE Patent tarnny members are listed in annex
`
`'T'
`
`later document published after the international filing date
`or priority date and not in conflict with the application but
`nvent on
`cited '? understand the principle or theory underlying the
`'X' document of particular relevance; the claimed invention
`wnnot be considered novel or cannot be considered to
`involve an inventive step when the document is taken alone
`particular relevance, the claimed invention
`'Y' document of
`-
`.
`-
`-
`mnnot be considered to involve an inventive step when the
`document is combined with one or more other such docu—
`ments. such combination being obvious to a person skilled
`i“ “‘9 a“.
`'&' document member of the same patent family
`
`Date of the actual completion of the international search
`
`Date oi mailing of the intemationai search report
`
`28 October 2004
`
`Name and mailing address of the BA
`European Patent Office. PB. 5815 Patentlaan 2
`TNil.-(- 2280 HV Fiijswiik
`e . +31—70) 340—2040, Tx. 31 651 epo nl,
`Fax: (+31-70) 340—3016
`
`Form PCTIISN'Zto (second sheet) (Jamary 2004)
`
`05/11/2004
`
`Authorized officer
`
`-
`5‘ ndel : U
`
`

`

`C.(Conflnuatlon) DOCUMENTS CONSIDERED To BE RELEVANT
`
`Citation of document. with indication, where appropriate, of the relevant passages
`
`Relevant to claim No.
`
`
`
`‘
`PC I . -52004/020484
`
`US 2003/068366 A1 (CHUNGI SHUBHA
`10 April 2003 (2003-04—10)
`example 2
`
`ET AL)
`
`ET AL)
`
`
`
`
`
`
`
`
` US 6 417 196 Bl
`
`
`(DANIEL JANE ELLEN
`9 July 2002 (2002—07—09)
`cited in the application
`column 5,
`line 17 — line 67
`
`
`
`
`
`
`
`EP 0 280 999 A (WARNER LAMBERT CO)
`7 September 1988 (1988-09-07)
`cited in the application
`
`claim 1
` US 6 086 919 A (BAUER BRIGITTE
`
`
`
`
`11 July 2000 (2000—07—11)
`column 3,
`line 32 — line 36
`examples 9,11
`
`ET AL)
`
`
`
`
`
`
`Faun PCT/ISA/21o (omthuaflon 0! second sheet) (January 2004)
`
`

`

`nation on patent family members
`
`
`
`Patent document
`cited In search report
`
`Publicatlon
`date
`
`Patent family
`member(s)
`
`PC1 -52004/020484
`Publication
`date
`
`09-04-1991
`
`US 5006344
`
`100321 T
`15-02-1994
`2019324 A1
`10-01-1991
`299154 A5
`02—04-1992
`69006125 D1
`03-03-1994
`19-05-1994
`69006125 T2
`28-02—1994
`408273 T3
`16-01-1991
`0408273 A1
`16-12-1994
`2062376 T3
`18-10-1999
`2965633 82
`01-03-1991
`3048623 A
`———___——______————_——__—_—.___—_———————_——_————————_——_ ——______._—_—___
`
`
`
`US 2002131999
`19-09-2002
`11—07-2002
`2330904 A1
`16-09-2004
`776522 B2
`18-07-2002
`1004402 A
`29-08-2002
`10164343 A1
`04-09—2002
`____——___—___——___._—__——_—___—_.__.___________._______—————______-_-———
`2372702 A ,8
`
`
` 67090 T
`US 4830853 16-05-1989
`15—09-1991
`604061 82
`06—12—1990
`21-04—1988
`7939787 A
`10-03—1992
`1297024 C
`17-10-1991
`3772924 01
`21—04-1988
`543587 A
`27—04-1988
`0264887 A1
`01-11—1993
`2040726 T3
`21-04—1988
`874594 A
`3002698 T3
`25—01-1993
`85694 A
`26-08-1994
`10—08—1994
`60773 Bl
`2703906 82
`26-01—1998
`10-05-1988
`63104931 A
`9600430 81
`06-01—1996
`874352 A
`21—04—1988
`221954 A
`27—03—1990
`08-08-1991
`25582 A
`01—11-1987
`85942 A ,B
`95494 G
`28—10-1994
`8707132 A
`26—04-1989
`—~—__———__——-_———__.___________________.___—————____—__——————_—__—__—_
`
`
` US 2003068366
`10-04-2003
`
`2461958 A1
`13-03—2003
`1429729 A1
`23-06-2004
`03020243 A1
`13-03-2003
`—_————______————_——______._____._——_..____——__——__—_———_____.__——__—-___
`
`
`
`2002161020 A1
`
` 31-10-2002
`
`09-07-2002
`US 6417196
`755616 82
`19-12-2002
`3979399 A
`20-12-1999 '
`9910947 A
`06-03-2001
`2330581 A1
`09-12-1999
`1144598 T
`07-04-2004
`1083931 A1
`21-03-2001
`0102260 A2
`28-03—2002
`27398 A
`05-04-2001
`2002516881 T
`11-06-2002
`20006148 A
`04-12-2000
`25-10-2002
`508544 A
`05-11-2001
`344586 A1
`20-04—2001
`200003600 T2
`565455 B
`11-12-2003
`
`Form PCT[ISA/210 (pawn lamlly annex) (January 2004)
`
`

`

`nation on patent family members
`
`Patent docum