(12) United States Patent
`Diederich et al.
`
`I 1111111111111111 11111 lllll lllll 111111111111111 1111111111 111111111111111111
`US006677320B2
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,677,320 B2
`Jan.13,2004
`
`(54) PARENTERAL BISPHOSPHONATE
`COMPOSITION WITH IMPROVED LOCAL
`TOLERANCE
`
`(75)
`
`Inventors: Anke Diederich, Basel (CH); Pierre
`Goldbach, Rixheim (FR); Thomas
`Pfister, Sissach (CH)
`
`(73) Assignee: Hoffmann-La Roches Inc., Nutley, NJ
`(US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 49 days.
`
`(21) Appl. No.: 09/758,605
`
`(22) Filed:
`
`Jan. 11, 2001
`
`(65)
`
`Prior Publication Data
`
`US 2001/0011082 Al Aug. 2, 2001
`
`(30)
`
`Foreign Application Priority Data
`
`Jan. 20, 2000
`
`(EP) ............................................ 00101044
`
`Int. Cl.7 ................................................ A61K 31/66
`(51)
`(52) U.S. Cl. ....................... 514/102; 514/103; 514/104;
`514/107; 514/108
`(58) Field of Search ................................. 514/102, 103,
`514/104, 107, 108
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,962,432 A
`4,054,598 A
`4,252,742 A
`4,267,108 A
`4,327,039 A
`4,407,761 A
`4,621,077 A
`4,624,947 A
`4,666,895 A
`4,719,203 A
`4,746,654 A
`4,761,406 A
`4,777,163 A
`4,784,993 A
`4,876,248 A
`4,886,499 A
`4,922,077 A
`4,927,814 A
`4,942,157 A
`4,970,335 A
`
`6/1976 Schmidt-Dunker ......... 424/204
`10/1977 Blum et al. ... ... .. ... ... 260/502.5
`2/1981 Blackwell, III et al.
`.... 564/447
`5/1981 Blum et al. ... ... .. ... . 260/326.61
`4/1982 Blum et al. ... ... .. ... ... 260/502.5
`10/1983 Blum et al. ... ... .. ... ... 260/502.5
`11/1986 Rosini et al.
`............... 514/108
`11/1986 Blum et al. ................. 514/108
`5/1987 Bosies et al. ............... 514/108
`1/1988 Bosies et al. ............... 514/108
`5/1988 Breliere et al. ............. 514/108
`8/1988 Flora et al. ................... 514/86
`10/1988 Bosies et al. ................. 514/80
`11/1988 Bosies et al. ................. 514/93
`10/1989 Breliere et al. ............. 514/108
`12/1989 Cirelli et al.
`............... 604/131
`5/1990 Gordon ................. 219/121.68
`5/1990 Gall et al.
`.................. 514/108
`7/1990 Gall et al.
`.................. 514/108
`11/1990 Isomura et al. ............... 562/13
`
`4,971,958 A
`5,002,937 A
`5,019,651 A
`5,616,571 A *
`5,730,715 A *
`
`11/1990
`3/1991
`5/1991
`4/1997
`3/1998
`
`Bosies et al. . . . . . . . . . . . . . . . . . 514/89
`Bosies et al. . . . . . . . . . . . . . . . 514/108
`Kieczykowski ... .. ... ... ... 562/13
`Daifotis et al. ............. 514/102
`Sage, Jr. et al. . . . . . . . . . . . . . . 604/20
`
`FOREIGN PATENT DOCUMENTS
`
`DE
`DE
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`WO
`WO
`WO
`WO
`
`42 44 422
`42 44 423
`022 751
`170 228
`0 203 649
`197 478
`252 504
`252 505
`258 618
`273 190
`350 002
`449 405
`WO 90/00798
`WO 95/31203
`WO 96/05842 Al *
`WO 01/28555
`
`6/1994
`6/1994
`1/1981
`2/1986
`3/1986
`10/1986
`1/1988
`1/1988
`3/1988
`7/1988
`1/1990
`10/1991
`1/1990
`11/1995
`2/1996
`4/2001
`
`OTHER PUBLICATIONS
`
`Abstract of Japanese Patent 080922102.
`Quimby et al., J. Org. Chem., vol. 32, pp. 4111-4114 (1967).
`Abstract for B2.
`Abstract for B3.
`Abstract for BS.
`Abstract for B7.
`* cited by examiner
`
`Primary Examiner-Theodore J. Criares
`Assistant Examiner-Jennifer Kim
`(74) Attorney, Agent, or Firm-George W. Johnston;
`Patricia S. Rocha-Tramaloni; Bernard Lau
`
`(57)
`
`ABSTRACT
`
`The present invention relates to a parenteral composition
`comprising a bisphosphonic acid or a pharmaceutically
`acceptable salt thereof (bisphosphonate) as active compo(cid:173)
`nent and a pharmaceutically acceptable chelating agent,
`processes of the preparation of this composition, and meth(cid:173)
`ods of their use in the treatment and prevention of diseases
`involving bone resorption, especially osteoporosis, Paget's
`disease, hypercalcemia of malignancy, and metabolic bone
`disease. The compositions are especially useful for improv(cid:173)
`ing the local tolerance of the active component when admin(cid:173)
`istered parenterally.
`
`2 Claims, 4 Drawing Sheets
`
`APOTEX EXHIBIT 1063
`Apotex v. Alkermes
`IPR2025-00514
`
`

`

`U.S. Patent
`
`Jan.13,2004
`
`Sheet 1 of 4
`
`US 6,677,320 B2
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`

`

`U.S. Patent
`
`Jan. 13,2004
`
`Sheet 2 of 4
`
`US 6,677,320 B2
`
`Fig.3
`
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`
`Fig. 4
`
`

`

`U.S. Patent
`
`Jan.13,2004
`
`Sheet 3 of 4
`
`US 6,677,320 B2
`
`Fig. 5
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`
`

`

`U.S. Patent
`
`Jan. 13,2004
`
`Sheet 4 of 4
`
`US 6,677,320 B2
`
`Fig. 7
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`

`

`US 6,677,320 B2
`
`1
`PARENTERAL BISPHOSPHONATE
`COMPOSITION WITH IMPROVED LOCAL
`TOLERANCE
`
`2
`SUMMARY OF THE INVENTION
`
`5
`
`The problem is solved, according to the present invention,
`by a parenteral composition comprising a bisphosphonate
`and a pharmaceutically acceptable chelating agent.
`It has surprisingly been found that administering a bis(cid:173)
`phosphonate in a composition comprising a pharmaceuti(cid:173)
`cally acceptable chelating agent clearly improves the
`duration, frequency and intensity of side effects. The pres-
`10 ence of an additional bivalent cation chelator, especially
`EDTA and DTPA, substantially improved the adverse local
`reaction at the application sites when compared with the
`corresponding formulation without this additional bivalent
`cation chelator. A pharmaceutically acceptable excipient
`15 may also be added to the composition.
`
`BACKGROUND OF THE INVENTION
`The present invention relates to a parenteral composition
`comprising a bisphosphonic acid or a pharmaceutically
`acceptable salt thereof (bisphosphonate) as active
`component, a pharmaceutically acceptable chelating agent
`and pharmaceutically acceptable excipients, processes of the
`preparation of this composition, and methods of their use in
`the treatment and prevention of diseases involving bone
`resorption, especially osteoporosis, Paget's disease, hyper(cid:173)
`calcemia of malignancy, and metabolic bone disease. The
`compositions are especially useful for improving the local
`tolerance of the active component when administered
`parenterally, especially by the subcutaneous route.
`Bisphosphonates, i.e. bisphosphonic acids or soluble,
`pharmaceutically acceptable salts thereof, are synthetic ana(cid:173)
`logs of the naturally occurring pyrophosphate. Due to their 20
`marked affinity for solid-phase calcium phosphate, bispho(cid:173)
`sphonates bind strongly to bone mineral. Pharmacologically
`active bisphosphonates are well known in the art and are
`potent inhibitors of bone resorption and are therefore useful
`in the treatment and prevention of diseases involving abnor- 25
`mal bone resorption, especially osteoporosis, Paget's
`disease, hypercalcemia of malignancy, and metabolic bone
`disease.
`Bisphosphonates as pharmaceutical agents are described
`for example in EP-A-170,228, EP-A-197,478, EP-A-22,
`751; EP-A-252,504, EP-A-252,505, EP-A-258,618, EP-A-
`350,002, EP-A-273,190, WO-A-90/00798, etc.
`Pharmaceutical forms of marketed bisphosphonates are
`oral formulations (tablets or capsules) or solutions for intra(cid:173)
`venous injection or infusion. They are systemically well 35
`tolerated when administered at therapeutic doses. However,
`bisphosphonates as a class are irritant to skin and mucous
`membranes resulting in digestive tract side effects, e.g.
`esophageal adverse events or gastrointestinal disturbances.
`In consequence, the oral route of administration has to 40
`follow inconvenient recommendations of use for the patient.
`The intravenous route of administration is complicated by
`adverse events in case of application failure. If the vein is not
`exactly met or if the drug is administered inadvertently by
`the paravenous route, severe local tissue reaction are 45
`induced including necroses. Thus, there is a substantial need
`to improve the pharmaceutical formulation of bisphospho(cid:173)
`nates in order to reduce or avoid tissue damage after
`parenteral administration, especially by the subcutaneous
`route.
`The pathophysiological mechanism of bisphosphonate
`induced tissue damage is unknown. As the local reactions
`are similar for different bisphosphonates, at least those
`induced by nitrogen-containing bisphosphonates (amino(cid:173)
`bisphosphonates), a common mechanism must be assumed. 55
`The delay in onset and progress of local reactions may
`indicate the involvement of the unspecific immune defense
`system.
`Attempts were made to improve tissue tolerance of bis(cid:173)
`phosphonates by developing suspensions of insoluble or 60
`poorly soluble salts of bisphosphonates providing local
`sustained release, e.g. described in EP 449,405, DE-A-
`4244422 and DE-A-4244423. However, this approach
`proved to improve only slightly the local tolerance.
`The problem underlying the present invention is therefore 65
`to provide a composition which is able to mm1m1ze or
`suppress the above mentioned disadvantages.
`
`30
`
`50
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`FIG. 1 depicts a graph of the mean grade of swelling after
`s.c. injection of ibandronate solution, pH 7.4 with and
`without 0.1 % EDTA (n=9).
`FIG. 2 depicts a bar graph of the mean diameter of
`subcutaneous findings 9 days after s.c. injection of ibandr(cid:173)
`onate solution, pH 7.4 with and without 0.1 % EDTA (n=9).
`FIG. 3 depicts a graph of the mean grade of swelling after
`s.c. injection of ibandronate solution, pH 7.4 with and
`without EDTA (n=9). Data with 0.1 % EDTA are combined
`with results of the first test (n=18).
`FIG. 4 depicts a bar graph of the mean diameter of
`subcutaneous findings 9 days after s.c. injection of ibandr(cid:173)
`onate solution, pH 7.4 with and without EDTA (n=9). Data
`with 0.1 % EDTA are combined with results of the first test
`(n=18).
`FIG. 5 depicts a graph of the mean grade of swelling after
`s.c. injection of ibandronate solution, pH 7.4 with and
`without 1 % DTPA (n=12).
`FIG. 6 depicts a bar graph of the mean diameter of
`subcutaneous findings 9 days after s.c. injection of ibandr(cid:173)
`onate solution, pH 7.4 with and without DTPA (n=12).
`FIG. 7 depicts a graph of the mean grade of swelling after
`s.c. injection of alendronate solution, pH 7.4 with and
`without 1 % EDTA (n=9).
`FIG. 8 depicts a bar graph of the mean diameter of
`subcutaneous findings 9 days after s.c. injection of alendr(cid:173)
`onate solution, pH 7.4 with and without EDTA (n=9).
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Unless otherwise indicated the following definitions are
`set forth to illustrate and define the meaning and scope of the
`various terms used to describe the invention herein.
`The term "bisphosphonate" means compounds character(cid:173)
`2
`- bonds. If the two bonds are located
`ised by two C-PO3
`on the same carbon atom, the compounds are called geminal
`bisphosphonates. It should be noted that the term "bispho(cid:173)
`sphonate" as used herein in referring to the therapeutic
`agents of the present invention are meant to also encompass
`diphosphonates, biphosphonic acids, and diphosphonic
`acids, as well as salts and derivatives of these materials. The
`use of a specific nomenclature in referring to the bisphos(cid:173)
`phonate or bisphosphonates is not meant to limit the scope
`of the present invention, unless specifically indicated.
`The term "chelating agent" or "chelator" means an
`organic or inorganic compound, which forms via two or
`more of its functional groups stable ring-shaped complexes
`with metal cations. It should be noted that bisphosphonates
`
`

`

`US 6,677,320 B2
`
`4
`employed in the instant invention. Examples of base salts of
`bisphosphonic acids include ammonium salts, alkali metal
`salts such as potassium and sodium (including mono, di- and
`tri-sodium) salts (which are preferred), alkaline earth metal
`5 salts such as calcium and magnesium salts, salts with
`organic bases such as dicyclohexylamine salts, N-methyl(cid:173)
`D-glucamine, and salts with amino acids such as arginine,
`lysine, and so forth. The non-toxic, physiologically accept(cid:173)
`able salts are preferred. The salts may be prepared by
`10 methods known in the art, such as described in European
`Patent Pub. No. 252,504 or in U.S. Pat. No. 4,922,077.
`In a preferred embodiment of the present invention, the
`term "bisphosphonate" of the present invention corresponds
`to compounds of formula
`
`15
`
`20
`
`(I)
`
`P(O)(OH)2
`
`P(O)(OH)2~A
`
`X
`
`30
`
`3
`also have chelating activity. The term "chelating agent" is
`therefore understood to be a chelator which sequesters metal
`ions competitively to the bisphosphonate used as the active
`component in the pharmaceutical composition.
`The term "pharmaceutically acceptable" as used herein
`means that the salts or chelating agents present a medically
`acceptable toxicity risk when administered to a patient
`according to established medical procedures.
`The term "pharmaceutically acceptable salt" refers to
`ammonium salts, alkali metal salts such as potassium and
`sodium (including mono, di- and tri-sodium) salts (which
`are preferred), alkaline earth metal salts such as calcium and
`magnesium salts, salts with organic bases such as dicyclo(cid:173)
`hexylamine salts, N-methyl-D-glucamine, and salts with
`amino acids such as arginine, lysine, and so forth.
`The term "alkyl", alone or in combination, means a
`straight-chain, branched-chain, or cyclic alkyl group con(cid:173)
`taining a maximum of 30, preferably a maximum of 10, and
`more preferably a maximum of 7, carbon atoms, e.g.,
`methyl, ethyl, n-propyl, 2-methylpropyl (iso-butyl),
`1-methylethyl (iso-propyl), n-butyl, 1,1-dimethylethyl
`(t-butyl), and pentyl. The term "alkyl" also comprises the
`above defined groups, optionally substituted with phenyl,
`pyridyl, furanyl, pyrrolidinyl, imidazolyl, amino, mono- or 25
`dialkylamino, hydroxy, SH, and alkoxy.
`The term "diluent" means an ingredient in a medicinal
`preparation which lacks pharmacological activity but is
`pharmaceutically necessary or desirable. For example a
`diluent may be a liquid for the dissolution of drug(s) to be
`injected, e.g. water.
`The term "solvents" refers to a liquid that holds another
`substance in solution, i.e., dissolves it, e.g. water.
`The term "preservatives" refers to a substance added to a
`pharmaceutical preparation to prevent bacterial growth.
`The term "device" means a contrivance for a specific
`purpose. In the present invention the purpose is to enable,
`support or facilitate parenteral drug administration.
`The term "local anaesthetic" refers to a compound that
`reversibly depresses neuronal function at the site of
`application, producing loss of ability to perceive pain and/or
`other sensations, e.g. lidocaine hydrochloride.
`In more detail, the present invention is directed to a
`parenteral composition comprising a bisphosphonate and a
`pharmaceutically acceptable chelating agent. The parenteral
`compositions may have the form of a liquid, e.g. an aqueous
`solution, or a sterile powder and/or lyophilisate. A liquid,
`e.g. water, may be added to the sterile powder and/or
`lyophilisate to give a solution for administration.
`In a preferred embodiment of the present invention, the
`above composition is a liquid, preferably an aqueous solu(cid:173)
`tion.
`Bisphosphonates as pharmaceutical agents are described
`for example in U.S. Pat. No. 4,666,895, U.S. Pat. No. 55
`4,719,203, EP-A-252,504, EP-A-252,505, U.S. Pat. No.
`4,777,163, U.S. Pat. No. 5,002,937 and U.S. Pat. No.
`4,971,958.
`Methods for the preparation of bisphosphonic acids may
`be found in, e.g., U.S. Pat. No. 3,962,432; U.S. Pat. No. 60
`4,054,598; U.S. Pat. No. 4,267,108; U.S. Pat. No. 4,327,039;
`U.S. Pat. No. 4,407,761; U.S. Pat. No. 4,621,077; U.S. Pat.
`No. 4,624,947; U.S. Pat. No. 4,746,654; U.S. Pat. No.
`4,922,077; U.S. Pat. No. 4,970,335; U.S. Pat. No. 5,019,651;
`U.S. Pat. No. 4,761,406; U.S. Pat. No. 4,876,248; J. Org. 65
`Chem. 32, 4111 (1967) and EP-A-252,504. The pharmaceu(cid:173)
`tically acceptable salts of bisphosphonic acids may also be
`
`wherein A and X are independently selected from the group
`consisting of hydrogen, hydroxy, halogen, amino, SH,
`phenyl, alkyl, mono- or dialkylamino, mono- or
`dialkylaminoalkyl, alkoxy, thioalkyl, thiophenyl, and aryl or
`heteroaryl moieties selected from the group consisting of
`phenyl, pyridyl, furanyl, pyrrolidinyl, imidazolyl, and
`benzyl, wherein the aryl or heteroaryl moiety is optionally
`substituted with alkyl.
`In the foregoing chemical formula, A can include X and
`X include A such that the two moieties can form part of the
`same cyclic structure.
`The foregoing chemical formula is also intended to
`encompass carbocyclic, aromatic and heteroaromatic struc-
`35 tures for the A and/or X substituents, e.g. naphthyl, quinolyl,
`isoquinolyl, adamantyl, and chlorophenylthio.
`Preferred structures are those in which A is selected from
`the group consisting of hydrogen, hydroxy, and halogen, an
`X is selected from the group consisting of alkyl, halogen,
`40 thiophenyl, thioalkyl and dialkylaminoalkyl.
`More preferred structures are those in which A is selected
`from the group consisting of hydrogen, hydroxy, and Cl and
`X is selected from the group consisting of alkyl, Cl, chlo(cid:173)
`rophenylthio and dialkylaminoalkyl.
`Even more preferred structures refer to the above defined
`compounds with the proviso that alendronate is not
`included.
`Most preferred is when Ais hydroxy and Xis (N-methyl(cid:173)
`N-pentyl)amino-ethyl, i.e. ibandronate.
`Examples of bisphosphonates, i.e. bisphosphonic acids
`and pharmaceutically acceptable salts thereof which may be
`employed as active ingredients in the instant invention
`include:
`a) 4-amino-l-hydroxybutylidene-1,1-bisphosphonic acid
`( alendronate ),
`b) N-methyl-4-amino-l-hydroxybutylidene-1,1-
`bisphosphonic acid,
`c) 4-(N,N-dimethylamino )-1-hydroxybutylidene-1,1-bis(cid:173)
`phosphonic acid,
`d) 3-amino-l-hydroxypropylidene-1,1-bisphosphonic
`acid (pamidronate ),
`e) 3-(N-methyl-N-pentyl) amino-l-hydroxypropane-1,1-
`bisphosphonic acid (ibandronic acid),
`f) [3-(N-methyl-N-pentyl) amino-l-hydroxypropane-1,1-
`bisphosphonic acid, monosodium salt, monohydrate]
`(ibandronate ),
`
`45
`
`50
`
`

`

`US 6,677,320 B2
`
`10
`
`40
`
`1)
`
`5
`g) l-hydroxy-3-(N-methyl-N-pentylamino )propylidene-
`1,1-bisposphonic acid,
`h) 1-h ydroxy-2-[ 3-pyridinyl]e thylidene -1, 1-
`bisphosphonic acid (risedronate ),
`i) 4-(hyroxymethylene-1,1-bisphosphonic acid) 5
`piperidine,
`j) cycloheptylaminomethylene-1,1-bisposphonic acid
`( cimadronate ),
`k) 1,1-dichloromethylene-1,1-diphosphonic acid and the
`dissodium salt ( clodronate ),
`l-hydroxy-3-(1-pyrrolidiny 1)-propy lidene-1, 1-
`bisphosphonic acid (EB-1053),
`m) l-hydroxyethane-1,1-diphosphonic acid ( etidronic
`acid),
`n) 6-amino-l-hydroxyhexylidene-1,1-bisphosphonic acid
`(neridronate ),
`o) 3-( dimethylamino )-1-hydroxypropylidene-1,1-
`bisphosphonic acid ( olpadronate ),
`p) [2-(2-pyridinyl)ethylidene ]-1,1-bisphosphonic acid 20
`(piridronate ),
`q) ( 4-chlorophenyl)thiomethane-1,1-diphosponic acid
`(tiludronate ),
`r) l-hydroxy-2-(lH-imidazol-1-y l)ethy lidene-1, 1- 25
`bisphosphonic acid (zolendronate ).
`s) [( cycloheptylamino )-methylene ]-bisphosphonic acid
`(icadronate ), and/or
`t) [1-Hydroxy-2imidazo-(l,2-a) pyridin-3-ylethylidene ](cid:173)
`bisphosphonic acid and pharmaceutically acceptable 30
`salts thereof.
`In a preferred embodiment of the invention, bisphospho(cid:173)
`nates may be selected from the group consisting of com(cid:173)
`pounds b) to t) and pharmaceutically acceptable salts
`thereof.
`Preferred are bisphosphonates selected from the group
`consisting of cimadronate, clodronate, tiludronate,
`etidronate, ibandronate, risedronate, piridronate,
`pamidronate, zolendronate and pharmaceutically acceptable
`salts thereof.
`In a more preferred embodiment of the present invention,
`the bisphosphonate is 3-(N-methyl-N-pentyl) amino-l(cid:173)
`hydroxypropane-1,1-bisphosphonic acid (ibandronic acid)
`or pharmaceutically acceptable salts thereof, or even more
`prefer ab 1 y 3 - ( N - met h y 1- N - pent y 1) amino - 1 - 45
`hydroxypropane-1,1-bisphosphonic acid, monosodium salt,
`monohydrate.
`The pharmaceutically chelating agent or chelator or a
`pharmaceutically acceptable salt thereof according to the
`present invention is a compound, which forms via two or
`more of its functional groups stable ring-shaped complexes
`with metal cations, e.g. preferably a polyacetic acid or a
`pharmaceutically acceptable salt thereof like EDTA and
`DTPA. Chelating agents are complexes, which unlike simple
`ligands, e.g. ferrocyanide (Fe(CN) 6
`4
`-), which form complex 55
`salts by a single bond provided by a lone electron pair, are
`capable of forming more than one bond. Ethylene diamine,
`for example, is bidentate (two links), tripyridyl is tridentate
`(three) and ethylene diamine tetraacetic acid (EDTA) is
`hexadentate (six) which makes it particularly effective as a 60
`pharmaceutical chelating agent. One of the consequences of
`chelation is the formation of a cyclic structure which has
`high thermodynamic and thermal stability analogous to
`aromatic rings. Furthermore, the chelate complex is usually
`more stable than the ligand, since two bonds must rupture, 65
`and although one may break, reformation occurs before the
`other can. This is known as the chelate effect.
`
`6
`Preferably the chelating agent is a bivalent cation chelator
`and more preferably, the chelator is selected from the group
`c~nsisting of ethylenediaminetetraacetic acid (EDTA),
`d1ethylenetriaminepentaacetic acid (DTPA), ethylene
`glycol-bis(~-aminoethyl ether)-tetraacetic acid (EGTA), N
`(hydroxyethyl) ethylenediaminetriacetic acid (HEDTA),
`nitrilotriacetic acid (NTA), triethanolamine,
`8-hydroxyquinoline, citric acid, tartaric acid, phosphoric
`acid, gluconic acid, saccharic acid, thiodipropionic acid,
`acetonic dicarboxylic acid, lecithin, di(hydroxyethyl)
`glycine, phenylalanine, tryptophan, glycerin, sorbitol and
`pharmaceutically acceptable salts thereof.
`More preferably the chelating agent is selected from the
`group consisting of EDTA, DTPA, citric acid, tartaric acid,
`phosphoric acid, gluconic acid or a pharmaceutically accept-
`15 able salt thereof and even more preferably the pharmaceu(cid:173)
`tically chelating agent is EDTA and DTPA or a pharmaceu(cid:173)
`tically acceptable salt thereof.
`In a preferred embodiment of the present invention the
`molar ratio between the bisphosphonate and the pharmaceu(cid:173)
`tically acceptable chelating agent is about 1:0.01 to about
`1:500, more preferably about 1:0.1 to about 1:50, and even
`more preferably is about 1:10.
`For example, a formulation containing 1 mg ibandronate/
`ml physiological saline adjusted to pH 7.4. EDTA was added
`to the ibandronate solution at a concentration range of 0.1 to
`10 mg/ml. This corresponds to molar ibandronate to EDTA
`ratios of approximately 1:0.1 to 1:10. The improving effect
`of EDTA was shown to be dose-related. At the lowest ratio
`of 1:0.1 there was still some beneficial effect and at the
`highest ratio of 1: 10, the local adverse reactions were still
`not completely abolished. Thus, much higher and lower
`molar ratios can be expected to be also useful to improve the
`local tolerance of parenterally administered bisphosphonate
`formulations. In addition, the effect of EDTA on alendronate
`35 induced local reaction as well as the efficacy of DTPA as
`chelating agent could also be demonstrated.
`The composition as defined above may contain one or
`more additional pharmaceutically acceptable chelating agent
`(s) as defined above.
`The excipients may be selected diluents, solvents and/or
`preservatives, e.g. water, alcohols, polyols, glycerine, and
`vegetable oils. The compositions according to the present
`invention may comprise one or more of these pharmaceu(cid:173)
`tically acceptable excipients.
`In a preferred embodiment of the present invention the
`composition as defined above may comprise a bisphospho(cid:173)
`nate or a pharmaceutically acceptable salt thereof, a phar(cid:173)
`maceutically acceptable chelating agent, a tonicity agent ( a
`tonicity adjusting agent as described below), a pH adjusting
`50 agent (i.e. acid, base, buffer as described below), and a
`solvent. Optionally these compositions may contain in addi(cid:173)
`tion a local anaesthetic.
`In a more preferred embodiment of the present invention,
`the pH of the solution of the above defined compositions is
`in the range of 2-10, preferably 4-9, more preferably 6-8,
`and most preferably 7-8, e.g. about 7.4.
`In an even more preferred embodiment of the present
`invention the above defined composition is a parenteral
`composition comprising
`a) 0.1-10 mg 3-(N-methyl-N-pentyl) amino-l(cid:173)
`hydroxypropane-1,1-bisphosphonic acid, monosodium
`salt, monohydrate and
`b) 0.5-50 mg EDTA, Na2 , 2H2 0.
`For example, the above composition may comprise
`a) 0.1-10 mg 3-(N-methyl-N-pentyl) amino-l(cid:173)
`hydroxypropane-1,1-bisphosphonic acid, monosodium
`salt, monohydrate;
`
`

`

`US 6,677,320 B2
`
`8
`The invention also relates to the use of the above compo(cid:173)
`sition for the preparation of medicaments useful for the
`prevention of tissue damage after parenteral administration
`of bisphosphonates, preferably by administration of an aque(cid:173)
`ous solution.
`In addition, the invention also refers to a device for local
`and systemic sustained release comprising a composition as
`defined above. For example, such devices may consist of
`implanted osmotic pumps or externally portable infusion
`10 pumps connected to a supply tube and/or a subcutaneously
`inserted cannula.
`Further, the invention also refers to a device for enabling,
`facilitating or supporting parenteral administration of a
`composition as defined above. For example, the device may
`be used to achieve local and systemic sustained release
`comprising portable infusion pumps connected to a supply
`tube and/or a subcutaneously inserted cannula (e.g. Portable
`Injection Appliance; U.S. Pat. No. 4,886,499) or to reduce
`local pain caused by the injection, for example needle free
`injectors ( e.g. MicroPor™, Medi-jector™).
`Further the invention also relates to injectable
`formulations, which release a composition as defined above
`in a sustained fashion and may reduce local pain caused by
`injection. For example, the sustained release formulation
`may comprise depot forming compounds such as different
`pharmaceutically acceptable oils, thickening agents
`( carboxymethylcellulose, poloxamer, gelatin), biodegrad(cid:173)
`able microparticle forming polymers (lactide/glycolide
`polymers, polyanhydrides, chitosan) or pharmaceutically
`acceptable polyelectrolytes (Albumin, Protamin).
`The invention will be now illustrated in details by the
`following examples and figures.
`
`35
`
`EXAMPLES
`
`Example 1
`
`7
`b) 0.5-50 mg EDTA, Na2 , 2H2 0;
`c) about 9.0 mg sodium chloride;
`d) sodium hydroxide q.s. to about pH 7.4; and
`e) water for injection q.s. to 0.5 or 1.0 ml.
`In more detail, a parenteral composition may comprise 5
`about 1.125 mg ibandronate sodium salt, about 10 mg
`EDTA, Na2 , 2H2 0, about 9.0 mg sodium chloride, sodium
`hydroxide q.s. to pH 7.4 and water for injection q.s. to 1.0
`ml.
`Preferably, a parenteral composition may comprise about
`1.125 mg ibandronate sodium salt, about 10 mg EDTA, Na2 ,
`2H20, about 5.78 mg lidocaine hydrochloride, about 9.0 mg
`sodium chloride, sodium hydroxide q.s. to pH 7.4 and water
`for injection q.s. to 1.0 ml.
`Further, the invention includes a process for preparing a 15
`composition as defined above, comprising mixing at least
`one bisphosphonate with at least one pharmaceutically
`acceptable chelating agent and a pharmaceutically accept(cid:173)
`able excipient.
`The invention also comprises a process for preparing a 20
`composition as defined above by mixing at least one bis(cid:173)
`phosphonate with at least one pharmaceutically acceptable
`chelating agent and a local anaesthetic.
`The compositions of the present invention are useful for
`the treatment and prevention of diseases involving bone 25
`resorption, especially osteoporosis, Paget's disease, hyper(cid:173)
`calcemia of malignancy, and metabolic bone disease. The
`invention further comprises a method for the treatment and
`prevention of diseases involving bone resorption, especially
`osteoporosis, Paget' s disease, hypercalcemia of malignancy, 30
`and metabolic bone disease comprising the step of admin(cid:173)
`istering to a patient a composition as defined above.
`The invention further includes devices for local and
`systemic sustained release comprising a composition as
`defined above.
`In more detail, the composition as defined above may
`contain additional excipients selected from solvents and
`co-solvents (water for injection, ethanol, glycerol, propylene
`glycol, polyethylene glycol, different oils), solubilising,
`wetting, suspending, emulsifying or thickening agents 40
`( carboxymethylcellulose, Cremophore EL, desoxycholate
`sodium, gelatin, lecithin, polysorbate 20 and 80,
`poloxamer), antioxidants and reducing agents ( ascorbic
`acid, bisulfite sodium, metabisulfite sodium), antimicrobial
`preservatives (benzyl alcohol, paraben propyl and methyl), 45
`buffers and pH adjusting agents ( acetate, citrate, lactate,
`hydrochloric acid, sodium hydroxyde ), bulking agents,
`protectants, and tonicity adjustors (sodium chloride,
`glucose, mannitol), or a local anesthetic (lidocaine,
`benzocaine, buvicaine, procaine, tetracaine ).
`In a preferred embodiment of the present invention the
`composition is a parenteral composition comprising a bis(cid:173)
`phosphonate and a pharmaceutically acceptable chelating
`agent(s) as defined above.
`The parenteral route of administration of the compositions 55
`as defined above generally comprises subcutaneous,
`intramuscular, intravenous, transdermal, intradermal,
`intranasal, intraarterial and intraperitoneal injection or infu(cid:173)
`sion. Preferably the parenteral route comprises
`subcutaneous, intramuscular and intravenous injection or 60
`infusion, and more preferable the subcutaneous injection or
`infusion.
`Further, the invention refers to the use of the above
`defined compositions for the preparation of medicaments
`useful for treatment and prevention of diseases involving 65
`bone resorption, especially osteoporosis, Paget's disease,
`hypercalcemia of malignancy, and metabolic bone disease.
`
`Local Tolerance Test I
`Groups of 3 rats were treated with test formulations
`containing 1 mg ibandronate/ml physiological saline buff(cid:173)
`ered at pH 7.4. One group of rats received the test formu(cid:173)
`lation without any additional additive, another group
`received the test solution with 1 mg EDTNml as an additive.
`The back of the rat was shaved one day before treatment. A
`volume of 0.5 ml each was injected subcutaneously at three
`different sites of the right part of shaved back. The left side
`of the back was treated with the corresponding formulation
`without ibandronate (placebo). Local reactions were
`assessed by a scoring system for swelling: 0=no reaction,
`0.5=barely perceptible swelling, l=slight swelling,
`50 2=moderate swelling, 3=marked swelling, 4=severe swell(cid:173)