(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2004/0063670 A1
`
` Fox et al. (43) Pub. Date: Apr. 1, 2004
`
`
`US 20040063670A1
`
`(54) USE OF BISPHOSPHONATES FOR PAIN
`TREATMENT
`
`(86) PCT No.:
`
`PCT/EP01/13836
`
`(76)
`
`Inventors: Alyson Fox, London (GB); Jonathan
`Green, Arlesheim (CH); Terence
`O’Reilly, Basel (CH); Laszlo Urban,
`London (GB); Katharine Walker,
`Princeton, NJ (US)
`
`Correspondence Address:
`THOMAS HOXIE
`NOVARTIS, CORPORATE INTELLECTUAL
`PROPERTY
`ONE HEALTH PLAZA 430/2
`EAST HANOVER, NJ 07936-1080 (US)
`
`(21) Appl. No.:
`
`10/432,847
`
`(22) PCT Filed:
`
`Nov. 27, 2001
`
`(30)
`
`Foreign Application Priority Data
`
`(GB) ......................................... 00291112
`NOV. 29, 2000
`Publication Classification
`
`Int. Cl.7 ..................................................... A61K 31/66
`(51)
`(52) U.S.Cl.
`.............................................................. 514/102
`
`ABSTRACT
`(57)
`A method for the treatment of pain, in particular antinoci-
`ceptive or anti-allodynic treatment of pain, in a patient in
`need of such treatment, e.g. a patient with osteoporosis or
`osteopenia, a tumour patient or a patient suffering from an
`inflammatory disease, which comprises administering an
`effective amount of a bisphosphonate, e.g. zoledronic acid or
`salts or hydrates thereof, to the patient.
`
`Grun. Exh. 1007
`
`PGR for US. Patent No. 9,539,268
`
`Grun. Exh. 1007
`PGR for U.S. Patent No. 9,539,268
`
`

`

`US 2004/0063670 A1
`
`Apr. 1, 2004
`
`USE OF BISPHOSPHONATES FOR PAIN
`TREATMENT
`
`[0001] This invention relates to pharmaceutical composi-
`tions and uses, in particular to pharmaceutical compositions
`comprising bisphosphonates and to new therapeutic uses of
`bisphosphonates.
`
`[0002] Bisphosphonates are widely used to inhibit osteo-
`clast activity in a variety of both benign and malignant
`diseases which involve excessive or inappropriate bone
`resorption. These pyrophosphate analogs not only reduce the
`occurrence of skeletal related events but they also provide
`patients with clinical benefit and improve survival. Bispho-
`sphonates are able to prevent bone resorption in vivo; the
`therapeutic efficacy of bisphosphonates has been demon-
`strated in the treatment of osteoporosis, osteopenia, Paget’s
`disease of bone, tumour-induced hypercalcemia (TIH) and,
`more recently, bone metastases (BM) and multiple myeloma
`(MM) (for review see Fleisch H 1997 Bisphosphonates
`clinical. In Bisphosphonates in Bone Disease. From the
`Laboratory to the Patient. Eds: The Parthenon Publishing
`Group, New York/London pp 68-163). The mechanisms by
`which bisphosphonates inhibit bone resorption are still not
`completely understood and seem to vary according to the
`bisphosphonates studied. Bisphosphonates have been shown
`to bind strongly to the hydroxyapatite crystals of bone, to
`reduce bone turn-over and resorption, to decrease the levels
`of hydroxyproline or alkaline phosphatase in the blood, and
`in addition to inhibit the formation, recruitment, activation
`and the activity, of osteoclasts. Recently farnesyl diphos-
`phate synthase, an enzyme of the mevalonate pathway of
`cholesterol biosynthesis, has been identified as the molecu-
`lar target of nitrogen-containing bisphosphonates (reviewed
`in Rogers M J, Gordon S, Benford H L, Coxon F P, Luckman
`S P, Monkkonen J, Frith J C. 2000. Cellular and molecular
`mechanisms
`of
`action
`of
`bisphosphonates. Cancer
`88(suppl):2961-2978)
`
`[0003] Bone pain resulting from structural damage, peri-
`osteal irritation, and nerve entrapment is the most common
`complication of both benign and metastatic bone disease,
`and presents a significant problem in both hospital and
`community practice (Coleman, 1997, Cancer 80; 1588-
`1594).
`
`[0004] MM is a plasma-cell malignancy characterized by
`the proliferation and the accumulation of malignant plasma
`cells within the bone marrow. The main clinical conse-
`quences are lytic bone lesions associated with pathologic
`fractures and bone pain. These lesions result from an exces-
`sive bone resorption, frequently leading to hypercalcemia.
`Bisphosphonates have been introduced for the long-term
`treatment of MM in combination with conventional chemo-
`therapy. It has been shown recently that bisphosphonates
`such as clodronate and pamidronate can reduce the occur-
`rence of skeletal related events such as lytic bone lesions and
`pathologic fractures and can relieve associated bone pain
`and improve the quality of life of patients (Laktinen et al.
`Lancet 1992, 340, 1049-1052; McCloskey et al. B. J. Hae-
`matol., 1998, 100, 317-325; and Berenson et al. N. Eng. J.
`Med. 1996, Vol. 334, No. 8, 488-493). Similar effects have
`been reported in breast cancer patients treated with bispho-
`sphonates (Hortobagyi G N, Theriault R L, Porter L,
`Blayney D, Lipton A, Sinoff C, Wheeler H, Simeone J F,
`Seaman J, Knight R D. Efficacy of pamidronate in reducing
`skeletal complications in patients with breast cancer and
`lytic bone metastases. Protocol 19 Aredia Breast Cancer
`Study Group., N Engl J Med. 1996;335:1785-91; Kanis J A,
`
`Powles T, Paterson A H G, McCloskey E V, Ashley S.
`Clodronate decreases the frequency of skeletal metastases in
`women with breast cancer. Bone 1996; 19: 663-7.)
`
`It has now been found surprisingly that certain
`[0005]
`bisphosphonates exert profound and apparently direct pal-
`liative effects on pain in in vivo animal models. For
`example, zoledronic acid has been found to reverse
`mechanical hyperalgesia in rat models of chronic inflam-
`matory and neuropathic pain, with a fast onset of action and
`efficacy of up to about 100%. Additionally zoledronic acid
`has been found to reduce mechanical allodynia and reduce
`hind limb sparing in a rat model of bone cancer pain. These
`results indicate that zoledronic acid and similar bisphospho-
`nates may have direct, fast acting, anti-nociceptive and
`anti-allodynic activity on pain.
`
`a
`invention provides
`[0006] Accordingly the present
`method for the treatment of pain in a patient in need of such
`treatment, which comprises administering an effective
`amount of a bisphosphonate to the patient.
`
`[0007] The invention further provides use of a bisphos-
`phonate in the preparation of a medicament for the treatment
`of pain.
`
`[0008] The invention yet further provides use of a bispho-
`sphonate to treat pain associated with diseases or pathologi-
`cal conditions in mammals.
`
`[0009] The present invention is particularly applicable to
`the palliative treatment of pain, i.e. the direct relief of pain
`in addition to the relief of pain as the result of amelioration
`of the underlying disease or medical condition, which is the
`cause of the pain. Thus, advantageously the invention pro-
`vides methods and uses for the direct analgesic or acute
`treatment of pain.
`
`[0010] Preferably the invention is used for the direct
`treatment of pain in diseases and medical conditions in
`which bisphosphonates are used to inhibit osteoclast activ-
`ity. For example,
`the invention may be used for direct
`treatment of pain in diseases and conditions which involve
`excessive or inappropriate bone loss e.g. as the result of
`inappropriate osteoclast activity. Examples of such diseases
`and conditions include benign diseases and conditions such
`as osteoporosis of various genesis, Pagets disease, osteoar-
`thritis, RA, periodontal disease; and especially malignant
`diseases such as MM and TIH and BM associated with
`various cancers, e.g. cancer of the breast, prostate, lung,
`kidney, ovary, or osteosarcoma. Generally the invention may
`be used to treat pain in other circumstances where bispho-
`sphonates are used and pain is encountered, e.g. when
`bisphosphonates are use in bone fracture healing, osteone-
`crosis or treatment of prosthesis loosening.
`
`invention
`[0011] The uses and methods of the present
`represent an improvement to existing therapy of malignant
`diseases in which bisphosphonates are used to prevent or
`inhibit development of bone metastases or excessive bone
`resorption, and also for the therapy of inflammatory diseases
`such as rheumatoid arthritis and osteoarthritis, as well as for
`all forms of osteoporosis and osteopenia.
`
`[0012] Thus in the present description the terms “treat-
`ment” or “treat” refer to both prophylactic or preventative
`treatment as well as curative or palliative treatment of
`pain,in particular anti-nociceptive and anti-allodynic treat-
`ment of pain, especially treatment of bone pail
`
`

`

`US 2004/0063670 A1
`
`Apr. 1, 2004
`
`[0013] Thus in particular embodiments the invention pro-
`vides:
`
`[0020] wherein
`
`a method for the treatment of bone pain in a
`[0014]
`patient in need of such treatment which comprises
`administering an effective amount of a bisphospho-
`nate to the patient;
`
`use of a bisphosphonate in the preparation of
`[0015]
`a medicament for the treatment of bone pain; or
`
`use of a bisphosphonate as an agent for treat-
`[0016]
`ment of bone pain.
`
`[0017] The bisphosphonates used in the present invention
`are typically those which relieve pain, in particular those
`which have an anti-nociceptive or anti-allodynic, and pref-
`erably rapid onset, activity on pain.
`
`[0018] Thus, for example, suitable bisphosphonates for
`use in the invention may include the following compounds
`or a pharmaceutically acceptable salt thereof, or any hydrate
`thereof: 3-amino-1-hydroxypropane-1,1-diphosphonic acid
`(pamidronic acid), e.g. pamidronate (APD); 3-(N,N-dim-
`ethylamino)-1-hydroxypropane-1,1-diphosphonic acid, e.g.
`dimethyl-APD;
`4-amino-1-hydroxybutane-1,1-diphospho-
`nic acid (alendronic acid), e.g. alendronate; 1-hydroxy-
`ethidene-bisphosphonic acid, e.g. etidronate; 1-hydroxy-3-
`(methylpentylamino)-propylidene-bisphosphonic
`acid,
`ibandronic acid, e.g. ibandronate; 6-amino-1-hydroxyheX-
`ane-1,1-diphosphonic acid, e.g. amino-hexyl-BP; 3-(N—me-
`thyl-N-n-pentylamino)-1-hydroxypropane-1,1-diphospho-
`nic
`acid,
`e.g. methyl-pentyl-APD (=BM 21.0955);
`1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid,
`e.g. zoledronic acid; 1-hydroxy-2-(3-pyridyl)ethane-1,1-
`diphosphonic acid (risedronic acid), e.g. risedronate, includ-
`ing N—methyl pyridinium salts thereof, for example N-me-
`thyl pyridinium iodides such as NE-10244 or NE-10446;
`1-(4-chlorophenylthio)methane-1,1-diphosphonic
`acid
`(tiludronic acid), e.g. tiludronate; 3-[N-(2-phenylthioethyl)-
`N—methylamino]-1-hydroxypropane--1,1-diphosphonic
`acid; 1-hydroxy-3-(pyrrolidin-1-yl)propane-1,1-diphospho-
`nic acid, e.g. EB 1053 (Leo); 1-(N-phenylaminothiocarbo-
`nyl)methane-1,1-diphosphonic
`acid,
`e.g.
`FR 78844
`(Fujisawa); 5-benzoyl-3,4dihydro-2H-pyrazole-3,3-diphos-
`phonic acid tetraethyl ester, e.g. U-81581 (Upjohn); 1-hy-
`droxy-2-(imidazo[1,2-a]pyridin-3-yl)ethane-1,1-diphospho-
`nic acid, e.g. YM 529;
`and 1,1-dichloromethane-1,1-
`diphosphonic acid (clodronic acid), e.g. clodronate.
`
`[0019] Preferably the bisphosphonates for use in the
`invention are the nitrogen containing bisphosphonates. For
`the purposes of the present descxription a nitrogen contain-
`ing bisphosphonate is a compound which in addition to the
`characteristic geminal bisphosphate (P—C—P) moiety
`comprises a nitrogen containing side chain, e. g. a compound
`of formula I
`
`RX
`
`P(0R)2
`X
`
`P(OR)2
`
`[0021] X is hydrogen, hydroxyl, amino, alkanoyl,or
`an amino group substituted by C1-C4 alkyl or
`alkanoyl;
`
`[0022] R is hydrogen or C1-C4 alkyl and
`
`[0023] RX is a side chain which contains an option-
`ally substituted amino group, or a nitrogen contain-
`ing heterocycle (including aromatic nitrogen-con-
`taining heterocycles),
`
`and pharmaceutically acceptable salts thereof or
`[0024]
`any hydrate thereof.
`
`[0025] Particularly preferred nitorogen containing bispho-
`sphonates are those having side chains containing nitrogen-
`containing heterocycles, most especially containing aro-
`matic nitrogen-containing heterocycles.
`
`[0026] Thus in one embodiment a particularly preferred
`bisphosphonate for use in the invention comprises a com-
`pound of Formula 1'
`
`Ir
`
`[0027] wherein
`
`[0028] Het is an imidazole, oxazole, isoxazole, oxa-
`diazole, thiazole, thiadiazole, pyridine, 1,2,3-triaz-
`ole, 1,2,4-triazole or benzimidazole radical, which is
`optionally substituted by alkyl, alkoxy, halogen,
`hydroxyl carboxyl an amino group optionally sub-
`stituted by alkyl or alkanoyl radicals or a benzyl
`radical optionally substituted by alkyl, nitro, amino
`or aminoalkyl;
`
`[0029] A is a straight-chained or branched, saturated
`or unsaturated hydrocarbon moiety containing from
`1 to 8 carbon atoms;
`
`[0030] X is a hydrogen atom, optionally substituted
`by alkanoyl, or an amino group optionally substi-
`tuted by alkyl or alkanoyl radicals, and
`
`[0031] R is a hydrogen atom or a C1-C4 alkyl radical,
`
`[0032]
`
`and the pharmacologically acceptable salts thereof.
`
`In a further embodiment a particularly preferred
`[0033]
`bisphosphonate for use in the invention comprises a com-
`pound of Formula II
`
`

`

`US 2004/0063670 A1
`
`Apr. 1, 2004
`
`[0045] Examples of particularly preferred bisphophonates
`for use in the invention are:
`
`11
`
`2-(1-Methylimidazol-2-yl)-1-hydroxyethane-
`[0046]
`1,1-diphosphonic acid;
`
`2-(1-Benzylimidazol-2-yl)-1-hydroxyethane-
`[0047]
`1,1-diphosphonic acid;
`
`2-(1-Methylimidazol-4-yl)-1-hydroxyethane-
`[0048]
`1,1-diphosphonic acid;
`
`1 -Amino-2-(1 -methylimidazol-4-yl)ethane- 1,
`[0049]
`1 -diphosphonic acid;
`
`1 -Amino-2-(1 -benzylimidazol-4-yl)ethane-1 ,
`[0050]
`1 -diphosphonic acid;
`
`2-(1-Methylimidazol-2-yl)ethane-1,1-diphos-
`[0051]
`phonic acid;
`
`2-(1-Benzylimidazol-2-yl)ethane-1,1-diphos-
`[0052]
`phonic acid;
`
`2-(Imidazol-1 -yl)-1 -hydroxyethane-1 ,1 -
`[0053]
`diphosphonic acid;
`
`[0054]
`acid;
`
`2-(Imidazol-1 -yl)ethane- 1 ,1 -diphosphonic
`
`2-(4H- 1 ,2,4-triazol-4-yl)-1 -hydroxyethane-1 ,
`[0055]
`1 -diphosphonic acid;
`
`[0056]
`acid;
`
`[0057]
`acid;
`
`2-(Thiazol-2-yl)ethane-1 ,1 -diphosphonic
`
`2-(Imidazol-2-yl)ethane- 1 ,1 -diphosphonic
`
`2-(2-Methylimidazol-4(5) -yl)ethane- 1, 1 -
`[0058]
`diphosphonic acid;
`
`2-(2-Phenylimidazol-4(5)-yl)ethane-1,1-
`[0059]
`diphosphonic acid;
`
`2-(4,5-Dimethylimidazol- 1-yl)- 1 -hydroxy-
`[0060]
`ethane-1 ,1 -diphosphonic acid, and
`
`2-(2-Methylimidazol-4(5)-yl)-1-hydroxy-
`[0061]
`ethane-1,1-diphosphonic acid,
`
`it
`P(OR)2
`T
`Het’ — C — C—X”
`
`H 8 I
`P(OR)2
`||0
`
`[0034] wherein
`is a substituted or unsubstituted het-
`[0035] Het'
`eroaromatic five-membered ring selected from the
`group consisting of imidazolyl, imidazolinyl, isox-
`azolyl, oxazolyl, oxazolinyl, thiazolyl, thiazolinyl,
`triazolyl, oxadiazolyl and thiadiazolyl wherein said
`ring can be partly hydrogenated and wherein said
`substituents are selected from at least one of the
`
`group consisting of C1-C4 alkyl, C1-C4 alkoxy, phe-
`nyl, cyclohexyl, cyclohexylmethyl halogen and
`amino and wherein two adjacent alkyl substituents of
`Het can together form a second ring;
`[0036] Y is hydrogen or C1-C4 alkyl;
`[0037] X" is hydrogen, hydroxyl amino, or an amino
`group substituted by C1-C4alkyl, and
`[0038] R is hydrogen or C1-C4 alkyl;
`[0039]
`as well as the pharmacologically acceptable salts
`and isomers thereof.
`
`In a yet further embodiment a particularly preferred
`[0040]
`bisphosphonate for use in the invention comprises a com-
`pound of Formula III
`
`III
`
`0 |
`
`|P
`
`(0H)2
`Het”—C—C—R2
`
`IP
`
`(OH)2
`||0
`
`H2
`
`[0041] wherein
`[0042] Het" is an imidazolyl, 2H-1,2,3-, 1H-1,2,4- or
`4H-1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
`oxadiazolyl, thiazolyl or thiadiazolyl radical which is
`unsubstituted or C-mono- or di-substituted by lower
`alkyl, by lower alkoxy, bX phenyl which may in turn
`be mnon- or disubstituted by lower alkyl,
`lower
`alkoxy and/or halogen, by hydroxy, by di-lower
`alkylamino, by lower alkylthio and/or by halogen
`and is N—substituted at a substitutable N-atom by
`lower alkyl or by phenyl-lower alkyl which may in
`turn be mono- or di-substituted in the phenyl moiety
`by lower alkyl, lower alkoxy and/or halogen, and
`[0043] R2 is hydrogen, hydroxy, amino, lower alky-
`lthio or halogen, lower radicals having up to and
`including 7 C-atoms,
`or a pharmacologically acceptable salt thereof.
`
`[0044]
`
`[0062]
`
`and pharmacologically acceptable salts thereof.
`
`[0063] The most preferred bisphosphonate for use in the
`invention is 2-(imidazol-1yl)-1-hydroxyethane-1,1-diphos-
`phonic acid (zoledronic acid) or a pharmacologically accept-
`able salt thereof or any hydrate thereof.
`
`[0064] Pharmacologically acceptable salts are preferably
`salts with bases, conveniently metal salts derived from
`groups Ia, Ib, 11a and 11b of the Periodic Table of the
`Elements, including alkali metal salts, e.g. potassium and
`especially sodium salts, or alkaline earth metal salts, pref-
`erably calcium or magnesium salts, and also ammonium
`salts with ammonia or organic amines.
`
`[0065] Especially preferred pharmaceutically acceptable
`salts are those where one, two, three or four, in particular one
`or two, of the acidic hydrogens of the bisphosphonic acid are
`replaced by a pharmaceutically acceptable cation, in par-
`ticular sodium, potassium or ammonium, in first instance
`sodium.
`
`

`

`US 2004/0063670 A1
`
`Apr. 1, 2004
`
`[0066] Avery preferred group of pharmaceutically accept-
`able salts is characterized by having one acidic hydrogen
`and one pharmaceutically acceptable cation, especially
`sodium, in each of the phosphonic acid groups.
`
`[0067] All the bisphosphonic acid derivatives mentioned
`above are well known from the literature. This includes their
`
`e.g. EP-A-513760, pp. 13-48). For
`manufacture (see
`example,
`3-amino-1-hydroxypropane-1,1-diphosphonic
`acid is prepared as described e.g. in US. Pat. No. 3,962,432
`as well as the disodium salt as in US. Pat. Nos. 4,639,338
`and 4,711,880, and 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-
`diphosphonic acid is prepared as described e.g. in US. Pat.
`No. 4,939,130. See also US. Pat. Nos. 4,777,163 and
`4,687,767.
`
`[0068] The bisphosphonates (hereinafter referred to as the
`Agents of the Invention) may be used in the form of an
`isomer or of a mixture of isomers where appropriate, typi-
`cally as optical isomers such as enantiomers or diastereoi-
`somers or geometric isomers, typically cis-trans isomers.
`The optical isomers are obtained in the form of the pure
`antipodes and/or as racemates.
`
`[0069] The Agents of the Invention can also be used in the
`form of their hydrates or include other solvents used for their
`crystallisation.
`
`[0070] The Agents of the Invention (the bisphosphonates)
`are preferably used in the form of pharmaceutical compo-
`sitions that contain a therapeutically effective amount of
`active ingredient optionally together with or in admixture
`with inorganic or organic, solid or liquid, pharmaceutically
`acceptable carriers which are suitable for administration.
`
`for
`[0071] The pharmaceutical compositions may be,
`example, compositions for enteral, such as oral, rectal,
`aerosol inhalation or nasal administration, compositions f6r
`parenteral, such as intravenous or subcutaneous administra-
`tion, or compositions for transdermal administration (e.g.
`passive or iontophoretic).
`
`the pharmaceutical compositions are
`[0072] Preferably,
`adapted to oral or parenteral (especially intravenous, intra-
`arterial or transdermal) administration. Intravenous and oral,
`first and foremost intravenous, administration is considered
`to be of particular importance. Preferably the bisphospho-
`nate active ingredient is in the form of a parenteral, most
`preferably an intravenous form.
`
`[0073] The particular mode of administration and the
`dosage may be selected by the attending physician taking
`into account the particulars of the patient, especially age,
`weight, life style, activity level, hormonal status (e.g. post-
`menopausal) and bone mineral density as appropriate. Most
`preferably, however,
`the bisphosphonate is administered
`intravenously.
`
`[0074] The dosage of the Agents of the Invention may
`depend on various factors, such as effectiveness and duration
`of action of the active ingredient, mode of administration,
`warm-blooded species, and/or sex, age, weight and indi-
`vidual condition of the warm-blooded animal.
`
`[0075] Normally the dosage is such that a single dose of
`the bisphosphonate active ingredient
`from 0.002-20.0
`mg/kg, especially 0.01-10.0 mg/kg,
`is administered to a
`warm-blooded animal weighing approximately 75 kg. If
`desired, this dose may also be taken in several, optionally
`equal, partial doses.
`
`“mg/kg” means mg drug per kg body weight of the
`[0076]
`mammal—including man—to be treated.
`
`[0077] The dose mentioned above—either administered as
`a single dose (which is preferred) or in several partial
`doses—may be repeated,
`for example once daily, once
`weekly, once every month, once every three months, once
`every six months or once a year.
`In other words,
`the
`pharmaceutical compositions may be administered in regi-
`mens ranging from continuous daily therapy to intermittent
`cyclical therapy.
`
`[0078] Preferably, the bisphosphonates are administered
`in doses which are in the same order of magnitude as those
`used in the treatment of the diseases classically treated with
`bisphosphonic acid derivatives, such as Paget’s disease,
`tumour-induced hypercalcemia or osteoporosis.
`In other
`words, preferably the bisphosphonic acid derivatives are
`administered in doses which would likewise be therapeuti-
`cally effective in the treatment of Paget’s disease, tumour-
`induced hypercalcaemia or osteoporosis, i.e. preferably they
`are administered in doses which would likewise effectively
`inhibit bone resorption. For example,
`for
`the preferred
`nitrogen-containing bisphosphonates, e.g. zoledronic acid
`and salts thereof, doses of bisphosphonate in the range from
`about 0.5 to about 20 mg, preferably from about 1 to about
`10 mg, may be used for treatment of human patients.
`
`[0079] Formulations in single dose unit form contain
`preferably from about 1% to about 90%, and formulations
`not in single dose unit form contain preferably from about
`0.1% to about 20%, of the active ingredient. Single dose unit
`forms such as capsules, tablets or dragees contain e.g. from
`about 1 mg to about 500 mg of the active ingredient.
`
`and
`enteral
`for
`[0080] Pharmaceutical preparations
`parenteral administration are, for example, those in dosage
`unit forms, such as dragees, tablets or capsules and also
`ampoules. They are prepared in a manner known per se, for
`example by means of conventional mixing, granulating,
`confectioning, dissolving or lyophlising processes.
`
`[0081] For example, pharmaceutical-preparations for oral
`administration can be obtained by combining the active
`ingredient with solid carriers, where appropriate granulating
`a resulting mixture, and processing the mixture or granulate,
`if desired or necessary after the addition of suitable adjuncts,
`into tablets or dragée cores. Suitable carriers are especially
`fillers, such as sugars, for example lactose, saccharose,
`mannitol or sorbitol, cellulose preparations and/or calcium
`phosphates, for example tricalcium phosphate or calcium
`hydrogen phosphate, and also binders, such as starch pastes,
`using,
`for example, corn, wheat,
`rice or potato starch,
`gelatin, tragacanth, methylcellulose and/or polyvinylpyrroli-
`done and,
`if desired, disintegrators, such as the above-
`mentioned starches, also carboxymethyl starch, crosslinked
`polyvinylpyrrolidone, agar or alginic acid or a salt thereof,
`such as sodium alginate. Adjuncts are especially flow-
`regulating agents and lubricants, for example silicic acid,
`talc, stearic acid or salts thereof, such as magnesium or
`calcium stearate, and/or polyethylene glycol. Dragee cores
`are provided with suitable coatings that may be resistant to
`gastric juices, there being used, inter alia, concentrated sugar
`solutions that optionally contain gum arabic, talc, polyvi-
`nylpyrrolidone, polyethylene glycol and/or titanium dioxide,
`or lacquer solutions in suitable organic solvents or solvent
`mixtures or, to produce coatings that are resistant to gastric
`
`

`

`US 2004/0063670 A1
`
`Apr. 1, 2004
`
`juices, solutions of suitable cellulose preparations, such as
`acetylcellulose phthalate or hydroxypropylmethylcellulose
`phthalate. Colouring substances or pigments may be added
`to the tablets or dragee coatings, for example for the purpose
`of identification or to indicate different doses of active
`
`ingredient.
`
`[0082] Other orally administrable pharmaceutical prepa-
`rations are dry-filled capsules made of gelatin, and also soft,
`sealed capsules made of gelatin and a plasticiser, such as
`glycerol or sorbitol. The dry-filled capsules may contain the
`active ingredient in the form of a granulate, for example in
`admixture with fillers, such as lactose, binders, such as
`starches, and/or glidants, such as talc or magnesium stearate,
`and, where appropriate, stabilisers.
`In soft capsules the
`active ingredient is preferably dissolved or suspended in
`suitable liquids, such as fatty oils, paraffin oil or liquid
`polyethylene glycols, it being possible also for stabilisers to
`be added.
`
`[0083] Parenteral formulations are especially injectable
`fluids that are effective in various manners, such as intra-
`arterially,
`intramuscularly,
`intraperitoneally,
`intranasally,
`intradermally, subcutaneously or preferably intravenously.
`Such fluids are preferably isotonic aqueous solutions or
`suspensions which can be prepared before use, for example
`from lyophilised preparations which contain the active
`ingredient alone or together with a pharmaceutically accept-
`able carrier. The pharmaceutical preparations may be steri-
`lised and/or contain adjuncts, for example preservatives,
`stabilisers, wetting agents and/or emulsifiers, solubilisers,
`salts for regulating the osmotic pressure and/or buffers.
`
`[0084] Suitable formulations for transdermal application
`include an effective amount of the active ingredient with
`carrier. Advantageous carriers include absorbable pharma-
`cologically acceptable solvents to assist passage through the
`skin of the host. Characteristically, transdermal devices are
`in the form of a bandage comprising a backing member, a
`reservoir containing the compound optionally with carriers,
`optionally a rate controlling barrier to deliver the active
`ingredient of the skin of the host at a controlled and
`predetermined rate over a prolonged period of time, and
`means to secure the device to the skin.
`
`[0085] The following Examples illustrate the invention
`described hereinbefore.
`
`In the following Examples the term “active ingre-
`[0086]
`dient” is to be understood as being any one of the bispho-
`sphonic acid derivatives mentioned above as being useful
`according to the present invention.
`
`EXAMPLES
`
`Example 1
`
`[0087] Capsules containing coated pellets of active ingre-
`dient, for example, disodium pamidronate pentahydrate, as
`active ingredient:
`
`Core pellet:
`
`active ingredient (ground)
`Microcrystalline cellulose
`
`(Avicel ® PH 105)
`
`197.3 mg
`52.7 mg
`
`250.0 mg
`
`-continued
`
`+ Inner coating:
`
`Cellulose HP-M 603
`Polyethylene glycol
`Talc
`
`+ Gastric juice-resistant outer coating:
`
`Eudragit ® L 30 D (solid)
`Triethyl citrate
`Antifoam ® AF
`Water
`Talc
`
`10.0 mg
`2.0 mg
`8.0 mg
`
`270.0 mg
`
`90.0 mg
`21.0 mg
`2.0 mg
`
`7.0 mg
`
`390.0 mg
`
`[0088] A mixture of disodium pamidronate with Avicel®
`PH 105 is moistened with water and kneaded, extruded and
`formed into spheres. The dried pellets are then successively
`coated in the fluidized bed with an inner coating, consisting
`of cellulose HP-M 603, polyethylene glycol (PEG) 8000 and
`talc, and the aqueous gastric juice-resistant coat, consisting
`of Eudragit® L 30 D, triethyl citrate and Antifoam AF. The
`coated pellets are powdered with talc and filled into capsules
`(capsule size 0) by means of a commercial capsule filling
`machine, for example Hofliger and Karg.
`
`Example 2
`
`[0089] Monolith adhesive transdermal system, containing
`as active ingredient, for example, 1-hydroxy-2-(imidazol-1-
`yl)-ethane-1,1-diphosphonic acid:
`
`Composition:
`
`polyisobutylene (PIB) 300
`(Oppanol B1, BASF)
`PIB 35000
`(Oppanol B10, BASF)
`PIB 1200000
`(Oppanol B100, BASF)
`hydrogenated hydrocarbon resin
`(Escorez 5320, Exxon)
`1-dodecylazacycloheptan-2—one
`(Azone, Nelson Res, Irvine/CA)
`active ingredient
`
`Total
`
`5.0 g
`
`3.0 g
`
`9.0 g
`
`43.0 g
`
`20.0 g
`
`20.0 g
`
`100.0 g
`
`[0090] The above components are together dissolved in
`150 g of special boiling point petroleum fraction 100-125 by
`rolling on a roller gear bed. The solution is applied to a
`polyester film (Hostaphan, Kalle) by means of a spreading
`device using a 300 mm doctor blade, giving a coating of
`about 75 g/m2. After drying (15 minutes at 60° C.), a
`silicone-treated polyester film (thickness 75 mm, Laufen-
`berg) is applied as the peel-off film. The finished systems are
`punched out in sizes in the wanted form of from 5 to 30 cm2
`using a punching tool. The complete systems are sealed
`individually in sachets of aluminised paper.
`
`

`

`US 2004/0063670 A1
`
`Apr. 1, 2004
`
`Example 3
`
`[0097] Neuropathic hyperalgesia
`
`[0091] Vial containing 1.0 mg dry, lyophilized 1-hydroxy-
`2-(imidazol-1-yl)ethane-1,1-diphosphonic
`acid
`(mixed
`sodium salts thereof). After dilution with 1 ml of water, a
`solution (concentration 1 mg/ml)
`for
`iv.
`infusion is
`obtained.
`
`Composition:
`
`active ingredient (free diphosphonic acid)
`mannitol
`Trisodium citrate x 2 H20
`water
`water for injection
`
`ca.
`
`1.0 mg
`46.0 mg
`3.0 mg
`1 ml
`1 ml.
`
`In 1 ml of water, the active ingredient is titrated
`[0092]
`with trisodium citrate><2 H20 to pH 6.0. Then, the mannitol
`is added and the solution is lyophilized and the lyophilisate
`filled into a Vial.
`
`Example 4
`
`[0093] Ampoule containing active ingredient, for instance
`disodium pamidronate pentahydrate dissolved in water. The
`solution (concentration 3 mg/ml) is for iv. infusion after
`dilution.
`
`Composition:
`
`active ingredient
`(A 5.0 mg of anhydrous active ingredi-
`ent)
`mannitol
`water for injection
`
`19.73 mg
`
`250 mg
`5 ml.
`
`Example 5
`
`The Effect of Bisphosphonates in Rat Models of
`Inflammatory and Neuropathic Pain
`
`[0094] Methods
`
`[0095]
`
`Inflammatory hyperalgesia
`
`[0096] Mechanical hyperalgesia was examined in a rat
`model of inflammatory pain. Paw withdrawal thresholds to
`an increasing pressure stimulus were measured by the Ran-
`dal-Sellito technique using an analgesymeter (Ugo Basile,
`Milan), in naive animals prior to an intraplantar injection of
`complete Freund’s complete adjuvant (FCA) into the left
`hind paw. 24 h later paw withdrawal thresholds were mea-
`sured again prior to (predose) and then from 10 min to 6 h
`following drug or vehicle administration. Reversal of hype-
`ralgesia in the ipsilateral paw was calculated according to
`the formula:
`
`1 _ postdose threshold— predose threshold X 100
`‘7
`0 reversa _
`naive threshold— predose threshold
`
`[0098] Mechanical hyperalgesia was examined in a rat
`model of neuropathic pain induced by partial ligation of the
`left sciatic nerve. Approximately 14 days following surgery
`mechanical withdrawal thresholds of both the ligated (ipsi-
`lateral) and non-ligated (contralateral) paw were measured
`prior to (predose) and then from 10 min to 6 h following
`drug or vehicle administration. Reversal of hyperalgesia at
`each time point was calculated according to the formula:
`
`% reversal =
`ipsilateral threshold postdose — ipsilateral threshold predose
`contralateral threshold predose — ipsilateral threshold predose X 100
`
`[0099] All experiments were carried out using groups of 6
`animals. Stock concentrations of drugs were dissolved in
`distilled water and subsequent dilutions were made in 0.9%
`saline for subcutaneous administration in a volume of 4
`
`mlkg'l. All drugs were made up in plastic Vials and kept in
`the dark.
`
`[0100] Statistical analysis was carried out on withdrawal
`threshold readings (g) using ANOVA with repeated mea-
`sures followed by Tukey’s HSD test. Efficacy refers to the
`maximal reversal of hyperalgesia observed at the doses used.
`
`[0101] Results
`
`inflammatory hyperalgesia
`In a model of
`1.
`[0102]
`induced by unilateral hindpaw injection of complete Fre-
`und’s adjuvant Zoledronate (0.003-0.1 mgkg'1 s.c.) pro-
`duced a dose-dependant reversal of mechanical hyperalge-
`sia. The effect was rapid in onset, with a maximal reversal
`of 100% within 30 min, and of short duration with no
`significant activity 3 h following administration. Some con-
`tralateral activity was observed at the highest dose.
`
`2. Pamidronate (0.03-1mgkg'l s.c.) and Clodronate
`[0103]
`(0.3-10 mgkg'1 s.c.) were both ineffective in reversing
`inflammatory mechanical hyperalgesia, but rather produced
`slight reductions of paw withdrawal thresholds at the highest
`doses tested.
`
`3. In a model of chronic neuropathic pain induced
`[0104]
`by unilateral partial sciatic nerve ligation. Zoledronate
`(0.003-0.1 mgkg'1 s.c.) produced a moderate 40% reversal
`of mechanical hyperalgesia which was maximal within 30
`min of administration. However, there was also a significant
`reduction in contralateral paw withdrawal thresholds at the
`highest dose.
`
`4. Pamidronate (0.03-1 mgkg'1 s.c.) was only
`[0105]
`weakly active in the model of neuropathic pain, producing
`a