Q European Patent office
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`Office européen des brevets
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`69 Publication number:
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`7
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`EUROPEAN PATENT APPLICATION
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`@ Application number: 90830564.2
`
`@ Date of filing: 05.12.90
`
`@ Int. Cl.5: A61K 37/30, A61K 9/12,
`A61 K 47/18
`
`Date of publication of application:
`10.06.92 Bulletin 92/24
`
`@ Applicant: DR. A. TOSI FARMACEUTICI S.R.L.
`Corso Della Vittoria, 12/B
`I-28100 Novara(|T)
`
`Designated Contracting States:
`AT BE CH DE DK ES FR GB GR IT LI LU NL SE @ Inventor: Tosi, Silvana
`Corso Della Vittoria, 12/B
`I-28100 Novara(|T)
`Inventor: Dondi, Giancarla
`Corso Della Vittoria, 12/B
`I-28100 Novara(|T)
`
`Representative: Bianchetti, Giuseppe
`Studio Consuienza Brevettuale Via Rossini,
`
`8 I
`
`-20122 Milan(lT)
`
`@ Caicitonin compositions for intranasai administration.
`
`@ The invention relates to stable in the air pharmaceutical composition for the intranasai administration
`containing a) calcitonin dissolved in b) a citrate buffered aqueous solution at pH 4.0 stabilized by a sodium p-
`hydroxybenzoates mixture and containing sodium edetate. Said composition is administered in the form of a
`nasal spray.
`
`EP0489217A1
`
`Rank Xerox (UK) Business Services
`
`   
`


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`Lannett Holdings, Inc. LAN 1027
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`

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`EP 0 489 217 A1
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`invention relates to a set of galenic compositions containing calcitonin as the active
`The present
`ingredient. The compositions object of the present invention, which can be administered by the intranasal
`route, consist of calcitonin (preferably from salmon) dissolved in a citrate buffered solution at pH 4.0
`containing a methyl and propyl p-hydroxybenzoates mixture (as sodium salts), said compositions are
`characterized in containing also sodium edetate (ethylenediaminetetraacetic acid tetrasodium salt).
`Calcitonin, both from salmon and from other species, is biochemically defined as a long chain peptide
`hormon pharmacologically active in the osteoporosis therapy,
`in the Paget's disease, in the hypercalcemia
`and it acts by inhibiting physiological or pathological bony resorption.
`Its amino acidic nature makes it
`ineffective by oral administration while some drawbacks occur when calcitonin is injected, due to painful
`reactions in patients.
`lntranasal administration of calcitonin as well as that of other polypeptide drugs, has been for a long
`time the object of several studies on international scientific papers and it constitutes the subject—matter of
`many patent specifications.
`the lntranasal
`Calcitonin formulations containing hydroxybenzoates and buffers of various kind for
`administration are already well-known (UK 1,354,526). It is also well-known that, during the production stage,
`these solutions require to be protected against oxygen both under inert gas streaming into the solutions,
`and by introducing an inert gas into the containers.
`relating to
`Sensitivity of calcitonin solutions to atmospheric oxygen is confirmed by EP-A-363876,
`calcitonin solutions containing only sodium chloride, which are administered from specific containers filled
`with nitrogen.
`Now it has surprisingly been found that adding sodium edetate to calcitonin aqueous solutions,
`preferably containing also methyl and propyl p-hydroxybenzoates, makes the solutions perfectly stable to
`oxygen thus allowing to operate during production without protecting with inert gases, and to pack the
`solutions in normal containers which in their turn require no protection with inert gases. The advantages that
`come from the invention, both in operative simplicity terms and in cost
`terms and easy storage of
`pharmaceutical compositions, are evident.
`Therefore,
`the present
`invention provides pharmaceutical compositions containing a) calcitonin dis-
`solved in b) a citrate buffered aqueous solution at pH 4.0, optionally added with methyl and/or propyl p-
`hydroxybenzoates, characterized in that they further contain c) sodium ethylenediaminetetraacetate.
`Preferably,
`the compositions according to the invention consist of solutions containing about 100 to
`about 5000 |.U. of calcitonin (preferably salmon's calcitonin, i.e. salcatonin) per millilitre; a buffer formed by
`citric acid and sodium citrate dihydrate in such a quantity to adjust pH to 4.0;
`1
`to 2 mg methyl p-
`hydroxybenzoate and 0.1 to 0.5 mg propyl p-hydroxybenzoate (both of them as sodium salts); and 0.5 to
`1.5 mg of sodium edetate (ethylenediaminetetraacetic acid tetrasodium salt).
`Particularly preferred pharmaceutical compositions are those containing, per millilitre, 250 to 2000 |.U.
`salcatonin; 6.27 to 18.8 mg citric acid; 6.19 to 18.56 mg sodium citrate dihydrate; 0.75 to 2.25 mg methyl p-
`hydroxybenzoate sodium salt; 0.11 to 0.34 mg propyl p-hydroxybenzoate sodium salt; and 0.5 to 1.5 mg
`ethylenediaminetetraacetic acid tetrasodium salt.
`the preparation of said
`A further object of
`the present
`invention is provided by a process for
`compositions, comprising 1) dissolving appropriate calcitonin amounts in a citrate buffered aqueous solution
`at pH 4, optionally added with methyl and propyl p-hydroxybenzoates in the abovestated ratios, and further
`containing an appropriate sodium edetate amount, 2) filtrating and 3) packing in appropriate containers,
`being all the process steps carried out without inert gases protection.
`The stability of
`the preparations object of
`the invention was determined according to well-known
`methods, both in the presence of nitrogen atmosphere and in the lack of the same. At the end of the
`stability test, carried out within a 24 month interval, calcitonin content
`in the solution under nitrogen
`atmosphere is not significantly different from the one obtained for the solution without nitrogen atmosphere.
`Therefore, for instance, both solutions degrade less than 10% within 2 years at 20°C. Moreover, both
`solutions, stored for 4 months at 5° and 20° C, undergo no significant degradation (lower than 1.5%).
`A higher degradation was observed at 30°C for 3 months (about 4.5%), such value is anyway lower
`than the one expected for a pure aqueous solution.
`Also bottles, from which half content had already been sprayed, were kept under control. Tests were
`performed under the same conditions reported by F.U. (Official Italian Pharmacopoeia),
`IX Edition, Vol
`II,
`page 1414, for calcitonin injectable preparations, except inert gas protection.
`Results are reported in Table n. 1 for the intact bottle and in Table n. 2 for bottles part of the content of
`which had already been dispensed, to confirm pack tightness and long-term stability even after partial use.
`Results confirm that there is no difference between the intact product and the used product. Results
`obtained after 2 years are whithin the limits established by F.U.,
`IX Edition for injectable preparations (80-
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`EP 0 489 217 A1
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`121%).
`Definitely lower results were obtained on preparations obtained in the same manner but without sodium
`edetate, intact (Table 3) and subjected to partial dispensing (Table 4).
`The Applicant carried out stability tests even against possible microbial contaminations.
`The compositions were stored at 30° C for 3 months in a glass bottle. Tests were carried out according
`to the process by S. Urban in Acta Pharmacol. Technol., 22, 247-253, 1976. Concerning this, classical
`bacteria, such as E. coli ATCC 8739, Pseud. aeruginosa TFCC 9027, Staph. aureus ATCC 6538 and
`classical fungi
`like Candida albicans ATCC 10231, Aspergillus niger ATCC 16404 and Sacch. cerevisiae
`ATCC 9763 were used. Bacteria and fungi were added to the solution so that a cell number of about 2x105
`organisms in the inoculated liquid was obtained. After 4 hour incubation the number of microorganisms was
`remarkably reduced, going to less than 0.2% and 5 weeks later no living cells were noticed in the solution.
`Such negativeness lasted till the end of the stability tests.
`The results obtained from clinical tests showed that the composition is well tolerated, except for a slight
`tingling sensation in rare cases.
`The following examples illustrate the invention.
`
`EXAMPLE 1
`
`500.000 |.U. salcatonin are dissolved in 900 ml distilled water containing 12.53 g citric acid, 12.37 g
`sodium citrate dihydrate, 1.5 g methyl p-hydroxybenzoate sodium salt, 0.23 g propyl p-hydroxybenzoate
`sodium salt, 1 g sodium edetate. Distilled water is added up to 1000 ml. After filtration on 0.2 um filters, the
`solution is shared among glass bottles fitted with a 0.1 ml dispenser at a time, corresponding to 50 l.U.
`salcatonin.
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`EXAMPLE 2
`
`is repeated using a double amount of salcatonin,
`The process described in Example 1
`|.U. Each dispensing from the bottle corresponds to 100 |.U. salcatonin.
`
`i.e. 1.000.000
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`EP 0 489 217 A1
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`EP 0 489 217 A1
`
`ethylenediaminetetraacetate is further contained.
`
`Pharmaceutical compositions according to claim 1, further containing methyl and/or propyl p-hydrox-
`ybenzoates.
`
`Pharmaceutical compositions according to claims 1 o 2, characterized in that calcitonin is contained in
`amounts from about 100 to about 5000 |.U. per millilitre.
`
`Pharmaceutical compositions according to the preceding claims, each millilitre thereof containing:
`from 250 to 2000 |.U. calcitonin;
`from 6.27 to 18.8 mg citric acid;
`from 6.19 to 18.56 mg sodium citrate dihydrate;
`from 0.75 to 2.25 mg methyl p-hydroxybenzoate sodium salt;
`from 0.11 to 0.34 mg propyl p-hydroxybenzoate sodium salt; and
`from 0.5 to 1.5 mg ethylendiaminotetracetic acid tetrasodium salt.
`
`Pharmaceutical compositions according to the preceding claims characterized in that calcitonin is
`salmon calcitonin (salcatonin).
`
`Claim for the following Contracting States : ES, GR
`
`1. A process for
`liquid, stable in the air, pharmaceutical compositions containing
`the preparation of
`calcitonin, for intranasal administration, characterized in dissolving from 250 to 2000 |.U. calcitonin per
`millilitre of final solution, into an aqueous solution containing from 6.27 to 18.8 mg citric acid; from 6.19
`to 18.56 mg sodium citrate dihydrate; from 0.75 to 2.25 mg methyl p-hydroxybenzoate sodium salt;
`from 0.11
`to 0.34 mg
`propyl
`p-hydroxybenzoate
`sodium salt;
`and from 0.5 to
`1.5 mg
`ethylenediaminetetraacetic acid tetrasodium salt; for each millilitre of the final solution;
`filtering the obtained solution and packing the same in suitable containers; being all the process steps
`carried out without inert gases protection.
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`gt;'i:}:eanPatent
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`EUROPEAN SEARCH REPORT
`
`ApplicationNumber
`
`EP
`
`90 83 0564
`
`
`
`
`DOCUMENTS CONSIDERED TO BE RELEVANT
`
`can 0
`g ry
`
`Citation of document with indication, where appropriate,
`of relevant passages
`
`Relevnnt
`
`to Cllllll
`
`CLASSIFICATION OF THE
`APPLICATION (Int Cl-5)
`
`X
`
`
`
`
`
`1-5
`
`1
`
`(RORER INTERNATIONAL)
`EP-A-0 358 234
`* Claims 1,3; page 2,
`lines 49-50; page
`11,
`lines 23-27,33-39; page 12,
`lines
`1-9; page 13, example 8; page 16,
`example 14 *
`
`(ESSETI s.a.s.
`EP-A-0 418 697
`LABORATORIO CHIMICO FARMACO BIOLOGICO
`01 A.
`IEVOLI & C.)
`* Claims 1,4-6; page 3,
`examples 1-4 *
`
`lines 50-53;
`
`
`
`
`(TEIJIN LTD)
`EP-A-0 399 781
`* Page 2,
`lines 6-8; page 4,
`lines
`
`
`
`
`
`
`E
`
`A
`
`
`
`The present search report has been drawn up for all claims
`Plane of Iearch
`Date of completion of the search
`
`TECHNICAL FIELDS
`SEARCHED (Int. Cl.5)
`
`Exnniner
`
`
`
`
`
`05-07-1991
`
`VENTURA AMAT A.
`
`
`
`
`
`THE HAGUE
`
`
`
`
`
`EPOFORM150003.32(P0101)
`
`T : theory or principle underlying the invention
`CATEGORY OF CITED DOCUMENTS
`E : earlier patent document, but published on, or
`after the filing date
`: particularly relevant if taken alone
`D : document cited in the application
`: particularly relevant if combined with mother
`L: document cited for other reasons
`document of the same category
`......................................................................................................
`: technological background
`: non-written disclosure
`& : member of the same patent family, corresponding
`: intermediate document
`document
`
`
`
`
`“UO>r<>¢