9 European Patent office
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`Office européen des brevets
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`® Publication number:
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`0
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`@
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`EUROPEAN PATENT APPLICATION
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`@ Application number: 91118477.8
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`@ Int. C|.5: C07K 15/00, A61 K 9/06
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`@ Date of filing: 30.10.91
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`Priority: 20.11.90 IT 4849290
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`@ Date of publication of application:
`27.05.92 Bulletin 92/22
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`® Applicant: ISTITUTO FARMACO BIOLOGICO
`RIPARI-GERO S.p.A.
`Via Montearioso, 11
`I-53035 Monteriggioni (Siena)(lT)
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`Designated Contracting States:
`AT BE CH DE DK ES FR GB GR IT LI LU NL SE
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`® Inventor: Bolasco, Franco
`Via Montearioso 11
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`I-53035 Monteriggioni (Siena)(lT)
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`Representative: Minoia, Fabrizio
`Studio Consulenza Brevettuale Via Rossini,
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`8 I
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`-20122 Milano(lT)
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`@ Aqueous compositions containing calcitonin for the nasal administration.
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`@ Aqueous compositions for the nasal administration, containing calcitonin and cetylpyridinium chloride, have a
`surprisingly high bio-availability.
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`EP0486854A1
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`Lannett Holdings, Inc. LAN 1026
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`Rank Xerox (UK) Business Services
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`

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`EP 0 486 854 A1
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`The present invention relates to aqueous compositions containing calcitonin, for the nasal administra-
`tion, which compositions have a higher bio-availability than that of the already known ones, such as those
`described in UK Pat. n: 1.354.126 and in Italian Pat. N. 1.172.324.
`
`The cited British patent relates to "nasal" aqueous compositions (said definition will be used hereinafter
`for shortness) containing, besides calcitonin, sodium phosphate, citric acid, sodium chloride, glycerin,
`sorbitol, methyl paraben and propyl paraben. On the other hand, the Italian patent claims nasal composi-
`tions containing calcitonin, benzalkonium chloride, sodium chloride and HCl
`to pH 3.7. According to this
`patent, benzalkonium chloride allows to avoid contamination by micro—organisms, as well as to improve the
`bio-availability of the active ingredient.
`Now,
`it has surprisingly been found that nasal aqueous compositions containing calcitonin and
`cetylpyridinium chloride, adjusted to pH 4 by means of acetate buffer, besides having a very good stability
`to micro—organisms, also have a markedly improved bio-availability.
`Preferably, the used calcitonin is salmon calcitonin, which will be present in the compositions of the
`invention in amounts from 100 to 5,000 l.U., preferably from about 250 to about 2,500 |.U., per ml of ready-
`to-use aqueous solution.
`Cetylpyridinium chloride, of formula :
`
`C1‘
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`\ /
`
`N9
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`(CH2)l5—CH3
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`is a quaternary salt, also named Cepacol®, Cetamium®, which is in form of a water-soluble white powder
`melting at 77-83°C. According to the invention,
`it
`is used in amounts ranging from 0.01 to 0.4 mg/ml of
`ready-to-use aqueous solution, preferably from 0.05 to 0.2 mg/ml.
`The acetate buffer
`is used in the amount necessary to adjust pH of
`preferably 4.0.
`instillation or, preferably, as a nasal
`The compositions of the invention can be administered by nasal
`spray. For this purpose, suitable dosers are used delivering 0.1 ml of the composition for unit dose, which is
`equivalent to 25-250 |.U. of calcitonin, according to the above mentioned preferred calcitonin concentrations.
`The following examples further illustrate the invention. All the described operation are effected under
`nitrogen.
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`the composition to 3.8-4.2,
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`10
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`15
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`20
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`25
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`30
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`35
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`40
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`EXAMPLE A
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`1,000,000 |.U. of salmon calcitonin is dissolved in 800 ml of bidistilled water, and a standard acetate
`buffer solution is added thereto to pH about 4, then 0.12 g of cetylpyridinium chloride and again bidistilled
`water to 1,000 ml final volume are added. The solution is filtered through a filter candle and filled into spray
`closers delivering 0.1 ml per unit dose (= 100 |.U. of calcitonin).
`
`45
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`EXAMPLE B
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`50
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`The procedure according to Example A is repeated so that the delivered unit dose of nasal composition
`(0.1 ml) contains 150 |.U of salmon calcitonin.
`
`EXAMPLE C
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`55
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`The procedure of Example A is repeated, but with half the amount of calcitonin. Therefore, the nasal
`sprays will deliver 50 |.U. of salmon calcitonin per unit dose.
`The compositions of the invention proved to be stable to contamination by such agents as :
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`EP 0 486 854 A1
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`Aspergillus niger
`Candida albicans
`Escherichia coli
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`Staphylococcus aureus
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`Pseudomonas aeruginosa
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`10
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`which were added to the compositions in amounts of about 105 micro—organisms in the inoculated liquid
`(according to the procedure described in Acta Pharm. Technol. 22, 247, (1976)), and after incubation for
`some hours, turned out to be nearly disappeared. No alive cells wfie revealed by a control effected on the
`solution two months later.
`
`the composition of Example A was compared with a composition of the same calcitonin
`Moreover,
`concentration, prepared according to Italian Pat. N. 1,172,324. The test was carried out on 20 healthy
`volunteers of both sexes : after administration of doses of 100 |.U. calcitonin, blood withdrawals were
`effected at different times and calcitonin plasma levels (in pc/ml of plasma) were evaluated. The mean
`results can be summarized as follows :
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`
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`The above data clearly show that the increase in bio—availability is markedly significant.
`
`Claims
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`1.
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`2.
`
`3.
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`4.
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`5.
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`Intranasal aqueous pharmaceutical compositions containing calcitonin, with pH adjusted to 3.8-4.2 by
`means of acetate buffer, characterized in that they contain cetylpyridinium chloride.
`
`Pharmaceutical compositions as claimed in claim 1, containing from about 100 to about 5,000 l.U. of
`calcitonin and from 0.01 to 0.4 mg of cetylpyridinium chloride per ml of solution.
`
`Pharmaceutical compositions as claimed in the preceding claims, containing from about 25 to about
`2,500 |.U. of calcitonin and from 0.05 to 0.2 mg of cetylpyridinium chloride per ml of solution.
`
`Pharmaceutical compositions as claimed in the preceding claims, buffered to pH 4.
`
`Pharmaceutical compositions as claimed in the preceding claims, in form of spray to be administered in
`form of unit doses equivalent to 25-250 |.U. of calcitonin.
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`20
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`25
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`30
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`35
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`40
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`45
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`50
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`55
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`CU7K15/DU
`A61K9/06
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`VD-A-9 (103 796 (SCHIAPPARELLI SALUTE)
`* page 2, Hne 18 — 11ne 26 *
`* page 4, Hne 7 - line 9 *
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`(ARFDUR PHARMACEUTICAL CWPANY)
`EP-A-U 115 627'
`* page 5,
`line 19 — ‘line 22 *
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`EP-A-0 193 372 (TEIJIN LIMITED)
`" column 2,
`line 2 *
`* column 3,
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`GB-A-2 127 689 (SANIIJZ)
`* the who’le document *
`& IT-A-1 172 324
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`1-5
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`1-5
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`"line 24 - line 41 *
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`cmegory
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`Y
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`Y
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`Y
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`Y
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`D
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`Y
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`A
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`322°“"“‘°"‘
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`EUROPEAN SEARCH REPORT
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`“"’“°‘“°“”“"“"'
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`EP
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`91 11 8477
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`'— DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Citation of document with indicfion, where appropriate,
`of relevant passages
`
`Relevant
`to claim
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`CLASSIFICATION OF THE
`APPUCATION (1M- (15)
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`PATENT ABSTRACTS OF JAPAN
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`1 August 1988
`vol. 12, no. 279 (C—517)(3126)
`& JP-A-63 057 527 ( TOYO JOZO ) 12 March 1988
`* abstract *
`
`EP-A-0 093 373 (BERNSTEIN, J, ET AL)
`* page 4,
`line 11; claim 12 *
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`—————
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`1-5
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`1-5
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`1-mmcA1,mws
`SEARCHED 0'“-C‘-5)
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`can
`Aim
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`document EPOFORMISMMJ2
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`(P0601)
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`CATEGORY OF CITED DOCUMENTS
`
`: particularly relevnnt if taken nlone
`: partiailerly relevant if combined with anothc
`document of the same category
`: technological background
`: non-written disclosure
`: intermediate document
`
`T : thwry or principle underlying the invention
`E : eaflier patalt document, but published on, or
`aft: the filing date
`D : docuinmt cited in the application
`: docunimt cited for other reasons
`: manber at the same patent family, corresponding
`
`The present search report has been drown up for all claims
`Place of search
`Dun of eelylntlon of the arch
`BERLIN
`30 JANUARY 1992
`
`Ex-Int
`AVEDI KIAN P, F,