Europaisches Patentamt
`Q European Patent Office
`
`Office européen des brevets
`
`llllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll
`® Publication number:
`0
`7
`
`69
`
`EUROPEAN PATENT APPLICATION
`
`® Application number: 903093711
`
`@ Int. Cl.5: A61K 9/06, A61 K 37/43
`
`@ Date of filing: 28.08.90
`
`
`
`@ Priority: 29.08.89 JP 222283/89
`
`Date of publication of application:
`20.03.91 Bulletin 91/12
`
`® Applicant: SUMITOMO PHARMACEUTICALS
`COMPANY, LIMITED
`2-8, Doshomachi 2-chome, Chuo-ku
`Osaka-shi Osaka 541 (JP)
`
`@ Designated Contracting States:
`AT BE CH DE DK ES FR GB GR IT LI LU NL SE
`
`® inventor: Fujioka, Keiji
`1-27-5-206, Tsukaguchicho
`Amagasaki-shi, Hyogo 661(JP)
`Inventor: Takada, Yoshihiro
`4-37-1-813, Senriyamanishi
`Suita-shi, Osaka 565(JP)
`inventor: Aisaka, Ayumi
`2-1, Kikusuidori
`Moriguchi-shi, Osaka 570(JP)
`
`Representative: Kearney, Kevin David
`Nicholas et al
`KILBURN & STRODE 30 John Street
`London, WC1N 2DD(GB)
`
`@ Low-irritative nasal preparation.
`
`@ A GRF-containing nasal preparation is improved in irritation to nasal mocosa by adding sodium chloride
`and/or sugar alcohols such as mannitol or sorbitol thereto.
`
`EP0417930A1
`
`   
`


`
`Lannett Holdings, Inc. LAN 1025
`
`Xerox Copy Centre
`
`

`
`EP 0 417 930 A1
`
`LOW-IRRITATIVE NASAL PREPARATION
`
`invention relates to a low-irritative nasal preparation of growth hormone releasing factor
`This
`(hereinbelow referred to as GRF).
`GRF is a peptide which shows growth hormone releasing activity in a living body and temporary or long
`term administration thereof has been tried from a standpoint of clinical medicines of human being and
`veterinary for diagnosis or treatment.
`GRF is so far administered mainly by injections, since it is bioactive peptide and is easily inactivated by
`proteases and hardly absorbed when it
`is orally administered. However, a development
`in a more
`convenient administration method other than injections is expected, since injection is painful and is
`inconvenient.
`
`Recently, attention has been paid to intranasal administration so far as peptide and protein drugs are
`concerned.
`it is found that GRF is able to be absorbed through nasal mucosa, and various investigations
`have been made in this respect. However. an application of an aqueous GRF solution obtained by simply
`dissolving GRF in a water is not useful, since retention time of the solution in the nasal cavity is so short
`and molecular weight of GRF is so large that absorption rate of GRF is not high. Accordingly,
`it
`is
`necessary for a nasal preparation of GRF to make concentration of GRF in the preparation as high as
`possible and to apply a large amount of GRF in order to have GRF absorbed across nasal mucous
`membrane. However, GRF is somewhat irritative to mucosa and a nasal preparation of GRF having enough
`concentration for clinical effects gives no good feeling after being administered.
`It
`is difficult
`to apply
`aqueous solution of concentrated GRF for practical use as a nasal preparation as it is, for example, for the
`treatment of dwarfism, since there is a possibility to injure nasal mucosa due to administration for a long
`period.
`One of approaches is addition of absorption enhancers in order to improve bioavailability of hardly
`absorbable drugs such as peptides and polypeptides. As to GRF, addition of materials such as saponin or
`bile acid salts to the preparation are proposed in order to promote absorption rate through nasal mucosa
`(JP 62426135). However, these absorption enhancers are,
`in themselves, somewhat
`locally toxic and
`irritative to mucous membranes. Their irritation are rather stronger than those of GRF. Accordingly, the
`addition of these absorption enhancers is not practical, since nasal mucosa is rather more irritated even if
`GRF concentration be lowered, and there is a fear of injurious influence on nasal mucosa after a long term
`
`repeated administrations. Another approach is to decrease relative osmotic pressure of the preparations to
`not more than 1, preferably not more than 0.5 in order to improve absorption of GRF, through nasal mucosa
`into blood circulation (JP 63-303931) where local toxicity and irritation are not so large. However, the latter
`approach is not always suitable for less irritative preparations, since wider range of osmotic pressure is
`required from a practical point of view, depending on varieties and desired concentrations of GRF.
`There is another problem on GRF solubility in making preparations of GRF, besides irritation. Solubility
`of GRF is influenced by kinds and concentrations of materials coexisted in aqueous solution, and by ionic
`strength, pH, etc. Solubility of GRF may decrease according to kinds and concentrations of the materials i
`added. Materials which are active for decreasing irritation of GRF are n_ot suitable as an additive, as long as
`solubility of GRF is decreased by addition thereof, since no aqueous solution or suspension of GRF having
`concentration and homogeneniety enough for clinical application is obtained. Almost all preparations to be
`applied to mucous membranes such as nasal preparations and eye drops are controlled with respect to
`irritation thereof by addition of various kinds of organic or inorganic salts to such a level
`that osmotic
`pressure of the preparations is almost the same as the physiological osmotic pressure. in the case of GRF.
`however, no desired preparation is obtained depending on inorganic salts which are usually employed as
`isotonizers, because some of them hinder GRF from being dissolved and GRF is crystalized or precipitated.
`it is necessary to consider this sort of property of GRF in the investigation of methods for decreasing
`irritation of a nasal preparation of GRF.
`It has been very difficult to develop a nasal preparation of GRF,
`since properties of materials which are to be used as additives have to be taken into consideration in the
`case of GRF.
`
`Although a nasal preparation of GRF practically applicable as clinical medicines is expected, such
`preparation has not yet been in the market because of its irritation to mucosa and difficulty in preparation.
`After strenuous effort to obtain a nasal preparation of GRF without irritation to mucosa, the present
`inventors have unexpectedly found that addition of sodium chloride and/or sugar alcohols serves to
`decrease irritation of a nasal preparation of GRF.
`Sodium chloride is an inorganic salt which is familiar as isotonizers for injections and eye drops. Sugar
`alcohols are polyhydric alcohols obtained by reducing carbonyl groups of sugar molecules and are also
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`EP 0 417 930 A1
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`injections and eye drops. Although
`isotonizers, stabilizers, etc. for oral preparations,
`familiar as diluents,
`sodium chloride and sugar alcohols are familiar as additives to pharmaceuticals, the purpose of addition in
`this invention is not conventionally simple isotonization but decrease of irritation which prevents GRF from
`being used as a nasal preparation. it is surprising that these generally used additives have such effects of
`decreasing irritation of a nasal preparation of GRF to nasal mucosa.
`GRF is a peptide which shows growth hormone releasing activity and the activity is observed in several
`kinds of peptides each of which is composed of 44, 40, 37 or 29 amino acids. Their derivatives are also
`known.
`in this invention, any GRF is employed as long as it shows growth hormone releasing activity. For
`example, GRF may be any of the above GRF composed of 44, 40, 37 or 29 amino acids, their derivatives,
`analogues or a mixture thereof. GRF used in this invention may be obtained by extraction from living
`bodies, chemical synthesis or recombinant DNA method and it is not limited by the preparing method.
`Nasal administration is a method to deliver medicines through nasal mucosa into the body and it is
`actually performed by spraying or dropping mainly aqueous solution into nasal cavity. Accordingly,
`preference is solution which may be sprayed or dropped. Lyophilized preparation may be prepared in
`consideration of stability of GRF in storage, which is used after reconstitution with a solvent at the time of
`use. Dosage form of this invention is not limited to those described in the above examples and may be
`others such as suspensions or gels.
`Content of GRF in the preparations is usually 0.001 to 10 WN%, preferably 0.01 to 10 W/V°/o in
`aqueous solution or suspension but this invention is not specifically limited by the content of GRF in the
`preparation.
`Sugar alcohols used in this invention may be naturally obtained ones or artificially and chemically
`synthesized ones. Examples are mannitol or sorbitol.
`The decreasing effect in irritation of a nasal preparation of GRF is obtained by simple adding sodium
`chloride and/or sugar alcohols to aqueous solution or suspension of GRF. These additives may be used
`singly or in combination of not less than two. For example, combinations of sodium chloride - mannitol,
`sodium chloride - sorbitol, sodium chloride - mannitol - sorbitol, and mannitol - sorbitol may be used. There
`is no limitation in an amount of these additives to GRF preparation in principle, but it may preferably be
`0.01 to 10 WN%, more preferably 0.1 to 3 W/V% in the case of sodium chloride and 0.1 to 30 W/V°/o, more
`preferably 1 to 15 WN% in the case of sugar alcohols in an aqueous solution or suspension.
`These additives may be added to either lyophillzed preparation or reconstitution solvent when lyophiliz-
`ed dosage form is employed.
`It is generally preferred in consideration of safety of GRF that osmotic pressure of a nasal preparation
`does not extremely differ from the physiological osmotic pressure and it is preferred in this invention that
`the relative osmotic pressure of the preparation is between 0.5 and 3.0 at the time of administration. The
`relative osmotic pressure described here is expressed by a relative ratio to the physiological osmotic
`pressure and that of 0.9 % aqueous sodium chloride solution is determined to be 1.
`Preferred pH of a nasal preparation of GRF in this invention is 2 to 7 in consideration of stability of
`GRF.
`
`The nasal preparation of GRF in this invention is prepared by a known method or a similar method
`thereto. For example, it is prepared by mixing, dissolving, dispersing, suspending, emulsifying or homogen-
`izing necessary components at any order. Pharmaceuticaily acceptable additives such as buffers, stabiliz-
`ers, isotonizers, solubilizers, disintegrators, dispersing agents, suspensioners, emulsifiers, preservatives and
`pH adjusters may be added, if necessary, to the preparation. However, these additives should not decrease
`solubility of GRF and should not give no good influence to processing of the GRF preparation at the
`targeted concentration.
`It
`is further preferred that a powdered formulation which is to be used after
`reconstitution at the time of use, is prepared by lyophilizing the obtained aqueous solution in consideration
`of stability of GRF in storage.
`The present nasal preparation of GRF containing sodium chloride and/or sugar alcohols is low in
`irritation to nasal mucosa and gives no injury to nasal mucosa after a clinically effective amount of GRF is
`repeatedly administered to nasal cavity for a long period of time. Accordingly,
`the preparation of this
`invention is extremely suitable for nasal administration and it enables to administer GRF for a long period of
`time by a painless, simple and convenient method of patient's own spray or dropping to nasal cavity and to
`have growth hormone releasing activity effectively exhibited without adverse reactions.
`The invention is explained in more detail and concretely by the following experiments and examples.
`
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`Experiment 1
`
`
`
`

`
`EP 0 417 930 A1
`
`In order to study the reducing effect in irritation of the nasal preparation of this invention, eye dropping
`tests were carried out to rabbits by a method described below and the irritation was compared with other
`GRF preparations.
`A solution each of additives and GRF(1 -44) in distilled water for injection was controlled to pH about 5
`by adding an appropriate amount of hydrochloric acid or sodium hydroxide. These solutions were subjected
`to sterile filtration to obtain GRF preparations containing sodium chloride (sample 1), sugar alcohols
`(samples 2 and 3), other additives than the above (samples 4 and 5), respectively, and a low concentration
`GRF preparation containing an absorption enhancer (sample 6) and an aqueous solution of GRF without any
`additive (sample 7). Concentrations of additives and GFlFs are shown in Table 1 where amounts of additives
`in samples 1
`to 5 were controlled so that relative osmotic pressure of each aqueous solution would be
`about 1.
`
`Table 1
`
`Sample
`
`Additive (mg/ml)
`
`GRF
`(mg/ml)
`
`Sodium chloride
`D-Mannitol
`D-Sorbitol
`
`
`
`
`Glycine
`Citric acid
`
`Saponin
`None
`
`Fifty tut each of the above experimental sample was dropped into eyes of 5 rabbits per group and
`irritation to eye mucosa was evaluated.
`Evaluation was made by observation of eye condition after dropping; it was scored 0 when no blink was
`observed, 1 for 1
`to 2 blinks, 2 for 3 to 5 blinks, 3 for not less than 6 blinks, and 4 when eyes were kept
`closed and not opened for not less than 5 seconds. The less score shows the less irritation to eye mucosa.
`Results are shown in Table 2. Obviously reduction of irritation was observed in the GRF preparations of this
`invention (samples 1
`to 3). On the other hand, no reduction of irritation was observed by additives other
`than sodium chloride and sugar alcohols for simple isotonization (samples 4 and 5). The strongest irritation
`was observed in the sample 6 in which an absorption enhancer was added even though the concentration of
`GRF was lower than in other samples. Addition of the absorption enhancer enlarged irritation to mucosa.
`As shown in the above results, reduction in irritation of GRF was specifically obtained by addition of
`sodium chloride or sugar alcohols.
`
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`EP 0 417 930 A1
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`Table 2
`
`Score
`
`2
`
`1
`
`1
`
`1
`
`01
`
`score-
`
`
`
`1—
`nnnn s
`
`Rabbit No.
`
`
`
`
`
`
`
`12
`
`12
`
`*7
`
`CO
`
`
`
`Rabbit No.
`
`Score
`
`Rabbit No.
`
`Score
`
`11
`
`)
`
`2
`
`12
`
`2
`
`13
`
`1
`
`14)
`
`1
`
`15
`
`1
`
`<2°>
`
`5
`
`Rabbit N0.
`
`Score
`
`Rabbit No.
`Score
`
`Rabbit No.
`
`
`Experiment 2
`
`Experiment 1 was repeated except that GRF preparations containing sodium chloride (sample 8), sugar
`alcohols (samples 9 and 10), and sodium chloride and sugar alcohols (samples 11 to 13), respectively, GRF
`preparations containing other additives than sodium chloride and sugar alcohols (samples 14 and 15), a low
`concentration GHF preparation containing an absorption enhancer (sample 16) and an aqueous solution of
`GRF without any additive (sample 17). Concentrations of additives and GRF in each sample are shown in
`Table 3 where amounts of additives in samples 8, 9, 10, 14 and 15 were controlled so that relative osmotic
`pressure of each aqueous solution would be 1, and those in samples 11, 12 and 13 were controlled so that
`relative osmotic pressures would be 1.5 (= 1.0 based on sodium chloride plus 0.5 based on mannitol), 1.0
`and 1.5 (= 1.0 based on mannitol plus 0.5 based on sodium chloride), respectively.
`
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`so
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`
`EP 0 417 930 A1
`
`Table 3
`
`Sample
`
`Additive (mg/ml)
`
`8
`9
`10
`
`14
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`30
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`40
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`
`
`
`Results are shown in Table 4. Obviously reduction of irritation was observed in the GRF preparations of
`this invention (samples 8 to 13).
`The irritation of aqueous solution of GRF without any additive (sample 17) is apparently reduced by
`addition of sodium chloride or sugar alcohols of this invention (samples 8 to 10). Furthermore, the same or
`more improved reduction in irritation was observed by addition of sodium chloride and sugar alcohols at the
`same time (samples 11 to 13), compared with the preparation containing sodium chloride or sugar alcohols.
`On the other hand, no reduction of irritation was observed by additives other than those included in this
`invention (samples 14 and 15') and no reduction in irritation of GRF was observed by simple isotonization
`with materials other than sodium chloride or sugar alcohols. The strongest irritation was observed in the
`sample 16 in which an absorption enhancer was added even though the concentration of GRF was lower
`than that in other samples. Addition of the absorption enhancer enlarged irritation to mucosa.
`As shown in the above results, reduction in irritation of GRF was specifically obtained by addition of
`sodium chloride or sugar alcohols and particularly,
`the reduction appeared very strongly in the GRF
`preparation containing sodium chloride and sugar alcohols at the same time.
`
`GRF
`(mg/ml)
`
`1
`1
`1
`
`1 1
`
`1
`
`.5
`
`Sodium chloride
`D-Mannitol
`D-Sorbitol
`
`(9)
`53)
`(
`)
`(5
`
`Sodium chloride
`D-Mannitol
`
`(4.5
`(26
`
`(4.5)
`(53)
`
`
`
`

`
`EP 0 417 930 A1
`
`Table 4
`
`Rabbit No.
`
`211
`
`216
`
`218
`
`222
`
`223
`
` IV0)N l\)O)m-L
`
`
`
`Score
`
`0
`
`...i._i.“I [U\IIV[0
`l\)G)( N:
`Rabbit No.
`Score EEE
`0)
`C»)03
`(.000O
`Rabbit No.
`l\Jl\)
`—L—kIQ)
`
`l\JD001L0
`(D—L_.\.“I
`
`l\>Ca>01CA)_.(J1_;Q)
`
`l\>O)O
`
`r\:0:H!
`
`l\)01[U
`
`l\)O‘!-5
`
`[0IVGt01C040)
`
`E
`N901CD
`
`IV
`
`—|L—.L
`
`._x
`
`Rabbit No.
`
`251
`
`25\l
`
`12
`
`13
`
`Rabbit No.
`
`CDCD0OOO—:WCD(D
`Rabbit No.I Score
`262- Score
`
`
`
`
`
`
`
`14
`
`5
`
`6
`
`Rabbit No.
`CD0O -x(D
`
`Rabbit No.
`
`We
`Rabbit No.
`
`Score
`
`17
`
`Rabbit No.
`
`Score
`
`
`
`317
`
`(.0[U(A)i\)N
`
`l\)l\)
`
` )
`
`
`
`318
`
`R3(/3|\)[OCD\I-I3CA300
`
`311
`
`312
`
`313
`
`314
`
`319
`
`N)0000IU
`
`320
`
`00I\')—'~CD0'1I'\)
`
`E
`
`
`
`
`
`mN)—-ozon0:—a El
`[U(.0(10[U00|\)-PC‘)[U
`
`12
`
`P0 _.a.
`
`3
`
`E .4 DJ
`
`
`
`_;_;01oo
`
`75
`
`20
`
`25
`
`30
`
`35
`
`40
`
`Examples of this invention are presented below, but it
`limited thereto.
`
`is needless to say that this invention is not
`
`Example 1
`
`in solution of sodium chloride (18 mg) in distilled water for injection (2 ml), was dissolved GRF(1—29) (2
`45 mg) and pH of the resulting solution was adjusted to 5 by adding hydrochloric acid. This solution was
`subjected to sterile filtration to obtain a nasal preparation of GRF with low irritation. Relative osmotic
`pressure was about 1.
`
`50 Example 2
`
`In solution of D—mannitol (30 mg) in distilled water for injection (1 ml), was dissolved GRF(1—44) (1 mg)
`and pH of the resulting solution was adjusted to 5 by adding hydrochloric acid. This solution was subjected
`to sterile filtration to obtain a nasal preparation of GRF with low irritation. Relative osmotic pressure was
`about 0.6.
`
`55
`
`Example §
`
`

`
`EP 0 417 930 A1
`
`in solution of sodium chloride (40 mg) in distilled water for injection (5 ml), was dissolved GRF(1-44) (10
`mg) and pH of the resulting solution was adjusted to 5 by adding hydrochloric acid. The solution was
`subjected to sterile filtration and 1 ml each was dispensed in vials and lyophilized. After nitrogen gas was
`introduced, the vials were closed with rubber stoppers and cap—sealed to obtain nasal preparations of GRF
`with low irritation for reconstitution at the time of use. Relative osmotic pressure when reconstituted with 1
`ml each of distilled water for injection at the time of use was about 0.9.
`
`Example E
`
`in solution of D-sorbitol (150 mg) in glycine buffer (pH 5, 5 ml), was dissolved GRF(1-44) (15 mg). After
`the resulting solution was subjected to sterile filtration,
`1 ml each was dispensed in vials and lyophilized.
`After nitrogen gas was introduced, the vials were closed with rubber stoppers and cap-sealed to obtain
`nasal preparations of GRF with low irritation for reconstitution at the time of use. Relative osmotic pressure
`when reconstituted with 1 ml each of distilled water for injection at the time of use was about 1.6.
`
`Example 5
`
`in solution of D-mannitol (250 mg) in phosphate buffer (pH 5, 10 ml), was dissolved GRF(1—29) (40 mg).
`After the resulting solution was subjected to sterile filtration,
`1 ml each was dispensed in vials and
`lyophilized. After nitrogen gas was introduced, the vials were closed with rubber stoppers and cap-sealed to
`obtain nasal preparations of GRF with low irritation for reconstitution at the time of use each. Relative
`osmotic pressure when reconstituted with 1 ml each of distilled water for injection at the time of use was
`about 1.5.
`
`Example 6
`
`In solution of sodium chloride (68 mg) in distilled water for injection (5 ml), was dissolved GRF(1-44)
`(2.5 mg) and pH of the resulting solution was adjusted to 5 by adding hydrochloric acid. This solution was
`subjected to sterile filtration to obtain a nasal preparation of GRF with low irritation. Relative osmotic
`pressure was about 1.5.
`
`Example 7
`
`In solution of sodium chloride (270 mg) in distilled water for injection (10 ml), was dissolved GRF(1-29)
`(1 mg). After the resulting solution was subjected to sterile filtration,
`1 ml each was dispensed in vials and
`lyophilized. After nitrogen gas was introduced, the vials were closed with rubber stoppers and cap—sealed to
`obtain nasal preparations of GRF with low irritation for reconstitution at the time of use. Relative osmotic
`pressure when reconstituted with 1 ml each of distilled water for injection at the time of use was about 3.
`
`Example §
`
`in solution of D-mannitol (100 mg) and sodium chloride (18 mg) in distilled water for injection (2 ml),
`was dissolved GRF(1-44) (2 mg) and pH of the resulting solution was adjusted to 5 by adding hydrochloric
`acid. This solution was subjected to sterile filtration, to obtain a nasal preparation of GRF with low irritation.
`Relative osmotic pressure was about 1.9.
`
`Claims
`
`1. A low-irritative nasal preparation which comprises an effective amount of GRF and sodium chloride, or
`sugar alcohols or sodium chloride and sugar alcohols.
`2. A low-irritative nasal preparation as claimed in Claim 1 characterised in that the said sugar alcohols are
`mannitol or sorbitol.
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`EP 0 417 930 A1
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`the GRF in the said
`
`3. A nasal preparation as claimed in Claim 1 or Claim 2 characterised in that
`preparation is present in an amount of 0.001 to 10 W/V%.
`to 3 characterised in that the GRF is a peptide
`4. A nasal preparation as claimed in any one of Claims 1
`composed of 44, 40, 37 or 29 amino acids, their derivatives, their analogues, or a mixture thereof.
`5. A nasal preparation as claimed in any one of Claims 1
`to 4 characterised in that the sodium chloride is
`present in an amount of 0.01 to 10 WN%.
`6. A nasal preparation as claimed in any one of Claims 1
`present in an amount of 0.1 to 30 WN%.
`7. A nasal preparation as claimed in any one of Claims 1
`preparation is adjusted to 2 to 7.
`8. A method of reducing irritation of nasal mucosa by adding sodium chloride, or sugar alcohols or sodium
`chloride and sugar alcohols to a GRF-containing nasal preparation.
`9. A preparation as claimed in any one of Claims 1 to 7 for use as a medicament.
`10. A nebulizer, or dropping bottle or resealable tube charged with GRF and sodium chloride NaC1 and/or
`one or more sugar alcohols.
`11. The use of GRF and sodium chloride and/or one or more sugar alcohols in the preparation of a
`therapeutic composition for nasal administration having low or no irritative effect on the nasal mucosa.
`
`to 5 characterised in that the sugar alcohols are
`
`to 6 characterised in that the pH of the said
`
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`

`
`EUTOPEBH
`
`Patent Office
`
`0
`
`EUROPEAN SEARCH
`
`REPORT
`
`Application Number
`
`EP 90 30 9377
`
`DOCUMENTS CONSIDERED TO BE RELEVANT
`Citation of document with indication. where appropriate,
`Relevant
`of relevant passages
`to claim
`
`Category
`
`CLASSIFICATION OF THE
`APPLICATION (Int. cl.5)
`
`X
`
`(PIERREL SpA)
`EP-A-0 301 392
`* Claims 1,2,6; examples 1-11 *
`
`A 61 K 9/06
`A 61 K 37/43
`
`TECHNICAL FIELDS
`SEARCHED (int. C|.5)
`
`The present search l'€D0l’t has been drawn up for all claims
`
`Place of search
`
`Date of completion of search
`
`Examiner
`
`A
`The Hague
`CATEGORY OF CITED DOCUMENTS
`: particularly relevant if taken alone
`: particularly relevant if combined with another
`document of the same catagory
`2
`technological background
`: non-written disclosure
`_
`:
`intermediate document
`:
`theory or principle underlying the invention
`
`PEETERS J.C.
`18 December 90
`E: earlier patent document, but published on, or after
`the filing date
`D: document cited in the application
`L: document cited for other reasons
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`8.: member of the same patent family, corresponding
`document