Europaisches Patentamt
`European Patent Office
`Office europeen des brevets
`
`(n) Publication number: 0 329 4 6 0 B 1
`
`EUROPEAN PATENT S P E C I F I C A T I O N
`
`19
`
`12
`
`© Date of publication of patent specification
`20.05.92 Bulletin 92/21
`
`© int. ci.5: A61K 31/365, A61K 31/71,
`A61K 47/06, AO 1N 4 3 / 9 0
`
`© Application number: 89301547.9
`
`(22) Date of filing : 17.02.89
`
`(54) Stabilised macrolide compositions.
`
`(30) Priority : 18.02.88 GB 8803836
`
`(43) Date of publication of application
`23.08.89 Bulletin 89/34
`
`(45) Publication of the grant of the patent :
`20.05.92 Bulletin 92/21
`
`(73) Proprietor : AMERICAN CYANAMID
`COMPANY
`One Cyanamid Plaza
`Wayne New Jersey 07470 (US)
`
`(72) Inventor : Eastlick, David Thomas
`Benrigg Highfield Road
`Grance-over-Sands Cumbria (GB)
`
`@ Designated Contracting States :
`AT BE CH DE ES FR GB GR IT LI LU NL SE
`
`(74) Representative : Skailes, Humphrey John et al
`Frank B. Dehn & Co. Imperial House 15-19
`Kingsway
`London WC2B 6UZ (GB)
`
`(56) References cited :
`EP-A- 0 045 655
`EP-A- 0 102 721
`EP-A- 0 116 401
`EP-A- 0 146 414
`CH-A- 408 284
`FR-A- 2 570 390
`
`CO
`o
`CO
`
`o>
`CM
`CO
`
`LU
`
`Note : Within nine months from the publication of the mention of the grant of the European patent, any
`person may give notice to the European Patent Office of opposition to the European patent granted.
`Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been
`filed until the opposition fee has been paid (Art. 99(1) European patent convention).
`
`Jouve, 18, rue Saint-Denis, 75001 PARIS
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 001
`
`

`
`EP 0 329 460 B1
`
`Description
`
`5
`
`This invention relates to improvements in the stability of antibiotic compounds.
`UK Patent Specification Nos 2166436, 2176182 and 2187742 and European Patent Specification No.
`170006 describe antibiotic compounds, designated Antibiotics S541, prepared by fermentation of Strep-
`tomyces microorganisms and chemical derivatives thereof. Such compounds have antibiotic, and, in particular,
`anti-endoparasitic, anti-ectoparasitic, anti-fungal, insecticidal, nematicidal and acaricidal activity and are of spe-
`cial interest for use in agriculture, horticulture and animal and human health. They are also of use as inter-
`mediates in the preparation of other active compounds.
`We have discovered that these antibiotic compounds tend to be unstable under normal conditions of pre-
`paration, use and storage. We have now found that the stability of the compounds can be considerably enh-
`anced when they are in the presence of an antioxidant. Thus, any loss due to instability of the compounds during
`preparation can be minimised by addition of an antioxidant. In a similar way, the shelf-life of the compounds
`can be increased if admixed with an antioxidant, thereby allowing for the compounds to be prepared well in
`advance of their intended use. In the presence of an an tioxidant, the compounds also have increased protection
`against photodegradation, and this allows for the compounds to be readily stored.
`Thus, according to one aspect of the invention, we provide a composition containing an antibiotic S541
`compound preparable by fermentation of a Streptomyces microorganism or a chemical derivative thereof in the
`presence of an antioxidant as defined below.
`The fermented compounds will in general be Antibiotic S541 compounds or derivatives thereof produced
`by an Antibiotics S541 producing microorganism belonging to the genus Streptomyces, especially an Antibio-
`tics S541 producing strain of the species Streptomyces thermarchaensis or Streptomyces cyaneogriseus non-
`cyanogenus. Particular examples of suitable strains include Streptomyces thermarchaensis NCIB 12015
`[deposited 10th September 1984], Streptomyces thermarchaensis NCIB 12111, NCIB 12112, NCIB 12113,
`25 NCIB 12114 [all deposited 26th June 1985] and Streptomyces cyaneogriseus noncyanogenus NRRL 15773
`[deposited 3rd May 1984] and mutants of all these strains.
`Particular fermented compounds which may be recovered have the formula (I)
`
`w
`
`15
`
`20
`
`30
`
`35
`
`40
`
`45
`
`so
`
`55
`
`( I )
`
`(where R1 is a methyl, ethyl or isopropyl group and R2 is a hydrogen atom or a methyl group).
`An important group of derivatives which may be used in the compositions of the invention is described in
`GB 2192630A, particularly 23[E]-methoxyimino Factor A.
`The antioxidant for use in the composition according to the invention will in general be an antioxidant that
`is capable of reacting with free radicals, and may be a C1_12 alkyl gallate such as ethyl, propyl, octyl or dodecyl
`gallate; benzyl hydroxybenzoate; butylated hydroxyanisole; butylated hydroxytoluene; quinones and salts
`thereof, for example C^ alkyl hydroquinones such as t-butyl hydroquinone and salts thereof, eg the sodium
`salts; nordihydroguaiaretic acid; or tocopherols such as a-tocopherol. We have found butylated hydroxytoluene
`to be particularly useful.
`The antioxidant may be present in the compositions according to the invention in amounts ranging from
`0.005 to 1 %, especially 0.02 to 0.3% with respect to the antibiotic compounds. If desired, a mixture of antioxid-
`ants may be present in the compositions.
`The antibiotic compounds may be in a partially or wholly purified form either as a solid or as a solution in
`
`2
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 002
`
`

`
`EP 0 329 460 B1
`
`a suitable solvent, for example a ketone such as acetone, an alcohol such as methanol, a hydrocarbon such
`as hexane, a halogenated hydrocarbon such as chloroform or methylene chloride, an ester such as ethyl ace-
`tate, or acetonitrile. Suitable methods for the preparation of the antibiotic compounds in these forms are des-
`cribed in UK Patent Specification Nos. 2166436, 2176182 and 2187742 and European Patent Specification
`No. 170006.
`Where the compositions of the invention are to be used in human or veterinary medicine, or in agriculture,
`horticulture or forestry they may also contain one or more suitable carriers or excipients. Thus in a further aspect
`of the invention we provide a composition comprising an antibiotic compound preparable by fermentation of a
`Streptomyces microorganism or a chemical derivatives thereof and an antioxidant together with one or more
`carriers or excipients.
`Examples of suitable carriers and excipients are those described in the aforementioned UK and European
`Patent specifications.
`Where the compositions according to the invention have antibiotic activity e.g. antihelminthic activity, for
`example against nematodes, and in particular, anti-endoparasitic and anti-ectoparasitic activity, they can be
`used in the treatment of animals and humans with endoparasitic, ectoparasitic and/or fungal infections and in
`agriculture, horticulture and forestry as pesticides to combat insect, acarine and nematode pests. They may
`also be used generally as pesticides to combat or control pests in other circumstances, e.g. in stores, buildings
`or other public places or location of the pests.
`Thus according to a further aspect of the invention we provide a composition comprising an antibiotic S541
`compound preparable by fermentation of a Streptomyces microorganism or a chemical derivative thereof and
`an antioxidant optionally also containing one or more carriers or excipients for use as an antibiotic in the treat-
`ment of humans or animals or for combatting pests, for example in agriculture, horticulture or forestry.
`In general, the compositions may be applied either to the host (animal or human or plants or other vege-
`tation) or to the pests themselves or a locus thereof in accordance with conventional practice.
`The compositions according to the invention may be prepared by admixture of the desired ingredients, and
`according to a further aspect of the invention we provide a process for the preparation of a composition com-
`prising admixing an antibiotic compound preparable by fermentation of a Streptomyces microorganism or a
`chemical derivative thereof and an antioxidant together, where desired, with one or more carriers or excipients.
`The compositions may be prepared by mixing or blending the ingredients in a conventional manner. Thus,
`in one embodiment a suitable antibiotic compound in a partially purified form in solution may be treated with
`the antioxidant and, if desired, subsequently co-precipitated from the resulting solution or suspension by the
`addition or an anti-solvent or by pH adjustment. In another embodiment, a suitable antibiotic compound in a
`partially or wholly purified form as a solid may be blended with the antioxidant, together, where desired, with
`one or more carriers or excipients by intimate mixing.
`The fermented antibiotic compounds may be isolated from fermentation broth using the methods described
`in UK Patent Specification 2166436, 2176182 or2187742 or European Patent Specification 170006. Inafurther
`aspect of the present invention we provide for the isolation of an antibiotic S541 compound prepared by fer-
`mentation of a Streptomyces microorganisms in the presence of an antioxidant.
`According to a further aspect of the invention we provide a method of stabilising Antibiotics S541 com-
`pounds preparable by fermentation of a Streptomyces microorganism or chemical derivatives thereof which
`comprises contacting the said compound with an antioxidant in any conventional way.
`The following Examples illustrate the invention. All temperatures are in °C.
`In the following Examples 1 to 5 the increased stability of Factor A [a compound of Formula (I) in which R1
`is an isopropyl group and R2 is a hydrogen atom] is demonstrated by comparing changes in potency using accel-
`erated temperature techniques. Potency was measured by high performance liquid chromatography using a
`Spherisorb ODS2 chromatograph.
`
`5
`
`w
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`Example 1
`
`so
`
`A sample of Factor A (in a partially purified form) was dissolved in acetone to give a 5% w/v solution. The
`solution was divided into aliquots. To one aliquot was added butylated hydroxytoluene (25 ppm with respect
`to the volume of acetone), while nothing was added to a second aliquot. Both aliquots were separately preci-
`pitated by the simultaneous addition of the acetone solution (1 volume) and cold water containing 1% v/v sul-
`phuric acid (3 volumes) to a stirred vessel, maintaining the temperature at 0-5°. The solid was filtered, washed
`55 with 3 volumes of cold water and dried.
`A portion of each solid was heated at 50° for two weeks in a sealed vial, followed by reassay. The following
`results were obtained.
`
`3
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 003
`
`

`
`EP 0 329 460 B1
`
`Added b u t y l a t e d hydroxytoluene (ppm)
`
`Change in (%) Potency
`
`Example 2
`
`None
`
`-26.3
`
`25
`
`- 1 . 1
`
`Following the method of Example 1 using butylated hydroxytoluene (250 ppm with respect to the volume
`of acetone) the following results were obtained.
`
`Added b u t y l a t e d hydroxytoluene (ppm)
`
`None
`
`250
`
`Change in (%) Potency
`
`-36.8
`
`no change
`
`Example 3
`
`Following the method of Example 1 using propyl gallate (250 ppm with respect to the volume of acetone)
`the following results were obtained.
`
`Added propyl gallate (ppm)
`
`Change in (%) Potency
`
`Example 4
`
`None
`
`-27.3
`
`250
`
`- 8 . 8
`
`Following the method of Example 1 using t-butyl hydroquinone (250 ppm with respect to the volume of
`acetone) the following results were obtained.
`
`Added t-butyl hydroquinone (ppm)
`
`Change in (5S) Potency
`
`Example 5
`
`None
`
`"27.3
`
`250
`
`" 8 . 8
`
`Dry Factor A was blended with butylated hydroxytoluene (250 ppm) by shaking followed by intimate mixing
`in a mortar and pestle. A portion of the solid, along with a portion to which no butylated hydroxytoluene had
`been added, was heated at 50° for two weeks in a sealed vial followed by reassay. The following results were
`obtained:
`
`Added b u t y l a t e d hydroxytoluene (ppm)
`
`Change in Potency
`
`(S)
`
`None
`
`-23.0
`
`250
`
`- 1 0 . 0
`
`Example 6
`
`Exposure of Factor A to UV Light
`
`Procedure of Example 5 was followed and the solids either stored under refrigeration or stored at ambient
`temperature with exposure to ultraviolet light. The following results were obtained:-
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 004
`
`

`
`EP 0 329 460 B1
`
`MEASURED POTENCY {%)
`Start
`3 days 7 days 10 days
`
`100.0
`
`100.0
`
`101.2
`
`98.8
`
`100.0
`
`92.8
`
`83.5
`
`8 4 . 3
`
`100.0
`
`100.0
`
`100.5
`
`100.1
`
`100.0
`
`100.8
`
`92.5
`
`92.5
`
`Nn hnl-yl al-prl _
`hydroxy-
`toluene
`
`Added
`b u t y l a t e d
`hyHrnvy-
`toluene
`(250 ppm)
`
`Stored under
`r e f r i g e r a t i o n
`
`Exposed UV light *
`Ambient t e m p e r a t u r e
`
`Stored under
`r e f r i g e r a t i o n
`
`Exposed UV light *
`Ambient temperature
`
`* A mercury UV lamp (wavelength 366nm)
`
`The following are examples of formulations according to the invention. The term 'Active Ingredient' as used
`hereinafter means a compound of the formula (I) or a derivative thereof. In all of these compositions an anti-
`oxidant is additionally included, e.g. in an amount of 0.02 - 0.3%.
`
`T a b l e t
`Method of manufacture - wet g r a n u l a t i o n
`
`Active I n g r e d i e n t
`Magnesium s t e a r a t e
`Maize starch
`Sodium s t a r c h g l y c o l a t e
`Sodium l a u r y l s u l p h a t e
`M a c r o c r y s t a l l i n e c e l l u l o s e
`
`S 3
`S 3
`2 5 0 . 0
`2 5 0 . 0
`4 . 5
`4 . 5
`2 2 . 5
`2 2 . 5
`9 . 0
`9 . 0
`A. 5
`4 . 5
`to t a b l e t core weight of 450mg
`to t a b l e t core weight of 450mg
`
`Add sufficient quantity of a 1 0% starch paste to the active ingredient to produce a suitable wet mass for granu-
`lation. Prepare the granules and dry using a tray or fluid-bed drier. Sift through a sieve, add the remaining ingre-
`dients and compress into tablets.
`If required, film coat the tablet cores using hydroxypropylmethyl cellulose or other similar film-forming ma-
`terial using either an aqueous or non-aqueous solvent system. A plasticizer and suitable colour may be included
`in the film-coating solution.
`
`V e t e r i n a r y t a b l e t for s m a l l / d o m e s t i c animal u s e
`Method of manufacture - dry g r a n u l a t i o n
`
`Active I n g r e d i e n t
`Magnesium s t e a r a t e
`M i c r o c r y s t a l l i n e c e l l u l o s e to
`core weight of
`
`t a b l e t
`
`mq
`mq
`
`5 0 . 0 5 0 . 0
`
`7 . 5 7 . 5
`
`7 5 . 0
`7 5 . 0
`
`Blend the active ingredient with the magnesium stearate and microcrystallise cellulose. Compact the blend into
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 005
`
`

`
`EP 0 329 460 B1
`
`slugs. Breakdown the slugs by passing through a rotary granulator to produce free-flowing granules. Compress
`into tablets.
`The tablet cores can then be film-coated, if desired, as described above.
`
`Veterinary intrammary i n j e c t i o n
`
`Active I n g r e d i e n t
`P o l y s o r b a t e 60
`White Beeswax
`Arachis oil
`
`mq/dose
`150mg
`
`Range
`0.05 - 1 .0g
`
`3.0% w/w)
`6. OS w/w)
`91 .OS w/w)
`
`)
`to 3g )
`)
`
`to 3 or 15g
`
`Heat the arachis oil, white beeswax and polysorbate 60 to 160°C with stirring. Maintain at 160°C for two
`hours and then cool to room temperature with stirring. Aseptically add the active ingredient to the vehicle and
`disperse using a high speed mixer. Refine by passing through a colloid mill. Aseptically fill the product into sterile
`plastic syringes.
`
`Veterinary s l o w - r e l e a s e b o l u s
`% w/w
`
`Active I n g r e d i e n t
`Colloidal s i l i c o n
`dioxide
`M a c r o c r y s t a l l i n e
`c e l l u l o s e
`
`)
`2.0)
`)
`to 1 0 0 . 0 )
`
`Range
`0 . 2 5 - 2 g
`to r e q u i r e d
`f i l l weight
`
`Blend the active ingredient with the colloidal silicon dioxide and microcrystalline cellulose by using a suit-
`able aliquot blending technique to achieve a satisfactory distribution of active ingredient throughout the carrier.
`Incorporate into the slow release device and give (1) a constant release of active ingredient or (2) a pulsed
`release of active ingredient.
`
`Veterinary oral d r e n c h
`
`fl„Hwo Tnnr^iPnh
`Active I n g r e d i e n t
`Polysorbate 85
`Benzyl alcohol
`Propylene glycol
`Phosphate buffer
`Water
`
`% w/v
`% w/v
`0.35
`0 . 3 5
`5 . 0
`3 . 0
`3 0 . 0
`as pH 6 . 0
`to 1 0 0 . 0
`
`Range
`0.01 - 2% w/v
`
`Dissolve the active ingredient in the Polysorbate 85, benzyl alcohol and the propylene glycol. Add a pro-
`portion of the water and adjust the pH to 6.0 - 6.5 with phosphate buffer, if necessary. Make up to final volume
`with the water. Fill the product into the drench container.
`
`6
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 006
`
`

`
`EP 0 329 460 B1
`
`V e t e r i n a r y oral p a s t e
`
`Active I n g r e d i e n t
`Saccharin sodium
`P o l y s o r b a t e 85
`Aluminium d i s t e a r a t e
`F r a c t i o n a t e d coconut oil
`
`% w/w
`4.0
`2 . 5
`3 . 0
`5 . 0
`to 1 0 0 . 0
`
`Ranqe
`1 - 20%
`
`Disperse the aluminium distearate in the fractionated coconut oil and polysorbate 85 by heating. Cool to
`room temperature and disperse the saccharin sodium in the oily vehicle. Disperse the active ingredient in the
`base. Fill into plastic syringes.
`
`Granules for v e t e r i n a r y i n - f e e d a d m i n i s t r a t i o n
`% w/w
`2.5 '
`to 1 0 0 . 0
`
`Active I n g r e d i e n t
`Calcicm s u l p h a t e , hemi-hyd r a t e
`
`Ranqe
`0.05-5% w/w
`
`Blend the Active Ingredient with the calcium sulphate. Prepare the granules using a wet granulated process.
`Dry using a tray or fluid-bed drier. Fill into the appropriate container.
`
`Veterinary P o u r - o n
`
`Active I n g r e d i e n t
`Dimethyl sulphoxide
`Methyl Isobutyl ketone
`Propylene glycol (and pigment)
`
`. % w/v
`2.0
`1 0 . 0
`3 0 . 0
`to 1 0 0 . 0
`
`Ranqe
`Ranqe
`0.1
`0.1
`to 30%
`to 30%
`
`Dissolve the active ingredient in the dimethyl sulphoxide and the methyl isobutyl ketone. Add the pigment
`and make up to volume with the propylene glycol. Fill into the pour-on container.
`
`E m u l s i f i a b l e C o n c e n t r a t e
`
`Active i n g r e d i e n t
`50g
`Anionic e m u l s i f i e r
`40g
`( e . g . Phenyl sulphonate CALX)
`Non-ionic e m u l s i f i e r
`60g
`( e . g . Synperonic NP13) *
`Aromatic s o l v e n t (e.g. Solvesso 100)
`
`to 1 l i t r e .
`
`Mix a l l i n g r e d i e n t s , s t i r u n t i l d i s s o l v e d .
`
`* Trademark of ICI
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 007
`
`

`
`EP 0 329 460 B1
`
`G r a n u l e s
`(a) Active i n g r e d i e n t
`50g
`Wood r e s i n
`40g
`Gypsum granules (20-60 mesh)
`(e.g. Agsorb 100A)
`
`to 1kg
`
`(b) Active i n g r e d i e n t
`50g
`Synperonic NP13 *
`40g
`Gypsum g r a n u l e s (20-60 mesh)
`
`to 1 k g .
`
`Dissolve all i n g r e d i e n t s in a v o l a t i l e solvent e.g. m e t h y l e n e
`c h l o r i d e , add to g r a n u l e s tumbling
`in mixer. Dry to remove s o l v e n t .
`
`* Trademark of ICI
`
`Claims
`
`1 . A stabilised composition comprising a compound of formula (I)
`
`(where R1 is a methyl, ethyl or isopropyl group and R2 is a hydrogen atom or a methyl group) or a derivative
`thereof and, as an antioxidant, a C^^ alkyl gallate; benzyl hydroxybenzoate; butylated hydroxyanisole; buty-
`lated hydroxytoluene; a quinone or a salt thereof; nordihydroguaiaretic acid; or a-tocopherol.
`2. A composition according to claim 1 in which in the compound of formula (I) R1 is an isopropyl group and
`R2 is a hydrogen atom.
`3. A composition according to claim 1 inwhich the antioxidant is butylated hydroxytoluene.
`4. A composition according to claim 1 which contains 0.005 to 1% of the antioxidant, by weight of the com-
`pound of formula (I) or derivative thereof.
`5. A composition according to claim 1 in a form suitable for use as a pesticide and containing one or more
`carriers or excipients.
`6. A method of preparing a composition according to claim 1 which comprises admixing the compound of
`formula (I) or derivative thereof with the antioxidant.
`
`8
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 008
`
`

`
`EP 0 329 460 B1
`
`7. A method according to claim 6 in which said compound and antioxidant are co-precipitated from solution.
`8. A method of stabilising a compound of formula (I) as defined in claim 1 or a derivative thereof, which
`comprises contacting said compound with an antioxidant, said antioxidant being a C^2 alkyl gallate; benzyl
`hydroxybenzoate; butylated hydroxyanisole; butylated hydroxytoluene; a quinone or a salt thereof; nordihyd-
`roguaiaretic acid; or a-tocopherol.
`
`Patentanspruche
`
`1. Stabilisierte Zusammensetzung, enthaltend eine Verbindung der Formel (I)
`
`OH
`
`OR2
`
`(worin R1 eine Methyl-, Ethyl- oder Isopropylgruppe bedeutet und R2 fur ein Wasserstoffatom odereine Methyl-
`gruppe steht) oder ein Derivat hiervon und als ein Antioxidans ein C^^-Alkyl ga leat;Benzylhydroxybenzoat;
`butyliertes Hydroxyanisol; butyliertes Hydroxytoluol; ein Chinon oder ein Salz hiervon; Nordihydroguaiaretin-
`saure; oder a-Tocopherol.
`2. Zusammensetzung gemali Anspruch 1, worin in der Verbindung der Formel (I) R1 fur eine Isopropyl-
`gruppe steht und R2 ein Wasserstoffatom ist.
`3. Zusammensetzung gemali Anspruch 1 , worin das Antioxidans butyliertes Hydroxytoluol ist.
`4. Zusammensetzung gemali Anspruch 1, die 0,005 bis 1 % des Antioxidans, bezogen auf das Gewicht
`der Verbindung der Formel (I) oder von dessen Derivat, enthalt.
`5. Zusammensetzung gemali Anspruch 1 in einer fur die Verwendung als Pestizid geeigneten Form, ent-
`haltend einen oder mehrere Trager oder Exzipienten.
`6. Verfahren zur Herstellung einer Zusammensetzung gemali Anspruch 1, das das Mischen einer Verbin-
`dung der Formel (I) oder von dessen Derivat mit dem Antioxidans umfalit.
`7. Verfahren gemali Anspruch 6, worin die Verbindung und das Antioxidans aus einer Losung coprazipitiert
`werden.
`8. Verfahren zur Stabilisierung einer Verbindung der Formel (I) wie in Anspruch 1 definiertodereines Deri-
`vats hiervon, das das Inkontaktbringen der Verbindung mit einem Antioxidans umfalit, wobei das Antioxidans
`ein C^^-Alkylgaleat; Benzylhydroxybenzoat; butyliertes Hydroxyanisol; butyliertes Hydroxytoluol; ein Chinon
`oder ein Salz hiervon; Nordihydroguaiaretinsaure; oder a-Tocopherol ist.
`
`Revendications
`
`1 . Composition stabilisee comprenant un compose de formule (I)
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 009
`
`

`
`EP 0 329 460 B1
`
`OH
`
`9H3
`
`CH3
`
`CH3 II';
`
`H
`
`OR2
`
`(ou R1 est un groupement methyle, ethyle ou isopropyle et R2 est un atome d'hydrogene ou un groupement
`methyle) ou un derive de celui-ci et comme antioxydant un gallate d'alkyle en C^2 ; un hydroxybenzoate de
`benzyle ; un hydroxyanisole butylate ; un hydroxytoluene butylate ; une quinone ou un sel de celle-ci ; I'acide
`nordihydroguaiaretique ; ou I'a-tocopherol.
`2. Composition selon la revendication 1 dans laquelle le compose de formule (I) R1 est un groupement iso-
`propyle et R2 un atome d'hydrogene.
`3. Composition selon la revendication 1 dans laquelle I'antioxydant est de I'hydroxytoluene butylate.
`4. Composition selon la revendication 1 qui contient de 0,005 a 1% d'antioxydant, par rapport au poids du
`compose de formule (I) ou d'un derive de celui-ci.
`5. Composition selon la revendication 1 dans une forme approprie a une utilisation comme pesticide et
`contenant un ou plusieurs vehicules ou excipients.
`6. Methode de preparation d'une composition selon la revendication 1 qui comprend un melange du
`compose de formule (I) ou d'un derive de celui-ci avec I'antioxydant.
`7. Methode selon la revendication 6 dans laquelle led it compose et I'antioxydant sont co-precipites a partir
`d'une solution.
`8. Methode de stabilisation d'un compose de formule (I) tel que defini dans la revendication 1 ou d'un derive
`de celui-ci qui comprend la mise en contact dud it compose avec un antioxydant, ledit antioxydant etant un gal-
`late d'alkyle en C^2 ; un hydroxybenzoate de benzyle ; un hydroxyanisole butylate ; un hydroxytoluene buty-
`late ; une quinone ou un sel de celle-ci ; I'acide nordihydroguaiaretique ; ou I'a-tocopherol.
`
`10
`
`Par Pharm., Inc.
`Exhibit 1006
`Page 010