WO01/32142
`
`PCT/GB00/04143
`
`-4-
`
`cyclosporins, e.g. cyclosporin A. dihydrocyclosporin C, cyclosporin D and
`dihydrocyclosporin D.It is also useful with other water-insoluble substances such
`as, for example, water-insoluble peptides, or water-insoluble antimicrobialor
`antineoplastic substances. Examples include desmopresin, calcitonin, insulin,
`lenprolide, erythropoetin, a cephalosporin, vincristine, vinblastine, taxol, etoposide
`or mixtures thereof.
`In the compositions of the invention, component(a) is in solution in
`component (b). Component(b) can be a propylene glycol ester of a fatty acid or a
`mixture of any two or more such esters. The fatty acids may optionally be derived
`from a vegetable oil and are preferably Cg - C29 residues. Particular preferred
`compoundsare propylene glycol monocaprylate (Caprgol 90) and propylene
`glycol monolaurate (Lauroglycol 90). Weprefer to formulate the composition
`such that the weight ratio of component(a) to component(b) is from about 1:1 to
`about 1:10 but ratios outside this range can be usedif desired.
`These compounds, whichincrease the bioavailability of the active
`material can be used alone or in combination with one or more ofthe glycerides
`described in EP 0760237. For example, oleoyl macrogol-6 glycerides (Labrafil M
`1944 CS), linoleoyl macrogol-6 glycerides (Labrafil M 2125 CS), and
`caprylocaproyl macrogol-8 glycerides (Labrasol) are particularly preferred
`compoundsfor use with the oils employedin the present invention.
`Component(c) is a surfactant to provide the preconcentrate mixture
`and, where employed,the fully formed microemulsion with stability. Those
`skilled in the art will be aware of many surfactants which can be used, but we
`prefer to use polyoxyl 40 hydrogenatedcastoroil, polyoxyethylene-sorbitan
`monooleate, polyoxyethylene-sorbitan monopalmitate, polyoxyethylene-sorbitan
`monolaurate or polyoxyethylene sorbitan monostearate.
`If desired, the surfactant
`can be mixed with a phospholipid, such as lecithin. Weprefer to use a weight ratio
`of component(a) to surfactant of about 1:1 to about 1:50, but ratios outside this
`range can also be employedif desired. When a phospholipid is included in the
`
`TEVA - EXHIBIT 1004 (PART 4 OF 5)
`
`0604
`
`0604
`
`TEVA - EXHIBIT 1004 (PART 4 OF 5)
`
`

`

`WO 01/32142
`
`PCT/GB00/04143
`
`-5-
`
`composition, we prefer to use a weight ratio of component(a) to phospholipid of
`about 1:05 to about 1:5.0, but, again, other ratios can be used.
`
`In the case where the composition of the invention is provided as a
`
`microemulsion, component(d) is a hydrophilic phase. The preferred materialis
`propylene glycol or diethylene glycol monoethy]ether (transcutol) but other
`substances can be used. Ethanol cannot be present. Water can of course also be
`presentbutit is not preferred. Despite the use of propylene glycol, component(a)
`remains wholly dissolved in the oil phase (component(b)).
`Microemulsionsare transparent due to the very small particle size of
`the dispersed phase,typically less than 200 nm. Such small droplets produce only
`weak scattering of visible light when compared with that from the coarse droplets
`(1 -10 nm) of normal emulsions. An essential difference between microemulsions
`and emulsionsis that microemulsions ferm spontaneously and, unlike emulsions.
`
`required little mechanical work in their formulation. General reviews on
`microemulsions are provided by Attwood D. et al J. Colloid Interface Sci 46:249
`
`and Kahlweit M. et al J. Colloid Interface Sci 118:436.
`
`The microemulsions can be formed bydiluting with aqueousliquid
`(e.g. water, fruit juice, milk etc.) to form an oil-in-water microemulsion,e.g. for
`oral administration. This aids in ready absorption as the surface area of the fat
`globulesis largely increased. Therole played bybile salts in theinitial step of
`fragmentation of fat globules, essential for fat digestion, is circumvented.
`The rate determining factor for the absorption of drugin the vehicle
`is not the enzymatic metabolism oftriglycerides but rests primarily in the
`breakdownofthe fat globules into micro particles since the enzymes(lipases) act
`mainly at the surface ofthe fat globules.
`In the microemulsions of the invention, the amounts of the
`
`components, in percent by weight, are as follows:
`
`0605
`
`0605
`
`

`

`WO 01/32142
`
`PCT/GB00/04143
`
`Component
`Active pharmaceutical
`
`Oil phase
`
`Surfactant
`
`General
`1-12%
`
`20-80%
`
`20-40%
`
`-6-
`
`Usual
`2.5-10%
`
`30-60%
`
`25-60%
`
`Preferred
`7-10%
`
`25-40%
`
`40-50%
`
`25-30%
`20-50%
`10-60%
`Hydrophilic phase
`In the microemulsions, the weight percent of hydrophilic phase is
`generally up to about 75%, most usually from 15 to 50%, and preferably from 35
`
`to 50%.
`
`In the case where the composition of the present inventionis
`provided as a blend of preconcentrate and solid carrier, component(e) is employed
`instead of component(d). Preferred solid carriers include colloidal silicon dioxide
`and polyvinyl pyrrolidone (cross Povidone)but other suitable inert solid
`substancescan also be used, as will be clear to those skilled in the art. Typically,
`
`the solid carrier will be in the form of a dry powder. Generally, the preconcentrate
`mixture (comprising active material, oil and surfactant) is simply blended with the
`solid material such that the oily preconcentrate is absorbed by the material.
`Preferably, the blended mixture is provided in the form of a free-flowing powder.
`Such a powder can then be easily coated, for example, into a hard gelatin capsule
`or, alternatively, compressedinto tablets, for instance. The technique of absorbing
`an oily phase (in this case an oily preconcentrate) on to a solid phase such as
`colloidal silicon dioxide followed by formulation into a final dosage form is a
`technique well knownbythoseskilled in the art of formulation,so further details
`
`are considered unnecessary.
`Both the microemulsion and solid compositions can consist only of
`the components described, or they can contain other substances. For example, in
`order to prevent oxidation/ rancidification of the natural oils, an antioxidant, e.g. 0-
`to copherol can be used. Propyl gallate may be used as an alternative.
`In order that the invention may be more fully understood, the
`
`following examplesare given by wayofillustration only.
`
`0606
`
`0606
`
`

`

`WO01/32142
`
`PCT/GB00/04143
`
`-7-
`
`Examples 1-3
`
`Examples of compositions comprising a blend of preconcentrate and
`
`solid carrier are:
`
`Example 1
`
`Imusporin-25
`
`Component
`
`Cyclosporin USP
`
`mg/capsule
`
`25
`
`Glyceryl! Monolinoleate (Maisine 33-1)
`
`17.25
`
`Propylene glycol monocaprylate
`
`(Capryol 90)
`
`Polyoxyl 35 Castor Oil NF (Cremophor
`
`EL)
`
`Colloidal silicon dioxide
`
`Crospovidone USP (PVP CL-M)
`
`Net Fill Wt/cap (mg)
`
`17.25
`
`50.00
`
`52.50
`
`13.00
`
`175.00
`
`Example 2
`
`Imusporin-50
`
`Component
`
`Cyclosporin USP
`
`Glyceryl Monolinoleate (Maisine 33-1)
`
`Propylene glycol monocaprylate
`
`(Capryol 90)
`
`Polyoxyl 35 Castor Oil NF (Cremophor
`
`EL)
`
`Colloidal silicon dioxide
`
`Crospovidone USP (PVP CL-M)
`
`Net Fill Wt/cap (mg)
`
`mg/capsule
`
`50.00
`
`34.50
`
`34.50
`
`100.00
`
`105.00
`
`26.00
`
`350.00
`
`0607
`
`0607
`
`

`

`WO 01/32142
`
`PCT/GBO00/04143
`
`-8-
`
`Example 3
`
`Imusporin- 100
`Component
`Cyclosporin USP
`Glyceryl Monolinoleate (Maisine 33-1)
`
`mg/capsule
`100.00
`69.00
`
`Propylene glycol monocaprylate
`(Capryol 90)
`
`Polyoxyl 35 Castor Oil NF (Cremophor
`EL)
`
`Colloidal silicon dioxide
`
`Crospovidone USP (PVP CL-M)
`Net Fill Wt/cap (mg)
`
`69.00
`
`200.00
`
`210.00
`
`$2.00
`700.00
`
`1
`
`2
`
`4
`5
`
`6
`
`7
`
`8
`
`The blended preparations were madeas follows:
`Mix Maisine 35-1, Capryol 90 and Cremophor ELin a clean jacketed
`
`vessel.
`Add Cyclosporin to the above vessel understirring, continue stirring for
`about 70-75 mins. If required, heat the blend to not more than 50°C till the
`
`drug dissolves completely.
`Cool the above blend to room temperature andstrain through 150#.
`Sift Aerosil and Crospovidone through 20# and 40# respectively. Mix ina
`
`suitable mixer.
`
`Adsorb the above blend (step 4) over the mixture of Aerosil and
`
`Crospovidone.
`Pass the powderblend of Cyclosporin through 20#.
`Fill this blend in hard gelatin capsules or compressed withtablets.
`The blends were then either
`fill
`into hard gelatin capsules or
`
`compressedinto tablets.
`
`0608
`
`0608
`
`

`

`WO 01/32142
`
`PCT/GB00/04143
`
`-9-
`
`Examples 4 - 8
`
`Microemulsions of the invention were made of the compositions
`
`indicated, by dissolving the cyclosporin A in the oils and then formingtheoil-in-
`
`water emulsions. The procedure was:
`(a)
`dissolve the cyclosporin A in the mixture of oils with slight warming
`and understirring to obtain a clear yellow liquid. Confirm the
`
`complete dissolution of the drug by microscopy.
`
`(b)
`
`(c)
`(d)
`
`addthe surfactant withstirring.
`
`add the hydrophilic phase with stirring
`addthe alpho tocopherol and mix thoroughly.
`
`Preparation of microemulsion for administration in Soft Gelatin
`
`Example 4
`
`capsules:
`Component
`Capryol 90
`Castoroil
`
`Polyoxyl-40 hydrogenated
`
`Castoroil
`
`a-tocopherol
`Propylene glycol
`Cyclosporin A
`
`Example 5
`
`mg/capsule
`130
`130
`
`400
`
`-
`
`10
`200
`100
`
`Component
`Capryol 90
`Maisine
`
`Preparation of microemulsion for administration asoralsolution:
`mg/capsule
`150
`125
`
`0609
`
`0609
`
`

`

`WO 01/32142
`
`PCT/GB00/04143
`
`-10-
`
`425
`
`225
`
`100
`
`Polysorbate-80
`(Tween 80)
`
`a-tocopherol
`
`Transcutol
`
`Cyclosporin A
`
`Example 6
`
`Preparation of microemulsion for administration as oral solution
`
`Component
`
`Capryol 90
`
`Polyoxyl-40 hydrogenated castoroil
`
`a-tocopherol
`
`Propylene glycol
`
`Cyclosporin A
`
`Example 7
`
`mg/capsule
`
`275
`
`425
`
`10
`
`225
`
`100
`
`Preparation of microemulsion for administration as oral solution:
`
`% 1
`
`30
`
`130
`
`400
`
`10
`
`200
`
`100
`
`Component
`
`Capryol 90
`
`Lauroglycol 90
`
`Polysorbate 80 (Tween 80)
`
`a-tocopherol
`
`Propylene glycol
`
`Cyclosporin A
`
`Example 8
`
`Preparation of microemulsion for administration as oral solution:
`
`0610
`
`0610
`
`

`

`WO 01/32142
`
`PCT/GB00/04143
`
`Component
`
`Capryol 90
`
`Maisine
`
`Polyoxyl-40 hydrogenated castoroil
`
`a-tocopherol
`
`Transcutol
`
`Cyclosporin A
`
`-11-
`
`mg/capsule
`
`14
`
`15
`
`45
`
`1
`
`25
`
`10
`
`Theoral solution whichis filled into bottles can be administered
`
`using a syringe or more preferably with the aid of a metered dose pump with a
`
`dropper actuator.
`The compositions described in Examples 4 to 8 were subjected to
`stability examinations under accelerated conditions of temperature and humidity.
`The solutions were stored at RT (25°C + 2°C). Ref 40°C-80% RH and 45°C,after
`
`filling into flint glass vials.
`Simultaneously with the examination of solutions prepared according
`to the process of the invention,the stability of the commercially available Neoral
`capsules containing 100mg cyclosporin A per capsule was also examined.
`It was
`observed from the above examination that the stability of solutions prepared
`
`according to the process of invention did not differ from the stability of the
`
`commercially available composition.
`
`0611
`
`0611
`
`

`

`WO01/32142
`
`PCT/GB00/04143
`
`-12-
`
`CLAIMS:
`
`A pharmaceutical composition in the form of a preconcentrate mixed
`1.
`either with a liquid hydrophilic phase to form a stable oil-in-water microemulsion
`or with a solid carrier to form a stable, solid blend of carrier and preconcentrate,
`
`which composition is substantially free from ethanol and comprises:
`a)
`a water-insoluble pharmaceutically active material,
`b)
`one or more propylene glycolesters of a fatty acid;
`
`c)
`d)
`
`surfactant; and either
`a hydrophilic phase, wherein component(a) has been wholly directly
`dissolved in component(b) and component(b) is dispersed astiny
`
`particles in component(d); or
`
`e)
`
`a solid carrier.
`
`A composition accordingto claim 1, which compositionis a
`2.
`microemulsion comprising components(a), (b), (c) and (d).
`
`A composition according to claim 1, which compositionis a blend of
`3.
`said preconcentrate and said solid carrier comprising components(a), (b), (c) and
`
`(e).
`
`A composition according to claim 1, 2 or 3, wherein component(a)
`4.
`is a cyclosporin, or another water-insoluble peptide, or a water-insoluble
`antimicrobial or antineoplastic substance or mixtures thereof.
`
`A composition according to claim 4, wherein component(a)is
`5.
`cyclosporin A, dihydrocyclosporin C, cyclosporin D or dihydrocyclosporin D,or
`desmopresin,calcitonin, insulin, leuprolide, erythropoetin, a cephalosporin,
`vincristine, vinblastine, taxol or etoposide or mixtures thereof.
`
`0612
`
`0612
`
`

`

`WO 01/32142
`
`PCT/GBO00/04143
`
`-13-
`
`6.
`
`A composition according to any preceding claim, wherein
`
`component(b) is a propylene glycol ester of C2 to Cy. fatty acids.
`
`7.
`
`A composition according to any preceding claim, wherein said
`
`surfactant is polyoxyl 40 hydrogenated castor oil, polyoxyethylene-sorbitan
`
`monooleate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene-sorbitan
`
`monolaurate or polyoxyethylene-sorbitan monostearate or mixturesthereof.
`
`8.
`
`A composition according to any preceding claim, wherein
`
`component(c) further comprises a phospholipid.
`
`9.
`
`A composition according to any preceding claim, wherein the weight
`
`ratio of component(a) to component (b) is from 1:1 to 1:10.
`
`10.
`
`A composition according to claim 8 or 9, wherein the weight ratio of
`
`component(a) to said phospholipid is from 1:0.5 to 1:5.0.
`
`11.
`
`A composition according to any preceding claim, wherein the weight
`
`ratio of component(a) to said surfactant is from 1:1 to 1:5.0.
`
`12.
`A composition according to any of claims 1-9 and containing
`component(e), wherein component(e)is colloidal silicon dioxide, polyvinyl
`
`pyrrolidone or a mixturethereof.
`
`13.
`
`A soft gelatin capsule or oral administration fluid which comprises a
`
`composition as claimed in any of claims | to 11
`
`0613
`
`0613
`
`

`

`WoO01/32142
`
`PCT/GB00/04143
`
`-14-
`
`A tablet or hard gelatin capsule which comprises a composition as
`14,
`claimed in any of claims 1 to 12 whenin said solid form.
`
`15.
`
`A process for making a composition according to claim 1, which
`
`comprises dissolving component(a) in component(b) optionally with component
`
`(c), and then mixing the resulting solution either with component(d) or with
`
`component (e) and component(c) if not includedearlier.
`
`16.
`
`A process according to claim 150, wherein a preconcentrate
`
`composition is mixed with component(d).
`
`17.
`
`A processaccording to claim 15, wherein a preconcentrate
`
`composition is mixed with component(e).
`
`18.
`
`A method of making a pharmaceutical composition according to any
`
`of claims 1 to 11, which method comprisesfirst forming a preconcentrate by
`
`directly dissolving component(a) in component(b), the preconcentrate also
`containing component(c) but being free from hydrophilic phase, and then mixing
`
`the preconcentrate with the hydrophilic phase, to form said stable oil-in-water
`
`microemulsion, the composition being free from ethanol.
`
`19.
`
`A method of making a pharmaceutical composition according to any
`
`of claims 1-12, which method comprisesfirst forming a preconcentrate by directly
`
`dissolving component(a) in component(b), the preconcentrate also containing
`component(c), and then mixing the preconcentrate with the solid carrier, to form a
`solid, stable composition if preconcentrated and carrier, the composition being free
`
`from ethanol.
`
`0614
`
`0614
`
`

`

`
`PCT/GB 00/04143
` A. CLASSIFICATION OF SUBJECT MATTER
`
`IPC 7
`A61K9/107
`A61K9/14
`A61K9/48
`
`
` According to International Patent Classification (IPC) orto both nationat classification and IPC
`
`
`
`Minimum documentation searched (classification system followed by classification symbols)
`
`IPC 7
`A61K
`
`
`
`
`Documentation searched other than minimum documentation to the extent that such documents are included in thefields searched
`
`
`
`Electronic data base consulted during the international search (name of data base and. where practical, search terms used)
`
`
`
`EPO-Internal, WPI Data, PAJ, BIOSIS, CHEM ABS Data
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`EP 0 760 237 A (CIPLA LIMITED)
`5 March 1997 (1997-03-05)
`cited in the application
`page 2,
`line 3 -page 2,
`page 2,
`line 34 -page 2,
`examples 5-9
`
`line 4
`line 46
`
`INTERNATIONALSEARCH REPORT
`
`Interr
`
`jal Application No
`
`B. FIELDS SEARCHED
`
`C. DOCUMENTS CONSIDEREDTO BE RELEVANT
`
`Category °|Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.
`
`
`
`
`WO 99 44584 A (NOVARTIS ERFIND VERWALT
`
`GMBH ;HAEBERLIN BARBARA (CH); NOVARTIS AG)
`
`
`10 September 1999 (1999-09-10)
`
`
`page 1,
`line 9 -page 1,
`line 30
`
`
`page 3,
`line 27 “page”4,
`line 3
`
`
`ET AL)
` US 5 543 393 A (KIM JUNG W
`
`6 August 1996 (1996-08-06)
`
`example 8
`
`Patent family members arelisted in annex. ° Special categories of cited documents:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Date of the actual completion of the international search
`
`
`05/02/2001
`26 January 2001
`
`Authorized officer
`Nameandmailing address of the ISA
`European Patent Office, P.B. 5818 Patentiaan 2
`
`NL - 2280 HV Rijswijk
`
`
`
`Tel. (431-70) 340-2040, Tx. 31 651 epo ni,
` Borst, M
`
`Fax: (431-70) 340-3016
`
`Form PCT/SA/210 (second sheet) (July 1992)
`
`
`
`-/--
`
`Further documentsare listed in the continuation of box C.
`
`"A" documentdefining the general state of the art whichis not
`considered to be of particular relevance
`*E" earlier document but published on or after the international
`filing date
`*L* document which may throw doubts onpriority claim(s) or
`whichis cited to establish the publication date of another
`citation or other special reason (as specified)
`"O° documentreferring to an oral disclosure, use, exhibition or
`other means
`*P* document published prior to the international filing date but
`later than the priority date claimed
`
`"T’
`
`later documentpublishedafter the internationalfiling date
`orpriority date and not in conflict with the application but
`cited to understandthe principle or theory underlying the
`invention
`*x* documentof particular relevance:the claimed invention
`cannot be considered novelor cannot be considered to
`involve an inventive step when the documentis taken alone
`*Y* documentof
`i
`.
`i
`i
`5
`particular relevance; the claimed invention
`cannot be consideredto involve an inventive step when the
`document is combined with one or more other such docu-
`ments, such combination being obvious to a person skilled
`in the art.
`*&* document memberof the same patent family
`Date of mailing of the international search report
`
`page 1 of 2
`
`0615
`
`0615
`
`

`

`
`
`INTERNATIONAL SEARCH REPORT
`Information on patent family members
`
`intern
`
`jal Application No
`
`PCT/GB 00/04143
`
`Patent document
`cited in search report
`
`EP 0760237
`
`WO 9944584
`
`A
`
`A
`
`Publication
`date
`
`05-03-1997
`
`10-09-1999
`
`US 5543393
`
`A
`
`06-08-1996
`
`WO 9840051
`
`GB 2222770
`
`A
`
`A
`
`17-09-1998
`
`21-03-1990
`
`Patent family
`member(s)
`
`706995 B
`6216296 A
`5929030 A
`
`2836199 A
`1012400 A
`9908597 A
`1059913 A
`2775596 A
`2350791 A
`20004299 A
`
`7709194 A
`2161343 A
`1121694 A
`0702562 A
`955042 A
`9501701 T
`9522982 A
`146671 B
`954245 A
`
`Publication
`date
`
`01-07-1999
`06-03-1997
`27-07-1999
`
`20-09-1999
`03-10-2000
`14-11-2000
`20-12-2000
`10-09-1999
`13-12-2000
`29-08-2000
`
`11-09-1995
`31-08-1995
`01-05-1996
`27-03-1996
`29-11-1995
`18-02-1997
`31-08-1995
`17-08-1998
`22-12-1995
`
`0973502 A
`
`26-01-2000
`
`403435 B
`214289 A
`627220 B
`4140089 A
`1003105 A
`60525 B
`1332150 A
`679118 A
`1711 A
`3930928 A
`171433 B
`2020738 A
`894342 A,B,
`2636534 A
`89100583 A,B
`86593 A
`9500318 A
`60764 B
`91642 A
`1232243 B
`1996397 C
`2121929 A
`7025690 B
`148748 B
`235524 B
`256007 B
`87586 A
`5749 A
`8902315 A
`180362 B
`230660 A
`91731 A,B
`8903042 A
`50793 G
`
`25-02-1998
`15-07-1997
`20-08-1992
`22-03-1990
`26-11-1991
`28-07-1995
`27-09-1994
`31-12-1991
`06-05-1994
`22-03-1990
`28-10-1996
`16-09-1991
`17-03-1990
`23-03-1990
`31-10-1990
`27-08-1993
`30-10-1995
`10-08-1994
`12-04-1994
`28-01-1992
`08-12-1995
`09-05-1990
`22-03-1995
`17-08-1998
`15-12-1999
`01-05-2000
`07-05-1991
`20-12-1996
`17-04-1990
`30-12-1996
`25-06-1992
`30-03-1990
`11-05-1990
`25-06-1993
`
`AU
`AU
`US
`
`AU
`BE
`BR
`EP
`FR
`GB
`NO
`
`AU
`CA
`CN
`EP
`FI
`JP
`WO
`KR
`NO
`
`EP
`
`AT
`AT
`AU
`AU
`BE
`BG
`CA
`CH
`CY
`DE
`DK
`ES
`FI
`FR
`GR
`HK
`HU
`IE
`IL
`IT
`JP
`uP
`JP
`KR
`KR
`KR
`LU
`LV
`NL
`NO
`NZ
`PT
`SE
`SG
`
`Form PCT/ISA/210 (patent family annex) (July 1992)
`
`page 1 of 2
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`

` INTERNATIONAL SEARCH REPORT
`Interr
`aal Application No
`
`PCT/GB 00/04143
`
`
`
`WO 98 40051 A (ABBOTToeeet.——
`Category °*|Citation of document.with indication,where|Cratonofdocumentwinndcatonwmereapprpaieotmerevanipassaies|ofthe relevant passages Relevant toclaim No.
`
`
`
`
`
`17 September 1998 (1998-09-17)
`
`
`
`examples 21,23,24
`
`line 5 -page 6,
`line 8
`page 6,
`
`
`page 6,
`line 34 “page”7,
`line 2
`
`
`GB 2 222 770 A (SANDOZLTD)
`
`
`21 March 1990 (1990-03-21)
`
`examples 1.5.-1.10.
`
`
`
`Form PCT/SA/210 (continuation of second sheet) (July 1992)
`
`page 2 of 2
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`0617
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`

`INTERNATIONAL SEARCH REPORT
`Information on patent family members
`
`Interr
`
`Nal Application No
`
`PCT/GB 00/04143
`
`Patent document
`cited in search report
`
`Publication
`date
`
`GB 2222770
`
`A
`
`Patent family
`member(s)
`
`5962017
`6024978
`6007840
`5741512
`5866159
`5916589
`5962014
`5342625
`
`8907066rPPrPrPprrrpr>p
`
`Publication
`date
`
`05-10-1999
`15-02-2000
`28-12-1999
`21-04-1998
`02-02-1999
`29-06-1999
`05-10-1999
`30-08-1994
`29-05-1991
`
`
`
`Form PCT/SA/210 (patent family annex) (July 1992)
`
`page 2 of 2
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`

`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`14 June 2001 (14.06.2001)
`
`
`
`PCT
`
`UY EMEAATEA
`
`(10) International Publication Number
`WO 01/41671 A2
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ,
`(21) International Application Number:©PCT/US00/33236
`DE, DK, DM,DZ, EE, ES, FI, GB, GD, GE, GH, GM,HR,
`HU,ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR,
`LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ,
`NO, NZ, PL, PT, RO, RU, SD, SE, SG, SL, SK, SL, TJ, T™,
`TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW.
`
`(51) International Patent Classification’:
`
`AGOIF
`
`(22) International Filing Date: 7 December 2000 (07.12.2000)
`
`(25) Filing Language:
`
`English
`
`(26) Publication Language:
`
`English
`
`(30) Priority Data:
`MI99A002641
`
`7 December 1999 (07.12.1999)
`
`IT
`
`except US):
`(for all designated States
`(71) Applicant
`TRANSNEURONIKX, INC. [US/US]; 100 Stierli Court,
`Suite 106, Mt. Arlington, NJ 07856 (US).
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): CIGAINA, Balerio
`{ITAT]; Via 4 Novembre, 3/a, I-31050 Villorba (IT).
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,IE,
`IT, LU, MC, NL, PT, SE, TR), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`Without international search report and to be republished
`upon receipt of that report.
`
`(74) Agents: SAMPLES, Kenneth, H. et al.; Fitch, Even,
`Tabin & Flannery, Suite 1600, 120 South LaSalle Street,
`Chicago, TL 60603 (US).
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes and Abbreviations" appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`AANA
`
`671A2
`O01/41
`
`(54) Title: REMOVABLE GASTRIC BAND
`
`(37) Abstract: A removable gastric band is provided which can be used to control obesity by allowing control and/or modification
`of the diameter of a patient’s stomach. More specifically, the present removable gastric band comprises an elongated body having
`a first or distal zone, a second or middle zone, a third or proximal zone and a closure mechanism, wherein the closure mechanism
`~~ allows the elongated body to close around a portion of the stomach, preferably the proximal tract of the stomach, wherein the closure
`mechanism comprises at least one aperture in the first zone and a button in the second zone, and wherethe button can be inserted into
`the aperture to close the elongated body around,andholdit to, the portion of the stomach. The removable gastric band can beeasily
`paired with the use of a gastric electrostimulator and may be useful, therefore, for inducing forced slimming in the initial phase of
`treatment for morbigenous obesity. Such electrostimulation devices may either be incorporated into the removable gastric band or
`located at a distance from the removable gastric band.
`
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`

`WO 01/41671
`
`PCT/US00/33236
`
`REMOVABLE GASTRIC BAND
`
`Related Application
`This application claims priority from Italian Patent Application Number
`Mi99A002641, filed December 7,1999.
`
`Field of the Invention
`
`The present invention relates to a removable gastric band which can
`be used to control obesity by allowing contro! and/or modification of the
`diameter of a patient’s stomach.
`
`10
`
`15
`
`20
`
`25
`
`Backgroundof the invention
`Laparoscopic banding systemsare available which provide for the use
`of an elongated main part that is placed around the stomach and closed over
`the stomachso as to reduce the diameter of the stomach to be able to treat
`
`the patient's obesity. Such currently available bands, however, present some
`drawbacksessentially due to the difficulty of application and/or removal of the
`gastric band.
`In fact, normally, the current bands’ meansof closing the
`elongated main part are almost always hard to manipulate; moreover, their
`connection entails the use of additional instruments and/or devicesthat
`further complicate the application and/or later removal of the gastric band for
`the surgeon.
`
`Furthermore, to be able to remove the known bands, which must
`necessarily be done after a more orless long time interval, it is necessary to
`execute an additional surgical intervention and, consequently, to administer
`more anesthesia to the patient. The application and/or removal of the known
`bands also require the application of suture stitches, in addition to another
`intervention and more anesthesia.
`In particular, the bands used today are
`also hard to remove becausethey presentlittle resistance to tissue adhesions
`and lack sufficient mechanical integrity to withstand tensile forces, both of
`whichhindertheir removal unless the patient is undergoing surgery.
`
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`WO 01/41671
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`PCT/US00/33236
`
`It is desirable, therefore, to provide an improved gastric band whichis
`both easier to implant within the patient and, when necessary, to remove from
`the patient.
`
`Summary of the Invention
`The present invention provides a removable gastric band which can be
`used to control obesity by allowing control and/or modification of the diameter
`of a patient’s stomach. More specifically, the present invention provides a
`removable gastric band comprising an elongated body havinga first or distal
`zone, a second or middle zone, a third or proximal zone and a closure
`mechanism, wherein the closure mechanism allows the elongated body to
`close around a portion of the stomach, preferably the proximal tract of the
`stomach, wherein the closure mechanism comprises a button in the first zone
`and at least one aperture in the second zone, such that the button can be
`inserted into the aperture to close the elongated body around, and hold it to,
`the portion of the stomach.
`
`The present invention provides a removable gastric band comprising
`an elongated body having a first zone, a second zone, a third zone, and a
`closure mechanism, wherein the closure mechanism allows a portion of the
`elongated body to close around a section of the stomach, wherein the closure
`mechanism comprisesa button in the first zone and at least one aperturein
`the second zone, such that the button can be inserted into the aperture to
`close the portion of the elongated body around, and hold it to, the section of
`the stomach, and wherein the portion of the elongated bodyis essentially
`planar in cross section.
`
`The present invention also provides a methodfor treatment of obesity
`or for reducing weight in a patient, said method comprising:
`(1) positioning a removable gastric band around a section of the
`
`patient's stomach;
`
`10
`
`15
`
`20
`
`25
`
`(2) locking the removable gastric band around the section of the
`
`30
`
`patient’s stomach; and
`
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`WO 01/41671
`
`PCT/US00/33236
`
`(3) adjusting the removable gastric band to control the stomach’s
`
`diameter in the section of the patient’s stomach,
`
`wherein the removable gastric band comprises an elongated body
`
`having a first zone, a second zone, a third zone, and a closure mechanism,
`
`wherein the closure mechanism allows a portion of the elongated body to
`
`close around the section of the patient’s stomach, wherein the closure
`
`mechanism comprises a buttonin the first zone and at least one aperture in
`
`the second zone, suchthat the button can be inserted into the aperture to
`
`close the portion of the elongated body around, and holdit to, the section of
`
`10
`
`the stomach, and wherein the portion of the elongated body is essentially
`
`planar in cross section.
`The task proposedbythe presentinventionis the realization of a
`
`removable gastric band that eliminates the above-noted drawbacksof the
`
`knowngastric bands. Within the scopeof this task, one important purpose of
`
`15
`
`the invention is to realize a removable gastric band that can be removed
`
`without having to subject the patient to further intervention and, consequently,
`
`to additional general anesthesia.
`
`Yet another purposeof the invention is to realize a removable gastric
`
`band that is easy to remove becauseit is highly resistant to adhesion to the
`
`20
`
`tissue and has sufficient mechanical integrity to withstand tensile forces
`
`during removal. Yet another purposeof the invention is to realize a
`
`removable gastric band that can be applied without necessarily having to use
`
`suture stitches.
`
`Yet another purposeof the invention is to realize a removable gastric
`
`25
`
`band that can be applied and/or removed by the surgeon very simply and
`
`without having to use additional instruments or devices for that purpose.
`
`Another purposeof the invention is to realize a removable gastric bandthatis
`
`extremely easy to manipulate, so that it can be easily placed in and/or
`
`removed from the patient.
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`WO 01/41671
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`PCT/US00/33236
`
`Brief Description of the Drawings
`
`Figure 1 illustrates the gastric band according to the invention.
`Figure 2 shows schematically the gastric band according to the
`invention being applied to the proximal tract of a patient's stomach;
`
`Figure 3 showsthe gastric band according to the invention applied to
`
`the proximal tract of the patient’s stomach;
`
`Figure 4 showsthe gastric band according to the invention inflated so
`
`as to compressa portion of the patient’s stomach;
`
`Figure 5A showsin cross-sectional view (along line A-A in Figure 1) the
`inner surface of the gastric band compressing the patient’s stomach before
`
`the gastric band has been inflated;
`
`Figure 5B showsin cross-sectional view (along line A-A in Figure 1) the
`inner surface of the gastric bandin relation to the patient’s stomach after the
`
`gastric band has been inflated:
`
`Figure 5C showsin cross-section sectional view a reinforcing member
`or element located within the elongated perimeter (i.e., the rib connecting the
`inner and outer surfaces, thereby forming an inflatable chamber or cavity) of
`the gastric band which reduces the tendencyof the gastric band to twist
`
`around its longitudinal axis;
`
`10
`
`15
`
`20
`
`Figure 6A is a view of the gastric band attached to the patient's
`
`stomach with the inflation mechanism positioned to allow for inflation; and
`
`Figure 6B is an expandedview ofthe inflation mechanism.
`
`Detailed Description of the Invention
`
`With reference to the figures described above, the removable gastric
`band according to the invention, indicated as a whole with reference number
`
`25
`
`1, comprises an elongated body 3 havinga first or distal zone 30, a second or
`
`middle zone 32, a third or proximal zone 34, and a closure mechanism 2 for
`
`closing the elongated body 3 back uponitself so as to surround a portion,
`
`preferably the proximal tract, of the patient's stomach 4. The closure
`
`30
`
`mechanism 2 preferably comprises a button 6 in the first zone 30 and a
`
`corresponding aperture 5 in the second zone 32 wherebythe button 6 can fit
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`WO 01/41671
`
`PCT/US00/33236
`
`through the aperture 5 andfix or lock the elongated body 3 back ontotoitself.
`
`Oncelockedinto place, the gastric band 1 completely encircles and
`
`compressesa portion of the patient’s stomach (see, e.g., Figures 3 and 4).
`
`Although only one aperture 5 is shown within the second zone 32, a plurality
`
`of such apertures can be provided if desired; using such a plurality of
`
`apertures allows the surgeon to more closely adjust the diameter of the
`
`encircling portion of the gastric band to the particular patient’s situation and
`
`needs.
`
`Appropriately, button 6 is suitably shaped and sized to allow it to be
`
`10
`
`internally introduced into aperture 5, as well as to close, in an extremely
`
`simple but secure manner, the elongated main part 3 around stomach 4 and
`keepit i