W0 01/32142
`
`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 antimicrobial or
`
`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 C3 - C20 residues. Particular preferred
`
`compounds are propylene glycol monocaprylate (Caprgol 90) and propylene
`
`glycol monolaurate (Lauroglycol 90). We prefer 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 used if desired.
`
`These compounds, which increase the bioavailability of the active
`
`material can be used alone or in combination with one or more of the 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 macrogo1—8 glycerides (Labrasol) are particularly preferred
`
`compounds for use with the oils employed in 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 hydrogenated castor oil, 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. We prefer 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 employed if desired. When a phospholipid is included in the
`
`TEVA - EXHIBIT 1004 (PART 4 OF 5)
`
`0604
`
`0604
`
`TEVA - EXHIBIT 1004 (PART 4 OF 5)
`
`

`
`W0 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 l: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 material is
`
`propylene glycol or diethylene glycol monoethyl ether (transcutol) but other
`
`substances can be used. Ethanol cannot be present. Water can of course also be
`
`present but it is not preferred. Despite the use of propylene glycol, component (a)
`
`remains wholly dissolved in the oil phase (component (b)).
`
`Microemulsions are 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 emulsions is that microemulsions form 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 1l8:436.
`
`The microemulsions can be formed by diluting with aqueous liquid
`
`(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
`
`globules is largely increased. The role played by bile salts in the initial step of
`
`fragmentation of fat globules, essential for fat digestion, is circumvented.
`
`The rate determining factor for the absorption of drug in the vehicle
`
`is not the enzymatic metabolism of triglycerides but rests primarily in the
`
`breakdown of the fat globules into micro particles since the enzymes (lipases) act
`
`mainly at the surface of the 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
`
`General
`
`Active pharmaceutical
`
`l- 12%
`
`Oil phase
`
`Surfactant
`
`20-80%
`
`20-40°/o
`
`Hydrophilic phase
`
`10-60%
`
`-6-
`
`Usual
`
`2.5- 1 0%
`
`30-60%
`
`25-60%
`
`20-50%
`
`Preferred
`
`7 -1 0%
`
`25-40%
`
`40-50%
`
`25-3 0%
`
`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 invention is
`
`provided as a blend of preconcentrate and solid carrier, component (e) is employed
`
`instead of component (cl). Preferred solid carriers include colloidal silicon dioxide
`
`and polyvinyl pyrrolidone (cross Povidone) but other suitable inert solid
`
`substances can 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, compressed into 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 known by those skilled in the art of formulation, so filrther 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. D-
`
`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 examples are given by way of illustration only.
`
`0606
`
`0606
`
`

`
`W0 01/32142
`
`PCT/GB00/04143
`
`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
`
`mg/capsule
`
`50.00
`
`Glyceryl Monolinoleate (Maisine 33-1)
`
`34.50
`
`Propylene glycol monocaprylate
`
`(Capryol 90)
`
`Polyoxyl 35 Castor Oil NF (Cremophor
`
`EL)
`
`Colloidal silicon dioxide
`
`Crospovidone USP (PVP CL-M)
`
`Net Fill Wflcap (mg)
`
`34.50
`
`100.00
`
`105.00
`
`26.00
`
`350.00
`
`0607
`
`0607
`
`

`
`WO 01/32142
`
`PCT/GBO 0/041 43
`
`Example 3
`
`Imusporin- 100
`
`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
`
`100.00
`
`69.00
`
`69.00
`
`200.00
`
`210.00
`
`52.00
`
`700.00
`
`1
`
`2
`
`4
`
`5
`
`6
`
`7
`
`8
`
`The blended preparations were made as follows:
`
`Mix Maisine 35-1, Capryol 90 and Cremophor EL in a clean jacketed
`
`vessel.
`
`Add Cyclosporin to the above vessel under stirring, 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 and strain through 150#.
`
`Sifi Aerosil and Crospovidone through 20# and 40# respectively. Mix in a
`
`suitable mixer.
`
`Adsorb the above blend (step 4) over the mixture of Aerosil and
`
`Crospovidone.
`
`Pass the powder blend of Cyclosporin through 20#.
`
`Fill this blend in hard gelatin capsules or compressed with tablets.
`
`The blends were then either
`
`fill
`
`into hard gelatin capsules or
`
`compressed into tablets.
`
`0608
`
`0608
`
`

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

`
`W0 01/32142
`
`PCT/GB00/04143
`
`-10-
`
`425
`
`1 0
`
`225
`
`100
`
`Polysorbate-80
`(Tween 80)
`
`on-tocopherol
`
`Transcutol
`
`Cyclosporin A
`
`Example 6
`
`Preparation of microemulsion for administration as oral solution
`
`Component
`
`Capryol 90
`
`Polyoxyl-40 hydrogenated castor oil
`
`on-tocopherol
`
`Propylene glycol
`
`Cyclosporin A
`
`Example 7
`
`mg/capsule
`
`275
`
`425
`
`10
`
`225
`
`100
`
`Preparation of microemulsion for administration as oral solution:
`
`Component
`
`Capryol 90
`
`Lauroglycol 90
`
`Polysorbate 80 (Tween 80)
`
`oz-tocopherol
`
`Propylene glycol
`
`Cyclosporin A
`
`Example 8
`
`%
`
`13 O
`
`130
`
`400
`
`10
`
`200
`
`100
`
`Preparation of microemulsion for administration as oral solution:
`
`0610
`
`0610
`
`

`
`W0 01/32142
`
`PCT/GB00/04143
`
`Component
`
`Capryol 90
`
`Maisine
`
`Polyoxyl-40 hydrogenated castor oil
`
`cc-tocopherol
`
`Transcutol
`
`Cyclosporin A
`
`-11-
`
`mg/capsule
`
`14
`
`15
`
`45
`
`1
`
`25
`
`10
`
`The oral solution which is 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 :t 2°C). Ref 40°C-80% RH and 45°C, afier
`
`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
`
`

`
`W0 01/32142
`
`PCT/GB00/04143
`
`-12-
`
`CLAIMS:
`
`1.
`
`A pharmaceutical composition in the form of a preconcentrate mixed
`
`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)
`
`b)
`
`c)
`
`d)
`
`a water-insoluble pharmaceutically active material;
`
`one or more propylene glycol esters of a fatty acid;
`
`surfactant; and either
`
`a hydrophilic phase, wherein component (a) has been wholly directly
`
`dissolved in component (b) and component (b) is dispersed as tiny
`
`particles in component (d); or
`
`e)
`
`a solid carrier.
`
`2.
`
`A composition according to claim 1, which composition is a
`
`microemulsion comprising components (a), (b), (c) and (d).
`
`3.
`
`A composition according to claim 1, which composition is a blend of
`
`said preconcentrate and said solid carrier comprising components (a), (b), (c) and
`
`(6)-
`
`4.
`
`A composition according to claim 1, 2 or 3, wherein component (a)
`
`is a cyclosporin, or another water-insoluble peptide, or a water-insoluble
`
`antimicrobial or antineoplastic substance or mixtures thereof.
`
`5.
`
`A composition according to claim 4, wherein component (a) is
`
`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
`
`

`
`W0 01/32142
`
`PCT/GB00/04143
`
`-13-
`
`6.
`
`A composition according to any preceding claim, wherein
`
`component (b) is a propylene glycol ester of C12 to C13 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 mixtures thereof.
`
`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 120.5 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 mixture thereof.
`
`13.
`
`A soft gelatin capsule or oral administration fluid which comprises a
`
`composition as claimed in any of claims 1 to 11
`
`0613
`
`0613
`
`

`
`W0 01/32142
`
`PCT/GB00/04143
`
`-14-
`
`14.
`
`A tablet or hard gelatin capsule which comprises a composition as
`
`claimed in any of claims 1 to 12 when in 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 ((1) or with
`
`component (e) and component (c) if not included earlier.
`
`16.
`
`A process according to claim 150, wherein a preconcentrate
`
`composition is mixed with component (d).
`
`17.
`
`A process according 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 comprises first 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 comprises first 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
`
`

`
`HVTEJUVAJTCNNAJISFDARIHJIREPCHRT
`
`lnterr
`.ial Application No
`
`PCT/GB 00/04143
`
`
`
`A. CLASSIFICATION OF SUBJECT MATTER
`A61K9/14
`A61K9/48
`IPC 7
`A61K9/107
`
`
`
`
`
`
`According to international Patent Classification (IPC) orto both national classification and IPC
`B. FIELDS SEARCHED
`
`
`
`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 the fields 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
`
`
`
`
`
`
`
`
`
`
`
`1,2,
`4-11,
`13—16,18
`
`Citation of document. with indication, where appropriate, of the relevant passages
`
`Relevant to claim No.
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Category °
`
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`N0 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
`
`US 5 543 393 A (KIM JUNG W
`6 August 1996 (1996-08-06)
`example 8
`
`ET AL)
`
`_./__
`
`
`
`
`Further documents are listed in the continuation of box C.
`
`O Specie“ Cmegories of cited doc” mems :
`'A' document defining the general state of the art which is not
`considered to be of particular relevance
`
`'T'
`
`later document published after the international filing date
`or priority date and not in conflict with the application but
`cued ‘O understand the pmcwe or theory undeflying me
`invention
`
`Patent family members are listed in annex.
`
`
`
`
`
`
`'E' earlier document but published on or after the international
`.X. document of pamcutar relevance. me claimed invemion
`filing date
`cannot be considered novel or cannot be considered to
`'L' document which may throw doubts on priority c|aim(s) or
`involve an inventive step when the document is taken alone
`which is cited to establish the publication date of another
`.
`-
`.
`-
`-
`-
`or reason as
`Y “Z§#.’I3‘?'Ee°L§.?§i'§$'lZ3§‘T3'?.¥5.§l3Z'éififdififi ;".;:"x:2n
`'0' document referring to an oral disclosure. use, exhibition or
`document is combined with one or more other such docu-
`other means
`ments, such combination being obvious to a person skilled
`'P' document published prior to the international filing date but
`i" me 3"-
`later than the priority date claimed
`'8.‘ document member of the same patent family
`Date of mailing of the international search report
` Date of the actual completion of the international search
`
`
`.
`
`
`
`05/O2/2001
`26 January 2001
`Authorized officer
`
`Name and mailing address of the ISA
`
`European Patent Office, P.B. 5818 Patentlaan 2
`NL — 2280 HV Ftljswiik
`
`Tel. (+31 -70) 340-2040, Tx. 31 651 epo nl.
`
`Borst, M
`Fax: (+31—7o) 340-3016
`
`Form PCT/ISA/210 (second sheet) (July 1992)
`
`
`
`page 1 of 2
`
`0615
`
`
`
`
`
`
`0615
`
`

`
`IPTTEHPbATT()DLA11SEDARHCIIIREJNDITT
`Information on patent family members
`
`Intern
`
`.ial Application No
`
`PCT/GB 00/04143
`
`Patent document
`cited in search report
`
`EP 0760237
`
`NO 9944584
`
`A
`
`A
`
`Publication
`date
`
`05-03-1997
`
`10-09-1999
`
`US 5543393
`
`A
`
`06-08-1996
`
`NO 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 8
`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
`N0
`
`AU
`CA
`CN
`EP
`FI
`JP
`NO
`KR
`NO
`
`EP
`
`AT
`AT
`AU
`AU
`BE
`BG
`CA
`CH
`CY
`DE
`DK
`ES
`FI
`FR
`GR
`HK
`HU
`IE
`IL
`IT
`JP
`JP
`JP
`KR
`KR
`KR
`LU
`LV
`NL
`NO
`NZ
`PT
`SE
`SG
`
`Form PCT/ISA/210 (palenl family annex) (July 1992)
`
`page 1 of 2
`
`0616
`
`0616
`
`

`
` INTERNATIONAL SEARCH REPORT
`lnterr
`nal Application No
`
`C.(ContInuation) DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Category °
`
`Citation of document. with indication,wnere appropriate, of the relevant passages
`
`Relevant to claim N0.
`
`PCT/GB 00/04143
`
`
`
`
`
`
`N0 98 40051 A (ABBOTT LAB)
`17 September 1998 (1998-09-17)
`
`
`
`exampies 21,23,24
`iine 8
`page 6,
`iine 5 -page 6,
`page 6,
`line 34 -page 7, 11ne 2
`
`
`
`
`
`
`
`
`1,2,
`GB 2 222 770 A (SANDOZ LTD)
`21 March 1990 (1990-03-21)
`4-11,
`
`
`13-16,18
`
`exampies 1.5.-1.10.
`
`Forrn PCT/ISA/210 (continuation oi second sheet) (Juiy 1992)
`
`page 2 Of‘ 2
`
`0617
`
`

`
`UVTEHUVAJI(HVAl.SEHARIHJIEPCHRT
`Information on patent lamily members
`
`lnten
`
`,na| Application No
`
`PCT/GB oo/04143
`
`Patent document
`cited in search report
`
`Publication
`date
`
`Patent family
`member(s)
`
`GB 2222770
`
`A
`
`5962017 A
`6024978 A
`6007840 A
`5741512 A
`5866159 A
`5916589 A
`5962014 A
`5342625 A
`8907066 A
`
`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/ISA/210 (patent lamiiy arnex) (July 1992)
`
`page 2 of 2
`
`0618
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`0618
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`

`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`14 June 2001 (14.06.2001)
`
`(43) International Publication Date
`
`||l|||ll|l||||llllllll||||||l||Illllll|||l||||I||||||l|I||||ll||l|l|||||l|||||||
`
`(10) International Publication Number
`
`W0 01/41671 A2
`
`(51) International Patent Classification7:
`
`A6lF
`
`(21) International Application Number:
`
`PCT/US00/33236
`
`(22) International Filing Date: 7 December 2000 (07.12.2000)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`MI99A0O264l
`
`7 December 1999 (07.12.1999)
`
`IT
`
`except US):
`(for all designated States
`(71) Applicant
`TRANSNEURONIX, INC. [US/US]; 100 Stierli Court,
`Suite 106, Mt. Arlington, NJ 07856 (US).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ,
`DE, DK, DM, DZ, EE, ES, F1, GB, GD, GE, GH, GM, HR,
`HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR,
`Ls’ LT, LU’ Ly’ MA, MD, MG, MK, MN, MW, MX’ MZ,
`NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM,
`TR, T1.’ TZ, UA, UG, US, UZ, VN’ YU’ ZA, ZW‘
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`[G3, 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 pagent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`_
`_
`,
`P“b1‘sh.°d‘
`(72) Inventor; and
`(75) Inventor/Applicant (for US Only): CIGAINA’ Balerio — Without international search report and to be republished
`[IT/IT}; via 4 Novembre, 3/a, 1—31os0 Villorba (IT).
`“P0” recap’ °f’h"’ ’eF"”’"
`
`(74) Agents: SAMPLES, Kenneth, H. et a1.; Fitch, Even,
`Tabin & Flannery, Suite 1600, 120 South LaSa1le Street,
`Chicago, IL 60603 (US).
`
`For two-letter codes and other abbreviations, refer to the ”Guid-
`arzce Notes on Codes and Abbreviations " appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`||||l|||l||||||||||||||||||l|||||l||||||||||||||||||||||||||||||||||||||l|||||||
`
`011671A2
`
`(54) Title: REMOVABLE GASTRIC BAND
`
`(57) 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
`Q. 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 where the button can be inserted into
`the aperture to close the elongated body around, and hold it to, the portion of the stomach. The removable gastric band can be easily
`O paired with the use of a gastric electrostimulator and may be useful, therefore, for inducing forced slimming in the initial phase of
`g 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.
`
`0619
`
`0619
`
`

`
`WO 01/41671
`
`PCT/US00/33236
`
`REMOVABLE GASTRIC BAND
`
`Related Application
`
`This application claims priority from Italian Patent Application Number
`
`Ml99AO02641, 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 control and/or modification of the
`
`diameter of a patient’s stomach.
`
`10
`
`15
`
`20
`
`25
`
`Background of the Invention
`
`Laparoscopic banding systems are available which provide for the use
`
`of an elongated main part that is placed around the stomach and closed over
`
`the stomach so as to reduce the diameter ofthe stomach to be able to treat
`
`the patient’s obesity. Such currently available bands, however, present some
`
`drawbacks essentially due to the difficulty of application and/or removal of the
`
`gastric band.
`
`In fact, normally, the current bands’ means of closing the
`
`elongated main part are almost always hard to manipulate; moreover, their
`
`connection entails the use of additional instruments and/or devices that
`
`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 or less 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 because they present little resistance to tissue adhesions
`
`and lack sufficient mechanical integrity to withstand tensile forces, both of
`
`which hinder their removal unless the patient is undergoing surgery.
`
`0620
`
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`

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`WO 01/41671
`
`PCT/US00/33236
`
`It is desirable, therefore, to provide an improved gastric band which is
`
`both easier to implant within the patient and, when necessary, to remove from
`
`the patient.
`
`Summagg 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 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 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 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 portion of the elongated body around, and hold it to, the section of
`
`the stomach, and wherein the portion of the elongated body is essentially
`
`planar in cross section.
`
`The present invention also provides a method for 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
`
`0621
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`0621
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`

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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 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 portion of the elongated body around, and hold it to, the section of
`
`the stomach, and wherein the portion of the elongated body is essentially
`
`planar in cross section.
`
`The task proposed by the present invention is the realization of a
`
`removable gastric band that eliminates the above-noted drawbacks of the
`
`known gastric bands. V\fithin the scope of this task, one important purpose of
`
`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 purpose of the invention is to realize a removable gastric
`
`band that is easy to remove because it is highly resistant to adhesion to the
`
`tissue and has sufficient mechanical integrity to withstand tensile forces
`
`during removal. Yet another purpose of the invention is to realize a
`
`removable gastric band that can be applied without necessarily having to use
`
`suture stitches.
`
`Yet another purpose of the invention is to realize a removable gastric
`
`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 purpose of the invention is to realize a removable gastric band that is
`
`extremely easy to manipulate, so that it can be easily placed in and/or
`
`removed from the patient.
`
`10
`
`15
`
`20
`
`25
`
`0622
`
`0622
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`

`
`WO 01/41671
`
`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 shows the gastric band according to the invention applied to
`
`the proximal tract of the patient’s stomach;
`
`Figure 4 shows the gastric band according to the invention inflated so
`
`as to compress a portion of the patient’s stomach;
`
`Figure 5A shows in 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 shows in cross-sectional view (along line A-A in Figure 1) the
`
`inner surface of the gastric band in relation to the patient’s stomach after the
`
`gastric band has been inflated;
`
`Figure 5C shows in 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 tendency of the gastric band to twist
`
`around its longitudinal axis;
`
`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 expanded view of the inflation mechanism.
`
`Detailed Description of the Invention
`
`VVlth reference to the figures described above, the removable gastric
`
`band according to the invention, indicated as a whole with reference number
`
`1, comprises an elongated body 3 having a 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 upon itself so as to surround a portion,
`
`preferably the proximal tract, of the patient’s stomach 4. The closure
`
`mechanism 2 preferably comprises a button 6 in the first zone 30 and a
`
`corresponding aperture 5 in the second zone 32 whereby the button 6 can fit
`
`10
`
`15
`
`20
`
`25
`
`30
`
`0623
`
`0623
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`

`
`WO 01/41671
`
`PCT/US00/33236
`
`through the aperture 5 and fix or look the elongated body 3 back onto to itself.
`
`Once locked into place, the gastric band 1 completely encircles and
`
`compresses a portion of the patient’s stomach (see, e.g., Figures 3 and 4).
`
`Although only one aperture 5 is shown within the second zone