1
`
`3M COMPANY 2005
`Mylan Pharmaceuticals Inc. v. 3M Company
`IPR2015-02002
`
`

`
`2
`
`

`
`have become the most predominant.
`Terbutaline sulfate, albuterol, meta-
`proterenol sulfate, ipratropium bro-
`mide, beclomethasone diproprionate,
`flunisolide and disodium cromoglycate
`are common examples of drugs deliv-
`ered in this type of
`formulation.
`Suspension type MDIs are likely to
`remain popular,
`since the much
`forecast replacement of dichlorodi-
`fluoromethane (CFC-12) by 1,1,1,2
`tetrafluoroethane (HFC-134a)* is like-
`ly to produce propellants with even
`less drug solubilizing potential than
`those in use today. The advantages of
`suspension type MDIs are:
`A. Wide Applicability—No minimum
`solubility is required, though it is prob-
`able that Ostwald ripening will be a prob-
`lem if the drug exhibits “significant”
`solubility in the propellant, but not
`enough to allow its formulation as a high
`volatility solution aerosol.
`B. Improved Chemical Stability-
`Drug remains in the solid phase, reduc-
`ing the probability of chemical degrada-
`tion.
`C. Relatively large doses of drugs can
`be delivered per actuation—For example,
`Intal"’ MDI (Fisons) delivers 5mg of
`disodium cromoglycate per shot.
`Unfortunately,
`suspension type
`MDIs have some disadvantages asso-
`ciated with them:
`A. Reduced Physical Stability—Sus-
`pended drug particles have a tendency
`to either sink or float unless their densi-
`ty exactly matches that of the pro-
`pellant. This potentially causes two
`problems:
`1. Unreproducible dose delivery can
`result from delays between shaking
`and firing the MDI.
`2. Patients must vigorously shake
`the MDI before use.
`B. Sub-optimal Respirable Fraction-
`The size of the resulting aerosol cannot
`be less than the size of the primary par-
`ticles used in its manufacture. Solution
`aerosols can theoretically produce in-
`finitely small particles.
`C. Suspension type MDIs are more
`complex to manufacture than solution
`MDIs.
`"
`D. Higher Propellant Leakage Rate-
`High concentration suspension type
`MDIs are potentially problematic due to
`drug particles preventing proper valve
`Operation.
`
`In order to produce a robust. ef-
`ficacious product, the MDI formulator
`Should consider several factors during
`
`'Editor's note: A discussion of potential phar-
`maceutical propellants in light of the CFO phase-
`°“t can be found in the August 1990 issue of
`Aenosot Ace.
`in the cover story “A Status
`R5901? CF'C’s in Pharmaceutcal Aerosols," by
`Tfilmuce M. Coyne.
`
`the course of product development.
`Some of these are common to both
`types of MDI formulation, for exam-
`ple: chemical stability of the drug,
`uniformity of dose, total number of
`doses per unit, packaging component
`compatibility and extractables from
`valve elastomers. However, several
`factors are specifically of interest in
`the formulation of suspension type
`MDIs:
`
`the
`
`A. Starting particle size of
`primary drug particles.
`B. Crystal growth of the primary drug
`particles in the liquefied propellant.
`C. Sedimentation of primary drug par-
`ticles in the liquefied propellant.
`D. Flocculation of primary drug par-
`ticles in the liquefied propellant.
`E. Effect of sedimentation and floc-
`culation on dose uniformity.
`F. Effect of suspension concentration
`
`Figure 2. Appearance of several experimental MDI formulations. (left to right) 0.25,
`0.5, 1, 2, 5, and 60 minutes following shaking. (A) 1%w/v drug. 0.5°/ow/w sorbitan
`trioleate in 60%w/w CFC-12 and 40%w/w CFC-114: (Bl 1%w/v drug, 0.5%w/w sor-
`bitan triolaate in CFC-12; (C) 1%w/v drug. 0.5%w/w soya lecithin in CFC-12. Courtesy
`of Fisons Pharmaceutical Division.
`
`V - AEROSOL AGE, October 1990
`L
`
`3
`
`23
`
`

`
`4
`
`

`
`5
`
`

`
`6
`
`

`
`7
`
`

`
`Aerosol
`
`Services
`Company, Inc.
`
`THE West Coast Contract Packager:
`
`For Service (‘all
`818—968-8531
`
`llil
`
`co-.cs-<,-tmcim:
`
`‘B
`
`Emu» m,:».«
`
`425 So. Ninth Avenue /City of Industry, California 91746
`Circle Reader’s Service Card No. 155
`
`AEROSOLS -
`
`& LIQUIDS
`CONFIDENCE
`Drug licensed, quality control
`per GMP, computerized
`materials control, complete
`laboratory facilities and staff.
`
`SERVICE
`Full compounding facilities,
`six flexible filling lines,
`including a clean room and
`a professional staffat
`your service.
`
`~
`0
`
`Your Source For
`
`Table Four
`
`AEROSOL
`EQUIPMEN4
`
`.
`
`.
`
`.
`
`..
`
`Mexican Productions for 1989 and 1990 (est.l,
`b Product Cate or
`
`Category
`Personal Products
`Insecticides
`Household Products
`Industrial Products
`Paints
`Medical Products
`
`1989
`17.1MM
`14.9
`5.0
`45
`4.6
`3.0
`
`1990 (est.); Er percentages
`17.9MM
`34%
`15.2
`29
`5.3
`10
`4.7
`9
`5.2
`10
`3.7
`7
`
`quet, tennis and domino tournaments
`and other opportunities for communi«
`cation. Some of the most magnificent
`prehistoric ruins in the Western Hemi-
`sphere are within a 90 minute drive
`from Cancun. They include the mile-
`square archeological site of Chichen
`Itza, where an estimated 12,000
`virgins were thrown into a huge well
`with unscalable limestone walls, the
`famous ruins of Tulum, with the main
`pyramid and altar built overlooking
`the Caribbean, and even a small min on
`Cancun itself. Many of the delegates
`brought their families and stayed two
`or three extra days in order to see and
`enjoy this picturesque Mayan area of
`Mexico, some 1200 miles by road from
`Mexico City. All in all, this was a con-
`
`vention to be remembered, sparked by
`the vigor and confidence of the Mex-
`ican aerosol industry as they move for-
`ward into the 19903. u
`
`consulting on
`aerosols
`
`litigation services
`
`patents
`
`special services
`
`Walter C. Beard, Inc.
`Middlebury, Conn. 06762 U.S.A.
`208-758-2194 - Cable WCBI
`Fax: 203-598-3243
`
`We Are Exclusive
`East Coast Representatives For:
`TERCO, INC.
`Aerosol arid Bairicr Pkltilx I.iiios
`Tippers. O\‘err:iippei‘s. Cliziiigii Parts
`Pro-I*‘al)ric:ale(l (lzissiiig Hriuses
`o
`ENGINEERED Al.l'l'(‘)MATION. INC.
`Piickers. Dc-l’iic:l\’ers
`Custom Assiiiiibly Eqiiipiiiuiil
`0
`ANODE PRODUCTS COMPANY. INC.
`VVt1lPl' Balli Filtrnlioii Sysltriiis
`0
`From Pilot Plants to High Spocil
`Lilies. (ioiitarzt Us for a
`Fast. Kiirm'le(l_L;eal)le Rospoiise—
`Canada to Florirla
`Cz\I.L
`DOUG or DON BE.i\RDSV\'UR'l'H
`(203) 253-4011
`D. A. BEARDSWORTII ASSOCIATES. INC.
`660 Main St. South #3/‘Box 686
`Wuodbury, CT 06798
`
`Circle Reader's Service Card No. 156
`
`Trust Our Name
`
`Piedmont Laboratories is building a reputation as a
`quality contract packager on superior product and
`customer service that really cares.
`We have a large. new facility located in the beautiful
`rolling countryside outside of Atlanta, Georgia, and
`welcome your visit and the opportunity to talk about
`yourfilling needs.
`Our dedicated lines for household, auto. industrial and
`personal products are licensed by the EPA and FDA and
`equipped to fill all types of barrier cans.
`
`PIEDMONT
`
`LABORATORIES
`Specizilists in (,,‘.niiri'-act P:lCl(k1,Ll,lltl_[ nfAci'nsols ziml Liqiiiils.
`
`2030 Old Candler Road, Gainesville, Georgia 30501
`(404) 5340300 TELEX 54307 FAX (404)535-8132
`
`Circle ‘Reader’s Service Card No. 157
`
`8
`
`AEROSOL AGE, October 1990
`
`

`
`0 Contract
`Packaging
`0 Custom
`
`Formulation
`
`CONTACT:
`
`PAUL HOLBFIOOK
`713-444-6454
`
`AEROSOLS V/JJQUIDS
`0 Insecticides “~‘ Household
`
`0 Toiletries
`
`Circle Reader's Service Card No. 159
`
`I
`
`I
`
`IHN Geciren & nssocmres
`Consultants to the
`Chemical Industry
`7 Snourdon, Dove Conuon, (R 92679
`(714) 589-6233 - FR)! (7I4) 58945271
`
`Particle Size Analysers
`stop-action laser holography
`0 Size Distribution
`0 Concentration
`- Shape
`Laboratory Testing Service
`Custom Designed Systems
`(815) 389-2136
`olllrler PHDTDGRAPHIC LABDRATEIRIEEI
`1120 Manchester Rd.
`Since
`1972
`South Beloit,
`II. 51080
`
`
`
`Circle Reader's Service Card No. 153
`
`Metered Dose Inhalers
`Begins on page 22
`
`light some of the pitfalls that may be
`encountered during the formulation,
`scale-up and manufacture of suspen-
`sion type metered dose inhalers. In
`order to produce an elegant, safe, and
`efficacious product
`the formulator
`should try to minimize apparently
`trivial idiosyncracies associated with
`the formulation. The additive effect of
`these “minor" problems can conspire
`to prevent; commercialization of an
`otherwise effective drug. These chal-
`lenges are likely to increase over the
`coming years since formulators will be
`presented with alternatives to CFC
`propellants, with which they have lit-
`tle experience. H
`
`Acknowledgement
`I would like to thank Fisons Pharmaceutical Divi-
`sion, Lougnoorough, England, for granting me per-
`mission to present data generated while I was
`employed there. Specifically,
`I am indebted to: Clive
`Booles, Lynn Brown. Andy Ludzig. Janet Mldgley.
`Steve NlCli0lS, Phil Warrington and Paul Wright.
`
`20 MM.
`BOTTLE CHIMPING
`HEADS
`tolerances than
`to lighter
`Manulaclureil
`anything on the market - at approximately
`113 lower cost. Try one lor sixty days
`— If It Is not Ihe BEST crimping head you have ever used,
`andior does NOT corracl your crimping problems - relurn
`ll llJ IIS M IIII GDSI.
`Please call Ior a crimping head on a trial basis andlor
`technical information.
`
`MENTON ENGINEERING C0.
`103 Old Colony Ave.
`P.0. Box 452
`E. Taunlan. MA 02718
`‘ Phone 1-508-824-3061
`
`Do you have obsolete Lithographed cans
`that are taking up valuable warehouse space?
`We have been turning unwanted obsolete lilhographecl con-
`tainers into saleable usable containers for many satisfied
`customers for the last 15 years—wheIher your obsoleies are triple-
`tites, aerosols or cone tops we can strip the lithography from these
`cons, quickly and economically without altering the physical pro-
`periies of the cans.
`
`We will buy your obsoletes or clean
`and return them to you, call us today.
`Joe or Mark Gregory
`
`I.I1'HO-OFF CORPORATION
`402 E. Roosevelt
`Wheaten, II. 60I 87
`
`Circle Readers Service Card No. 164
`
`Circle Reader’s Service Card No. 165
`
`AEROSOL AGE, October 1990
`k_
`
`9
`
`89
`
`0 Automotive CSA LIMITED, INC. F’.O. Box 690347/ Houston, Texas 77269-0347
`404-534-5171
`(203) 877-4151
`(708) 653-7979
`
`ENGINEERS AND TECHNICIANS
`
`Specializing in Aerosol and Liquid
`Filling Technology
`—Engineering Design and Project
`Management
`—Custom Machinery and Modifications
`—Turnkey Projects
`—Troub|e shooting
`—Training Programs
`H. WILLIAMS ASSOCIATES
`P.0. Box 907342 Northlake Station
`Gainesville, GA 30501-0906
`
`Circle Reader’s Service Card No. 162
`
`AEROSOLS
`NEW PRODUCT
`DEVELOPMENT Consultant
`PACKAGING
`LITIGATION
`PATENTS
`FORMULATION
`PRODUCTION
`PROBLEMS
`
`PO. Box 3397
`Milford, CT 06460
`
`Circle Reader's Service Card No. 163
`
`
`
`CONSULTING ON:
`- EPA/CPSC/OSHA/DOT/FDA Compliance
`0 Aerosol/Liquid Product Development
`- Custom Formulating &_ Packaging
`- Quality & Environmental Auditing
`' Operations Trouble Shooting
`0 Litigation Services
`
`Circle Reader’s Service Card No. 160
`
`BRUCE NELSON CUMPANY
`
`Project Engineering and New
`Product Development
`Product Liability Intervention
`& 24 hr. Hot-line service “800”
`
`Litigation Services and
`Product Failure analysis
`0 Lab and aerosol equipment
`- Quality & Safety auditing
`
`Box 674, W. Yarmouth, MA 02673
`tel. or fax 508-771-3607
`Circle Reader’s Service Card No. 161