111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US007157102Bl
`
`c12) United States Patent
`Nuwayser
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,157,102 B1
`Jan.2,2007
`
`(54) MULTI-LAYERED MICROCAPSULES AND
`METHOD OF PREPARING SAME
`
`(75)
`
`Inventor: Elie S. Nuwayser, Woburn, MA (US)
`
`(73) Assignee: Biotek, Inc., Woburn, MA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 170 days.
`
`(21) Appl. No.: 10/161,130
`
`(22) Filed:
`
`May 31, 2002
`
`(56)
`
`(51)
`
`Int. Cl.
`A61K 9116
`(2006.01)
`(2006.01)
`A61K 9/14
`(52) U.S. Cl. ...................... 424/490; 424/489; 424/497;
`424/452; 424/463
`(58) Field of Classification Search ................ 424/451,
`424/452,455,463,458
`See application file for complete search history.
`References Cited
`U.S. PATENT DOCUMENTS
`3,523,906 A
`8/1970 Hova eta!. ................. 252/316
`3,691,090 A
`9/1972 Kitajima et al . ............ 252/316
`3,737,337 A
`6/1973 Wuppertal-
`Elberfeld et a!. ........... 117/100
`6/1975 Fukushima eta!. ......... 252/316
`3,891,570 A
`6/1976 Morishita et al ............ 252/316
`3,960,757 A
`4,384,975 A * 5/1983 Fong ..................... 427/213.36
`4,389,330 A * 6/1983 Tice eta!. ............. 427/213.36
`4,499,096 A
`2/1985 Lotsof ........................ 514/214
`7/1985 Tice eta!. .................. 514/179
`4,530,840 A
`4,542,025 A
`9/1985 Tice eta!. .................... 424/78
`2/1986 Nuwayser et a!. ............. 427/3
`4,568,559 A
`4,582,835 A
`4/1986 Lewis et al ................. 514/282
`4,588,580 A
`5/1986 Gale et a!. .................... 424/21
`1111986 Nuwayser et a!. ..... 428/402.24
`4,623,588 A
`4,675,189 A
`6/1987 Kent et a!. .................. 424/490
`4,861,627 A * 8/1989 Mathiowitz et al. ... 427/213.31
`111990 Traber et al . ............... 514/255
`4,895,848 A
`111990 Tice eta!. .................. 424/422
`4,897,268 A
`
`4,919,916 A
`4,931,277 A
`4,935,428 A
`4,935,429 A
`4,942,182 A
`5,075,341 A
`5,100,669 A *
`5,100,916 A
`5,124,340 A
`5,140,032 A
`5,149,538 A
`5,223,497 A
`5,240,711 A
`5,256,669 A
`5,272,149 A
`5,298,622 A
`5,407,609 A
`5,474,786 A *
`
`4/1990 Golwyn ....................... 424/10
`6/1990 Fontaine et al .......... 424/195.1
`6/1990 Lewis
`........................ 514/282
`6/1990 Dackis et a!. ............... 514/288
`7/1990 Weiss et al ................. 514/812
`12/1991 Mendelson eta!. ......... 514/282
`3/1992 Hyon et a!. ................. 424/426
`3/1992 Johansson et a!. .......... 514/478
`6/1992 Jaffe et al ................... 514/356
`8/1992 Radecki . . . . . . . . . . . . . . . . . . . . . . 514/221
`9/1992 Granger et a!. ............. 424/449
`6/1993 Gawin et a!. . . . . . . . . . . . . 514/225 .2
`8/1993 Hille et al.
`. ................ 424/448
`10/1993 Askanazi eta!. ........... 514/282
`12/1993 Stalling ...................... 514/255
`3/1994 Portoghese eta!. ........... 546/15
`4/1995 Tice et a!.
`.................... 264/46
`12/1995 Kotwal et a!. .............. 424/472
`
`(Continued)
`OTHER PUBLICATIONS
`Amory et a!., "Testosterone Release from a Subcutaneous, Biode-
`gradable Microcapsule Formulation (Viatrel) in Hypogonadal
`Men," J Andrology, 23(1):84-91 (2002).
`(Continued)
`Primary Examiner-Lakshmi Channavajjala
`(74) Attorney, Agent, or Firm-Banner & Witcoff, Ltd.
`
`(57)
`
`ABSTRACT
`
`A multi -layered microcapsule containing one or more active
`ingredients and process for preparing the same is disclosed .
`The multi-layered microcapsule comprises an inner solid
`microparticle core, typically composed of a biodegradable
`polymer, and having one or more alternating layers of
`polymer, active ingredient or polymer/active ingredient mix-
`tures to produce a multi-layered microcapsule wherein the
`polymer or active ingredient in each layer may be the same
`or different or have the same or different concentration of the
`polymer or active ingredient in other layers.
`
`32 Claims, 9 Drawing Sheets
`
`24
`
`AMN1014
`IPR of Patent No. 7,919,499
`
`

`

`US 7,157,102 B1
`Page 2
`
`U.S. PATENT DOCUMENTS
`5,648,097 A
`7/1997 Nuwayser ................... 424/489
`6,123,965 A *
`9/2000 Jacob et a!.
`................ 424/489
`10/2001 Tice eta!. .................. 424/426
`6,306,425 B1
`OTHER PUBLICATIONS
`Comer et a!., "Depot naltrexone: long-lasting antagonism of the
`effects of heroin in humans," Psychopharmacology, 159:351-360
`(2002).
`Kranzler et al., "Sustained-Release naltrexone for Alcoholsim Treat-
`ment: A Preliminary Study," Alcoholism: Clin. and Exp. Res.,
`22(5): 1074-1079 ( 1998).
`Leary, "Drug for Heroin Addiction Is Being Marketed for Treatment
`of Alcholism," New York Times, p. A18, Jan. 18, 1995.
`Nath et a!., "Buprenorphine Pharmacokinetics: Relative Bioavail-
`ability of Sublingual Tablet and Liquid Formulations," J Clin.
`Pharm., 39:619-623 (1999).
`Nuwayser et a!., "Microencapsulation of Contraceptive Steroids,"
`Proc. llfn Inter. Symp. Control. Rei. Bioactive Mater., pp. 71-72
`(1984).
`Nuwayser and DeRoo, "Microencapsulation with Microfluidized
`Beds," Proc. 14th Inter. Symp. Control. Rei. Bioactive Mater., 2
`pages ( 1987).
`Injectable Naltrexone
`Nuwayser et a!., "Sustained Release
`Microcapsules," Proc. Inter Symp. Control. Rei. Bioactive Mater.,
`15:201-202 (1988).
`
`Injectable Methadone
`Nuwayser et al., "Sustained Release
`Microcapsules," Proc. Inter. Symp. Control. Rei. Bioactive Mater.,
`16:83-84 (1989).
`Injectable Naltrexone
`Nuwayser et a!., "Sustained Release
`Microcapsules," Proc. 5.2"d Ann. Sci. Meeting, L. Harris, ed. NIDA
`Research Monograph 105, 532, (1991).
`Nuwayser and Blaskovich, "In Vivo Studies of a One Month
`Injection for Buprenorphine," Proc. Inter. Symp. Control. Rei.
`Bioactive Mater., 19:168-169 (1992).
`Petry et a!., "A Comparison of four buprenorphine dosing regimens
`using open-dosing procedures: is twice-weekly dosing?" Addiction,
`95(7):1069-1077 (2000).
`Petry et al., "Examining the limits of the buprenorphine interdosing
`interval: daily, every-third-day and every-fifth-day dosing regi-
`mens," Addiction, 96(6):823-834 (2001).
`Przyborowski et a!., "Preparation of HSA Micro spheres in a One-
`Step Thermal Denaturation of Protein Aerosol Carried in Gas-
`Medium," Eur. J Nuc. Med., 7:71-72 (1982).
`Shah et al., "A biodegradable injectable implant for delivering
`micro and macromolecules using poly(lactic-co-glycolic )acid
`(PLGA) copolymers," J Controlled Release, 27:139-147 (1993).
`Williams et a!., "Microencapsulated Local Anesthetics," Proc. llfn
`Inter. Symp. Control. Rei. Bioactive Mater., pp. 69-70 (1984).
`* cited by examiner
`
`AMN1014
`IPR of Patent No. 7,919,499
`
`

`

`U.S. Patent
`
`Jan.2,2007
`
`Sheet 1 of 9
`
`US 7,157,102 B1
`
`22
`?
`
`0
`
`24
`
`~--...,..---34
`__,..c.-30
`
`----
`
`Figure 1
`
`AMN1014
`IPR of Patent No. 7,919,499
`
`

`

`""""' = N = """"'
`
`"'--...1
`""""' u.
`"'--...1
`rJl
`d
`
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`
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`N
`
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`"' N
`N
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`
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`
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`e •
`
`12 14 16 18 20 22 24 26
`I
`I
`
`EST RA-M. PRS
`
`I
`
`I
`
`I
`
`Therapeutic Level
`
`Serum Estradiol (pg/ml)
`
`Figure 2. Plasma Level of Beta-Estradiol from Estrel™
`
`Microcapsules in Five Women
`
`0
`0 IF I
`20
`40
`60
`80
`100
`120
`140
`160
`180
`200
`220
`240 ~--------------------------------------------------~
`
`I
`
`I
`
`TIME (Weeks)
`10
`I
`
`I
`
`8
`I
`
`6
`I
`
`4
`I
`
`2
`I
`
`-2
`
`AMN1014
`IPR of Patent No. 7,919,499
`
`

`

`""""' = N = """"'
`
`"'--...1
`""""' u.
`"'--...1
`rJl
`d
`
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`0 .....
`
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`
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`
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`
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`
`Irradiated
`609#28353~
`TESTO.PRS
`
`TIME (Days)
`
`:22 24 26 28 30
`
`I
`
`I
`
`I
`
`I
`
`•
`
`I
`
`I
`
`..... Microcapsules
`+ Microspheres
`
`Cumulative Percent Released
`
`Microspheres and Microcapsules (n=3)
`
`Figure 3. In Vitro Release of Testosterone from
`
`0
`0% ..
`10°!0
`20%
`30%
`40%
`50%
`60%
`70%
`SQOA,
`90o/o
`100~~~~~~~~~-------------------------------------,
`
`10 12 14 16 18 20
`
`. «
`
`I
`
`!I
`
`I
`
`I
`
`8
`I
`
`6
`I
`
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`
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`I
`
`AMN1014
`IPR of Patent No. 7,919,499
`
`

`

`'"""" = N =
`
`'""""
`
`"'--...1
`'"""" u.
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`rJl
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`
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`
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`
`TESTO.PRS
`
`TIME (Days)
`
`7 14 21 28 35 42 49 56 63 70 77 84 91 98
`I
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`
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`
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`
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`
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`
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`
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`
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`
`8.7 nmoi/L Threshhold
`
`I
`
`• ._a
`
`-14 -7 0
`01
`I
`5....
`
`I
`
`10
`
`15
`
`20
`25
`30
`
`35
`40--------------------------------------------~
`
`Plasma Testosterone Level ( nmoi/L)
`
`After Viatrel™ Testosterone Microcapsule Injection
`Figure 4. Plasma Testosterone in Human Subjects
`
`(n=7) (± SEM)
`
`-Threshhold
`... Average (n=7)
`I ±1 SEM
`
`AMN1014
`IPR of Patent No. 7,919,499
`
`

`

`""""' = N = """"'
`
`"'--...1
`""""' u.
`"'--...1
`rJl
`d
`
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`
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`
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`
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`
`e •
`
`NALMFN.PRS
`
`65
`
`60
`
`55
`
`50
`
`45
`
`+5% Natmefene
`... 2°h Nalmefene
`Wall Composition
`
`I
`
`~ •
`
`Cumulative Percent Released
`
`6QOA,
`70%
`80%
`90%
`1QQO!b I
`
`Figure 5. Effect of Wall Composition on 1n Vitro Release of
`
`Nalmefene from Microcapsules
`
`70
`0% ~--~----~--~---r--~----T---~--~--~~--~---r--~----T---~
`10%
`20°/o
`30°/o
`40%
`50%
`
`TIME (Days)
`40
`
`30
`
`35
`
`25
`
`20
`
`15
`
`1 0
`
`5
`
`0
`
`AMN1014
`IPR of Patent No. 7,919,499
`
`

`

`""""' = N = """"'
`
`"'-....1
`""""' u.
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`rJl
`d
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`
`NALMFN.PRS
`
`1
`
`54
`
`'I
`
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`
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`
`TIME (Days)
`12
`26
`I
`11
`
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`
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`
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`
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`
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`11
`
`Post-Nalmefene
`
`I
`
`1
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`35------------------------------------------------------------------------------~
`
`CJ20 mglkg IM
`Microcapsule Dose
`
`P re-Nalm efene
`
`Figure 6. Response of Nalmefene Microcapsule-
`
`Morphine Sulfate Challenge (n=3)
`Treated Monkeys to 3 mg/kg IM
`
`OVERT SIGNS (+SEM)
`
`AMN1014
`IPR of Patent No. 7,919,499
`
`

`

`""""' = N = """"'
`
`"'--...1
`""""' u.
`"'--...1
`rJl
`d
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`
`I
`
`6
`8
`10
`12
`14
`16
`18
`20
`22
`24--------------------------------------------------~
`
`... Double Dose
`~Single Dose
`:I: ±/SEM
`
`Plasma Naltrexone (ng/ml)
`
`Figure 7. Naltrexone Plasma Level in Six Human Subjects After Single
`
`and Double SC Injections of Depot rex TM
`
`NALT06 PRS
`
`40
`
`!l:e •-
`
`35
`
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`
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`
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`
`25
`:_
`
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`
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`
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`
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`
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`
`TIME (Days)
`15
`
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`
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`
`-
`
`6
`0---
`2·:8 8
`...
`
`0
`
`41 ~----x-
`
`AMN1014
`IPR of Patent No. 7,919,499
`
`

`

`""""' = N = """"'
`
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`""""' u.
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`rJl
`d
`
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`
`('D
`
`BUPRN-M.PRS
`GC-MS Utah
`
`49
`.
`
`42
`
`-
`
`35
`
`TIME (Days)
`21
`
`28
`
`14
`
`-
`
`7
`.
`
`0
`0 .
`
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`
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`
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`
`2.5--------------------------------------------------------------------------------------------
`
`Plasma nor-Buprenorphine (ng/ml)
`
`+ nor-Buprenorphine
`..;:.4. Buprenorphine
`I ±I SEM
`
`1.5
`
`2
`
`((Lot 058-Dose= 58 mg Buprenorphine Base)
`
`Figure 8. Plasma Level of Buprenorphine and nor-Buprenorphine in 5 Heroin Addicts
`
`Following SC Injection of Norvex™ Depot Buprenorphine Microcapsules
`
`AMN1014
`IPR of Patent No. 7,919,499
`
`

`

`""""' = N = """"'
`
`"'--...1
`""""' u.
`"'--...1
`rJl
`d
`
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`0 .....
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`
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`
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`
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`
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`0
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`
`~ = ~
`
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`
`e •
`
`BUPRN-M.PRS
`
`Post Depot Weeks
`
`6
`
`5
`
`4
`
`3
`
`1
`0
`
`Historical Control
`
`14
`
`I
`
`I
`
`11_6
`
`Figure 9. Effect of Norvex™ Depot Buprenorphine SC Injection
`
`on VAS Drug Effect in Response to Opioid Challenge
`
`in 5 Heroin Addicts
`
`VAS Score
`
`0
`5
`10
`15
`20
`25
`30
`35
`40
`45~
`50~--~-----------------------
`
`AMN1014
`IPR of Patent No. 7,919,499
`
`

`

`US 7,157,102 B1
`
`1
`MULTI-LAYERED MICROCAPSULES AND
`METHOD OF PREPARING SAME
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`Embodiments of the present invention relate generally to
`the field of microparticles for the controlled delivery of
`pharmacologically active agents over a prolonged period of
`time. In particular, embodiments of the present invention are
`directed to microparticles having one or more layers or
`coatings that are capable of delivering one or more phar-
`macologically active agents either simultaneously or in
`series over a prolonged period of time, at the same or
`different release rates. Embodiments of the present invention 15
`are further directed to methods for the production of micro-
`particles having a high concentration of active ingredient
`and a low residual solvent concentration.
`2. Description of Related Art
`Microparticles, suitable for the controlled release of an
`active ingredient, such as various drugs, and a process for
`preparing and using said microparticles, have been
`described for example, in U.S. Pat. No. 4,568,559, U.S. Pat.
`No. 4,623,588, and U.S. Pat. No. 5,648,097, all of which are
`hereby incorporated by reference in their entireties. As
`disclosed, microparticles are typically comprised of solid
`composite core material of a uniform dispersion of finely
`divided active ingredients or solid solution of a drug in a
`core-forming polymer and include a generally outer wall
`coating about the composite core material, to provide for the
`desired controlled or sustained release of the active ingre-
`dient from the microparticles. Further, the active ingredient
`may comprise a dissolved or finely divided, active, drug-
`type ingredient for the treatment of a marmnal and generally
`the core forming polymers would be comprised of a biode-
`gradable polymer with the outer uniform wall thickness also
`including a biodegradable polymer, with a size of typically
`less than about 200 microns to provide for an injectable form
`for the microparticles.
`The particles are typically prepared with varying organic
`solutions of the active ingredient and the core-forming
`polymer such as, for example, employing methylene chlo-
`ride to aid in the solution of the active ingredient and then
`removing the solvent to provide a dry composite admixture
`of the active ingredients and the core-forming polymer
`material. The dry composite admixture so prepared is then
`pulverized or ground-up and then screened to provide com-
`posite core particles of a defined particle size. The ground-
`up, reduced, and selected drug polymer admixture may then
`be coated with a film-forming polymer material to form a
`microcapsule having a generally uniform outer wall coating
`about the ground-up composite core material used.
`In other methods of making microparticles having a core
`of active ingredient material, a polymer material is dispersed
`in a solvent and blended with a solution containing an active 55
`ingredient to be encapsulated by the polymer. As solvent is
`withdrawn from the dispersion, e.g., by evaporation or
`extraction, microparticles of the polymer material form and
`encapsulate a solution of core active ingredient. See U.S.
`Pat. Nos. 3,523,906 and 3,737,337. U.S. Pat. No. 3,691,090
`describes a process in which a dispersion of a core material
`in organic solvent is added dropwise to an aqueous buffer,
`followed by evaporation of the organic solvent to yield
`microparticles containing a core material. U.S. Pat. No.
`3,891,570 describes a process for preparing micro spheres or
`microcapsules in which a solvent is used to dissolve or
`disperse the polymeric material and is removed by evapo-
`
`2
`ration. U.S. Pat. Nos. 4,389,330 and 4,530,840 describe
`processes of microencapsulating an active ingredient in
`which solvent used to dissolve or disperse polymer material
`is removed in a two-step process involving low pressure
`evaporation of a portion of the solvent followed by an
`extraction of the remaining solvent.
`Another method of preparing microparticles containing
`an active ingredient is to use a coacervating agent, such as
`silicone oil, which promotes polymer material to deposit as
`10 droplets of solvent swollen polymer on water droplets
`containing the active ingredient to be encapsulated. See U.S.
`Pat. Nos. 4,675,189 and 4,897,268. Other methods of pre-
`paring microparticles and microcapsules are disclosed in
`U.S. Pat. No. 4,542,025 and U.S. Pat. No. 5,407,609.
`Conventional methods of microencapsulation use a sur-
`factant at a concentration of greater than 0.1% to stabilize
`the emulsion formed when the polymer solution (usually
`dissolved in a solvent such as methylene chloride, ethyl
`acetate, methyl ethyl ketone, dimethyl sulfoxide or other
`20 suitable organic solvent) is combined with an aqueous
`solution of an active ingredient to be microencapsulated.
`Furthermore, conventional microparticles of many drugs
`having active ingredient concentrations, i.e., on the order of
`40% to 50% w/v, release their active ingredient content very
`25 rapidly and therefore caunot be used for long sustained
`delivery of the drug since a large portion of the drug is
`composed of active ingredient. As a result, their duration of
`activity is short. This occurs especially with drugs that
`require a high dose for therapeutic efficacy. In order to
`30 deliver a sustained dose from these drugs over a maximum
`period of time, it is essential that the microparticles have a
`high drug content. Another problem with conventional
`microparticles is that control of the rate of release of the drug
`from the microparticles is limited to varying the intrinsic
`35 properties of the microparticles such as the size of the
`microparticles, their drug content or the type of polymer
`used. The intrinsic methods for controlling the release of the
`drug are dependent on the properties of the microparticles
`themselves, and are not always available to the formulator
`40 because of limitations in the daily dose of the drug, the
`physical-chemical properties of the drug, desirable duration
`of activity, and rate of degradation of the polymer.
`Therefore, there is a need to develop methods for con-
`trolling the rate of release of the drug that are independent
`45 of intrinsic methods. There is also a need to develop
`microparticles having a high drug content that control the
`rate of release of the drug into surrounding media. Micro-
`particles prepared by conventional methods are generally
`more easily damaged by physical force since the majority of
`50 the microparticle is comprised of active ingredient and not
`the polymer which forms the matrix which holds the micro-
`particle together. As a result, microparticles having high
`drug concentrations and uniform structure from micropar-
`ticle to microparticle are generally difficult to prepare.
`Also, many conventional microcapsules share a common
`limiting feature in that they are designed to deliver a single
`active ingredient at a single release rate since existing
`methods of making microcapsules generally comprise form-
`ing a single polymer wall around a core containing a single
`60 active ingredient. Therefore, a need exists to develop micro-
`capsules which are capable of delivering one or more active
`ingredients at the same or different release rates over a
`prolonged period of time. A further need exists to provide a
`drug delivery device in the form of a multilayered micro-
`65 capsule which can be readily and simply designed to provide
`a specific desired release profile of one or more active
`ingredients tailored to optimize treatment of a particular
`
`AMN1014
`IPR of Patent No. 7,919,499
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`

`US 7,157,102 B1
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`3
`disease or condition within a mannnal, such as a human. A
`further need exists to develop therapeutic methods based
`upon the multilayered microcapsules of the present inven-
`tion for treating one or more disorders with a single micro-
`capsule design. A still further need exists to develop thera-
`peutic methods based upon the multilayered microcapsules
`of the present invention for treating a single disorder with a
`combination of active ingredients, which is connnonly
`referred to as a "cocktail therapy".
`An even still further need exists to provide for new and
`effective microcapsules which avoid at least some of the
`disadvantages of the prior art microcapsules, and which
`provide additional advantages of greater uniformity, size and
`ease in preparation and lower toxic solvent content than the
`prior art microcapsules.
`
`SUMMARY OF THE INVENTION
`
`Embodiments of the present invention relate to a multi-
`layered microcapsule for the controlled release within a
`mannnal, including a human, of one or more active ingre-
`dients such as drug compounds. The term "microcapsule" as
`used herein refers to an inner microparticle core also referred
`to as a "microsphere" which has been encapsulated by one
`or more layers of a polymer, active ingredient, or polymer/
`active and/or inactive ingredient composite or mixture,
`hereinafter referred to generally as "coating layers". The
`inner microparticle core may or may not include the active
`ingredient. For the purposes of describing the present inven-
`tion, the terms "emulsion", "dispersion" and "solution" shall
`be used as appropriate to refer to a mixture or combination
`of polymer and/or active medium and a liquid medium, such
`as a solvent, dispersing, or emulsifYing medium. The micro-
`capsules have certain physical characteristics useful for
`biodegradable delivery systems, including desirable solu-
`bilities and porosities for sustained delivery of an active
`ingredient in a relatively constant manner over periods of
`days, weeks, months, or years.
`According to an alternate embodiment of the present
`invention, a multilayered microcapsule for the controlled
`release of one or more active ingredients is provided that
`includes an inner solid microparticle core, a plurality of
`active ingredient layers with each active ingredient layer
`including an active ingredient alone or in combination with
`a first polymer, and at least one wall layer including a second
`polymer and being contiguous with an active ingredient
`layer. Active ingredient layers can be contiguous with each
`other or they may alternate with wall layers as desired to
`produce a desired active ingredient release profile into
`surrounding media.
`Alternate embodiments of the present invention are
`directed to multi-layered microcapsules which are capable
`of delivering one or more active ingredients either simulta-
`neously or in series over a prolonged period of time at the
`same or different release rates. Additional embodiments of
`the present invention are directed to pharmaceutically
`acceptable formulations which include the microcapsules of
`the present invention and to methods of treating individuals
`or preventing conditions in individuals. Still additional
`embodiments of the present invention relate to novel meth-
`ods for making a drug-loaded microparticle core and a
`multi-layered microcapsule.
`According to one embodiment of the present invention,
`the multi-layered microcapsules have one or more active
`ingredients contained in a single microcapsule. The multi-
`layered microcapsules are designed to include an inner solid
`microparticle core which may or may not contain an active
`
`4
`ingredient which is then coated with one or more alternating
`layers of polymer, active ingredient or polymer/active ingre-
`dient mixtures to produce a multi-layered microcapsule of
`the present invention wherein the polymer or active ingre-
`dient in each layer may be the same or different or have the
`same or different concentration of the polymer or active
`ingredient in other layers.
`Optionally and preferably, the microcapsule includes an
`outer wall layer as the exterior layer of the microcapsule
`10 which is contiguous with an active ingredient layer. The wall
`layer is formed from a biodegradable polymer of sufficient
`thickness and composition to control the rate of sustained
`release of active ingredient from the microcapsule. The outer
`wall layer may, for example, include a water-leachable
`15 material such as a drug or even a plasticizer which is leached
`out during use to provide pores in the outer wall layer to
`increase the rate of release of active ingredient in the interior
`of the microcapsule. It is envisioned that one or more wall
`layers, for example, 2, 3, 4, or 5 wall layers, may also be
`20 internal to the microcapsule and may separate active ingre-
`dient containing layers. Typically, where the polymer is a
`biodegradable polymer, the polymer would comprise a
`homo- or co-polymer of glycolide or lactide monomer.
`Embodiments of the present invention further include
`25 methods of making microparticles, which can be used as a
`core in the multi-layered microcapsule, having a high active
`ingredient concentration and a low concentration of residual
`solvent used in preparing the microparticles. More particu-
`larly, methods are disclosed herein for preparing a micro-
`30 particle containing an active ingredient wherein the active
`ingredient constitutes from 0.1 to 80% or more by weight of
`the microparticle. In the methods of the present invention a
`microparticle core is prepared by any of several well known
`methods such as casting and grinding, emulsification and
`35 solvent evaporation, spraying, palletizing, spinning or roll-
`ing, etc. The core microparticle may or may not contain one
`or more active ingredients or drugs or biologically active
`ingredients. In the methods of the present invention, an
`emulsion is formed at room temperature by mixing an
`40 organic phase, such as of a solubilized or dispersed polymer
`and an active ingredient, with an aqueous phase, such as
`water or an aqueous buffer. During the formation of micro-
`particles of the polymer and active ingredient, the tempera-
`ture of the emulsion is raised from room temperature, such
`45 as according to a preselected temperature gradient, to a
`preselected temperature depending on the polymer, active
`ingredient and solvent selected to form the microparticles.
`The temperature of the emulsion is increased with time in a
`manner to allow the solvent to slowly migrate out of the core
`50 microparticles leaving only low physiologically acceptable
`residual levels and without significantly disturbing the integ-
`rity of microparticle shape or structure, or microparticle drug
`delivery, drug content or other properties
`Embodiments of the present invention also include the
`55 process of preparing a multi-layered microcapsule for the
`sustained or controlled release of one or more active ingre-
`dients, which process comprises coating, such as by spray
`coating, one or more coating layers, preferably generally
`uniform in dimension, in sequence about a solid micropar-
`60 ticle core material, wherein the coating layers comprise one
`or more biodegradable polymers, one or more active ingre-
`dients or a mixture of one or more active ingredients and one
`or more biodegradable polymers, and then recovering a
`multi-layered microcapsule. Each coating layer may be an
`65 active ingredient containing layer having an active ingredi-
`ent alone or in combination with a polymer or it may be a
`wall layer of pure polymer.
`
`AMN1014
`IPR of Patent No. 7,919,499
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`

`US 7,157,102 B1
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`5
`Embodiments of the present invention also include using
`the microcapsules for the sustained or controlled release of
`active ingredient from the microcapsule over a defined time
`period into surrounding media, such as in a mammal. Useful
`time periods include one day, one week, one month, several
`months, one year or longer. The microcapsules of the
`invention may be administered and placed into the environ-
`ment to provide for the controlled release of active ingre-
`dient into the environment by a variety of techniques, for
`example an effective amount of the microcapsules may be 10
`administered to the animal orally, intranasally or parenter-
`ally e.g., intravenously, intramuscularly, subcutaneously,
`intraperitoneally, or the like.
`It is accordingly an object of the present invention to
`provide microcapsules having multiple layers of polymer, 15
`active ingredient or polymer/active ingredient admixture,
`(i.e. 2, 3, 4, 5, 6, 7, 8, 9, 10 or more layers) which are
`biocompatable and biodegradable and which can be used in
`a microcapsule delivery system. It is a further object of the
`present invention to provide methods of making micropar- 20
`ticles having a high concentration of active ingredient and a
`low concentration of residual solvent. It is a further object of
`the present invention to provide methods for the preparation
`of an active ingredient delivery system capable of delivering
`one or more active ingredients in a controlled fashion. It is 25
`a still further object of the present invention to provide
`methods of therapeutically treating individuals by using a
`microcapsule delivery system capable of delivering one or
`more active ingredients as a treatment for or prevention of
`certain disorders. Other objects, features or advantages of 30
`the present invention will become apparent from the fol-
`lowing description taken in conjunction with the accompa-
`nying drawings.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`In the course of the detailed description of certain pre-
`ferred embodiments to follow, reference will be made to the
`attached drawings, in which,
`FIG. 1 is a schematic illustrated diagram of a fluidized bed
`air suspension coating apparatus and process for the pro-
`duction of the microcapsules of the invention.
`FIG. 2 is a graphical representation of the blood level of
`estradiol hormone drug in five post-menopausal women
`from one embodiment of the multilayerd microcapsule of
`the present invention. The core of this microcapsule is
`composed of a polymer micro sphere. On top of this core is
`applied a layer of a mixture of polymer and estradiol
`hormone using the coating apparatus described in FIG. 1.
`Finally, a layer of polymer is applied to seal the hormone/
`polymer layer and to control the rate of release of the
`hormone from the multilayer microcapsule.
`FIG. 3 is a graphical representation of the in vitro release
`of testosterone drug from microspheres and microcapsules.
`The graph shows the significant increase in the duration of
`release from the microcapsules compared to the micro-
`spheres. The microcapsules represent another embodiment
`of the present invention.
`FIG. 4 is a graphical representation of the blood level of
`testosterone drug in seven hypogonadal men from the test-
`osterone containing microcapsules.
`FIG. 5 is a graphical representation of the in vitro release
`of the opioid and alcohol antagonistic drug nalmefene from
`another embodiment of the multilayered microcapsules of
`the present invention.
`FIG. 6 is a graphical representation of the effect of
`morphine injection challenge on the overt behavioral signs
`
`6
`of morphine in monkeys following nalmefene microcapsule
`injection. The monkeys were challenged with morphine
`sulfate over a period of 5 observation sessions (observation).
`Scoring continued at approximately bi-weekly intervals for
`8 weeks.
`FIG. 7 is a graphical representation of the blood level of
`the opioid antagonist drug naltrexone in twelve heroin
`addicts from one embodiment of the microcapsules of the
`present invention.
`FIG. 8 is a graphic representation of the blood level of
`buprenorphine in heroin addicts given a single depot dose of
`microcapsules.
`FIG. 9 is a graphic representation of the effect of a single
`injection of microcapsules containing 58 mg of Buprenor-
`phine on visual analog scaling (VAS) drug effect in response
`to opioid challenge in five heroin addicts.
`
`DETAILED DESCRIPTION OF CERTAIN
`PREFERRED EMBODIMENTS
`
`The principles of the present invention may be applied
`with particular advantage to provide a novel multi-layered
`microcapsule design that is capable of delivering a single
`active ingredient according to one or more controlled release
`rates if desired, or several active ingredients at one or more
`controlled release rates all from within a single microcap-
`sule. The microcapsules can be tailored in any layering
`configuration to achieve delivery of one or more active
`ingredients for a period of days to weeks to months to years
`through a single parenteral injection. By pre-selecting a
`multilayered-microcapsule design, one may tailor a long-
`term controlled release profile for a variety of active ingre-
`dients in a single microcapsule to treat or otherwise prevent
`35 a variety of diseases or conditions.
`According to the teachings of the present invention, the