(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2008/0274194 A1
`Miller et al.
`(43) Pub. Date:
`Nov. 6, 2008
`
`US 20080274194Al
`
`(54) STABILIZED HME COMPOSITION WITH
`SMALL DRUG PARTICLES
`
`(75) Inventors:
`
`_
`Dave A. Miller, Austin, TX (US);
`Jam" T- Mccwvilles Austin’ TX
`(US); James W. McGinity, Austin,
`TX (US); Robert 0. Williams,
`Austin, TX (US)
`
`Correspondence Address:
`CHALKER FLORES, LLP
`2711 LBJ FRWY, Suite 1036
`DALLAS, TX 75234 (US)
`
`(73) Assignee:
`
`BOARD OF REGENTS, THE
`UNIVERSITY OF TEXAS
`SYSTEM, Austin, TX (US)
`
`(21) Appl. No.:
`
`11/718,620
`
`(22) PCT Filed:
`
`Nov. 9, 2005
`
`(86) PCT No.:
`
`PCT/US05/40535
`
`§ 371 (0X1)’
`(2), (4) Date:
`
`Nov. 19, 2007
`
`Related US. Application Data
`
`(60) Provisional application No. 60/626,400, ?led on Nov.
`9, 2004, provisional application No. 60/681,279, ?led
`on May 16, 2005.
`
`Publication Classi?cation
`
`(51) Int. Cl.
`(2006.01)
`A61K 9/14
`(200601)
`A611) 43/00
`(52) us. Cl. ...................................................... .. 424/489
`
`ABSTRACT
`(57)
`A hot-melt extruded composition having ?nely divided drug
`containing particles dispersed Within a polymeric and/ or lipo
`phyllic carrier matrix is provided. The carrier softens or melts
`during hot-melt extrusion but it does not dissolve the drug
`containing particles during extrusion. As a result, a majority
`or at least 90% Wt. of the drug-containing particles in the
`extrudate are deaggregated during extrusion into essentially
`primary crystalline and/or amorphous particles. PEO is a
`suitable carrier material for drugs insoluble in the solid state
`in this carrier. Various functional excipients can be included
`in the carrier system to stabilize the particle size and physical
`state of the drug substance in either a crystalline and/ or amor
`phous state. The carrier system is comprised of at least one
`thermal binder, and may also contain various functional
`excipients, such as: super-disintegrants, antioxidants, surfac
`tants, Wetting agents, stabilizing agents, retardants, or similar
`functional excipients. A hydrophilic polymer, such as
`hydroxypropyl methylcellulose (HPMC E15), polyvinyl
`alcohol (PVA), or poloxamer, and/ or a surfactant, such as
`sodium lauryl sulfate (SLS), can be included in the composi
`tion. A process for preparing the extrudate is conducted at a
`temperature approximating or above the softening or melting
`temperature of the matrix and beloW the point of solubiliza
`tion of drug-containing particles in the carrier system, and
`beloW the recrystallization point in the case of amorphous ?ne
`drug particles.
`
`Stabilizing and non-solubiliszing carrier
`
`Fine drug particles
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 1 0f 20
`
`US 2008/0274194 A1
`
`Stabilizing and non-solubiliszing carrier
`
`Fine drug particles
`
`Fine drug particles
`
`Page 2
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 2 0f 20
`
`US 2008/0274194 A1
`
`9
`
`V . k
`
`X8
`
`Page 3
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 3 0f 20
`
`US 2008/0274194 A1
`
`ll. I I I l I II |l _ l. I: II II \\ _
`
`
`
`ans wbnowl
`
`cue Enema. -
`
`
`
`
`
`
`0E 885m “2%: I l I I - 83.
`
`Q2 Q2 Q2 8? o: 08
`
`oa?? \
`
`n
`
`
`
` . _ _ . _ h _ . ommdv
`
`
`
`
`
`0mm umugxm “$2.61 | 06 I l I I l
`
`
`
`
`
`$3. \
`
`
`o ONHRP | m6
`
`
`
`- n30. w
`F
`
`- 83 ,w\
`m
`
`W I
`
`0N .GE
`
`95 6Q
`
`
`
`0o.m> E?ozcb AOL PSEEQEE. . a: Em C N
`
` c2 09 03. our 02 om om 0v ow o . _ ¢ _ . _ _ _ _ _ _ _ _ - l
`
`
`86> 5225 6L a s8 ,5 9m.
`
`H \ l _...
`
`I m._‘.
`
`- $8.
`
`Heat Flow (Wig)
`
`Page 4
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 4 0f 20
`
`US 2008/0274194 A1
`
`FIG. 3A
`
`FIG. 35
`
`FIG. 3C
`
`Page 5
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 5 of 20
`
`US 2008/0274194 A1
`
`I
`
`
`
`us:9.3.N._._”0_>_n=._uOmn_IIII
`
`mg:Esosaznoma
`
`
`
`mg:cueos_n__._dmn_
`
`
`
`ms:2.“$3N._._”U_>_n=._”Om_n_IIIII
`
`o.mE~_
`
`\1
`
`M.Mmm9.mFaH
`
`9:
`
`2:
`
`
`
`wo.m>_mm..m>_::
`
`
`
`8..2=_m._8Em._.
`
`2..8..2:
`
`of
`
`om:
`
`8.9_mw._m>_cD
`
`oi.ow?9:8
`
`8
`
`ow
`
`om
`
`
`
`Govm._3EmqEm._.
`
`on.0_n_
`
`.5oxm
`
`Heat Flow (W/g)
`
`Page 6
`
`Page 6
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 6 0f 20
`
`US 2008/0274194 A1
`
`FIG. 4A
`
`FIG. 48
`
`FIG. 4C
`
`Page 7
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 7 0f 20
`
`US 2008/0274194 A1
`
`- ~ . _ . - . _ 0 egg
`
`2: Q8 2: 8F 02 8
`
`03> $225 .3 222328 “5 9m.
`
`
`
`
`
`wo.m> E2025 60v EBEmQEB.
`
`9» .QE
`
`ow
`
`cm
`
`an em
`
`T o6
`
`Heat Flow (W/g)
`
`Page 8
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 8 0f 20
`
`US 2008/0274194 A1
`
`Page 9
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 9 of 20
`
`US 2008/0274194 A1
`
`\./
`
`
`
`ms:EweN.:”2m6m._
`
`ms:Eauw._w“omn_IIII
`
`us:AEéN:”m._m”omn_
`
`ms:cuem._w”omn_
`
`U.mm.§.
`
`W10Elm6H
`
`WI.M
`
`
`
`wo.m>_mm.m>_cD
`
`
`
`Govm._3m_maEm._.
`
`om.0_u_
`
`8.2:9:ow_.
`
`
`
`8.9_mw._m>_c_._AOLEEm.mqEw._.
`
`am?89oioN_.
`
`e28
`
`8
`
`9.
`
`on
`
`Heat Flow (Wig)
`
`Page 10
`
`Page 10
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 10 0f 20
`
`US 2008/0274194 A1
`
`FIG. 6A
`
`FIG. 6B
`
`FIG. 6C
`
`Page 11
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 11 of 20
`
`US 2008/0274194 A1
`
`
`
`8.9.835G...ezfiaefi
`
`c28—as52:
`
`
`
`0o.m>_mm_m>E:Govm.3m_maEm.~
`
`2:2:oi.on.‘2:8
`
`8
`
`8
`
`om
`
`om.0_n_
`
`c‘
`
`Q9
`
`MI.Wmmo.mFmeH
`
`
`
`ms__._:5.B_:2§o_£”omn_III.
`
`I/.\
`
`
`
`ms__._Era~25.....eea_on.“omn.
`
`
`
`ms:seaN._.__Sv$Emxo_o%omn_
`
`
`
`ms:92SqaEea_ou“omn_IIIII
`
`Heat Flow (W/g)
`
`Page 12
`
`Page 12
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 12 of 20
`
`US 2008/0274194 A1
`
`1 20
`
`1 00
`
`g 80
`%
`2
`a: 6D -
`m
`o\°
`
`4D -
`
`20
`
`0
`
`1 20
`
`100 -
`
`I
`
`+ Danazol ?ne particle
`dispersion prior!»
`storage
`
`-I— Danazol?ne particle
`dispersion after 3
`month storage
`
`If
`80
`
`I
`100
`
`I
`120
`
`140
`
`Time (min)
`
`I
`
`L
`
`E 80
`a
`2
`& 60 '
`D
`o\ 40
`_
`
`20
`
`‘V
`
`A,
`.
`a
`I M + Danazol ?ne particle dispersion
`prior to storage
`—I— Danazol ?ne particle dispersion
`after 3 month storage
`—A- Amourphous danazol
`dispersion prior to storage
`——x—- Amourphous danazol
`dispersion alter 3 month
`
`'
`
`_
`
`__
`
`D
`
`I
`
`20
`
`I
`
`40
`
`If
`
`6D
`
`I
`
`80
`
`I
`
`100
`
`T—
`
`120
`
`140
`
`Time (min)
`FIG. 8
`
`Page 13
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 13 0f 20
`
`US 2008/0274194 A1
`
`V
`
`f
`
`(D QOFJ'ED
`
`2o
`
`40
`
`6'0
`
`140 160
`60 160 12'0
`Temperature (°C)
`FIG. 9
`
`{so 200
`
`a
`
`b
`
`A A ‘- 0 MW
`5101'52'o2'5 3B
`55
`4b
`45
`so
`2Theta
`FIG. 10
`
`e
`
`Page 14
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 14 0f 20
`
`US 2008/0274194 A1
`
`FIG.11B
`
`Page 15
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 15 0f 20
`
`US 2008/0274194 A1
`
`FIG. 11C
`
`5 1
`
`V k 2
`
`2 R
`
`K B 5
`'
`
`12.9)”.
`
`FIG. 11D
`
`Page 16
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 16 0f 20
`
`US 2008/0274194 A1
`
`1 0O
`
`9O -
`
`8O -
`
`70
`
`8
`g 60
`.9.’
`m 50 .
`D5
`0
`°\ 40 ~
`
`30 -
`
`20
`
`1O 4
`0
`0
`
`100
`
`90 -
`
`80 ~
`
`70 ~
`
`8 60 ~
`Q
`2 50 -
`§
`
`*5
`
`40-
`
`..i
`4- Hot-Melt Exlrudates of PvP-stabilized Amorphous ITZ
`+ PVP-stabilized Amorphous ITZ Particles
`+ Crystalline llraoonazole
`
`10
`
`2O
`
`30
`
`40
`
`50
`
`I
`60
`
`Time (min)
`
`i
`
`.
`
`30 _
`
`20 _
`
`10
`
`+ Extrudates of PVP-slabllized Amorphous ITZ Particles
`
`' + Extrudates of PVP-stabillzed Amorphous I‘IZ Particles
`(2 weeks 40°CI75% RH)
`+ PVP-stabilized Amorphous ITZ Particles
`—I-- PVP-stabilized Amorphous ITZ Particles
`(2 weeks 40°C/75% RH)
`
`0
`
`0
`
`I
`
`10
`
`a
`
`20
`
`‘I
`
`40
`
`F
`
`50
`
`60
`
`l
`
`30
`Time (min)
`FIG. 13_
`
`Page 17
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 17 0f 20
`
`US 2008/0274194 A1
`
`b
`
`C
`
`W 160
`
`20
`
`4b
`
`60
`
`8.0
`
`1210
`
`150
`160
`Temperature (°C)
`FIG. 14
`
`1530
`
`M M _‘ ___ C
`
`M Q‘
`wd
`
`a
`
`b
`
`e
`
`2 Theta
`FIG. 15
`
`Page 18
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 18 0f 20
`
`US 2008/0274194 A1
`
`
`
`
`
`wmmmw?m 0» e593 cowmbcmucoo
`
`w w a P
`
`c
`
`:0
`
`0
`
`+ + -0 F
`
`.m m .2 .2
`
`h u m 9 f B l
`
`m. % U P C m M )6 0 P .m
`
`s .M 0 E A S
`M W W. m ‘m
`
`w A m m m
`
`w w + + _
`
`M w m . M M w
`
`A B m 1 .m. .W
`
`m 5 ?5
`
`w .m w
`
`S S 0 M b n
`w m 4 B .m W -4
`h ..m 0%. a B
`w mm 8 m
`
`m w m
`
`1 l1
`
`6 A? 6
`
`O O O O 0 O 0 0 O O 0 0 0 0 O
`
`- - - _ T _ llllrlll
`
`
`
`[9,. III, 0
`
`o 0 0 0 O 0
`
`Time (hours)
`FIG..17
`
`Page 19
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 19 0f 20
`
`US 2008/0274194 A1
`
`100
`
`£1... A
`
`% Released
`
`90 -
`
`so -
`
`70 i
`
`50 A
`
`3O -
`2O _
`
`10
`
`0
`
`+ Extrudates of PVP-stabiiized Amorphous CBM Particles
`+ Extrudates of PVP-stabilized Amorphous CBM Particles
`(2 weeks 40°C/75% RH)
`+ PVP-stabiiized Amorphous CBM Particles
`—I—- PVP-stabiized Amorphous CBM Particles
`(2 weeks 40°CI75% RH)
`
`I
`
`1 0
`
`l
`
`20
`
`T
`
`30
`
`I
`
`40
`
`I
`
`50
`
`Time (min)
`
`25
`
`45
`
`55
`
`145
`
`155
`
`185
`
`125
`105
`8.5
`Temperature (°C)
`FIG. 19
`
`Page 20
`
`

`
`Patent Application Publication
`
`Nov. 6, 2008 Sheet 20 of 20
`
`US 2008/0274194 A1
`
`FIG; 20A
`
`FIG. 20B
`
`Page 21
`
`Page 21
`
`

`
`US 2008/0274194 A1
`
`Nov. 6, 2008
`
`STABILIZED HME COMPOSITION WITH
`SMALL DRUG PARTICLES
`
`FIELD OF THE INVENTION
`
`[0001] The present invention concerns a hot-melt extruded
`pharmaceutical composition comprising a therapeutic com-
`pound dispersed as fine particles in a stabilizing and non-
`solubilizing carrier system and a method of preparation
`thereof. The invention also concerns a process of preparing a
`hot-melt extruded pharmaceutical composition wherein
`small amorphous or crystalline particles ofa therapeutic com-
`pound are dispersed as individual particles during hot-melt
`extrusion and after storage for extended periods of time. The
`hot-melt extruded composition provides stable release prop-
`erties ofthe therapeutic compound over an extended period of
`storage.
`
`BACKGROUND OF THE INVENTION
`
`[0002] Many researchers have utilized hot-melt extrusion
`techniques to produce pharmaceutical preparations in various
`forms. Zhang and McGinity utilized hot-melt extrusion to
`produce sustained release matrix tablets with PEO and poly-
`vinyl acetate, and more generally non-film preparations with
`polyethylene oxide (PEO) (1 -3). Kothrade et al. demonstrated
`a method of producing solid dosage forms of active ingredi-
`ents in a vinyllactam co-polymeric binder by hot-melt extru-
`sion (4). Aitken-Nichol et al. used hot-melt extrusion methods
`to produce acrylic polymer films containing the active
`lidocaine HCl (5). Grabowski et al. produced solid pharma-
`ceutical preparations of actives in low-substituted hydrox-
`ypropyl cellulose using hot-melt extrusion techniques (6).
`Repka and McGinity used hot-melt extrusion processes to
`produce bioadhesive films for topical and mucosal adhesion
`applications for controlled drug delivery to various mucosal
`sites (7, 8). Robinson et al. produced effervescent granules
`with controlled rate of effervescence using hot melt extrusion
`techniques (3). Breitenbach and Zettler produced solid
`spherical materials containing biologically active substances
`via hot-melt extrusion (9). De Brabander et al. demonstrated
`sustained release mini-matrices by utilizing hot-melt extru-
`sion techniques (10, 11).
`[0003]
`Pharmaceutical formulations comprised of active
`compounds finely and homogenously dispersed in one or
`more polymeric carriers have been described as solid disper-
`sions, glass solutions, molecular dispersions, and solid solu-
`tions. The term solid dispersion has been used as a general
`term to describe pharmaceutical preparations in which the
`active compound is dispersed in an inert excipient carrier in a
`size range from course to fine. Glass solution, molecular
`dispersion, and solid solution refer specifically to prepara-
`tions in which amorphous forms of a crystalline active com-
`pound are formed in-situ and dispersed within the polymer
`matrix during the hot-melt extrusion process.
`[0004] Many researchers have produced such preparations
`with various active compounds and polymeric carriers using
`hot-melt extrusion techniques. Rosenberg and Breitenbach
`have produced solid solutions by melt extruding the active
`substance in a nonionic form together with a salt and a poly-
`mer, such as polyvinylpyrrolidone (PVP), vinylpyrrolidi-
`none/vinylacetate (PVPVA) copolymer, or a hydroxyalkyl-
`cellulose (12). Six et al., Brewster et al., Baert et al., and
`Verreck et al. have produced solid dispersions of itraconazole
`with improved dissolution rates by hot-melt extrusion with
`
`various polymeric carriers including hydroxypropylmethyl-
`cellulose, Eudragit E100, PVPVA, and a combination of
`Eudragit E100 and PVPVA (13-19). Rambaldi et al. produced
`solid dispersions of itraconazole by hot-melt extrusion with
`hydroxypropyl-beta-cyclodextrin and hydroxypropylmeth-
`ylcellulose for the improvement of aqueous solubility (20).
`Verreck et al. produced solid dispersions of a water-insoluble
`microsomal
`triglyceride transfer protein inhibitor with
`improved bioavailability by hot-melt extrusion (21). Huls-
`mann et al. produced solid dispersions of the poorly water
`soluble drug 17 [3-estradiol with increased dissolution rate by
`hot melt extrusion with polymeric carriers such as polyethyl-
`ene glycol, PVP, and PVPVA along with various non-poly-
`meric additives (22). Forster et al. produced amorphous glass
`solutions with the poorly water soluble drugs indomethacin,
`lacidipine, nifedipine, and tolbutamide in PVP and PVPVA
`demonstrating improved dissolution compared with the crys-
`talline forms (23). In this article, it is also seen that after
`storage of the extrudates at 25° C. and 75% relative humidity
`only compositions containing indomethacin and polymer in a
`one to one ratio remained completely amorphous. Formula-
`tions of the remaining drugs and formulations with increased
`indomethacin concentration showed recrystallization on stor-
`age. This
`recrystallization was
`shown to significantly
`decrease the dissolution rate of the active. It should also be
`
`noted that stability studies were not performed at elevated
`temperatures in this study. It would be expected that elevated
`temperatures would increase the occurrence and extent of
`recrystallization.
`[0005] The previous reference reveals the inherent instabil-
`ity of amorphous dispersions produced by hot-melt extrusion
`techniques. Although many articles demonstrate the produc-
`tion of amorphous solid dispersions and the resulting
`improvement of drug dissolution rate, very few discuss the
`stability of such preparations on storage. From the work of
`Foster et al. and an understanding of the thermodynamics of
`amorphous systems, it can be concluded that recrystallization
`of amorphous solid dispersion formulations on storage is a
`common problem. The amorphous state is thermodynami-
`cally metastable, and therefore it is expected that amorphous
`compounds will assume a stable crystalline conformation
`with time, as well as in response to perturbations such as
`elevations in temperature and exposure to moisture. In an
`extruded formulation, amorphous drug particles will agglom-
`erate and crystallize with increasing storage time, elevated
`temperature, or exposure to moisture, essentially precipitat-
`ing out of the carrier. This progression towards phase sepa-
`ration during storage results in a time dependant dissolution
`profile. A change in dissolution rate with time precludes the
`successful commercialization of a pharmaceutical product.
`[0006] The article by Foster et al. also demonstrates the
`limitation of drug loading in amorphous solid dispersions by
`hot-melt extrusion. It is seen in this article that recrystalliza-
`tion of indomethacin on storage is induced when the concen-
`tration of indomethacin is increased from 1:1 to 4:1 drug to
`polymer ratio. Six et al. demonstrated immiscibility of itra-
`conazole and Eudragit E100 when extruded at 140° C. and
`phase separation on processing at concentrations greater than
`13% and 20% (w/w) when extruded at 168° C. and 180° C.,
`respectively (14-16). Six et al. also demonstrated a single
`phase system of itraconazole and PVPVA at drug concentra-
`tions up to 80% (w/w), however only a slight improvement of
`the dissolution rate was achieved (16). Kearney et al. showed
`phase separation of an anti-inflammatory drug, CI-987, in
`
`Page 22
`
`Page 22
`
`

`
`US 2008/0274194 A1
`
`Nov. 6, 2008
`
`PVP at drug concentrations greater than 19% (w/w) for solid
`dispersions prepared by solvent evaporation methods (24).
`Verreck et al. demonstrated an amorphous dispersion of itra-
`conazole in HPMC at a concentration of 40% drug, with
`improved dissolution rate and chemical and physical stability
`for up to 6 months at various temperature and humidity con-
`ditions (17). In a follow up article, Six et al. showed phase
`separation of itraconazole from identical HPMC carrier sys-
`tems at a concentration of 60% drug (13).
`[0007] The difficulty of producing stable single phase
`amorphous dispersions ofhigh drug loading can be seen from
`references such as those given above. The appearance of a
`second phase of the active compound on processing or on
`storage would result in a time dependent biphasic dissolution
`profile, and would therefore not be considered an acceptable
`pharmaceutical preparation.
`[0008] Although there have been many reports of success-
`ful production of solid dispersions by hot-melt extrusion that
`show improved dissolution rates of poorly water soluble
`drugs, the absence of numerous marketed products based on
`this technology is evidence that stability problems remain a
`major obstacle for successful commercialization of such a
`pharmaceutical preparation.
`[0009] There are several methods well known in the phar-
`maceutical literature for producing fine drug particles in the
`micro or nanometer size range. These methods can be divided
`into three primary categories: (1) mechanical micronization
`(2) solution based phase separation and (3) rapid freezing
`techniques.
`[0010] Mechanical micronization is most commonly done
`by milling techniques that can produce particles in the range
`of 1 to 20 microns. The most common processes utilized for
`this type of mechanical particle size reduction are ball and jet
`milling. Milling drug particles by these processes can reduce
`primary drug particles to micron-sized particles, however
`high surface energy results in aggregation of primary par-
`ticles which to an extent negates the milling process. Nykarnp
`et al. and Carstensen et al. demonstrated a melt grinding and
`jet milling technique to produce drug loaded microparticles
`of polylactic acid or polylactic-co-glycolic acid with mean
`particle size in the range of four to six microns (25, 26).
`[0011] There are many solution based phase separation
`processes documented in the pharmaceutical literature for
`producing micro and nano-sized drug particles. Some of the
`more commonly known processes are spray drying, emulsi-
`fication/evaporation, emulsification/solvent extraction, and
`complex coacervation. Some of the lesser-known processes
`are, for the sake of brevity, listed below along with their
`respective illustrating references: a) gas antisolvent precipi-
`tation
`(GAS)—(27)
`and WO9003782
`EP0437451
`EP0437451 DK59091; b) precipitation with a compressed
`antisolvent (PCA)—(28) and U.S. Pat. No. 5,874,029; c)
`aerosol solvent extraction system (ASES)—(29); d) evapora-
`tive precipitation into aqueous solution (EPAS)—(30) US
`patent application 20040067251; e) supercritical antisolvent
`(SAS)—(31); f) solution-enhanced dispersion by supercriti-
`cal fluids (SEDS)—(32); g) rapid expansion from supercriti-
`cal to aqueous solutions (RESAS)—(33); and h) anti-solvent
`precipitation.
`[0012]
`Freezing techniques for producing micro or nano-
`sized drug particles are listed below along with their respec-
`tive illustrating references: a) spray freezing into liquid
`(SFL)—(34) WO02060411 USPTO App. # 2003054042 and
`2003024424; and b) ultra rapid freezing (URF)—(35).
`
`It should be noted that fine drug particles produced
`[0013]
`by solution-based phase separation or rapid freezing tech-
`niques are often amorphous in nature. Theses amorphous
`particles can be stabilized by compelxation or coating during
`the production process with one or more excipient carriers
`having high melting points or glass transition temperatures.
`Stabilized amorphous fine drug particles can be formulated
`into the present preparation in the same manner as crystalline
`fine drug particles. The high shear of the hot-melt extrusion
`process will effectively deaggregate and disperse the amor-
`phous drug particles (likely to be aggregated before extrusion
`due to high surface energy as stated in the next paragraph) into
`the stabilizing and non-solubilizing carrier thereby separating
`the aggregated particles into primary particles that are stabi-
`lized against aggregation and agglomeration on processing
`and storage by the carrier system. The excipient system with
`which the amorphous drug particles are complexed or coated
`will prevent recrystallization during hot-melt extrusion and
`storage of the amorphous drug-containing particle domains
`that are dispersed in the stabilizing and non-solubilizing car-
`rier matrix. The benefit of this form of an amorphous disper-
`sion compared to a traditional amorphous dispersion is that
`the formation of fine amorphous drug particles is not depen-
`dent on the solubility of the drug in the carrier system, since
`the amorphous drug particles are not formed in situ by the
`solubilization of the crystalline drug particles by the carrier
`system.
`It has been reported that fine drug particles produced
`[0014]
`by processes such as those listed above exhibit high surface
`energy resulting in strong cohesive forces between particles.
`Zimon showed that powders of fine particles are likely to
`aggregate because the force of detachment is dependent on
`particle mass which is small in the case of fine particles (36).
`The forces of cohesion between individual fine particles are
`therefore greater than the forces of detachment, and thus
`particle aggregates form. French et al. demonstrated that the
`forces of cohesion betweenparticles increase with decreasing
`particle size (37). Therefore, the extent of aggregation is
`increased as particle size is reduced.
`[0015] Aggregation offine particles results in an increase in
`the apparent particle size, consequently, particle size reduc-
`tion is somewhat negated. In order to achieve the full benefit
`of particle size reduction, i.e. accelerated dissolution rate,
`aggregates must be reduced to individual particles when
`dosed. Lui and Stewart demonstrated a reduction in dissolu-
`
`tion rate of benzodiazepines with an increasing extent of
`particle aggregation (38).
`[0016]
`Particle agglomeration with storage also causes an
`increase in apparent particle size, and a corresponding
`decrease in dissolution rate. Ticehurst et al. demonstrated
`
`agglomeration of micronized revatropate hydrobromide
`when stored at greater than 25% relative humidity (39).
`Therefore, in the production of an ideal solid dosage form
`containing fine drug particles, aggregates would be separated
`and stabilized as individual particles by a carrier system dur-
`ing processing. The carrier system would also function to
`impede particle aggregation and agglomeration on storage at
`ambient and accelerated temperature and humidity condi-
`tions.
`
`[0017] There have been few published reports of the suc-
`cessful incorporation of fine drug particles into a traditional
`dosage forms. Hu et al. developed an immediate release tablet
`of Danazol micronized powder by the SFL process, however
`only 5.3% drug loading was reported (40). Authors have also
`
`Page 23
`
`Page 23
`
`

`
`US 2008/0274194 Al
`
`Nov. 6, 2008
`
`reported on the oral delivery of fine drug particles in the form
`of a stabilized liquid suspension (41, 42). There are two
`important limitations of delivering fine drug particle formu-
`lations in a liquid suspension, namely the instability of the
`preparation and the commercial limitation of shipping sus-
`pensions. Liquid suspensions are known to be unstable on
`storage due to agglomeration, and sedimentation, as well as
`caking of suspended particles. Commercially it is not ideal to
`formulate a pharmaceutical preparation as a suspension due
`to the cost of shipping the excess weight ofthe liquid vehicle,
`as compared to a solid dosage form.
`[0018]
`Prior art examples such as those given above dem-
`onstrate the ongoing need for the advantageous properties of
`the present invention for the delivery of drug from a hot-melt
`extruded composition comprising fine drug particles.
`
`SUMMARY OF THE INVENTION
`
`[0019] The present invention seeks to overcome some or all
`of the disadvantages inherent in the above-mentioned com-
`positions and methods. The present invention allows for high
`drug loading of fine drug particles in a stable and easily
`portable solid dosage form. In addition, the preparation can
`be formulated to provide a variety of drug release profiles to
`most sites of administration.
`
`[0020] The present invention relates to pharmaceutical for-
`mulations comprised of active compounds finely and homog-
`enously dispersed in one or more polymeric carriers that are
`produced by hot-melt extrusion techniques. Such prepara-
`tions have been described as solid dispersions, glass solu-
`tions, molecular dispersions, and solid solutions.
`[0021] The composition herein may be formulated to avoid
`the problem of phase separation with increasing concentra-
`tion by incorporating into the carrier system crystalline fine
`drug particles or stabilized amorphous fine drug particles
`produced prior to extrusion. Additionally, by dispersing crys-
`talline or stabilized, preformed amorphous fine drug particles
`into the non-solubilizing, stabilizing carrier system via the
`high shear extrusion process, problems of recrystallization of
`amorphous domains, as well as particle aggregation and
`agglomeration are overcome.
`[0022] The present invention addresses the problem of
`physical instability of traditional solid dispersions and the
`resulting time-dependent drug release profile by dispersing,
`via hot-melt extrusion, fine drug particles in a thermodynami-
`cally stable crystalline state, or in a stabilized amorphous
`state into a polymeric carrier which will act to separate and
`isolate individual drug particles, thus preventing aggregation
`and agglomeration during processing and on storage. The
`carrier is formulated such that it will not substantially com-
`promise the integrity of the individual drug particles during
`extrusion, such as by dissolving all or a significant part of the
`drug particles.
`[0023] This invention also relates to the field of fine particle
`technology in that fine particles produced from any fine par-
`ticle production technology can be incorporated into the
`claimed pharmaceutical preparation.
`[0024] The present invention can be formulated to achieve
`an advantageous dosage form comprising fine drug particles.
`Processing powders of fine drug particles with a stabilizing
`and non-solubilizing carrier system by hot-melt extrusion one
`or more times reduces particle aggregation and stabilizes
`them as individual fine drug particles. The resulting product is
`
`a solid dispersion of fine particles stabilized by the carrier
`system, wherein the composition maintains primary particle
`integrity on storage.
`[0025] One aspect of the invention provides a hot-melt
`extruded pharmaceutical composition comprising an effec-
`tive amount of a therapeutic compound dispersed as fine
`particles in a stabilizing and non-solubilizing carrier system.
`The fine drug-containing particles are dispersed within the
`carrier system via hot-melt extrusion as discrete particles in a
`size range of less than one hundred microns, less than twenty
`microns, or less than five microns. A substantial majority, e.g.
`at least 75% wt., of the particles are not agglomerated or
`aggregated by the hot-melt extrusion process used to prepare
`the composition. In other words, at least 75% wt. of the
`particles are present in unagglomerated form.
`[0026] Another aspect of the invention provides a method
`ofpreparing a hot-melt extruded pharmaceutical composition
`comprising fine drug-containing particles dispersed in a sta-
`bilizing and non-solubilizing thermally processable carrier,
`the method comprising the steps of:
`[0027]
`providing a charge of fine drug-containing particles
`of a therapeutic compound;
`[0028]
`providing a charge of stabilizing and non-solubiliz-
`ing hot-melt extrudable carrier; and
`[0029] mixing and hot-melting extruding the charges to
`form the hot-melt extruded pharmaceutical composition;
`wherein a substantial majority ofthe fine drug particles are
`not agglomerated or aggregated as a result of the step of
`hot-melt extruding.
`[0030] The invention also provides a pharmaceutical solid
`dosage form having a stabilized release profile, the dosage
`form comprising a hot-melt extruded pharmaceutical compo-
`sition comprising fine drug particles of a therapeutic com-
`pound dispersed in a stabilizing and non-solubilizing carrier.
`[0031]
`In some embodiments, the stabilizing and non-solu-
`bilizing carrier is hot-melt extrudable meaning it can be hot-
`melt-extruded with no significant thermal degradation. The
`stabilizing and non-solubilizing carrier can also be thermally
`processable, meaning it softens and melts at the processing
`temperature with no significant thermal degradation. In some
`embodiments, a major portion of the stabilizing and non-
`solubilizing carrier is selected from the group consisting of
`polyethylene oxide; polypropylene oxide; polyvinylpyrroli-
`done; polyvinylpyrrolidone-co-vinylacetate; acrylate and
`methacrylate copolymers; polyethylene; polyeaprolactone;
`polyethylene-co-polypropylene;
`alkylcelluloses
`such as
`methylcellulose; hydroxyalkylcelluloses such as hydroxym-
`ethylcellulose, hydroxyethylcellulose, hydroxypropylcellu-
`lose, and hydroxybutylcellulose; hydroxyalkyl alkylcellulo-
`ses such as hydroxyethyl methylcellulose and hydroxypropyl
`methylcellulose; starches, pectins; polysaccharides such as
`tragacanth, gum arabic, guar gun1, sucrose sterate, xanthan
`gum,
`lipids, waxes, mono, di, and tri glycerides, cetyl
`alchohol, steryl alcohol. parafilm waxes and the like, hydro-
`genated vegetable and castor oil, glycerol monostearte, poly-
`olefins
`including xylitol, manitol, and Sorbitol, alpha
`hydroxyl acids including citric and tartaric acid edipic acid
`meleaic acid malic acid, citric acid, enteric polymers such as
`CAP, HPMC AS, shellac, and a combination thereof. The
`stabilizing and non-solubilizing carrier can further comprise
`surfactant carbohydrate, a high HLB surfactant, a low HLB
`surfactant, tablet excipient, filler, binder, disintegrant, super
`disintegrant, protein, peptide, enzyme, hormone, protein or a
`combination thereof. In some embodiments, the stabilizing
`
`Page 24
`
`Page 24
`
`

`
`US 2008/0274194 Al
`
`Nov. 6, 2008
`
`and non-solubilizing carrier is selected from the group con-
`sisting of fixed oil, nonpolar vehicle, and water miscible
`ingredients including alcohols and glycols such as the PEGs
`(poly (ethylene glycol)) and PG (propylene glycol).
`[0032] When provided as a pharmaceutical composition,
`the pharmaceutical composition (or do sage form) can provide
`an immediate or rapid release of therapeutic compound after
`exposure to an environment of use. Alternatively or addition-
`ally, the pharmaceutical composition (or dosage form) can be
`adapted to provide an extended release of therapeutic com-
`pound after exposure to an environment of use. Likewise, the
`pharmaceutical composition (or dosage form) can be adapted
`to provide a delayed release of therapeutic compound after
`exposure to an environment of use.
`[0033] A dosage form containing the pharmaceutical com-
`position can be selected from the group consisting of bead,
`tablet, pill, granulate, powder, capsule, tube, strand, cylinder,
`or film and can be further processed into a powder, pellets, or
`powder coatings for application on various substrates.
`[0034] The pharmaceutical dosage form can be formulated,
`for example, for transdermal, transmucosal, rectal, pulmo-
`nary, nasal, vaginal, ocular, or otic drug delivery, or as an
`implantable drug delivery device.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`[0035] The following figures form part of the present
`description and describe exemplary embodiments of the
`claimed invention. The skilled artisan will, in light of these
`figures and the description herein, be able to practice the
`invention without undue experimentation.
`[0036]
`FIGS. 1a and b depict cross-sectional front eleva-
`tion of an exemplary embodiment of a hot-melt extruded
`composition according the invention.
`[0037]
`FIGS. 211-20, 311-30, 4a-4-c, 511-50 and 6a-6c depict
`electron micrographs of control and exemplary sample for-
`mulations prepared as described herein.
`[0038]
`FIGS. 2d, 3d, 4d, 5d, and 6d depict DSC thermo-
`grams for control and exemplary sample formulations pre-
`pared as described herein.
`[0039]
`FIGS. 7-8 depict comparative drug release p