Note: Descriptions are shown in the official language in which they were submitted.
-
wo 94/12217 215 0 ~ 5 4 PCT/US93/11651
CYCLODEXTRIN AND POLYI~IER
BASED DRUG DELIVERY SYSTEM
F~LD OF IHE INVENTION
The present invention relates to pharm~ceutical formulations
comprising cyclodextrin or cyclodextrin derivatives, carboxy-co,-~ining
polymers and therapeutic agents. The invention further relates to topical
ophthalmic compositions comprising therapeutic agents, particularly, amino-
substituted sterold therapeutic agents, lightly cross-linked carboxy-containing
polymers and selected cyclodextrin derivatives. The invention further relates
to methods of stabilizing and solubilizing amino-substituted steroid therapeuticagents in formulations using cyclodextrin derivatives, in combination with
carboxy-containing polymers.
BACKGROUND
Some valuable therapeutic agents (drugs) are difficult to use because
of their low stability in water or body fluids. Some therapeutic agents suffer
from stability problems and they can cause irritation. Drug instability can
limit the usefulness of pharm~reufir~l compositions containing them by
shortening the shelf-life of the formulations and/or requiring stringent controlof storage conditions. The insolubility of some therapeutic agents can
seriously hamper efforts to utilize the compounds to their full potential
because low solubility limits their bioavailability. Some aminosteroids
illustrate these problems because they tend to be unstable and to have low
solubility in aqueous environments such as body fluids. Instability of
aminosteroids occurs primarily as a consequence of their antioxidative
~r~e~ lies. Because they are potent antioxidants, the aminosteroids are
especially sensitive to oxidative degradation. Moreover, these compounds are
-
WO 9~/12217 ` , - PCT/US93/11651
.
2 1 ~ 4 2
subject to hydrolytic degradation and rearrangement. There is thus a need
for improved pharm~celltir~l compositions comprising therapeutic drugs with
agents that stabilize and solubilize the pharmaceutical compositions and
ameliorate irritation. Providing compositions that deliver the therapeutic agentS to a target site over a prolonged period of time is also an objective for many
applications.
A number of publications are available pertaining to drug delivery
systems, cyclodextrin, and drugs combined with cyclodextrin or
pharm~eeutir~l vehicles. It has not been suggested, however, that
cyclodextrins and carboxy-containing polymers would, when combined,
stabilize and solubilize therapeutic agents and be compatible with one another.
It was also not known that aminosteroids disclosed in International Publication
No. WO 87/01706 and U.S. Patent No. 5,124,154 (discussed below) would
be co-llpatible or stable with the combination of carboxy-cont~ining polymers
with cyclodextrins. Publications pertinent to the background of the present
invention are identified below.
A variety of col"po~iLions have been formulated to deliver drugs to the
eye, skin and other parts of the body in a sllst~ined manner. Sust~ined release
ophth~lmic formulations of an ophth~lmic drug and a high molecular weight
polymer to form a highly viscous gel, for instance, have been described in
Schoenwald et al U.S. Patent No. 4,271,143, issued June 2, 1981 and
Schoenwald et al U.S. Patent No. 4,407,792, issued October 4, 1983.
U.K. Patent Application GB 2007091 A, published May 16, 1979,
describes an ophthalmic composition in the form of a gel comprising an
aqueous solution of a carboxyvinyl polymer, a water-soluble basic substance
and an ophthalmic drug, the gel having a pH of 5 to 8 and a viscosity of
1,000 centipoises to 100,000 centipoises at 20C.
WO 94112217 21~ ~ ~ 5 ~ PCT/US93/11651
U.K. Patent Application GB 2013084 A, published August 8, 1979,
describes an aqueous gel for application to the conjunctival sac of the eye
comprising an ophthalmic drug and a polymer having carboxylic or anhydride
functional groups and a molecular weight in excess of 1,000,000, such as
S carboxypolymethylene, carboxyvinyl and ethylene maleic anhydride polymers.
Robinson U.S. Patent No. 4,615,697, issued October 7, 1986,
discloses a controlled release composition and method of use based on a
bioadhesive and a treating agent, such as an anti-inflammatory agent. The
bioadhesive is a water-swellable, but water-insoluble~ fibrous, cross-linked
carboxy-functional polymer having a plurality of repeating units of which
about 80 percent contain at least one carboxyl functionality and a cross-linkingagent which is substantially free from polyalkenyl polyethers.
U.S. Patent No. 5,192,535, issued March 9, 1993 and ~ignecl to the
~ccignt~ hereof, describes formulation of lightly cross-linked polymers,
preferably ones prepared by suspension or emulsion polymerizing at least
about 90% by weight of a carboxyl-cont~ining monoethylenically unsaturated
monomer such as acrylic acid with from about 0.1 % to about 5% by weight
of a polyfunctional, and preferably difi-n~tion~l, cross-linking agent such as
divinyl glycol (3,4-dihydroxy-1,5-heY~ e), having a particle size of not
more than about 50 ~m in equivalent spherical diameter, with an ophth~lmic
meAir~ment, e.g., the steroid fluorometholone, into suspensions in aqueous
medium in which the amount of polymer ranges from about 0.1 % to about
6.5% by weight, based on the total weight of the aqueous suspension, the pH
is from about 3.0 to about 6.5, and the osmotic pressure (osmolality or
tonicity) is from about 10 mOsM to about 400 mOsM. These new topical
ophthalmic medicament delivery systems have suitably low viscosities which
permit them to be easily a(lmini~tered to the eye in drop form, and hence to
be comfortably ~dmini~tered in con~i~tent, accurate dosages. These
WO 94/12217 ~ PCT/US93/11651
2 1 5 ~ 4
suspensions will rapidly gel in the eye after coming into contact with the eye'stear fluid to a substantially greater viscosity than that of the originally-
introduced suspension and thus remain in place for prolonged periods of time
to provide sllct~ined release of the ophthalmic medicament. See International
Publication Number WO 92/00044 published January 9, 1992 and
International Publication No. WO 89/06964, published August 10, 1989.
International Publication No. WO 87/01706, published March 26,
1987, which discloses a number of aminosteroids and their therapeutic use in
a variety of contexts, as well as ~(lminictration techniques and dosages, does
not disclose treatment or prevention of ophthalmic dice~cec or disorders. Nor
does it disclose topical application to the eye or administration by intraocularinjection.
Applicants' U.S. Patent No. 5,124,154, discloses methods and
compositions which are ~lecigned to enhance the ability of the tissues of the
eye to respond to trauma, to aging, to surgery, to the threat of glaucoma by
increasing intraocular pr~s~ulc:, to thepotential loss of vision from progression
of macular degeneration and the like by supplementing, both acutely and
chronically, the natural ability of the eye to resist oxidative damage. In one
aspect, the '154 invention discloses methods and compositions for preventing
or treating ophthalmic ~ice~ces or disorders in a human or other animal that
is subject to intraocular damage (particularly oxidative intraocular damage)
and in need of improved visual function or prevention of its loss from such
damage, with an ophth~lmiç~lly effective amount of certain amino-substituted
steroids which function as a the-d~ulic agent (particularly an antioxidant
agent) is in an inert vehicle, to arrest processes (particularly oxidation
processes) ~l~m~ging to the eye.
WO 94/12217 2 ~ 5 ~ 5 ~ 4 PCT/US93tll651
Applicants' U.S. Patent No. 5,124,154 further relates to formulations
of aminosteroids with an app-opliate inert vehicle or carrier for prevention or
treatment of ophthalmic ~ es or disorders. Topical, intraocular and
systemic routes of ~dminictration are described. The term "inert vehicle" is
S broadly used in those earlier applications to optionally include adjuvants,
preservatives, buffers, demulcents and anything else that is essentially inert
relative to the therapeutic function (particularly the antioxidant function) of the
aminosteroids as that function relates to eye tissue. Topical form~ ion~
should generally include between 0.01 and 10% by weight, preferably between
0.1 and 5% by weight, of the amino-substituted steroid therapeutic agent in
a suitable polymeric carrier. Polymeric carriers include lightly cross-linked
carboxy-containing polymers (such as polycarbophil), dextran, cellulose
derivatives, polyethyleneglycol 400 and other polymeric demulcents. Other
additions taught as desirably included in the topical formulations include
lS sodium chloride, EDTA (disodium edetate), surfactants, and preservatives
such as BAK (benzalkonium chloride).
Cyclodextrins are cyclic oligos~ch~rides. The most common
cyclodextrins are ~-cyclodextrin, which is composed of a ring of six glucose
residues; ,6'-cyclodextrin, which is composed of a ring of seven glucose
residues; and ~y-cyclodextrin, which is composed of a ring of eight glucose
units. The inside cavity of a cyclodextrin is lipophilic, while the outside of
the cyclodextrin is hydrophilic; this combination of properties has led to
widespread study of the natural cyclodextrins, particularly in connection with
pharm~ceutic~l~, and many inclusion complexes with drugs have been
reported. ,l~-Cyclodextrin has been of special interest because of its cavity
size, but its relatively low aqueous solubility (about 1.8% w/v at 25C) and
attendant nephrotoxicity have limited its use in the pharm~eutic~l field.
WO 94/12217 ~ ~ ~ PCT/US93/11651 ~
21~5~ 6
Attempts to modify prope~ lies of the natural cyclodextrins have
resulted in the development of heptakis (2,6-di-O-methyl)-,~-cyclodextrin,
heptakis (2,3,6-tri-O-methyl)-,B-cyclodextrin, hydroxypropyl-,~-cyclodextrin,
~B-cyclodextrin-epichlorohydrin polymer and others. For a comprehensive
S review of cyclodextrins and their use in pharm~ceutic~l research, see Pitha et
al, in Controlled Drug Delivery~ ed. S.D. Bruck, Vol. I, CRC Press, Boca
Raton, Florida, 125-148 (1983). For an even more recent overview, see
Uekama et al, in CRC Critical Reviews in Therapeutic Dnlg Carrier Systems,
Vol. 3 (1), 1-40 (1987); Uekama, in Topics in Pharmaceutical Sciences 1987,
eds. D.D. Breimer and P. Speiser, Elsevier Science Publishers B.V.
(Biomedical Division), 1987, 181-194; and Pagington, Chemistry in Britain,
May 1987, 455-458.
Inclusion complexes of ~Y-"B- or ~y-cyclodextrin or their mixtures with
a variety of drugs have been described by numerous parties and various
advantages have been attributed to the complexes. These descriptions include
those documents s-~mm~rized in Bodor U.S. Patents Nos. 4,983,586 and
5,024,998, incorporated by reference herein in their entireties and relied upon.Particular reference may be made to Lipari U.S. Patent No. 4,383,992, which
describes inclusion complexes of ~-cyclodextrin itself with a variety of
steroidal hormones (corticosteroids, androgens, anabolic steroids, estrogens
and progestagens). The complexes are said to have improved water solubility
and increased therapeutic response in the eye. However, as noted above, ,~-
cyclodextrin has low aqueous solubility (about 1.8% w/v at 25) with
attendant nephrotoxicity.
Hydroxypropyl-~-cyclodextrin and its preparation by propylene oxide
addition to ~B-cyclodextrin were described in Gramera et al U.S. Patent No.
3,459,731 over 20 years ago. (Gramera et al also described the analogous
preparation of hydroxyethyl-,B-cyclodextrin by ethylene oxide reaction with ,~-
wo 94/12217 2 ~ ~ O ~ 9 PCT/US93/11651
cyclodextrin.) Much more recently, Pitha and co-workers have described the
improved pr~d~ion of this cyclodextrin derivative and its effects on the
dissolution of various drug molecules. Pitha U.S. Patent No. 4,596,795,
dated June 24, 1986, describes inclusion complexes of sex hormones,
S particularly te~lo~eroile, p~uge~ ulle and estradiol, with specific
cyclodextrins, preferably hydroxypropyl-,B-cyclodextrin and poly-,l~-
cyclodextrin. The complexes enable the sex hormones to be s~lcce~fully
delivered to the systemic circulation via the sublingual or buccal route; the
effectiveness of this delivery is believed to be due to "the high dissolution
power of hydrophilic derivatives of cyclodextrins, the non-aggregated structure
of their complexes with steroids, and their low toxicity and irritancy of mouth
tissue". Success with other cyclodextrins, including poly- y-cyclodextrin and
hydroxypropyl-~y-cyclodextrin, have also been noted in the Pitha patent. See
also Pitha et al, J. Pharm. Sci.. Vol. 74, No. 9, September 1985, 987-990,
concerning the same and related studies. Pitha et al also describe in the J.
Pharm. Sci. publication the storage stability of tablets containing a
testosterone/hydroxypropyl-,B-cyclodextrin complex and the lack of toxicity of
the cyclodextrin derivative itself, as well as the importance of the amorphous
nature of the cyclodextrin derivatives and their complexes with drugs in
improving dissolution p~u~llies.
The improved, optimized preparation and purification of
hydroxypropyl-,B-cyclodextrin has been described by Pitha et al, International
Journal of Pharm~reutics, 29, 73-82 (1986). In the same publication, the
authors have described increased water solubility for 32 drugs in concenL.~ted
(40 to 50%) aqueous solutions of hydroxypropyl-~-cyclodextrin; among the
drugs for which the authors have reported improved solubilization are
dexamethasone, estradiol, estriol, ethinylestradiol-3-methyl ether, ethisterone,17-methylte~ le~o.le norethindrone, progesterone, spironolactone and
testosterone. The authors inrlir~ted this to be an extension of their earlier
WO 9~/12217 ' . PCT/US93tll651
21~05~ 8
work with hydroxypropyl-,B-cyclodextrin, which was previously found
effective for oral ~mini~tration of the sex hormones to humans. Their later
work reported in Pitha et al, International Journal of Pharmaceutics, 29, 73-82
(1986), has also been described in Pitha U.S. Patent No. 4,727,064, dated
S February 23, 1988. That patent claims a composition cont~ining an
amorphous complex of cyclodextrin and a drug, and a method of producing
a stabilizing amorphous complex of a drug and a mixture of cyclodextrins
comprising (1) dissolving an intrinsically amorphous mixture of cyclodextrin
derivatives which are water soluble and capable of forming inclusion
complexes with drugs in water; and (2) solubilizing lipophilic drugs into
aqueous media to form a solution and form a solubilized drug/cyclodextrin
complex. The patent describes the preparation of various substituted
amorphous cyclodextrins, including hydroxypropyl-,B-cyclodextrin and
hydroxypropyl-~y-cyclodextrin, the latter by analogous conden~tion of
propylene oxide and y-cyclodextrin.
Uekama et al, CRC Critical Reviews in Therapeutic Drug Carrier
Systems, Vol. 3 (1), 1-40 (1987), have described the characteristics of various
cyclodextrins, including hydroxypropyl-~-cyclodextrin. The authors have
presented data showing improved solubilization in water in the presence of 15
mg/mL of hydroxypropyl-,~-cyclodextrin for the drugs carmofur, diazepam,
digitoxin, digoxin, flull)iplufe,l, indomethacin, isosorbide dinitrate, phenytoin,
prednisolone, plug~Lelune and testc sterone. Uekama et al have indic~t~i that
cyclodextrins at sufficiently high concentrations cause hemolysis, and that the
methylated cyclodextrins have higher hemolytic activity than the natural
cyclodextrins. Hydroxypropyl-,~-cyclodextrin is said to cause hemolysis
bçginning at 4.5 mM. The authors have further indicated that palell~eldl
lmini~tration of large doses of cyclodextrins should be avoided, but that " y-
cyclodextrin and hydroxypropyl-~B-cyclodextrin seem to be useful in drug
wo 94/12217 21 S O ~ 5 ~ PCT/US93/11651
solubilization for injections and liquid preparations used for mucous
membranes. "
JANSSEN PHARMACEUTICA N.V.'s International Patent
Application No. PCT/EP84/00417, published under International Publication
No. W085/02767 on July 4, 1985, has described pharmaceutical compositions
comprising inclusion compounds of drugs, which are unstable or only
sparingly soluble in water, with partially etherified ,B-cyclodextrin derivatives
having hydroxyalkyl and optionally additional alkyl groups. Among the
cyclodextrin derivatives contemplated is hydroxypropyl-~B-cyclodextrin, while
the drugs include nonsteroidal anti-rheumatic agents. steroids, cardiac
glycosides and derivatives of benzodiazepine, benzimidazole, piperidine,
piperazine, imidazole and triazole. Pharmaceutical compositions described in
WO 85/02767 include oral, parenteral and topical formulations, with 4 to 10%
solutions of cyclodextrin derivatives being used to solubilize various drugs.
Improved solubilities of indomethacin, digitoxin, proge~ une,
dexamethasone, hydrocortisone and diazepam using 10% hydroxypropyl-,6'-
cyclodextrin are reported.
The preparation of amorphous water-soluble cyclodextrin derivatives,
including 2-hydroxyethyl-,~-cyclodextrin,3-hydroxypropyl-~B-cyclodextrin and
2-hydroxypropyl-~y-cyclodextrin, is described by Irie et al, Pharmaceutical
Research, Vol. 5, No. 11, 1988, 713-717. That report also addresses the
distribution of the substituents among the glucose residues of the cyclodextrin
ring.
A pharm~ utical evaluation of hydroxyalkyl ethers of ,~-cyclodextrin
has been reported by Yoshida et al, International Journal of Pharm~celltics 46,
1988, 217-222. Aqueous solubilities, surface activities, hemolytic activity and
local irritancy are r~l)Gl led. The data suggest that hydroxyal~yl-~B-
Wo g~/12217 PCT/uS93/11651
2150~5~ lO
cyclodextrins overcome many of the undesirable characteristics of ,~-
cyclodextrin usage in pharm~rellticals.
JANSSEN PHARMACEUTICA N.V.'s European Patent Application
No. 86200334.0, published under EPO Publication No. 0197571 on October
15, 1986, describes y-cyclodextrin derivatives which are ~y-cyclodextrin
substituted with C,-C6 alkyl, hydroxy Cl-C6 alkyl, carboxy C,-C6 alkyl or C,-
C6 alkyloxycarbonyl C,-C6 alkyl or mixed ethers thereof. Among the specific
derivatives named are hydroxypropyl- y-cyclodextrin and hydroxyethyl-~-
cyclodextrin. Compositions comprising the cyclodextrin derivatives and a
drug are also described. See also coll~s~)onding Muller United States Patent
No. 4,764,604, dated August 16, 1988.
Uekama, in Topics in Pharmaceutical Sciences 1987, eds. D.D.
Breimer and P. Speiser, Elsevier Science Publishers B.V. (Biomef~
Division), 1987, 181-194, has described the effects on bio-pharrn~ceulir,~l
properties of maltosyl and glucosyl cyclodextrin derivatives, as well as
hydroxypropyl and other hydrophilic cyclodextrin derivatives, including
enhanced drug absorption. The my~h~ni~m of enhancing drug absorption is
described and the appale.~t stability constants for inclusion complexes of
various drugs with ,6'-cyclodextrin, dimethyl-,~'-cyclodextrin, hyd.op,upyl-,~-
cyclodextrin and maltosyl-,~'-cyclodextrin are given. Drugs studied with these
cyclodextrins include prednisolone, progesterone, spironolactone and
testosterone.
Koizumi et al, Chem. Pharm. Bull. 35 (8), 3413-3418 (1987), have
reported on inclusion complexes of poorly water-soluble drugs with glucosyl
cyclodextrins, namely 6-O-(Y-D-glucosyl-~-CD (G,-~-CD), 6-O-cY-D-glucosyl-
,B-CD (G,-,B-CD) and 6A, 6D-di-O-cY-D-glucosyl-,~-CD (2G,-~-CD).
-
wo 94/12217 21~ n 5 5 ~ PCT/US93/11651
11 ,
Okada et al, Chem. Pharm. Bull. 36(6), ~176-2185 (1988), have
reported on the inclusion complexes of poorly water-soluble drugs with
maltosyl cyclodextrins, namely 6-O-cY-maltosyl-cx-CD (G2-cY-CD), 6-O-~-
maltosyl-~'-CD (G2-,l~-CD), 6-O-o~-maltosyl- y-CD (G2-~y-CD), 6-O-~-
maltotriosyl-~-CD (G3-cY-CD), 6-O-~-maltotriosyl-,B-CD (G3-~-CD) and 6-O-
a!-maltotriosyl-~y-CD (G3- y-CD).
Yamamoto et al, in International Journal of Pharmaceutics 49, 163-171
(1989), have described physicochemical properties of branched ~'-cyclodextrins
such as glucosyl-,B-cyclodextrin, maltosyl-,B-cyclodextrin and dimaltosyl-~-
cyclodextrin, and their inclusion characteristics. Those authors report that thebranched ~-cyclodextrins are better solubilizers for poorly water-soluble drugs
and have less hemolytic activity than ~-cyclodextrin itself, and they suggest
that glucosyl-,~-cyclodextrin and maltosyl-k'-cyclodextrin may be espe~ lly
useful in ~Jarelltel~l prepal~lions.
J~p~n~se Kokai 63-135402 (TOKUYAMA SODA KK), published
June 7, 1988, describes compositions consisting of maltosyl-,B-cyclodextrin
and at least one of digitoxin, nifedipine, flurubiprophene, isosorbide nitrate,
phenytoin, progesLeloi1e or testosterone. The compositions have improved
water solubility and reduced erythrocyte destruction, are safe for humans and
can be used as injections, eye drops, syrups, and for topical and mucous
membrane application.
J~p~nese Kokai 62-281855 (DAIKIN KOGYO KK), published
December 7, 1987, describes stable, water-soluble inclusion compounds of
maltosyl-~-cyclodextrin with a variety of vitamins and hormones, e.g. steroid
hormones such as prednisolone, hydrocortisone and estriol. These lipophilic
vitamins and hormones can thus be used as aqueous solutions.
wO 94/12217 ~ PcT/uss3/11651
2~5~54 12
J~r~nese Kokai 63-036793 (NIKKEN CHEM KK), published
February 17, 1988, describes the preparation of dimaltosyl-~-cyclodextrin and
its general use in medicines.
S J~p~nçse Kokai 62-106901 (NIKKEN CHEM KK), published May 18,
1987, describes the p,c~pal~ion of diglucosyl-,B-cyclodextrin and its general
use for pharm~r~uti~l~.
J~r~n~se Kokai 61-236802 (NIKKEN CHEM KK), published October
'2, 1986, describes the preparation of maltosyl- y-cyclodextrin and its general
use with drugs.
J~r~nese Kokai 61-197602 (NIKKEN CHEM KK), published
September 1, 1986, describes the preparation of maltosyl-~-cyclodextrin and
its expected use in m~icines.
J~r~nese Kokai 61-070996 (NIKKEN CHEM KK), published April 11,
1986, describes the p,epaldtion of maltosyl-~-cyclodextrin and its general use
in pharmaceuticals.
J~p~n.ose Kokai 63-027440 (SANRAKU OCEAN), published
February 5, 1988, describes co.-.positions containing a water-insoluble or
slightly soluble drug together with glucosylated branched cyclodextrin.
Among the drugs mentioned are steroid hormones.
J~p~n~se Kokai 62-164701 (SHOKUHIN SANGYO BIO), published
July 21, 1987, describes the p,~a,~tion of diglucosyl-~-cyclodextrin and its
general use in me~icine
WO 9~/12217 215 0 ~ 5 4 PCT~US93/11651
13
J~p~n~Pse Kokai 62-003795 ('rOKUYAMA SODA KK), published
January 9, 1987, describes production of glucose and maltoligo~cch~ride (2-4
glucose units) derivatives of cY-, ,~- and y-cyclodextrin and their use as
stabilizers for pharm~euti(~
s
Bodor U.S. Patents Nos. 5,0`02,935, issued March 26, 1991, and
5,017,566, issued May 21, 1991, relate to stabilizing the reduce~,
dihydropyridine forms of dihydropyridine ~ pyridinium salt redox systems for
brain-targeted drug delivery by complexation with cyclodextrin selected from
the group consisting of hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and
maltotriosyl derivatives of ,B- and y-cyclodextrins. The compleY~Ps also
provide a means for increasing the ratio of initial brain to lung concentrationsof drug, leading to decreased toxicity. In selected instances, improved water
solubilities are noted as well. In a ~rerelled aspect, the redox system is a
redox carrier system and the reduced, dihydropyridine form can be
~,ese"ted by the formula [D-DHC] wherein [D] is a centrally acting drug
species and [DHC] is the reduced, biooxidizable, blood-brain barrier
penetrating, lipoidal form of a dihydropyridine ~ pyridinium salt redox
carrier. The "centrally acting" drug species is broadly defined and includes
many classes of drugs, including steroids and, specifically, anti-in~ oly
adrenal cortical steroids such as hydlocolLisone, bet~methesone, cortisone,
del~mPth~one, fl~lm~th~onP, fluprednisolone, meprednisone, methyl
prednisolone, prednisolone, prednisone, triamicinolone, cortodoxone,
fludrocortisone, flurandrenolone ~cetonide (flurandrenolide), par~mPth~one
and the like. The "dihydropyridine carrier" or "[DHC]" is defined as any
nontoxic carrier moiety comprising, cont~ining or including the
dihydropyridine nucleus, the only critPrinn being capacity for BBB peneLldLion
and in vivo oxidation to the CO~ onding qual~l"aly pyridium salt. Among
the specific redox carrier drugs for complexation with cyclodextrins in accord
WO 94/12217 ' , ~ PCT/US93/11651
215~5~
with the Bodor ~a~n~ are a number of steroid dcl;va~ s, in~ ing the
d~livali.~cs of desmeth~c~...e and hydlocu~ olle shown belaw:
C~2C 4~d C~33
c =0
H3_ L___OH
HO ~ _ _ CH3
H3C
15 ~/
o~
9-flouro-11~, 17-diLy~u~
methyl-21-{[(1-methyl-1,4-dihydro-
pylidin-3-yl)carbonyl]o~y}pregna-
1,4-diene-3,20-dione
(de~ameth~ ~on e-CDS)
CH3
C3201C~
C--O
H3C
HO ~__ OH
H3C ¦ ¦
40 ~' ~
~
11~, 17-diL~rd~ y-2l-{[(l-methyl-
1,4-dik~,~u~,.idi.l-3-yl)~l,u~l]-
~y}pregn ~ e.,c-3,20-dione
(h~L~ L~l.c-CDS)
SIJ~STITUTE SHEET ~RULE 26)
WO 94/12217 215 0 ~ 5 q PCT/US93/11651
The aforenoted Bodor patents propose complexation with the specific
cyclodextrin derivatives named in the preceding paragraph as a means for
overcoming the stability problems from which the dihydropyridine-cont~ining
redox compounds suffer; the patents note that even in the dry state, the redox
compounds are very sensitive to oxidation as well as to water addition. Such
complexation is also proposed in the Bodor patents as a means for providing
better brain to lung ratios of the redox compounds by preventing their
precipitation out of solution at the injection site or in the lungs. Successful
solubilization of a number of redox compounds is noted; however, Bodor
indicates that such results are not universal. For example, in the case of
estradiol, the redox derivative has about the same solubility in aqueous 50%
hydroxypropyl-,B-cyclodextrin as has the parent drug; in the case of
norethindrone, the redox drug has less than 1 % of the solubility in aqueous
50% hydroxypropyl-,B-cyclodextrin displayed by the parent drug.
Bodor U.S. Patents Nos. 4,983,586, issued January 8, 1991, and
5,024,998, issued June 18, 1991, relate to pharnl~elltic~l formulations for
pal~,lte.~l use. Aqueous parenteral solutions of drugs which are insoluble or
only sparingly soluble in water and/or which are unstable in water, combined
with cyclodextrin selected from the group consisting of hydroxypropyl,
hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ,~- and ~y-
cyclodextrins, provide a means for alleviating problems associated with drug
precipitation at the injection site and/or in the lungs or other organs following
parenteral ~dmini~tration. The pa-~-lte~l solutions contain from about 20%
to about 50% of the selected cyclodextrin(s). The drugs may be the
dihydropyridine forms of dihydropyridine ~ pyridinium salt redox systems (as
noted above in connection with the Bodor '935 and '566 patents) or other
poorly soluble or unstable drugs of many types, including steroids. Anti-
infl~mm~tory steroids such as dexamethasone, hydrocortisone and
prednisolone are mentiolled
WO 94/12217 ~ . - ; - PCT/US93/11651
.
16
21505~ ~
Recently, the solubilizing and stabilizing effects of hydroxypropyl-~-
cyclodextrin (HP~CD) on drugs have been reviewed by Thorsteinn Loftsson,
Pharm. Zt~. Wiss. 4/136: 5-10 (1991). Solubility enhancement for many
drugs in water has been accomplished by means of complexation with
HP~CD. The solubility of dexamethasone was increased 5,500 times and
intravenous ~Aminictration of the dey~meth~cone-Hp~cD complex gave higher
initial plasma levels of deY~meth~cone than those obtained after
dex~m~h~cQne phosphate dosing. The authors further note that
transdermal/topical nonocclusive aqueous vehicle systems are suggested to
avoid side-effects of occlusive systems, and that the improved water solubility
of many lipophilic drugs in aqueous HP,~CD solutions makes the nonocclusive
systems possible. Transdermal delivery of the steroids 17~-estradiol,
hydrocortisone and tP~c~leruile in aqueous HP~CD solutions have been
reported. See also Loftsson et al, Acta Pharm. Nord. 1(4), 185-193 (19~9),
which describes the effects of 2-hydroxypropyl-~-cyclodextrin on the aqueous
solubility of drugs, including dexamethasone, and the transdermal delivery of
17,B-estradiol. It has also been suggested that the hydroxy-propyl derivatives
of betacyclodextrin could be useful in solubilizing amino-substituted steroid
therapeutic agents of the type disclosed in the aforementioned International
Publication No. WO 87/01706 and U.S. Patent No. 5,124,154.
As previously noted, the literature has not suggested that
hydroxyalkylated or branched cyclodextrin derivatives would be con~aLible
with lightly crocclink~d carboxy-cont~ining polymers or that this combination
of materials could be used to stabilize and solubilize pharnl~eut~
formulations of therapeutic agents to provide remarkably stable compositions
whose drug release rate could be finely controlled.
O 94/12217 2 ~ PCT/US93/11651
S~JMMARY OF THE INVENTION
The present invention provides a pharmaceutical composition
comprising a therapeutic agent, an effective stabilizing amount of carboxy-
S containing polymer and cyclodextrin in an aqueous medium. The cyclodextrin
is selected from the group consisting of the hydroxypropyl, hydroxyethyl,
glucosyl, maltosyl and maltotriosyl derivatives of ~ and ~y-cyclodextrin,
modified or nonmodified.
It further provides a method for stabilizing and solubilizing a
therapeutic agent in a pharma(~eutical formulation, comprising combining the
therapeutic agent in an aqueous medium with an effective stabilizing amount
of carboxy-containing polymer and an amount of cyclodextrin sufficient to at
least partially solubilize the the~ ic agent. The cyclodextrin is sele~ted
from the group consisting of the hydroxypropyl, hydroxyethyl, glucosyl,
maltosyl and maltotriosyl derivatives of ~"B- and y-cyclodextrin, modified or
nonmodified.
The present invention further provides a method for stabilizing and
solubilizing an amino-substituted steroid therapeutic agent in a pharm~ceutica'lformulation, comprising combining the therapeutic agent in an aqueous
medium with an effective stabilizing amount of carboxy-containing polymer
and an amount of cyclodextrin sufficient to at least partially solubilize the
therapeutic agent. The cyclodextrin is selected from the group conci~ing of
the hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl
derivatives of cY, ,l~- and ~y-cyclodextrin, modified or nonmodified.
In yet another aspect, the present invention provides a pharm~euti~l
composition comprising an amino-substituted steroid therapeutic agent sele~t~d
from the group consisting of the C20 through C26 aminosteroids of the formula
WO 9~/12217 PCT/US93/11651
: 18
2l~as~
XI hereinbelow, and the pharm~l~eutically acceptable salts, hydrates and
solvates thereof, an effective stabilizing amount of a carboxy-containing
polymer and an amount of cyclodextrin sufficient to at least partially solubilize
said therapeutic agent, in an aqueous medium. The cyclodextrin being
selected from the group consisting of the hydroxypropyl, hydroxyethyl,
glucosyl, maltosyl and maltotriosyl derivatives of a!, ~- and y-cyclodextrin,
modified or nonmodified.
DETAILED DESCRIPIlON OF THE INVENTION AND THE
PREFERRED EMBODIMENTS
This invention compris~s pharm~eutical preparations cont~ining a
combination of carboxy-containing polymers and a molecular inclusion
chemical entity, cyclodextrin or a derivative of cyclodextrin, particularly ,~-
hydroxypropyl cyclodextrin, as a vehicle for delivering therapeutic agents.
Drugs used in the formulation can be hydrophobic organic compounds with
little solubility and they may be labile. The drug can also be a peptide or
protein from either a recombinant process or synthetic process, or a water
soluble drug. The advantages of the invention are most apparent, however,
in connection with drugs having low solubility in water or body fluids and/or
instability problems.
The combination of the present invention can be made without
experiencing adverse consequences of incompatibility of the components. For
instance, the improved solubility effect of the present invention might have
been neg~t~d by the polymer colll~Ling for the drug. In addition to n~g~ting
the desired improvement in solubility, and therefore bioavailability,
undersirable ~recil)iLaLion or agglomerated of particles may have occurred.
The me~h~ni~m of the present invention is not fully understood and
may be different for different thel~uLic agents. It is believed, however, that
.
,
"~o 94/12217 PCT/US93/11651
21~0~S l
19
stabilization of the drug may be achieved by cyclodextrin through molecular
inclusion of the drug in the cyclodextrin ring or by ionic attractive forces
between the drug and cyclodextrin. The polymer component of the present
invention, in most inst~nces, provides the greatest stabilizing influence. For
some drugs, particularly those that are positively charged, an ionic interactionmay be formed between the drug and the polymer. This interaction may
stabilize labile portions of the drug.
The drug can be partially or completely solubilized by ~-hydroxypropyl
cyclodextrin and/or other modified and nonmodified cyclodextrins. The term
partial solubilization refers to ~ degree of solubilization in excess of the
normal solubility for the particular drug. Increasing the solubility of
therapeutic agents typically also reduces irritation that would otherwise be
experienced. The degree of solubilization can be controlled by the type and
weight fraction of the cyclodextrin and the manufacturing procedures used and
the formulation. Although the present invention may incorporate drugs that
are highly soluble in water and body fluids, the fullest advantage of the
solubilizing effect of cyclodextrin will be realized in connection with drugs
that have low solubility in water or body fluids.
Soluble drugs may be released from gels containing formulations of the
present invention, through diffusion. Insoluble drugs can be solubilized by the
cyclodextrin and diffused out of the polymeric gel or be released from it as
the surrounding co.ll~onents of the formulation erode. By b~l~ncing the ratio
between the solubilized and insoluble form of the drug in the formulation, the
release profile of the drug from the delivery system can be mod~ tPd.
The amounts of cyclodextrin, carboxyl-containing polymer and drug
may be varied to accommol~tP different applications. Other characteristics
WO 94/12217 PCT/US93/11651 ~
2~5~4
such as pH and osmolality may also be tailored to suit requirements of
particular applications. In general, however, a stabilized, solubilized drug
delivery system will be an aqueous suspension at a pH of from about 3 to
about 9, preferably about 5 to about 8. For ophthalmic applications an 6
osmotic pies~ulc; of from about 10 to about 400 mOsM is desirable.
Generally, formulations may contain up to about 10%, more preferably about
0.1% to about 6.5% by weight, of the sllcpçncion~ of a lightly cross-linked,
carboxyl-containing polymer. Cyclodextrin may be present in amounts from
about 1% to about 50%. Suspensions of the present invention may have a
wide range of viscosities, but many formulations may have a viscosity of from
about 1,000 to about 100,000 centipoises. For ophthalmic applications the
viscosity will preferably be about 1,000 to about 30,000 centipoises for drops
and about 30,000 to about 100,000 centipoises for ribbons. Viscosities greater
than about 100,000 centipoises are ordinarily apl)ro~ iate for topical routes of~dminictration other than ophthalmic, e.g. dermal and local routes such as
nasal, buccal, rectal and vaginal, but viscosities for these applications may
also, in some inct~nces, be lower than 100,000 centipoises.
In topical pharmaceutical formulations of the present invention, the
polymer ranges from about 0.1 to about 10%, preferably about 0.1% to about
6.5 % and more preferably about 0.5 to about 2 % . The cyclodextrin
preferably makes up about 1 to about 50%, more preferably about 5% to
about 25%, dçpçn-iing on drug loading. Therapeutic agents (drugs) will
ordinarily make up about .01% to about 10% by weight of the composition,
preferably about 0.1% to about 5% of the composition.
The lightly cross-linked carboxy-cont~ining polymers for use in the
present invention are lightly cross-linked polymers of acrylic acid or the like
and are, in general, well-known in the art. See, for example, Robinson U.S.
Patent No. 4,615,697, and International Publication No. WO 89/06964,
~wo 91/12217 21~ 0 5 S ~ PCT/US93/11651
referred to hereinabove. These polymers are also described in United States
Patent 5, 192,535.
Suitable polymers are ones prepared from at least about 90% and
preferably from about 95% to about 99.9% by weight, based on the total
weight of monomers present, of one or more carboxyl-containing
monoethylenically unsaLuldted monomers. Acrylic acid is the pre~e,led
carboxyl-containing monoethylenically unsaturated monomer, but other
unsaturated, polymerizable carboxyl-cont~ining monomers, such as
methacrylic acid, ethacrylic acid"~-methylacrylic acid (crotonic acid), cis-~x-
methylcrotonic acid (angelic acid), trans-~-methylcrotonic acid (tiglic acid),
~-butylcrotonic acid, c~-phenylacrylic acid, o~-benzylacrylic acid, cY-
cyclohexylacrylic acid"B-phenylacrylic acid (cinnamic acid), coumaric acid
(o-hydroxycinn~mic acid), umbellic acid (p-hydroxycoumaric acid), and the
like can be used in addition to or instead of acrylic acid. The most p~er~lled
polymers are lightly cross-linked carboxy polymers. As will be understood
from the present disclosure, however, soluble carboxy polymers that are not
cross-linked may also be used. Examples of soluble polymers of the present
invention that are not cross-linked include polyacrylic acid polymers and
polymethacrylic acid polymers. Such polymers may be made by known
methods.
Preferred polymers are lightly cross-linked by using a small
percentage, i.e., less than about 5%, such as from about 0.01% to about 5%,
and preferably from about 0.2% to about 3%, based on the total weight of
monomers present, of a polyfunctional cross-linking agent. Included among
such cross-linking agents are non-polyalkenyl polyether difunctional cross-
linking monomers such as divinyl glycol; 3,4-dihydroxy-hexa-1,5-diene; 2,5-
dimethyl-l ,5-hPY~liPnP; divinylbenzene; N,N-diallylacrylamide; N,N-
diallylmeth~rrylamide and the like. Also included are polyalkenyl polyether
WO 9~/12217 22 PCT/US93/11651 0
2~5~
cross-linking agents containing two or more alkenyl ether groupings per
molecule, preferably alkenyl ether groupings containing terminal H2C=C<
groups, prepared by etherifying a polyhydric alcohol containing at least four
carbon atoms and at least three hydroxyl groups with an alkenyl halide such
as allyl bromide or the like, e.g., polyallyl sucrose, polyallyl pentaerythritol,
or the like; see, e.g., Brown U.S. Patent No. 2,798,053. Diolefinic non-
hydrophilic macromeric cross-linking agents having molecular weights of from
about 400 to about 8,000, such as insoluble di- and polyacrylates and
methacrylates of diols and polyols, diisocyanate-hydroxyalkyl acrylate or
methacrylate reaction products, and reaction products of isocyanate terrnin~t~d
prepolymers derived from polyester diols1 polyether diols or polysiloxane diols
with hydroxyalkylmethacrylates, and the like, can also be used as the cross-
linking agents; see, e.g., Mueller et al U.S. Patents Nos. 4,192,827 and
4,136,250.
The lightly cross-linked polymers can of course be made from a
carboxyl-containing monomer or monomers as the sole monoethylenically
unsaturated monomer present, together with a cross-linking agent or agents.
They can also be polymers in which up to about 40%, and preferably from
about 0% to about 20% by weight, of the carboxyl-cont~ining
monoethylenically unsaturated monomer or monomers has been replaced by
one or more non-carboxyl-col "i. i n i ng monoethylenically unsaturated monomerscont~ining only physiologically (and, where a~plup~iate, ophthalmologically)
innocuous substituents, including acrylic and methacrylic acid esters such as
methyl methacrylate, ethyl acrylate, butyl acrylate, 2-ethylhexylacrylate, octylmeth~.rylate, 2-hydroxyethyl-methacrylate, 3-hydroxypropylacrylate, and the
like, vinyl acetate, N-vinylpyrrolidone, and the like; see Mueller et al U.S.
Patent No. 4,548,990 for a more extensive listing of such additional
monoethylenically ~In~~ d monomers. Particularly preferred polymers are
lightly cross-linked acrylic acid polymers wherein the cross-linking monomer
-
~To 94ll22l7 215 0 5 S ~ PCTtUS93/11651
23
is 2,3-dihydroxyhexa-1 ,5-diene or 2,5-dimethylhexa-1 ,5-diene.
An especiallyplefel.ed lightlycross-linked carboxy-cont~iningpolymer
for use herein is polycarbophil, particularly NOVEON AA-1, a carboxyl-
cont~ining polymer prepared by suspension polymerizing acrylic acid and
divinyl glycol. NOVEON AA-1 (also called Carbopol 976) is commercially
available from The B.F. Goodrich Company. A different p~re~ d lightly
cross-linked carboxy-containing polymer for use herein is Carbopol 974P
which is prepared using a different polyfunctional cross-linking agent (of the
polyalkenyl polyether type).
The lightly cross-linked polymers used in practicing this invention are
preferably prepared by slls~n~ion or emulsion polymerizing the monomers,
using conventional free radical polymerization catalysts, to a dry particle sizeof not more than about 50 ~m in equivalent spherical diameter; e.g., to
provide dry polymer particles ranging in size from about 1 to about 30 ~m,
and preferably from about 3 to about 20 ~m, in equivalent spherical ~ meter.
In general, such polymers will range in molecular weight estimated to be
greater than about 250,000 and preferably greater than about 2,000,000.
The cyclodextrins conle",plated for use herein are hydroxypropyl,
hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of,B-cyclodextrin
and the corresponding derivatives of y-cyclodextrin. The hydroxyalkyl
groupings may contain one or more hydroxyl groups, e.g. hydroxypropyl (2-
hydroxypropyl, 3-hydroxypropyl), dihydroxypropyl and the like. The
glucosyl, maltosyl and maltotriosyl derivatives may contain one or more sugar
residues, e.g. glucosyl or diglucosyl, maltosyl or dimaltosyl. Various
IllLl~lules of the cyclodextrin derivatives may be used as well, e.g. a ",i~lureof maltosyl and dimaltosyl derivatives. Specific cyclodextrin derivatives for
use herein include hydroxypropyl-~B-cyclodextrin (HPCD or HPBCD),
.
W O 94/12217 PCTrUS93/11651
21~ 4 -; _
hydroxyethyl-,B-cyclodextrin (HEBCD), hydroxypropyl- y-cyclodextrin
(HPGCD), hydroxyethyl- y-cyclodextrin (HEGCD), dihydroxypropyl-,B-
cyclodextrin (2HPBCD), glucosyl-~-cyclodextrin (G,-~3-CD or G,BCD),
diglucosyl-,~-cyclodextrin (2GI-k'-CD or 2G,BCD), maltosyl-,~-cyclodextrin
S (G2-,B-CD or G2BCD), maltosyl- y-cyclodextrin (G2- y-CD or G2GCD),
maltotriosyl-,~-cyclodextrin (G3-~-CD or G3BCD), maltotriosyl- y-cyclodextrin
(G3- y-CD or G3GCD) and ~lim~l~osyl-~B-cyclodextrin (2G,-,B-CD or 2G2BCD),
and mixtures thereof such as maltosyl-,~-cyclodextrin/dimaltosyl-,B-
cyclodextrin.
Hydroxypropyl-~-cyclodextrin for use in the compositions and methods
of the present invention is commercially available. Altematively, it can be
prepared by known methods, especially by use of the optimized procedure of
Pitha et al, Intemational Joumal of Pharmaceutics, 29, 73-82 (1986) or by
modifications thereof as described in Bodor U.S. Patent No. 5,017,566 and
related Bodor patents referred to hereinabove. The other hydroxyalkyl
cyclodextrins inten(led for use herein can also be prepared by known
procedures, e.g. as described by Pitha et al or Bodor. The cyclodextrins
obtained in this manner are intrinsically amorphous mixtures; see Pitha et al,
J. Pharm. Sci., Vol. 74, No. 9, September 1985, 987-990 and Pitha U.S.
Patent No. 4,727,064.
The other cyclodextrins intended for use in the present invention, i.e.
the glucosyl, maltosyl and maltotriosyl derivatives of c~ - and ~y-
cyclodextrin, modified or nonmodified, are branched cyclodextrins which are
highly soluble in water as co-l,pal~d to the parent cyclodextrins. These
branched cyclodextrins can be produced by microbiological processes from the
parent cyclodextrins. Glucosyl-,~-cyclodextrins can be obtained from the
mother liquor of a large-scale ,B-cyclodextrin synthesis with Bacillus ohbensis
cyclom~lto(lextrin glucanotransferase; see Koizumi et al, Chem. Pharm. Bull.,
~o 94/12217 2 ~ i 4~ PCT/US93/11651
35 (8), 3413-3418 (1987) and reference cited therein. Maltosyl and
- maltotriosyl ,~- and y-cyclodextrins can be prepared from the parent
cyclodextrin and maltose or maltotriose through the reverse action of
Pseudomonas isoamylase or Klebsiella aerogenes pullulanase, while glucosyl-
~-cyclodextrin can be prepared by enzymatic hydrolysis of maltosyl-~-
cyclodextrin; see Okada et al, Chem. Pharm. Bull., 36 (6), 2176-2185 (1988)
and references cited therein. The preparation of maltosyl-~B-cyclodextrin by
reacting maltose with ,B-cyclodextrin in the presence of pullulanase is also
described in Japanese Kokai 61-287902, published Dec. 13, 1986, and
J~p~ne~e Kokai 61-197602, published Sept. l, 1986. A mixture of maltosyl-
~B-cyclodextrin and various flim~ltosyl-~B-cyclodextrins may be conveniently
employed. See also Kainuma et al U.S. Patent No. 4,668,626, issued May
26, 1987.
A variety of drugs may be used in formulations of the present
invention. Useful therapeutic agents include, but are not limited to:
demulcents (for relief of "dry eye"), antibiotics, antivirals, steroids, amino-
substituted steroids, including anti-inflammatory agents, peptides,
polypeptides, cardiotonics, antihypertensives, or antioxidants, antiallergics,
alpha- and betaadrenergic blocking agents, ophthalmic medicaments such as
~nti~t~ract agents, collagenase inhibitors, antiglaucoma agents and ophthalmic
antiinfl~mm~tory agents, ophthalmic lubricating agents, ophthalmic topical or
regional anesthetic agents, antiretinopathy agents, etc.
More specific therapeutic agents believed suitable for use in the present
invention include drugs such as idoxuridine, carbachol, beth~nechol, timolol,
atenolol, labetolol, metoprolol, nadolol, oxprenolol, pindolol, sotalol,
betaxolol, acebutolol, alprenolol, levobunolol, p-aminoclonidine, dipivefrin,
epinephrine, phenylephrine, phospholine, aceclidine, ~erner~ m,
cyclopentolate, homatropine, scopolamine, pilocarpine, ethacrynic acid,
WO 9~112217 ~ PCT/US93/11651 ~
2 ~ 26
furosemide, amiloride, bacitracin, neomycin, polymyxin, polymyxin B,
gramicidin, gentamycin, penicillins, erythromycin, slllf~ret~mide, tobramycin,
trospectomycin, vancomycin, ciprofloxacin, perfloxacin, olfloxacin, enoxacin,
naphazoline hydrochloride, clindamycin, isofluorophate, fluorometholone,
dexamethasone, hydrocortisone, fluorocinolone, medrysone,
methylprednisolone, fluticasone propionate, betamethasone, estradiol,
ibuprofen, flurbiprofen, naproxen, esters of ibuprofen, flurbiprofen, naproxen,
ketorolac, suprofen, intt;lrer~ils, cromolyn, gancyclovir, aminozolamide, all
trans-retinoic acid (Vitamin A) and the nontoxic, pharmaceutically acceptable
salts thereof. Pro-drug counterparts are also within the scope of the present
invention.
Topical or regional anesthetic agents include ones used duling
ophthalmic surgery or other ophthalmic procedures, such as lidoc~ine,
cocaine, benoxinate, dibucaine, proparacaine, tetracaine, etidoc~ine, procaine,
hexylcaine, bupivacaine, mepivacaine, prilocaine, chloroprocaine, ben70c~ine,
tetracaine, and the like, as well as their acid forms.
The drugs that may be ~dminictered include inorganic and organic
drugs that can be transported across a vessel, for example, drugs acting on the
central nervous system such as hypnotics and sedatives, mixtures thereof such
as pentobarbital sodium, phenobarbital, secobarbital, thiopental, etc.;
heterocyclic hypnotics such as dioxopiperidines, and glutarimides; hypnotics
and sedatives such as amides and ureas exemplified by diethylisovaleramide
and a bromo-isovaleryl urea; and hypnotic and sedative urethanes and
~liculf~n~$; narcotic antagonists such as naloxone and cyclazocine; psychic
energizers such as isoc~ox~zid, ni~l~mide, phenelzine, imipramine,
tranylcypromine and paragylene; tranquilizers such as chlolup,o~ ine,
p~ 7;i-~, fluphen~7inP, reserpine, deserpidine; meprobamate and
benzodiazepines such as chlol.lia~epoxide; anticonvulsants such as primidone,
~:VO 94/12;!17 2 1 5 0 5 ~ ~ PCT/US93/11651
27
diphenylhydantoin, ethyltoin, phenetruide and ethosuximide; muscle relaxants
and anti-parkinson agents such as mephenesin, methocarbomal,
trihexylphenidyl, biperiden and levo-dopa, also known as L-dopa and
L-,~-3-4dihydroxyphenyl~1~nine; analgesics such as morphine, codeine,
S meperidine and nalorphine, antipyretics and anti-infl~mm~tory agents such as
aspirin, salicylamide and sodium salicylamide; local anesthetics such as
procaine, lidocaine, n~ep~ine, piperocaine, tetracaine, and dibucane;
~nti.~p~modics and antiulcer agents such as atropine, scopolamine,
methscopolamine, oxyphenonium, papaverine and prostaglandins such as
PGEI, PGE2, PGFI,,, PGF23, and PGA; anti-microbials such as penicillin,
tetracycline, oxytetracycline, chlortetracycline, and chloramphenicol;
sulfonamides; anti-malarials such as 4-aminoquinolines, 8-aminoquinolines and
pyrimeth~mine; antivirals including idoxuridine, hormonal agents such as
prednisolone, prednisolone acetate, cortisone, cortisol and triamcinolone;
androgenic steroids, for example methyltestosterone and fluoxmesterone;
estrogenic steroids, for example, 17 ~-estradiol and ethinyl estradiol;
progestational steroids, for example, 17 ~-hydroxyproge~L~une acetate,
19-nor-ploge~.~erone, norethindrone and progesterone; sympathomimetic drugs
such as epinephrine, amphetamine, ephedrine, and norepinephrine;
cardiovascular drugs, for example, procainamide, amyl nitrite, nitroglycerin,
dipyridamole, sodium nitrate, and mannitol nitrate; diuretics, for example,
chlorothiæide, and flllmethi~7.ide; antiparasitic agents such as bephenium
hydroxynaphthoate, dichlorophen, dapsone and enitabes; neoplastic agents
such as mechloreth~mine, uracil mustard, S-fluorouracil, 6-thioguanine, and
procarbæine; hypoglycemic drugs such as insulin, isophane insulin
suspension, protamine zinc insulin suspension, globin zinc insulin, extended
insulin zinc suspension, and other like insulins derived from animal and
synthetic origin including tolbutamide, acetohexamide, tolazamide, and
chlo,~.,.,pamide; nutritional agents, for example vitamins such as ascorbic
acid, essential amino acids, essential elements such as iron, and es.senti~l fats;
WO 94/12217 PCTIUS93/11651 ~
215~S ~
28
. . ,
ophth~lmic drugs such as pilica~ e base, piloca~ e hydlochloride,
pilocal~iue nitrate, eserine, eserine salicylate, atropine sl.lf~te,
homatropine, and eucall~iue, and proteius or peptides such as human
epirlerm~l growth factor (hEGF), aFGF, bFGF, IL,lra, TGF-~B and
S g~mm~ tel~ron. The above drugs are further described in "The
ph~rmr, -l^gical Basis of Therapeutics," edited by Goo 1~n~n and Gilman,
published by The M~r.mill~n Culllpally.
Com~ouuds believed to be of particular interest in the plcsellt
10 invention include [4(N-hy~L~Ay~o)-2R-i~ u~yl-3~(thienyl-thiomethyl) -
succinyl]-~phenylalanine-N-metLylA .. . i~le, ((5)-4-methyl-2-[methyl-[4-(2-
methyl-;...i~lA,o[4,5-C]pyridin-1-y1methyl)-benzene sulphonyl]-acetate,
dexamethasone, e~ylLroluy~ and Lydl~c~ one.
In the pl~sent invention, the amino-sul~s~ ted steroid therapeutic
agents employed are the C20 through C26 aminosteroids of formula XI
(esl)ecially those which eA~hibit anti~y~ nt LuncLious)~ as set forth in
International Publication No. WO87/01706 and in applicants' U.S. Patent
No. 5,124,154, all of which are incorporated by lefercl,ce herein in their
eulilcLes and relied upon. The intended aminosteroids have the formula
Rll ~f R16
RIO ~ /
_ ~ - (XI )
R5 ~ j~
R6 R7
ST~TlJTE SHEtT ~RUL~ ~6~
~wo 94112217 215 0 S 5 i PCT/US93/11651
29
where:
(A-I) R6 is cY-R61:~'-R62, Rlo is ~-RIol ~7-Rlo2 and R7 is c~-H:~-H, where
one of R6l and R62 is -H, and the other is -H, -F, or Cl-C3 alkyl, R,02 is -CH3,Rlo, and R5 taken together are -(CH,)2-C(-R33)-CH= or
S -CH-CH-CO-CH=, where R33 is =O or ~-H:,l~-OR34 or c~-OR34:~-H, where
R34 is -H, -P( = O)(OH)2, -CO-CH3, -CO-C~H5, -CO-C6H5,
-CO-O-CH3 or -CO-O-C2Hs;
(A-II) R5 is C~-Rs3:,B-R5~, R6 iS ~-R63:~-R64~ Rlo iS ~X-RI03 ~-R104
and R7 is ~-H:~-H, where one of R63 and R64 is -H, and the other taken
together with one of R53 and R54 forms a second bond between C5 and C6, R~04
is -CH3, R,03 and the other of~ Rs3 and R54 taken together are -(CH2)2-
C(H)(OH)-CH2- or -(CH2)2-C[H][OP(=O)-(OH)21-CH,-;
(A-III) Rlo and R5 taken together are =CH-CH=
C(OR3)-CH= where R3 is -H, -P(=O)(OH)2, Cl-C3 alkyl, -CO-H, C2-C4
alkanoyl or benzyl, R6 is ~-R65:~B-R66 where one of R65 and R66 is -H, and the
other is -H, -F, or Cl-C3 alkyl and R7 is ~-H:~-H;
(A-IV) Rs is CY-R57:,B-Rs8, R6 is cy-R67:,l~-R68~ R7 is c~-H:~-H and
Rlo is ~-RI07:,B-Rl08, where one of R57 and R58 is -H, R,07 and the other of Rs7and R5% taken together are -(CH,)2-C(=R33)-CH2, where R33 is as defined
above, R,08 is -CH3, where one of R67 and R6~ is -H and the other is -H, -F,
or C,-C3 alkyl;
(A-V~ R6 is R69 R6~o~ R7 iS R79:R7l0, Rlo iS
cY-RIog:Rlolo, where one of R69 and R6lo is -H and the other taken together withone of R79 and R7~0 forms a second bond between C6 and C7, and the other of
R79 and R7,0 is -H, Rlolo is -CH3, Rlog and R5 taken together are -(CH2)2-
C(=R33)-CH= or -CH=CH-CO-CH=, where R33is as defined above; where:
(C-I) R" is a-RI~:,B-Rll2, where one of Rll, and Rll2 is taken
together with Rg to form a second bond between C9 and C" and the other of
Rll, and Rll2 is -H;
(C-II) Rg is -Cl and Rll is =O or cY-H:,~-RIl4 where Rll4 is -Cl
2 ~ , . PCT/USs3/11651
. . . 30
or -OH;
(C-III) R9 is -H or -F and R" is =O or cY-RIl5:,B-R~l6, where
one of Rlls and Rll6 is -H, and the other of R"5 and Rll6 is -H,
-OH or C,-C,2 alkoxy;
S (C-IV) R9 is -H or -F and Rl, is cY-O-CO-RIl,:~-H, where R"7
is
(A) C,-C3 alkyl,
(B) C,-C,2 alkoxy,
(C) furanyl,
(D) -NR,22RI23, where one of Rl~2 and Rl23 is -H, methyl
or ethyl and the other is -H, C, ,C4 alkyl or phenvl,
(E) -X3-Xl, where X3 iS -O- or a valence bond, where
Xl is phenyl optionally substituted with 1 through 2 -Cl, -Br, Cl-C3 alkoxy, -
COOH, -NH2, C,-C3 alkylamino, di(CI-C3)alkylamino, where the alkyl groups
are the same or different, l-pyrrolidinyl-, 1-piperidinyl, 1-heY~methylenimin~ -, 1-heptamethylenimino-, C2-C4 acylamino and -NH-CHO or with 1 -F or -
CF3;
where:
(D-I) R,6 is R,6~:R,62 and R,7 is Rl7l:RI72, where one of R,6, and
R,62 is -H or -CH3 and the other taken together with one of R,7l and Rln
forms a second bond between Cl6 and Cl7, and the other of R,7, and Rl72 is -
C(=Z)-(CH2)n-NR2lR2,0, where Z is =O, =CH2 or Rl79:-H where R,79 is -H
or -CH3, where n is 0 through 6, where
(A) R2, is
(1) -(CH2)m-NR2ll-X~, where m is 2, 3
or 4, where R2~l is -H or Cl-C3 alkyl, where X2 is: [A]
(a) pyridin-2-, 3- or 4-yl or the
N-oxide thereof optionally substituted by 1 or 2 R2,2, being the same or
different, where R2l2 is
(i) -F,
~0 94/12217 215 0 5 5 ~ PCT/US93/116~1
31
(ii) -Cl,
(iii) -Br,
(iv) C,-C5 alkyl,
(v) -cH2-cH =CH2,
(vi) -Xl, where X, is as defined
above,
(vii) -NR2~3R2l3 where the R2l3 s
are the same or different and are -H, Cl-c3 alkyl or
-CH2-CH =CH2,
(viii~) ~CH2~(CH2)q~CH2~N-~
where the atoms marked with an asterisk (*) are bonded to each other
resnlting in the formation of a ring, where q is 1 through 5,
(viii,B) CH2-CH2-(CH2)C-G-(CH2)d-
CH2-CH2-N-- where the atoms marked with an asterisk (*) are bonded to each
other resnlting in the formation of a ring, where G is -O-,
-S-, -SO-, -SO2- or -NHR2~4, where R2l4 is -H, Cl-C3 alkyl, or Xl as defined
above, where c and d are the same or different and are 0 through 2 with the
proviso that the total number of ring carbon atoms is 4, 5 or 6, [a]
(ix) 3-pyrrolin-1-yl, [b]
(x) pyrrol-l-yl optionally
substituted with Cl-C3 alkyl, [c]
(xi) piperidin-l-yl optionally
substituted with 1 or 2 C,-C3 alkyl, [d]
(xii) 1,2,3,6-tetrahydro-
pyridin-1-yl, [e]
(xiii) l-hexamethyleneimino
cont~ining a 3- or 4- double bond or 3- and 5-
double bonds, [f~
(xiv) 1 ,4-dihydro- 1 -pyridinyl
substituted in the 4 position by two C~-C3 alkyl being the same or
WO 9~/12217 PCT/US93/11651 ~
2 ~ 3
different, [g]
(xv) -OH,
(xvi) C,-C3 alkoxy,
(xvii) -NR2l7-(CH2)e-Q where
Q is 2-pyridinyl where R2,7 is -H or C,-C3 alkyl and e is 0 through 3 (1)
(xviii) pyridin-2-, 3- or
4-yl,
(b) 1,3,5-triazin-4-yl or the
N-oxide thereof optionally substituted at the 2- and/or 6- position with R2l2 asis defined above, , (4)
(c) pyrimidin-4-yl or the
N-oxide thereof optionally substituted at the 2- and/or 6- position with R2l2 as is defined above, (5)
(d) pyrimidin-2-yl optionally substituted
at the 4- and/or 6- position with 1 or 2 R2l2
as is defined above, (6)
(e) pyrazin-2-yl optionally substituted
with 1 or 2 R2l2 as is defined above, (7)
(f) imidazol-2-yl optionally substituted in
the 1 position with Cl-C3 alkyl or -X" where Xl is as defined above, and
further optionally substituted with 1 or 2 R2l2 as defined
above, ~8)
(g) 1,3,4-triazol-2-yl optionally
substituted in the 1 position with Cl-C3 alkyl or -Xl, where Xl is as defined
above, and further optionally substituted with R2l2 as defined above, (9)
(h) imid~7Ql-4- or 5-yl optionally
substituted in the 1 position with C,-C3 alkyl or -X" where Xl is as defined
above, and further optionally substituted with 1 or 2 R2~2 as defined
above, (10)
~WO 94/12217 215 Q ~ 5 ~ PCT/US93/11651
33
(i) benzo[b]thien-2-yl, (12a)
(j) indol-2-yl, (12b)
(k) benzo[b]thiazol-2-yl, (12c)
(I) benzimidazol-2-yl, (12d)
S (m) 4-[2-[4-[2,6-bis(1-pyrrolidinyl)-4-
pyrimidinyl]-l-piperazinyl]ethyl]piperazinyl, (13)
(n) 1,2,4-triazin-3-yl optionally
substituted at the 5- and/or 6- position with R2l2 as is defined above, (14)
(2) ( 1 -piperazinyl)-(C~-C4)alkyl optionally
substituted in the 4- position with -Xl or -X, as defined above, [B]
(3) -X2, as defined above, [O]
(4) -(CH2)m-X~ where m is as defined above and
where X4 iS
(a) -O-CH2CH2-Y, where Y is C,-C3
alkylamino, di(C,-C3)alkylamino where the alkyl groups are the same or
different, C3-C6 alkyleneimino, optionally substituted with 1 or 2 Cl-C3 alkyl,
(b) -NR220CH2CH2-Y, where R220 is
-H or C,-C3 alkyl and Y is as defined above,
(c) -(CH2)o-N(R220)-X2, where g is 2, 3
or 4, and where R220 and X2 are as defined above, [H]
(S) -(CH2)m-NR222R223, where R222 is
-H or Cl-C3 alkyl and R223 is -Xl or-X2 as defined above, or R222 and R223 are
taken together with the ~t~hed nitrogen atom to form a saturated mono-
nitrogen C3-C6 heterocyclic ring and where m is as defined
above, t
(6) -(CHCH3)b-(CH2)fR224, where b is
0 and f is 1 through 3 or b is one and f is 0 through 3, where R224 is phenyl
substituted with 1 through 3 -OH, Cl-C3 alkoxy, -NR225R226 where R22s and
R226 are the same or different and are -H, Cl-c3 alkyl or are taken together
with the attached niL,og~n atom to form a C4-C7 cyclic amino
WO 9-1/12217 PCT/US93/11651
2 1 5 ~
ring, [J]
(7) -(CH2)i-X2, where i is 1 through
4 and X1 is as defined above, [K]
(8) (1-piperazinyl)acetyl substituted
S in the 4-position by X2 where X2 is as defined above, [L]
(9) (1-piperazinyl)carbonylmethyl substituted in
the 4- position by -X2 where X2 is as defined above, and [M]
(B) R2,0 is
(1) -H,
(2) C~-C3 alkyl,
(3) Cs-C7 cycloalkyl,
(4) -(CH2)n,-NR",-X2, where m, R2ll
and X. are as defined above, [A]
(S) ( 1-piperazinyl)-(C2-C4)alkyl optionally
lS substituted in the 4- position with -X, or -X2 as defined above, [B]
(6) -(CH2)",-X4, where m and X4 are
as defined above, [H]
(7) -(CH2)m-NR222R223, where m,
R222 and R223 are as defined above, [I]
(8) -(CHCH3)b-(CH2)fR22~, where b,
f and R224 are as defined above, [J]
(C) R2l and R2,0 are taken together with
the attached nitrogen atom to form a heterocyclic ring selected from the group
consisting of
(1) 2-(carboxy)-1-pyrrolidinyl optionally as the
Cl-C3 alkyl ester or as a pharm~eutic~lly acceptable salt, [C-1]
(2) 2-(carboxy)-1-piperidinyl
optionally as the Cl-C3 alkyl ester or as a pharmaceutically acceptable
salt [C-2]
(3) 2-(carboxy)-1-hexamethylenPimino optionally
~0 94/12217 215 0 ~ ~ 4 PCT/US93/116~1
as the Cl-C3 alkyl ester or as a pharm~ el1ti~1ly acceptable
salt, tc-3
(4) 2-(carboxy)- 1 -heptamethylene-
imino optionally as the C,-C3 alkyl ester or as a pharm~e~ltirally acceptable
5 salt, [C-4]
(5) l-piperazinyl substituted in the
4- position with R228-CO-(CH2)j- where R228 is -X" -NR229Xl or 2-furanyl,
where R229 is -H or C,-C3 alkyl, where j is 0 through 3 and X, is as defined
above, [D]
(6) l-piperazinyl substituted in the
4- position with X2-(CH2)j-, where X2 and j are as defined above, [E]
(7) l-piperazinyl substituted in the
4- position with Xl-(CH2)j-, where Xl and j are as defined above, [F]
(8) 4-hydroxy-1-piperidinyl
substituted in the 4- position with Xl as defined above, [G]
(9) 1-piperazinyl substituted in the
4- position with X2-NR229-CO-(CH2)j-, where X2, R229 and i are as defined
above; [Nl
(D-II) Rl6 is cY-Rl63:~B-Rl64 where one of Rl63
and Rl64 is -H and the other is -H, -F, -CH3 or -OH, and Rl7 is
-CH-(CH2)p-NR2lR2l0, where p is 1 or 2, where R2l and R2l0 are as defined
above;
(D-III) R,6 is ~-RI65:,B-Rl66 and Rl7 is
~-RI75:~B-Rl76, where Rl65 is -H, -OH, -F or -CH3 and Rl66 is -H, -OH,
-F, or -CH3, with the proviso that at least one of Rl65 and Rl66 is -H, where
Rl7s is -H, -OH, -CH3, -CH2CH3, C2-C7 alkanoyloxy or -O-CO-Xl, where Xl
is as defined above, and where Rl76 is -C(=Z)-(CH~)n-NR2,R2,0, where Z, n,
R2l and R2l0 are as defined above;
(D-IV) the 16,17-acetonide of a compound where Rl65 is
-OH, Rl66 is -H, Rl75 is -OH and Rl76 is -C(=Z)-(CH2)n-NR2lR2l0, where Z,
WO 9~/12217 PCT/US93/11651 ~
215~$~ 36
n, -R2l and R2,0 are as defined above;
and pharm~ceutic~lly acceptable salts thereof,
and hydrates and solvates thereof;
with the following overall provisos that:
S (I) one of R,6, or R,62 is taken together with one of R,7,
or R,72 to form a second bond between Cl6 and Cl7, only when Rlo is a-R,0,:,B-
R,02, c~-RI03:~-Rl04, Ix-R,07:~-R,08 or ~-R~09:~-R~olo,
(II) R,7 is -CH-(CH2)p-NR2,R2,0, only when Rlo is cY-
R~ol ~-Rl02~ a-R~03:~-R~04, ~X-Rl07:~-Rl08 or ~-R~09 ~-Rlolo~
(III) R5 and Rlo taken together are
=CH-CH=C(OR3)-CH=, only when Rl7 is cY-RI75:,~-Rl76 or the
16,17-acetonide of a co",pou,~d where Rl6 is a-OH:~-H and Rl7 is ~x-OH:,l~-
C(=Z)-(CH2)n-NR2,R2,0, and
(IV) Rs is CY-R57:~-R58, only when R~7 is
~x-R~75:~5-R~76 or cx-OH:~B-C-(=Z)-(CH2)n-NR21R2l0, or the 16,17-acetonide
thereof.
More ple~ll~d are the C2, ~minost~roids of formula XI,
especially those which inhibit lipid peroxidation. Most preferred are the 21-
[4-(substituted-4-pyrimidinyl)-1-piperazinyl]-steroids, such as U-74006 (21-[4-
(2,6-dipyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16a-methylpregna-1,4,9(11)-
triene-3,20-dione), and the 21-[4-(substituted-2-pyridinyl)-l-pi~~ yl]-
steroids, such as U-74500 (21-[4-[5,6-bis(diethylamino)-2-pyridinyl]-1-
pi~l;~inyl]-16~-methylpregna-1,4,9(11)-triene-3,20-dione)andU-75412(21-
[4-(3-ethylamino-2-pyridinyl)-1-piperazinyl]-16cY-methylpregna-1,4,9(11)-
triene-3,20-dione), all, when in the unform~ ted state, preferably as a solid,
preferably cryst~lline, preferably relatively non-hygroscopic and
pharm~eutically acceptable salts, such as the meth~n~sulfonate salt of U74006
(U-74006F), the hydrochloride of U-74500 (U-74500A), and the hydrochloride
or maleic acid salt of U-75412 (U-75412A and U-75412E, resl)ec~ ely); See
Br~lghl~r et al, Biochemical Pharrnacology 37: 3853-3860 (1988). The
~0 94/12217 21~ 0 5 5 4 PCT/US93/11651
37
following are ~lu~hali~`e structures
~ N N ~N
N
C_O <~
~ CH3
Il I
0~
C~I3 - S02 - OH
CEI3
CH2
CE~2 N N ~ N _ CH2CH3
C O
~ CH2CH3
~ 3
I 1 CH2
O ~J C~3
HCl
SUBSTITUTE SHEET (RULE 26)
WO 94/12217 PCT/US93/11651 ~
2~.S~s ~ 38 CH3
lH2
NH
CH2 N N
IJ
C _ O N ~/
CH3
~\
~~
0~
HCI
The above-prefelled amino steroids are all exemplified as 21-
substituted-16a -mell~ gna-1,4,9(11)-triene-3,2û-diones. However, the
steroidal portion of these may be modified without substantially altering
their preferred nature. Thus, a class of preferred C2l amino-substituted
30 steroids may be represented by the formula I, below
StJBSTITUTE SHEET (RULE 26)
WO 94/12217 2 15 0 5 5 I PCT/US93/11651
39
CH2 X
I
C O
0 , C~qd~
~/ (I)
~
b
where:
a' is selected from the group 1,2-dihydro (saturated) and 1,2-dehydro (1,2-
double bond);
b' is selected from the group 6a-H, 6~-methyl and 6a-flouro;
c' is selected from the group 9,11-dihydro (saturated), 9(11)-dehydro
(double bond), 9a-H-lla-OH-11~3-H,9a-H-ll~-OH-llcr-H,9a-H-ll-
keto,9~-F-11~3-OH-lla-H and 9a-F-ll-keto;
d' isselectedfromthegroup 16a-methyl-16~-H-17a-H, 16,B-methyl-16a-H-
17a-H, 16-H2-17c~-H, 16-H-16,17-dehydro (double bond), and 16-methyl-
16,17-dehydro. Less preferably, a 17~-OH group can be present in~te~rl
of 17a-H when d' is not 16-H-16,17-dehydro or 16-methyl-16,17-dehydro;
and where:
X'is selecte-l from the complex 21-amino substituents Xl and X2 where
30
Xl is ~ N
N N _~/ N
f'
SU~STITUT~ SHEE~ ~RUL~ 26)
W O 94/12217 PCT~US93/11651 ~
?~5~
and
S X2 iS -- N N ~
where e' and f' may be the same or different and are selected from the
10group: H,NHR1' and NR1'R2', where R1' and R2' are C1 to C3 lower
aLt~yl or R1' and R2', taken toget_erwith N, co~ te a hetero~y.;lic ring;
preferably 1-ethyleneimino, 1-trimethyleneimino, 1-pyrrolidinyl, 1-
piperidinyl, 1-morpholinyl and 1-(4-methyl)pipelazL--yl.
15Ph~ çel~tically acceptable salts of the aminosteroids of formula
(XI) are frequently preferred over the fee base form because the salts are
more soluble in water and form cr~stals which are better suited to
ph~ cel~tical use. Preferred salts are those ~,~palcd by reacting the
free base of the aminosteroid of formula (XI) with an ~p,~ te1y
20 stoichiometrical amount of a ph~ çe~tically acceptable acid such as
hrdlc,chloric, hydroiodic, hydlobrol~ic, phosphoric, sulfuric, acetic, citric,
lactic, succinic, benzoic, pamoic, salicylic, cyclohexanes~llf~rnir7
methanesulfonic, ~-toluenesulfonic, naphthalenesulfonic, malic, o~alic,
fumaric or the like. Plcielled salts are those of L~dlocllloric,
25 methanesulfonic, maleic and fumaric acids.
Equivalent to the steroids of formula (XI) and t_eir
ph~ ce~tically acceptable acid addition salts for the purposes of l:his
invention are the ph~ centically acceptable Lydlates or solvates thereof,
30 in which form they can be i~ol~tetl
SUBS~ITlJTE SHEET IRULE 26~
WO 9~/12217 215 0 ~ 5 4 PCT/US93/11651
41
The aminosteroids can be ~(lminictered by a variety of routes for the
treatment or prevention of a variety of conditions, as noted in International
Publication No. WO 87/01706. For particular routes of ~minictration,
certain characteristics of the lightly cross-linked polymers need to be carefully
controlled. Thus, for example, aqueous suspensions containing polymer
particles ~lepared by snspencion or emulsion polymerization whose average
dry particle size is al)prGeiably larger than about 50 ~m in equivalent spherical
mett~r are less comfortable when administered to the eye than suspensions
otherwise identical in composition containing polymer particles whose
equivalent spherical diameters are, on the average, below about S0 ,um. It has
also been discovered that lightly cross-linked polymers of acrylic acid or the
like ~lGpa,ed to a dry particle size appreciably larger than about 50 ~m in
equivalent spherical diameter and then reduced in size, e.g., by mech~nically
milling or grinding, to a dry particle size of not more than about 50 ,um in
equivalent spherical di~meter do not work as well as polymers made by
suspension or emulsion polymerization.
In some prGfGllGd embodiments of the invention, the particles have a
narrow particle size distribution within a lO,L~m band of major particle size
distribution which contains at least 80%, more preferably at least 90%, most
preferably at least 95% of the particles. Also, there is no more than 20%,
preferably no more than 10%, and most preferably no more than 5% particles
of a size below 1 ~m. The presence of large amounts of such fines has been
found to inhibit the desired gelation upon eye contact. Apart from that, the
use of a monodispersion of particles will give maximum viscosity and an
increased eye residence time of the ophthalmic medicament delivery systems
for a given particle size. Monodisperse particles having a particle size of 30
~m and below are most plGf~ d. Good particle packing is aided by a
narrow particle size distribution.
Wo 94/12217 PCT/US93/11651
æ~a55 4 42
Aqueous solutions and suspensions for liquid oral ~mini~tration will
typically contain between about 0.05 and 5.0% by weight, preferably between
0.1 and 2.0% by weight of the amino-substituted steroid therapeutic agent;
that suitable adjuvants which may be used as carriers to provide wetability and
stability include propylene glycol, lightly cross-linked carboxy-cont~ining
polymers such as polycarbophil, ethyl cellulose, hydroxypropyl cellulose and
methyl cellulose; and that other additives, including sodium edetate, methyl
and propyl parabens, flavoring agents and colorants may also be employed,
if desired. Examples 7 and 8 in the parent and grandparent applications detail
the preparation of topical compositions containing the aminosteroid U-74006F,
U-74500A or U-75412A and a polycarbophil (NOVEON AA-l). A viscosity
of 5,000 cps or greater is noted in Example 7. Sodium chloride, EDT~,
sodium hydroxide and, optionally, the preservative benzalkonium chloride are
also present in the col"po~ilions.
In accordance with the invention, a stabilized sust~in~d release
aminosteroid delivery system comprises an aqueous suspension at a pH of
from about 3 to about 9 (preferably 5 to 8) and an osmotic pressure of from
about 10 to about 400 mOsM cont~ining from about 0.1% to about 6.5% by
weight, based on the total weight of the suspension, of a lightly cross-linked,
carboxyl-containing polymer prepared by polymerizing one or more carboxyl-
cont~ining monoethylenically unsaturated monomers and less than about 5%
by weight of a cross-linking agent, such weight percentages of monomers
being based on the total weight of monomers polymerized. Typically, the
suspension has an initial viscosity of from about 1,000 to about 30,000
centipoises and is ~rlminictrable to the eye in drop form, or in the form of a
ribbon at a viscosity of from about 30,000 to about 100,000 centipoises, but
considerably higher viscosities are acceptable for topical routes of
~lmini~tration other than ophthalmic, e.g. dermal, and local routes such as
nasal, buccal, rectal and vaginal. The polymer has an average particle size
WO 94/12217 21 ~ ~ ~ S ~ PCT/US93/11651
43
of not more than about 50 ~Lm, preferably not more than about 30 ~Lm, in
equivalent spherical ~ meter. In the case of topical ophthalmic delivery
systems, the pH of the suspension is from about S to about 9. The viscous gel
can remain in the eye for a prolonged period of time so as to release the
S aminosteroid therapeutic agent contained therein in suct~ined fashion.
The polymer is preferably prepared from at least about 50% by weight,
more preferably at least about 90% by weight, of one or more carboxyl-
containing monoethylenically unsaturated monomers. Desirably, the polymer
is prepared by suspension or emulsion polymerizing acrylic acid and a non-
polyalkenyl polyether difunctional cross-linking agent to a particle size of notmore than about 50 ,~Lm, preferably not more than about 30 ~m, in equivalent
spherical ~i~meter. A l,refelled cross-linking agent is divinyl glycol. It may
be desirable to replace up to about 40% by weight of the carboxyl-cont~ining
monoethylenically unsaturated monomers by one or more non-carboxyl-
cont~ining monoethylenically unsaturated monomers cont~ining only
physiologically (and, where al,~,opliate, ophthamologically) innocuous
substitllentc
The osmotic pressure is preferably achieved by using a physiologically
(and, where a~prop,iate, ophthalmologically) acceptable salt in an amount of
from about 0.01 % to about 1 % by weight, based on the total weight of the
suspen~ions. A pler~llcd salt is sodium chloride.
~minostt~roid of formula (XI) may be present in desired therapeutic
amount, preferably from about 0.01 % to about 10 % by weight, based on the
total weight of the suspension. Preferred aminosteroids include
U-74006, U-74500, U-75412, U-74006F, U-74500A, U-75412A and U-
75412-E and aminosteroids of forumula I.
WO 94/12215 ~ PCT/US93/11651
In a ~ ed method of preparing stable sustained release topical
ophthalmic delivery systems, the foregoing suspensions are prepared and
packaged at the desired viscosity of from 1,000 to about 30,000 centipoises,
for ~tlminictration to the eye in drop form. Upon ~minictration to the eye,
viscous gel remains in the eye for a prolonged period of time so as to release
in a sllst~in~d fashion the aminosteroid entrapped therein.
The present invention thus provides a stable ophth~lmic delivery
system that not only has the benefits of administration in drop form, but also
does not suffer from bre~down limitations due to administration at a viscosity
suitable for drops. Through ~(lm, inistration at a viscosity such that the
suspension can be reliably administered in drop form, but which actually
increases when the suspension is so administered, controlled release of
aminosteroid medicament is significantly enhanced.
As mentioned above, viscosities substantially over 30,000 cps are
generally not suitable for drops; also, viscosities over 100,000 are generally
not suitable as ribbons. When the viscosities are substantially lower than
1,000 cps, the ability of the gel to sustain itself after contact with tears is
impeded. When a suspension at a pH of from about 3 to about 6.5 and an
osmotic plessure of from about 10 to about 400 mOsM contacts the tear fluid,
there is an increased gelation with a pH change. As will be appreciated, tear
fluid is at a higher pH of about 7.2 to about 7.4. With the pH increase,
carboxylic acid (COOH) undergoes a sodium replacement (to COONa), and
the sodium form dissociates, causing the polymer to expand.
The relationships between the degree of cross-linking and between the
degree of cross-linking and particle siæ can become quite important variables.
Re~use the particles are present in a suspension, the degree of cross-linking
is ne~es.s~rily high enough to avoid substantial dissolution of the polymer. On
Wo 94/12217 215 0 ~ ; PCT/US93/11651
the other hand, since rapid gelation may be achieved at the time of a pH
change, the degree of cross-linking is necçss~rily low enough to permit
gelation. Moreover, if the polymer particle size is too large, in~ ced swelling
can tend to fill voids between large particles that are in contact with one
another, rather than causing gelation.
If the polymer were in a dissolved state, as it would be if there were
insufficient cross-linking because the ratio of cross-linker to monomer was too
low, particle size would be basically irrelevant. In a suspension, particle siæ
can be relevant to comfort. However, it has been found that in the system of
the present invention, the small particle size and light cross-linking
synergistically yield rapid gelation to a subst~n~i~lly increased viscosity whenthe pH changes such as when compositions of the present invention contact
tears fluid. In fact, above the 50 ,um size this advantage of subst~nti~lly
increased viscosity is not realized. Moreover, at the 50 ~Lm size, there is alsoreasonably good eye comfort.
In a most preferred form of the invention, the particles are not only
subject to the upper size limits described above, but also to a narrow particle
siæ distribution. Such use of a monodispersion of particles, which aids in
good particle packing, yields a maximum increased viscosity upon contact of
the suspension with the tears and increases eye re~idenre time. At least about
80%, more preferably at least about 90% and most preferably at least about
95%, of the particles should be within a no more than about 10 ~m band of
major particle size distribution, and overall (i.e., considering particles both
within and outside such band) there should be no more than about 20%,
preferably no more than about 10% and most preferably no more than about
5% fines (i.e., particles of a size below 1 ~m). It is also p~re..ed, as the
average particle size is lowered from the upper limit of 50 ~m, more
preferably 30 ~m, to lower sizes such as 6 ~m, that the band of major particle
wo 94/12217 - ~ PCT/US93/11651
)
2~3~ ~ 46
size distribution be also narrowed, for example to S ~Lm. Preferred sizes for
particles within the band of major particle distribution are less than about 30
,um, more preferably less than about 20 ,um, most preferably from about l ~Lm
to about S ,um.
It is apparent that, while the stable suct~ined delivery systems rli~cuc~ed
above are uniquely well-suited to ophthalmic ~lmini~tration~ the same systems
can be used for topical tre~tmen~ of skin and mucous membrane by local
application to tissue in need of treatment, such as dermal, nasal, vaginal and
rectal tissues. However, various features of the systems designed for
~rimini~tration to the eye can be modified in order to produce systems which
are even better suited to the contemplated non-ophthalmic route of
adrnini~tration. For example, larger amounts of cross-linking agents and/or
higher pH levels may be utilized to provide more viscous gels suited for
longer retention on the skin or in body cavities. Furthermore, when it is
desired to combine in a single composition the sn~t~ined release and prolonged
retention prope.Lies of the aminosteroid su~pen~ions described above with the
immP~ te release which aminosteroid solutions would provide, or when i~ is
desired to simply achieve the more immediate release and greater penetration
possible with solutions, be it for ophthalmic or other route of ~mini~tration,
yet other modific~tiQns of the invention can be made as described in more
detail hereinbelow.
As noted hereinabove, the stable compositions obtained in accord with
the foregoing dçt~ilPd description provide for sustained release of the
aminosteroid, by virtue of the fact that the aminosteroid is in suspension;
prolonged retention at the site of application can also be readily provided by
these compositions by virtue of their viscosity. However, immPAi~tP release
of the ~minos¢çroid and greater penetration (e.g. through the cornea or skin,
in the case of ophth~lmic or dermal application, respectively) are sometimes
WO 94/12217 215 0 5 ~ ~ PCT/US93/11651
47
desired, either in combination with or instead of the suct~ined
release/prolonged retention properties. The present invention provides for
modification of the method and compositions described above in order to
achieve these goals. Speci~lc~lly, the aminosteroid can be partially or
S completely solubilized in the ~minosttoroid/lightly cross-linked carboxy-
cont~ininp: polymer forrnulations by using an amount of cyclodextrin (as
defined and discussed in detail hereinabove) sufficient to at least partially
solubilize the aminosteroid. Addition of cyclodextrin reduces irritation
topically and ocularly. Moreover, if desired, sufficient cyclodextrin can be
utilized to subst~nti~lly completely solubilize the aminosteroid. The degree
of solubilization can be contro~led and the mixed solution/suspension or
complete solution which results is stable to degradation. The cyclodextrin
used can be any of the hydroxyalkylated or branched derivatives of ,B- and y-
cyclodextrins identified hereinabove. However, hydroxypropyl-~-cyclodextrin
is presently ~l~fell~d.
When compositions of the present invention are suspensions or
formulations intPn(led for ~lminictration to the eye, particle size and viscosity
of the polymers, may be less important particularly when the therapeutic agent
is completely solubilized. The cyclodextrin-containing compositions of the
present invention can be adapted for topical tre~tment of skin and mucous
membrane by local application to tissue in need of treatment, such as dermal,
nasal, vaginal and rectal tissues. The dosage loading for compositions of the
present invention may vary depending on the drug used, the route of
~iminictration selected and other factors f~mili~r to those skilled at methods
of formulating pharm~ceutic~l compositions.
In a typical method for stabilizing and partially or completely
solubilizing ~minost~roids in accord with the present invention, the selected
cyclodextrin (e.g. hydroxypropyl-,B-cyclodextrin) is employed in an amount
WO 94/12217 ;. ~ PCT/US93/11651 ~
2~5a~5~ 48
sufficient to solubilize at least a portion of the aminosteroid in the final
formulation; the cyclodextrin is thus utilized in an amount which is generally
from about 1.0 to about 20.0% or 30.0% by weight of the total composition,
but much larger amounts of cyclodextrin (e.g. up to about 50% by weight)
may be used when complete solubilization is desired, depending on the
insolubility of the particular aminosteroid selected, the amount of aminosteroidto be solubilized and the solubilizing power of the selected cyclodextrin. The
weight ratio of cyclodextrin to aminosteroid can range from about 1:1 to about
500:1. The selected polymer is generally used in an effective stabilizing
amount of from about 0. 1 % to about 2 % by weight of the final composition,
although additional polymer (up to about 6.5% by weight) can be present, if
desired. This amount can also to ~,~plessed as a weight to weight ratio of
polymer to aminosteroid from about 1:10 to about 20:1. Generally, the
cyclodextrin is dissolved in water, then the polymer is slowly dispersed
therein and stirred (typically, for a period of from about 15 minutes to 2
hours). Sodium chloride (from about 0 to 0.9% by weight) is added to adjust
osmolality and, optionally, EDTA may be added to complex metal ions. The
reslllt~nt mixture is generally heated (e.g. autoclaved) for a period of from
about 30 to about 90 minutes, then cooled. It is pl~fell~d to adjust the pH of
the mixture to be above about 6. This may be done by addition of a suitable
base such as sodium hydroxide. Separately, the aminosteroid (from about
0.01 to about 10.0% by weight of the total composition) is dissolved in a
strong acid solution (e.g. aqueous hydrochloric acid) and that solution is
combined with the polymer/cyclodextrin solution, the pH is adjusted to around
pH 6-7 with sodium hydroxide, and water is added as neces~ry to bring the
total volume to 100%. Compositions obtained in this manner can be solutions
or mixed sus~-n~ions/solutions; the degree of solubilization is controlled by
the concentr~tion of the cyclodextrin component. A le~resentative formulation
prepared as described in EXAMPLE 1 hereinbelow, having a 1% w/w
concentration of the l~lGse~l~tive aminosteroid U-74006F which is
~0 94/12217 215 0 5 5 4 PCT/US93/11651
49
approximately 75% solubilized, will be stable at room te~ dture and at
40C over a three month storage period. There is no significant loss of
aminosteroid concentration at either temperature. In this case, it is believed
that stability results from the stability of the non-dissolved aminosteroid, theinteraction of the aminosteroid with the polymer as discussed above in relation
to the non-cyclodextrin compositions, and the molecular inclusion of the
aminosteroid by the cyclodextrin. Solubili_ation is of course due primarily to
the presence of cyclodextrin. The main reason the aminosteroid is stable in
both formulations appears to be the presence of the cross-linked polymer and
its ionic interaction with the ~minosteroid.
The aminosteroids of formula XI are useful in the treatment of a
variety of medi~l conditions in warm-blooded ~nim~lc, including humans.
The present invention provides pharm~ eutical compositions for adminictration
in the tre~tmçnt or prevention of the various conditions for which the
aminosteroids are known to be useful, e.g. from International Publication No.
WO 87/01706, and from U.S. Patent No. 5,124,154. Briefly, such conditions
include spinal trauma; head injury (mild, moderate or severe); subarachnoid
hemorrhage (including theassociated cerebral vasospasm); skin graft rejection;
ischemic stroke; excessive mucous secretion; ~cthm~; muscular dystrophy;
shock (hemorrhagic, septic or tr~l~m~tic); cardiac toxicity induced by anti-
cancer agents such as adriamycin; Parkinsonism, ~l7h~imçr's disease and
other neurological disorders of a degenerative nature; severe burns; ARDS;
multiple sclerosis; organ damage occurring during reperfusion following
transplant; o~eo~ ~hlitis, rhP~m~toid arthritis and other infl~mm~tory ~licç~ces;
dermatological disorders such as infl~mm~tion and psoriasis; immunological
nephrotic syndrome; allergic reactions; systemic lupus erythematosis;
atherosclerosis; emphysema; met~ct~cPs and tumor growth; cluster headaches,
ulcers indllce~ by stress; complications from radiation damage, brain tumors
and damage after myocardial infarction; and burns and wounds (to promote
WO 94/12217 - ~ PCT/US93/116~1 ~
21~055 4 50
healing). The aminosteroids are further known to be useful in the prevention
of damage following cardiopulmonary resuscitation, cardiac infarction and
neurological or cardiovascular surgery; in the treatment and prevention of
many of the conditions for which glucocorticoid pharm~euticals are known
to be useful (some of which are listed hereinabove); in the trP~tment or
prevention of ophthalmic ~lice~cps or disorders such as cataracts, glaucoma or
the risk of glaucoma associated with significantly elevated intraocular
pressure, infl~mm~tory eye disease, retinal eye disease, intraocular pressure
rise due to uveitis, post-infarct ambolus, traumatic eye injury (such as blunt
trauma compression injury, hyphema, surgical trauma, etc.), neovascular or
ischemic eye disease (conditions in the eye involving ischemia such as corneal
edema from prolonged wearing of contact lenses and the like), bullous
kPr~titi~, dry eye including keratitis sicca, alkali burn and conditions arisingfrom transplantation of ocular cells.
The folegoillg is not meant to imply that each of the aminosteroids of
formula XI is useful for every condition noted above. However, one skilled
in the art can readily ascertain which aminosteroids are useful for which
purposes, for example, using assay procedures referred to in International
Publication No. WO 87/01706.
Routes of ~rlminictration~ frequency of ~11minictration and dosage levels
vary with the particular therapeutic agent selected, condition being treated,
severity of the condition, size, weight and age of the patient and other well-
known factors. Typical dosage ranges for intravenous or intramuscular
injection of ~minosteroids include from about 0.05 to about 100 mg/kg/day,
one to four times daily. The dosages will vary, of course, with the compound
s~lected Obviously, sl~spencion and solutions can be ~iminictPred by other
routes as well including topical (e.g., ophth~lmic, dermal or vaginal),
introcular, nasal and rectal ~dmini~tration.
~Wo 94/12217 2 1 5 0 5 S 4 PCT/US93/11651
Topical adminictration to the skin is generally preferred for the
treatment of many dermatological conditions, particularly skin infl~mm~tion
and psoriasis, but particularly serious dermal conditions may require systemic
~lminictration, alone or in conjunction with topical treatment. Here again, the
specific dosages selected will vary somewhat depending on the drug selected
and other factors noted above.
In the case of ophthalmic conditions, topical administration is
preferable when the target of the treatment is located in or near the anterior
chamber of the eye. By contrast, because the flow of aqueous humor is from
the ciliary body (behind the iris) forward towards the cornea before it exits
through the trabecular meshwork and Schlemm's canal, penetration of drugs
to the back of the eye when ~rlminict~red topically to the front of the eye
occurs with some difficulty. It is therefore often more effective to ~clminicterdrugs intended for the tre~tment of uveal and retinal ~lice~ces by the systemic
route where access to the eye occurs through the choroid plexus, or by the
intravitreal route. Some of the more severe eye ~lise~cPs affect those targets
which are difficult to treat effectively by the topical route and they can be
associated with markedly impaired vision or blindness. Accordingly, the
topical route is plefelled for convenience of individual patient self-
lminictration, and the intraocular and systemic routes are preferred for
surgical and presurgical ~lminictration.
In order to maintain an ocularly adequate therapeutic level of drug in
the back of the eye where surgery is not involved, or has been concluded, the
present invention also conte...plates the treatment of an ophthalmic disease by
~lminictration of a thel~peu~ically effective amount of amino-substituted
steroid antioxidant agent (including salts, hydrates or solvates), by oral or
intramuscular routes, in addition to the convenient topical route or by
intraocular injection.
.
WO 94/12217 52 PCT/US93/11651 ~
2lsass l
Aqueous solutions, aqueous suspensions, ointments, and gels are
preferably used for topical formulations, e.g. for ophthalmic or dermal
~mini~tration. The aqueous formulations may also contain liposomes for
creating a reservoir of dissolved amino-substituted steroid therapeutic agent
S for contact with the tear film. Particularly ~ felled among topicalformulations are gels, which enhance pre-corneal retention and protect the
amino-substituted steroids from degradation without the inconvenience and
impairment of vision associated with ointments.
Topical formulations should generally include between 0.01 and 10%
by weight, preferably between 0.1 and 5 % by weight, of the amino-substituted
steroid therapeutic agent, together with the amounts of polymer and/or
cyclodextrin noted hereinabove, in an aqueous medium.
Other additives which are desirably included in the topical formulations
include sodium chloride, EDTA (disodium edetate), pH adjusters, buffers,
surfactants, and preservatives like BAK (benzalkonium chloride).
A~mini~tration of the formulation to the eye or skin will typically be carried
out between one and four times a day, depending on the particular problem
being treated.
Formulations for ocular injection, intramuscular injection, oral
~(~mini~tration and other routes can be formulated in accord with techniques
well-known to those skilled in the art of pharmaceutical formulations. The
amounts of thçlAl~ulic agent, polymer and cyclodextrin as noted hereinabove
may typically be included in an aqueous medium; and as in the case of topical
formulations, other additives may be included just so long as they do not
interfere with the stabilization (and solubilization, when desired) and are
~ro~u~iate for the selectçd route of ~(~mini~tration. See, for example
applicants' parent application referenced hereinabove, and Rçmington's
~Wo 94/12217 2 15 0 ~ 5 ~ PCT/US93/11651
53
Pharmaceutical Sciences seventeen edition, ed. Alfonso R. Gennaro, Mack
Publishing Company, Easton, PA (1985) which is incorporated herein by
reference in its entirety and is relied upon.
The following examples are given for illustrative purposes only and
should in no way be construed as limiting the subject matter presently
disclosed and cl~im~d.
EXAMPLE 1
A 100 g batch of pharm~eutical composition may be prepared as
described below:
INGREDIENTCONCENTRATION (% w/w)
Aminosteroid U-74006F 1.0 %
Polycarbophil 976 (Noveon AA-l)1.0%
2-Hydroxypropyl-~B-cyclodextrin20.0%
EDTA 0. 1%
Hydrochloric Acid, 0.2 N 12.5 %
Sodium Hydroxide, 2 Nto adjust pH
Water,q.s.to 100%
The cyclodextrin (20 g) is dissolved in approximately 60 g of sterile water for
injection. The polymer is dispersed in the cyclodextrin solution, then the
mixture is stirred for about 1 hour at 400 rpm. Then, 0.1 g of EDTA is
added and stirred for 15 minutes. The mixture is autoclaved for 45 minutes
at 121C, then allowed to cool to room temperature. The aminosteroid (1 g)
is dissolved in 12.5 g of 0.2 N aqueous hydrochloric acid. The aminosteroid
solution is added to the cyclodextrin/polymer mixture by sterile filtration. ThepH is adjusted to about 7.2 with 2 N aqueous sodium hydroxide solution, the
final weight of the formulation is adjusted to 100 g sterile water by sterile
filtration. The formulation is sealed under a blanket of filtered nitrogen. The
WO 94/12217 PCT/US93/11651
2 ~ 5 ~ 54
aminosteroid is extensively solubilized in the resultant composition, but about
25% of the steroid rem~ined undissolved: The pH is physiological and the
osmolality is slightly hypotonic.
S The resultant composition is of particular interest for topical treatment
of ophthalmic conditions. Use of about 30 g of 2-hydroxypropyl-~-
cyclodextrin in the above procedure is expected to substantially completely
solubilize the aminosteroid.
The foregoing example can be repeated, substituting or adding one or
more other aminosteroid therapeu~tic agents selected from the C20 through C26
aminosteroids of the formula XI structure (especially those which exhibit
antioxidant functions), and pharm~elltically acceptable salts, hydrates, or
solvates thereof. One such agent is U-77372E. The structure of U-77372E,
21-[4-(4,6-bis-(2-pyridinyl)triazin-2-yl)-1-piperazinyl]-16~-methylpregna-
1,4,9(11)-triene-3,20-dione methanesulfonate, may be obtained from the
description in Braughler et al, Biochemical Pharmacolo~y 37:3856 (1988).
EXAMPLE 2
A 100 g batch of pharm~-eutic~l composition may be prepared as
described below:
INGREDIENT CONCENTRATION
(5)-4-methyl-2-{methyl-[4-(2-methyl- 0.3 %
imi~7O[4,5-C]pyridin-l-ylmethyl)-benzene
sulphonyl]-amino}pentanoic acid ethyl
ether (BB-882)
Polycarbophil (Noveon AA-1) 1.3 %
2-Hydroxypropyl-,l~-cyclodextrin (HPBC) 15.0 %
EDTA 0.1 %
Hydrochloric Acid, 0.2 N 12.5%
Sodium Hydroxide, 2 N to adjust pH
Water for injection q.s. to 100%
-
Wo 94/12217 215 0 5 5 4 PCT/US93/11651
The HPBC (15 g) is dissolved in approximately 60 g of sterile water for
injection. The polymer is dispersed in the HPBC solution, then the mixture
is stirred for about 1 hour at 400 rpm. Then, 0.1 g of EDTA is added and
stirred for 15 minutes. The mixture is autoclaved for 20 minutes at 121C,
then allowed to cool to room tem~ ture. BB-882 is a PAF-antagonist useful
as an antiinflamatory therapeutic agent. BB-882 (.3 g) is dissolved in 12.5 g
of 0.2 N hydrochloric acid. The BB-882 solution is added to the
HPBC/polymer mixture by sterile filtration while mixing. The pH is adjusted
to about 6.0 with 2 N sodium hydroxide solution and the final weight of the
formulation is adjusted to l00 g with sterile water by sterile filtration.
E~XAMPLE 3
A 100 g batch of pharm~reutical composition may be prepared as
described below:
INGREDIENT CONCENTRATION
[4(N-hydroxyamino)-2R-isobutyl-3S- 0.3 %
(thienyl-thiomethyl)-succinyl] -L-
phenyl~l~nine-N-methylamide (BB-94)
Polycarbophil (Noveon AA-1) 1.3 %
2-Hydroxypropyl-,B-cyclodextrin (HPBC)15.0 %
EDTA 0.1%
Hydrochloric Acid, 0.2 N 12.5 %
Sodium Hydroxide, 2 N to adjust pH
Water for injection q.s. to 100%
The HPBC (15 g) is dissolved in approximately 60 g of sterile water for
injection. The polymer is dispersed in the HPBC solution, then the mixture
is stirred for about 1 hour at 400 rpm. Then, 0.1 g of EDTA is added and
stirred for 15 minutes. The mixture is autoclaved for 20 minutes at 121C,
then allowed to cool to room telllpelature. BB-94 is a collogenase inhibitor.
The BB-94 (.3 g) is dissolved in 12.5 g of 0.2 N hydrochloric acid. The
aminosteroid solution is added to the HPBC/polymer mixture by sterile
wo g~/12217 PcT/US93/11651 ~
~15~55 ~ 56
filtration. The pH is adjusted to about 6.0 with 2 N sodium hydroxide
solution. The final weight of the formulation is adjusted to 100 g with sterile
water.
,, '
EXAMPLE 4
A 100 g batch of pharm~reutical composition may be prepared as
described below:
INGREDIENT CONCENTRATION
Levobunalol HCl 1.0%
Polycarbophil (Noveon AA-l) 1.3%
2-Hydroxypropyl-,~-cyclodextrin (HPBC)15.0%
EDTA 0. 1%
Hydrochloric Acid, 0.2 N 12.5%
Sodium Hydroxide, 2 N to adjust pH
Water for injection q.s. to 100%
The HPBC (15 g) is dissolved in approximately 60 g of sterile water for
injection. The polymer is dispersed in the HPBC solution, then the mixture
is stirred for about 1 hour at 400 rpm. Then, 0.1 g of EDTA is added and
stirred for 15 minutes. The mixture is autoclaved for 45 minutes at 121C,
then allowed to cool to room temperature. Levobunolol HC 1 is an
~ntigl~l~coma therapeutic agent. The levobunolol HCl (1 g) is dissolved in
12.5 g of water of pH 7.2. The levobunolol HC1 solution is added to the
HPBC/polymer ~ ulc by sterile filtration. The pH is adjusted to about 6.0
with 2 N sodium hydroxide solution by sterile filtration. The final weight of
the formulation is adjusted to 100 g with sterile water by sterile f1ltration.
EXAMPLE 5
A 100 g batch of pharm~r-eutir~l composition is prepared as described below:
wo 94/12217 215 0 5 5 ~ PCT/US93/11651
.
57
In~redient Concentration
L-Asparaginyl-L-Leucyl-Glycyl-L- 1 %
Valyl-S-Acet~midomethyl-L-
Cystein~mide Acetate (CBT-101)
Polycarbophil (Noveon AA- 1 ) 1 %
Sodium Glycocholate 1%
2-Hydroxypropyl-~-cyclodextrin 4 %
(HPBC)
Sodium Chloride (NaCl) 0.34%
Disodium Acetate (EDTA) 0.1%
Sodium Hydroxide, 10 N. to adjust pH
Water for iniection, q.s. to 100%
The polymer is dispersed in approximately 60 g of sterile water for injection,
stirred for 1 hour at 400 rpm. Then 0.1 g of EDTA is added and stirred for
15 minutes, 0.34 g of NaCl is added and stirred for 15 minutes, 1 g of sodium
glycocholate is added to the mixture, and stirred for 15 minutes. The mixture
is autoclaved for 45 minutes at 121 C, then allowed to cool to room
temperature. Dissolve HPBC (4 g) in 15 g of sterile water for injection, then
add 1 g of CBT-101 to the HPBC solution. Add the CBT-101/HPBC solution
to the polymer mixture by sterile filtration. The pH is adjusted to about 7-0
with 10 N. sodium hydroxide solution by sterile filtration. The final weight
of the formulation is adjusted to 100 g with sterile water by sterile filtration.
CBT-101 is useful in tre~tment of glaucoma.
wo 94/12217 PCT/US93/11651
2`~50~5~ 58
Although only plefell~d embodiments are specifically illustrated and
described herein, it will be appreciated that many modifications and variations
of the present invention are possible in light of the above teaching and within
the purview of the appended claims without departing from the spirit and
intended scope of the invention.
EXAMPLE 6
A 100 g batch of pharmaceutical composition may be prepared as
described below:
INGREDIENTCONCEN~RATION (% w/w)
Aminosteroid U-74006F 1.0%
Carbopol 910 2.0%
2-Hydroxypropyl-,B-cyclodextrin20.0 %
EDTA 0.1%
Hydrochloric Acid, 0.2 N 12.5%
Sodium Hydroxide, 2 Nto adjust pH
Water, q.s. to 100%
The cyclodextrin (20 g) is dissolved in approximately 60 g of sterile water for
injection. The polymer is dispersed in the cyclodextrin solution, then the
mixture is stirred for about 1 hour at 400 rpm. Then, 0.1 g of EDTA is
added and stirred for 15 minutes. The mixture is autoclaved for 45 minutes
at 121C, then allowed to cool to room temperature. The aminosteroid (1 g~
is dissolved in 12.5 g of 0.2 N aqueous hydrochloric acid. The aminosteroid
solution is added to the cyclodextrin/polymer mixture by sterile filtration. ThepH is adjusted to about 7.2 with 2 N aqueous sodium hydroxide solution, the
final weight of the formulation is adjusted to 100 g sterile water by sterile
filtration. The formulation is sealed under a blanket of filtered nitrogen.
