Note: Descriptions are shown in the official language in which they were submitted.
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INJECTABLE DEPOT FORMULATIONS AND METHODS FOR PROVIDING SUSTAINED
RELEASE OF POORLY SOLUBLE DRUGS COMPRISING NANOPARTICLES
FIELD OF THE INVENTION
The present invention comprises a pharmaceutical formulation comprising: a
compound of low water solubility, having a maximum average particle size; a
carrier; and at
least two surface stabilizers. The present invention also comprises methods of
treatment with
such a formulation and processes for making such a formulation.
BACKGROUND OF THE INVENTION
Unfortunately, many useful drugs have low solubility in water and, therefore,
are
difficult to formulate at convenient concentrations as solutions in an aqueous
vehicle. Even
when a suitable solvent is found as a vehicle for such a drug, there is often
a tendency,
particularly for a crystalline drug of low water solubility, to precipitate
out of solution and/or
crystallize when the drug comes in contact with water, for example in the
aqueous
environment of the gastrointestinal tract. Such precipitation and/or re-
crystallization can offset
or reduce the potential rapid onset benefits sought by formulating the drug as
a solution.
One problem with drugs and drug candidates of low water solubility is that it
is difficult
to evaluate their bioefficacy. Producing formulations with high
bioavailability is even more
difficult with poorly water soluble drugs. Special non-aqueous formulations
can be used, but
they are not really patient friendly.
There have been many formulations developed specifically for increasing the
aqueous solubility of poorly soluble drugs. Solid extrudates
(dispersion/solution) are an
attractive approach, but have not been used widely due to the required
increases in
temperature beyond melting points of drugs and polymers. Only a limited number
of
commercial formulations are available.
Oral delivery of peptide and protein drugs has been one of the most active
research
areas in drug delivery. Insulin has been used as a model drug in most studies
dealing with
oral administration of protein drugs. A number of approaches have been
developed and, in
fact, many of them showed transient control of glucose levels. While it may be
possible to
lower the glucose level for a short time by oral administration of insulin,
the issues of
reproducibility and the kinetics of absorption have to be very carefully
examined. No report in
the literature has shown the repeated administration of insulin resulting in
effective control of
the glucose level, and has induced the insulin effect at the right time. The
bioavailability is
also a great concern in the study of oral protein delivery. To date, all
studies have indicated
that only a very small fraction (<10%) of the total dose of orally
administered insulin is
bioavailable. A major concern is the waste of more than 90%o of the
administered insulin.
Targeted delivery of drugs to the colon has become popular in recent years
because
the delivery of drugs labile to acid and enzymes in a region that is less
hostile metabolically
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results in enhanced absorption of certain drugs. Drugs with poor solubility
may not dissolve in
the colon where there is not as much fluid as in the upper portion of the GI
tract. The current
technologies are mainly focused on delayed release, that is, no release until
the dosage form
reaches the colon. The time-delay approach relies on drug release following a
predetermined
lag time and would therefore be less dependable.
Nanotechnology presents an opportunity to increase the bioavailability of drug
particles. A decrease in particle size results in increased surface area,
which may result in
faster dissolution, normally by a small order of magnitude. In some cases,
this may be
enough to result in increased bioavailability. However, faster dissolution may
not be sufficient
to overcome exposure to acid and enzymes in the gut. Additionally, as in the
case with oral
insulin, this exposure may require higher dosing of the drug, resulting in
unnecessary and
potentially undesirable subject exposure to breakdown products as well as
create significant
waste.
A depot formulation is specially formulated to provide slow absorption of the
drug
from the site of administration, often keeping therapeutic levels of the drug
in the patient's
system for days or weeks at a time. Alternatively, a depot formulation may
provide
convenience for a patient in need of chronic medication. By delivering drug
without exposure
to the GI tract, the potential issue of drug degradation is avoided. Moreover,
a depot
formulation may provide better compliance due to the infrequent dosing regimen
and
convenience. Additional characteristics of a depot formulation that will
enhance patient
compliance are good local tolerance at the injection site and ease of
administration. Good
local tolerance means minimal irritation and inflammation at the site of
injection; ease of
administration refers to the size of needle and length of time required to
administer a dose of
a particular drug formulation.
U.S. Patent No. 6,232, 304 (granted May 15, 2001) describes a ziprasidone salt
solubilized with cyclodextrins for an immediate release intramuscular
injection formulation.
U.S. Patent No. 6,150, 366 (granted November 21, 2000) describes a
pharmaceutical
composition describing crystalline ziprasidone and a carrier.
U.S. Patent No. 6, 267, 989 (granted July 31, 2001) describes a water-
insoluble
crystalline drug to which a surface modifier is adsorbed in an amount
sufficient to maintain a
defined particle size.
U.S. Patent No. 5,145, 684 (granted September 8, 1992) describes low
solubility
crystalline drug substances to which a surface modifier is adsorbed in an
amount sufficient to
maintain a defined particle size.
U.S. Patent No. 5, 510, 118 (granted April 23, 1996) describes a
homogenization
process to obtain sub-micron drug substances without milling media.
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U.S. Patent No. 5, 707, 634 (granted January 13, 1998) describes a method
precipitating a crystalline solid from liquid.
U.S. Patent No. 5, 314, 685 (granted May 24, 1994) describes techniques for
solubilizing hydrophobic compounds with low water solubility.
U.S. Patent No. 4, 992, 271 (granted February 12, 1991) describes techniques
for
solubilizing hydrophobic compounds with low water solubility.
U.S. Patent Application Number 60/585411 (filed July 1, 2004) describes a high
pressure homogenization method to prepare nanoparticles.
WO 00/18374 (filed October 1, 1999) describes a controlled release
nanoparticle
composition.
WO 00/09096 (filed August 12, 1999) describes an injectable nanoparticle
formulation
of naproxen.
Certain potential pharmaceuticals are hydrophobic and typically have low
aqueous
solubility and hence low oral bioavailability. It is believed that the
invention provides an
acceptable depot formulation of low water solubility drug nanoparticles, which
is efficacious
and has an acceptable injection volume. In addition to enhancing patient
compliance, a
nanoparticle depot formulation of a low solubility drug may reduce overall
exposure to the
drug compared to oral capsules while providing sufficient exposure to ensure
efficacy.
SUMMARY OF THE INVENTION
In one embodiment, the present invention comprises a pharmaceutical
formulation
suitable for use as a depot formulation for administration via intramuscular
or subcutaneous
injection. The formulation comprises (1) a low solubility drug or
pharmaceutically acceptable
salt thereof; (2) a pharmaceutically acceptable carrier; and (3) at least two
surface stabilizers.
The formulations of the invention may, for example, comprise from two to ten
surface
stabilizers, preferably two to five surface stabilizers. In another
embodiment, the formulation
consists of two surface stabilizers. In another embodiment, the formulation
consists of three
surface stabilizers. In still another embodiment, the formulation consists of
two surface
stabilizers and a bulking agent.
In another embodiment, the present invention comprises processes for preparing
such a formulation.
In another embodiment, the present invention comprises the use of such a
composition as a medicament in the treatment of a wide range of disorders. In
yet another
embodiment, the present invention comprises methods of treating these
disorders.
DETAILED DESCRIPTION OF THE INVENTION
This detailed description of embodiments is intended only to acquaint others
skilled in
the art with Applicants' inventions, its principles, and its practical
application so that others
skilled in the art may adapt and apply the inventions in their numerous forms,
as they may be
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best suited to the requirements of a particular use. These inventions,
therefore, are not limited
to the embodiments described in this specification, and may be variously
modified.
A. Abbreviations and Definitions
Table A-1: Abbreviations
API Active pharmaceutical ingredient
AUC Area under the curve
Cmax Maximum serum concentration of compound
CPB Cloud point booster
DLS Dynamic light scattering
EPS Extrapyramidal symptoms
D[4,3] Volume average diameter
F bioavailability
FB Free base
Form. formulation
Gy Gray - a measure of irradiation dose
H hours
HCI Hydrochloride salt
IM intramuscular
IR Immediate release
Mes Mesylate salt
MI Milliliter
MW Molecular weight
ng nanograms
nm Nanometer
NMP N-methyl-pyrrolidone
PEG Polyethylene glycol
PK Pharmacokinetics
PVA polyvinylalcohol
PVP polyvinylpyrrolidone
PVP C15 A particular grade of PVP
PVP K30 A particular grade of PVP
RPM Revolutions per minute
RPS Reduced particle size
SAN Surface area to volume ratio
SBECD sulfobutylether-(3-cyclodextrin
SLS Sodium lauryl sulfate
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t1/Z Terminal elimination phase half-life
Tmax Time to maximum serum concentration of compound
v/v Volume by volume
VDss Volume of distribution at steady state
w/v Weight by volume
Z - Com. Ziprasidone compound
The term "compound" refers to a form of a therapeutic or diagnostic agent
which is a
component of an injectable depot formulation. The compound may be a
pharmaceutical,
including, without limitation, biologics such as proteins, peptides and
nucleic acids or a
diagnostic, including, without limitation, contrast agents. In one embodiment,
the compound
is crystalline. In another embodiment, the compound is amorphous. In another
embodiment,
the compound is a mixture of crystalline and amorphous forms. In another
embodiment, the
cor'npound has low water solubility. In another embodiment, the logP of the
compound is at
least about 3 or greater. In another embodiment, the compound has a high
melting point. A
high melting compound is one with a melting point greater than about 130
degrees Celsius.
A compound having "low water solubility" refers to any compound having a
solubility
in water, measured at 37 C, not greater than about 10 mg/ml. In another
embodiment, the
measured solubility is not greater than about 1 mg/mI. In another embodiment,
the measured
solubility is not greater than about 0.1 mg/mi. A synonymous term is "low
aqueous solubility."
Solubility in water for many drugs can be readily determined from standard
pharmaceutical reference books, for example The Merck Index, 13th ed., 2001
(published by
Merck & Co., Inc., Rahway, NJ); the United States Pharmacopoeia, 24th ed. (USP
24), 2000;
The Extra Pharmacopoeia, 29th ed., 1989 (published by Pharmaceutical Press,
London); and
the Physicians Desk Reference (PDR), 2005 ed. (published by Medical Economics
Co.,
Montvale, NJ).
For example, individual compounds of low solubility as defined herein include
those
drugs categorized as "slightly soluble", "very slightly soluble", "practically
insoluble" and
"insoluble" in USP 24, pp. 2254-2298; and those drugs categorized as requiring
100 ml or
more of water to dissolve I g of the drug, as listed in USP 24, pp. 2299-2304.
Exemplary compounds, include, without limitation; compounds from the following
classes: abortifacients, ACE inhibitors, a- and P-adrenergic agonists, a- and
(3-adrenergic
blockers, adrenocortical suppressants, adrenocorticotropic hormones, alcohol
deterrents,
aldose reductase inhibitors, aidosterone antagonists, anabolics, analgesics
(including narcotic
and non-narcotic analgesics), androgens, angiotensin II receptor antagonists,
anorexics,
antacids, anthelminthics, antiacne agents, antiallergics, antialopecia agents,
antiamebics,
antiandrogens, antianginal agents, antiarrhythmics, antiarteriosclerotics,
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antiarthritic/antirheumatic agents, antiasthmatics, antibacterials,
antibacterial adjuncts,
anticholinergics, anticoagulants, anticonvulsants, antidepressants,
antidiabetics, aritidiarrheal
agents, antidiuretics, antidotes to poison, antidyskinetics, antieczematics,
antiemetics,
antiestrogens, antifibrotics, antiflatulents, antifungals, antiglaucoma
agents,
antigonadotropins, antigout agents, antihistaminics, antihyperactives,
antihyperlipoproteinemics, antihyperphosphatemics, antihypertensives,
antihyperthyroid
agents, antihypotensives, antihypothyroid agents, anti-inflammatories,
antimalarials,
antimanics, antimethemoglobinemics, antimigraine agents, antimuscarinics,
antimycobacterials, antineoplastic agents and adjuncts, antineutropenics,
antiosteoporotics,
antipagetics, antiparkinsonian agents, antipheochromocytoma agents,
antipneumocystis
agents, antiprostatic hypertrophy agents, antiprotozoals, antipruritics,
antipsoriatics,
antipsychotics, antipyretics, antirickettsials, antiseborrheics,
antiseptics/disinfectants,
antispasmodics, antisyphylitics, antithrombocythemics, antithrombotics,
antitussives,
antiulceratives, antiurolithics, antivenins, antiviral agents, anxiolytics,
aromatase inhibitors,
astringents, benzodiazepine antagonists, bone resorption inhibitors,
bradycardic agents,
bradykinin antagonists, bronchodilators, calcium channel blockers, calcium
regulators,
carbonic anhydrase inhibitors, cardiotonics, CCK antagonists, chelating
agents, cholelitholytic
agents, choleretics, cholinergics, cholinesterase inhibitors, cholinesterase
reactivators, CNS
stimulants, contraceptives, debriding agents, decongestants, depigmentors,
dermatitis
herpetiformis suppressants, digestive aids, diuretics, dopamine receptor
agonists, dopamine
receptor antagonists, ectoparasiticides, emetics, enkephalinase inhibitors,
enzymes, enzyme
cofactors, estrogens, expectorants, fibrinogen receptor antagonists, fluoride
supplements,
gastric and pancreatic secretion stimulants, gastric cytoprotectants, gastric
proton pump
inhibitors, gastric secretion inhibitors, gastroprokinetics, glucocorticoids,
a-glucosidase
inhibitors, gonad-stimulating principles, growth hormone inhibitors, growth
hormone releasing
factors, growth stimulants, hematinics, hematopoietics, hemolytics,
hemostatics, heparin
antagonists, hepatic enzyme inducers, hepatoprotectants, histamine H2 receptor
antagonists,
HIV protease inhibitors, HMG CoA reductase inhibitors, immunomodulators,
immunosuppressants, insulin sensitizers, ion exchange resins, keratolytics,
lactation
stimulating hormones, laxatives/cathartics, leukotriene antagonists, LH-RH
agonists,
lipotropics, 5-lipoxygenase inhibitors, lupus erythematosus suppressants,
matrix
metalloproteinase inhibitors, mineralocorticoids, miotics, monoamine oxidase
inhibitors,
mucolytics, muscle relaxants, mydriatics, narcotic antagonists,
neuroprotectives, nootropics,
ovarian hormones, oxytocics, pepsin inhibitors, pigmentation agents, plasma
volume
expanders, potassium channel activators/openers, progestogens, prolactin
inhibitors,
prostaglandins, protease inhibitors, radio-pharmaceuticals, 5a-reductase
inhibitors,
respiratory stimulants, reverse transcriptase inhibitors, sedatives/hypnotics,
serenics,
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serotonin noradrenaline reuptake inhibitors, serotonin receptor agonists,
serotonin receptor
antagonists, serotonin uptake inhibitors, somatostatin analogs, thrombolytics,
thromboxane A2
receptor antagonists, thyroid hormones, thyrotropic hormones, tocolytics,
topoisomerase I
and II inhibitors, uricosurics, vasomodulators including vasodilators and
vasoconstrictors,
vasoprotectants, xanthine oxidase inhibitors, and combinations thereof.
Examples of suitable compounds include, without limitation, acetohexamide,
acetylsalicylic acid, alclofenac, allopurinol, atropine, benzthiazide,
carprofen, celecoxib,
chlordiazepoxide, chlorpromazine, clonidine, codeine, codeine phosphate,
codeine sulfate,
deracoxib, diacerein, diclofenac, diltiazem, estradiol, etodolac, etoposide,
etoricoxib,
fenbufen, fenclofenac, fenprofen, fentiazac, flurbiprofen, griseofulvin,
haloperidol, ibuprofen,
indomethacin, indoprofen, ketoprofen, lorazepam, medroxyprogesterone acetate,
megestrol,
methoxsalen, methylprednisone, morphine, morphine sulfate, naproxen,
nicergoline,
nifedipine, niflumic, oxaprozin, oxazepam, oxyphenbutazone, paclitaxel,
palperidone,
phenindione, phenobarbital, piroxicam, pirprofen, prednisolone, prednisone,
procaine,
progesterone, pyrimethamine, risperidone, rofecoxib, sulfadiazine,
sulfamerazine,
sulfisoxazole, sulindac, suprofen, temazepam, tiaprofenic acid, tilomisole,
tolmetic, valdecoxib
and ziprasidone.
Further exemplary compounds include, without limitation, Acenocoumarol,
Acetyldigitoxin, Anethole, Anileridine, Benzocaine, Benzonatate,
Betamethasone,
Betamethasone Acetate, Betamethasone Valerate, Bisacodyl,
Bromodiphenhydramine,
Butamben, Chlorambucil, Chloramphenicol, Chlordiazepoxide, Chlorobutanol,
Chlorocresol,
Chlorpromazine, Clindamycin Palmitate, Clioquinol, Cortisone Acetate,
Cyclizine
Hydrochloride, Cyproheptadine Hydrochloride, Demeclocycline, Diazepam,
Dibucaine,
Digitoxin, Dihydroergotamine Mesylate, Dimethisterone, Disulfiram, Docusate
Calcium,
Docusate Sodium, Dihydrogesterone, Enalaprilat, Ergotamine Tartrate,
Erythromycin,Erythromycin Estolate, Flumethasone Pivalate, Fluocinolone
Acetonide,
Fluorometholone, Fluphenazine Enanthate, Flurandrenolide, Guaifenesin,
Halazone,
Hydrocortisone,, Levothyroxine Sodium, Methyclothiazide, Miconazole,
Miconazole Nitrate,
Nitrofurazone, Nitromersol, Oxazepam, Pentazocine, Pentobarbital, Primidone,
Quinine
Sulfate, Stanozolol, Sulconazole Nitrate, Sulfadimethoxine, Sulfaethidole,
Sulfamethizole,
Sulfamethoxazole, Sulfapyridine, Testosterone, Triazolam, Trichlormethiazide,
and
Trioxsalen.
The term "surface stabilizer" as used herein, unless otherwise indicated,
refers to a
molecule that: (1) is adsorbed on the surface of a compound; (2) otherwise
physically adheres
to the surface of a compound; or (3) remains in solution with a compound,
acting to maintain
the effective particle size of the compound. A surface stabilizer does not
chemically react (i.e.
form a covalent bond) with the drug substance (compound). A surface stabilizer
also does
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not necessarily form covalent crosslinkages with itself or other surface
stabilizers in a
formulation and/or when adsorbed onto compound surfaces. In a preferred
embodiment of
the invention, a surface stabilizer on the surface of a compound or otherwise
in a formulation
of the invention is essentially free of covalent crosslinkages.
In one embodiment, a first surface stabilizer is present in an amount
sufficient to
maintain an effective average particle size of the compound. In a second
embodiment, one or
more surface stabilizers are present in an amount sufficient to maintain an
effective particle
size of the compound. In another embodiment, a surface stabilizer is a
surfactant. In another
embodiment, a surface stabilizer is a crystallization inhibitor.
The term "surfactant" refers to amphipathic molecules that consist of a non-
polar
hydrophobic portion, exemplified by a straight or branched hydrocarbon or
fluorocarbon chain
containing 8-18 carbon atoms, which is attached to a polar or ionic portion
(hydrophilic). The
hydrophilic portion may be nonionic, ionic or zwitterionic and accompanied by
counter ions.
There are several classes of surfactants: anionic, cationic, amphoteric,
nonionic and
polymeric. In the case of nonionic and polymeric surfactants, a single
surfactant may be
properly classified as a member of both categories. An exemplary group of
surfactants that
may be properly classified in this manner are the ethylene oxide-propylene
oxide co-
polymers, referred to as Pluronics (Wyandotte), Synperonic PE (ICI) and
Poloxamers
(BASF). Polymers such as HPMC and PVP may be classified as polymeric
surfactants.
Exemplary classes of surfactants include, without limitation: carboxylates,
sulphates,
sulphonates, phosphates, sulphosuccinates, isethionates, taurates, quarternary
ammonium
compounds, N-alkyl betaines, N-alkyl amino propionates, alcohol ethoxylates,
alkyl phenol
ethoxylates, fatty acid ethoxylates, monoalkaolamide ethoxylates, sorbitan
ester ethoxylates,
fatty amine ethoxylates, ethylene oxide-propylene oxide co-polymers, glycerol
esters, glycol
esters, glucosides, sucrose esters, amino oxides, sulphinyl surfactants,
polyoxyethylene allcyl
ethers, polyoxyethylene alkyl ethers, polyglycolized glycerides, short-chain
glyceryl mono-
alkylates, alkyl aryl polyether sulfonate, polyoxyethylene fatty acid esters,
polyoxyethylene
fatty acid ethers, polyoxyethylene stearates, copolymers of vinylacetate and
vinylalcohol, and
random copolymers of vinyl acetate and vinyl pyrrolidone.
Exemplary surfactants, include, without limitation: dodecyl hexaoxyethylene
glycol
monoether, sorbitan monolaurate, sorbitan monopaimitate, sorbitan
monostearate, sorbitan
mono-oleate, sorbitan tristearate, sorbitan trioleate, polyoxyethylene (20)
sorbitan
monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20)
sorbitan
monostearate, polyoxyethylene (20) sorbitan mono-oleate, polyoxyethylene (20)
sorbitan
tristearate, polyoxyethylene (20) sorbitan trioleate, linolin, castor oil
ethoxylates, Pluronic
F108, Pluronic F68, Pluronic F127, benzalkonium chloride, colloidal silicon
dioxide,
phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium,
carboxymethylcellulose
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sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, phthalate, noncrystalline cellulose, magnesium
aluminate
silicate, triethanolamine, polyvinyl alcohol (PVA), tyloxapol0,
polyvinylpyrrolidone (PVP),
sodium 1,4-bis(2-ethylhexyl) sulfosuccinate, sodium lauryl sulfate (SLS),
polyoxyethylene
(35) castor oil, polyethylene (60) hydrogenated castor oil, alpha tocopheryl
polyethylene
glycol 1000 succinate, glyceryl PEG 8 caprylate/caprate, PEG 32 glyceryl
laurate, dodecyl
trimethyl ammonium bromide, Aerosol OTO, Tetronic 9080, dimyristoyl
phophatidyl glycerol,
dioctylsulfosuccinate (DOSS),Tetronic 15080, Duponol PO, Tritons X-2000,
Crodestas F-
1100, p-isononylphenoxypoly-(glycidol), SA9OHCO, decanoyl-N-methylglucamide, n-
decyl
P-D-glucopyranoside, n-decyl (3-D-maltopyranoside, n-dodecyl (3- D-
glucopyranoside, n-
dodecyl (3-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-.(3-D-
glucopyranoside, n-
heptyl (3-D-thioglucoside, n-hexyl (3-D-glucopyranoside, nonanoyl-N-
methylglucamide, n-noyl
(3-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-(3-D-
glucopyranoside, octyl (3-D-
thioglucopyranoside, dextrin, guar gum, starch, Plasdone0 S630, Kollidone0 VA
64, polyvinyl
alcohol, behenalkonium chloride, benzethonium chloride, cetylpyridinium
chloride,
behentrimonium chloride, lauralkonium chloride, cetalkonium chloride,
cetrimonium bromide,
cetrimonium chloride, cethylamine hydrofluoride, chlorallylmethenamine
chloride
(Quaternium0-15), distearyldimonium chloride (Quaternium0-5), dodecyl dimethyl
ethylbenzyl ammonium chloride(Quaternium0-14), Quaternium0-22, Quaternium0-26,
Quaternium0-18 hectorite, dimethylaminoethylchloride hydrochloride, cysteine
hydrochloride,
diethanolammonium POE (10) oletyl ether phosphate, diethanolammonium POE
(3)oleyl
ether phosphate, tallow alkonium chloride, dimethyl
dioctadecylammoniumbentonite,
stearalkonium chloride, domiphen bromide, denatonium benzoate, myristalkonium
chloride,
laurtrimonium chloride, ethylenediamine dihydrochloride, guanidine
hydrochloride, pyridoxine
HCI, iofetamine hydrochloride, meglumine hydrochloride, methylbenzethonium
chloride, 7
myrtrimonium bromide, oleyltrimonium chloride, polyquaternium-1,
procainehydrochloride,
cocobetaine, stearalkonium bentonite, stearalkoniumhectonite, stearyl
trihydroxyethyl
propylenediamine dihydrofluoride, tallowtrimonium chloride, and
hexadecyltrimethyl
ammonium bromide.
The term "ethylene oxide-propylene oxide copolymers" refers to four types of
nonionic
block copolymers, of which Pluronic0 F108 is one, as described in Table A-2,
immediately
below:
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Formula Components of block copolymer
Ethylene oxide-propylene oxide copolymer prepared by reaction of
(EO)n(PO)m(EO)n poly(oxypropylene glycol) (difunctional) with ethylene oxide
Ethylene oxide-propylene oxide copolymer prepared by reaction of
poly(oxypropylene glycol) (difunctional) with mixed ethylene oxide and
propylene oxide, giving block copolymers
Ethylene oxide-propylene oxide copolymer prepared by reaction of
poly(ethylene glycol) (difunctional) with propylene oxide
(PO)n(EO)m(PO)n Ethylene oxide-propylene oxide copolymer prepared by reaction
of
poly(ethylene glycol) (difunctional) with mixed ethylene oxide and
propylene oxide, giving block copolymers
wherein m and n are varied systematically in each formula
The term "Pluronic F108" refers to the polyoxyethylene-polyoxypropylene block
copolymer that conforms generally to the formula
HO[CH2CH2O]n[CH(CH3)CH2O]m[CH2CH2O]nH in which the average values of n, m and
n are
respectively 128, 54 and 128.
The use of trade names herein is not intended to limit suitable species for
the
invention to those produced or sold by any one particular manufacturer, but
instead to assist
in defining embodiments of the invention.
The term "crystallization inhibitor" refers to a polymer or other substances
that can
substantially inhibit precipitation and/or crystallization of a poorly water-
soluble drug. In one
embodiment, a polymeric surfactant is a crystallization inhibitor. In another
embodiment, the
crystallization inhibitor is a cellulosic or non-cellulosic polymer and is
substantially water-
soluble. In another embodiment, the crystallization inhibitor is HPMC. In
another embodiment,
a crystallization inhibitor is polyvinylpyrrolidone (PVP).
It will be understood that certain polymers are more effective at inhibiting
precipitation
and/or crystallization of a selected poorly water soluble drug than others,
and that not all
polymers inhibit precipitation and/or crystallization as described herein of
every poorly water-
soluble drug. Whether a particular polymer is useful as a crystallization
inhibitor for a
particular poorly water soluble drug according to the present invention can be
readily
determined by one of ordinary skill in the art, for example according to Test
I, depicted in
Table A-3:
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Table A-3: Method to Test Crystallization Inhibitors for Efficacy
Step I A suitable amount of the drug'is dissolved in a solvent (e.g., ethanol,
dimethyl
sulfoxide or, where the drug is an acid or base, water) to obtain a
concentrated
drug solution.
Step 2 A volume of water or buffered solution with a fixed pH is placed in a
first vessel and
maintained at room temperature.
Step 3 An aliquot of the concentrated drug solution is added to the contents
of the first
vessel to obtain a first sample solution having a desired target drug
concentration.
The drug concentration selected should be one which produces substantial
precipitation and consequently higher apparent absorbance (i.e., turbidity)
than a
saturated solution having rio such precipitation.
Step 4 A test polymer is selected and, in a second vessel, the polymer is
dissolved in
water or a buffered solution with a fixed pH (identical in composition, pH and
volume to that used in step C) in an amount sufficient to form a 0.25% - 2%
w/w
polymer solution.
Step 5 To form a second sample solution, an aliquot of the concentrated drug
solution
prepared in step A is added to the polymer solution in the second vessel to
form a
sample solution having a final drug concentration equal to that of the first
sample
solution.
Step 6 At 60 minutes after preparation of both sample solutions, apparent
absorbance
(i.e., turbidity) of each sample solution is measured using light having a
wavelength
of 650 nm.
Step 7 If the turbidity of the second sample solution is less than the
turbidity of the first
sample solution, the test polymer is deemed to be a "turbidity-decreasing
polymer"
and is useful as a crystallization inhibitor for the test drug.
A technician performing Test I will readily find a suitable polymer
concentration for the
test within the polymer concentration range provided above, by routine
experimentation. In a
particularly preferred embodiment, a concentration of the polymer is selected
such that when
Test I is performed, the apparent absorbance of the second sample solution is
not greater
than about 50% of the apparent absorbance of the first sample solution.
Most surface stabilizers are described in detail in the Handbook of
Pharmaceutical
Excipients, published jointly by the American Pharmaceutical Association and
The
Pharmaceutical Society of Great Britain, the Pharmaceutical Press, 2000. The
surface
stabilizers are commercially available and/or can be prepared by techniques
known in the art.
Presentations of exemplary surfactants are given in McCutcheon, Detergents and
Emulsifiers,
Allied Publishing Co., New Jersey, 2004 and Van Os, Haak and Rupert, Physico-
chemical
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Properties of Selected Anionic, Cationic and Nonionic Surfactants, Elsevier,
Amsterdam,
1993.
The terms "pKa" and "Dissociation Constant" refer to a measure of the strength
of an
acid or a base. The pKa allows the determination of the charge on a molecule
at any given
pH.
The terms "IogP" and "Partition Coefficient" refer to a measure of how well a
substance partitions between a lipid (oil) and water. The Partition
Coefficient is also a very
useful parameter which may be used in combination with the pKa to predict the
distribution of
a compound in a biological system. Factors such as absorption, excretion and
penetration of
the CNS may be related to the Log P value of a compound and in certain cases
predictions
made.
The term "low aqueous solubility" refers to a therapeutic or diagnostic agent
with a
solubility in water of less than about 10 mg/mL. In another embodiment, the
solubility in water
is less than about 1 mg/mL.
The term "particle size" refers to effective diameter, in the longest
dimension, of
compound particles. Particle size is believed to be an important parameter
affecting the
clinical effectiveness of therapeutic or diagnostic agents of low aqueous
solubility.
The terms "average particle size" and "mean particle size" refer to compound
particle
size of which at least 50% or more of the compound particles are, when
measured by
dynamic light scattering. In an exemplary embodiment, an average particle size
of from about
120 nm to about 400 nm means that at least 50% of the compound particles have
a particle
size from about 120 nm to about 400 nm when measured by standard techniques,
as
indicated in other embodiments herein. In another embodiment, at least 70% of
the particles,
by weight, have a particle size of less than the indicated size. In another
embodiment, at least
90% of the. particles have the defined particle size. In yet another
embodiment, at least 95%
of the particles have the defined particle size. In another embodiment, at
least 99% of the
particles have the defined particle size. In other embodiments, different
measurement
techniques may be employed - such as laser diffraction.
B. Formulations
The present invention comprises, in part, novel injectable depot formulations
of low
solubility drugs. The present invention also comprises a method of treating
disorders suitable
for treatment with low solubility drugs.
In one embodiment of the invention, an injectable depot formulation comprises:
a) a
pharmaceutically effective amount of a compound selected from the group
consisting of a low
solubility drug and a pharmaceutically acceptable salt thereof, the compound
in the form of
nanoparticles having an average particle size of less than about 2000 nm; b) a
pharmaceutically acceptable carrier; and c) at least two surface stabilizers;
wherein at least
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one of the surface stabilizers is adsorbed on the surface of the
nanoparticles; and wherein the
combined amount of the surface stabilizers is effective to maintain the
average particle size of
the nanoparticles (Formulation 1).
Suitable acid addition salts are formed from acids which form non-toxic salts.
Examples include the acetate, adipate, aspartate, benzoate, besylate,
bicarbonate/carbonate,
bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate,
esylate, formate,
fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate,
hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate,
lactate,
malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,
nicotinate,
nitrate, orotate, oxalate, paimitate, pamoate, phosphate/hydrogen
phosphate/dihydrogen
phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate,
tosylate,
trifluoroacetate and xinofoate salts.
Suitable base salts are formed from bases which form non-toxic salts. Examples
include the aluminum, arginine, benzathine, calcium, choline, diethylamine,
diolamine,
glycine, lysine, magnesium, meglumine, olamine, potassium, sodium,
tromethamine and zinc
salts. Hemisalts of acids and bases may also be formed, for example,
hemisulphate and
hemicalcium salts. For a review on suitable salts, see Handbook of
Pharmaceutical Salts:
Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH,'2002).
The compound may also exist in unsolvated and solvated forms. The term
'solvate' is
used herein to describe a molecular complex comprising the compound of the
invention and
one or more pharmaceutically acceptable solvent molecules, for example,
ethanol. The term
'hydrate' is employed when said solvent is water.
A currently accepted classification system for organic hydrates is one that
defines
isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism
in
Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker,
1995). Isolated site
hydrates are ones in which the water molecules are isolated from direct
contact with each
other by intervening organic molecules. In channel hydrates, the water
molecules lie in lattice
channels where they are next to other water molecules. In metal-ion
coordinated hydrates,
the water molecules are bonded to the metal ion.
When the solvent or water is tightly bound, the complex will have a well-
defined
stoichiometry independent of humidity. When, however, the solvent or water is
weakly bound,
as in channel solvates and hygroscopic compounds, the water/solvent content
will be
dependent on humidity and drying conditions. In such cases, non-stoichiometry
will be the
norm.
Pharmaceutically acceptable salts of a low solubility drug may be prepared by
one or
more of three methods:
(i) by reacting the compound of formula I with the desired acid or base;
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(ii) by removing an acid- or base-labile protecting group from a suitable
precursor of the compound of formula I or by ring-opening a suitable cyclic
precursor, for
example, a lactone or lactam, using the desired acid or base; or
(iii) by converting one salt of a low solubility drug to another by reaction
with an
appropriate acid or base or by means of a suitable ion exchange column.
All three reactions are typically carried out in solution. The resulting salt
may precipitate out
and be collected by filtration or may be recovered by evaporation of the
solvent. The degree
of ionization in the resulting salt may vary from completely ionized to almost
non-ionized.
In another embodiment of the compound, the compound is crystalline.
In another embodiment of the injectable depot formulation, the
pharmaceutically acceptable
carrier is water.
In another embodiment of the injectable depot formulation, the nanoparticles
of the
compound have an average particle size of less than about 1500 nm. In still
another
embodiment, the nanoparticles have an average particle size of less than about
1000 nm. In
still another embodiment, the nanoparticles have an average particle size of
less than about
500 nm. In still another embodiment, the nanoparticles have an average
particle size of less
than about 350 nm.
In still another embodiment of the injectable depot formulation, the
nanoparticies have
an average particle size from about 120 nm to about 400 nm. In still another
embodiment, the
nanoparticles have an average particle size from about 220 nm to about 350 nm.
In another embodiment of the injectable depot formulation, the nanoparticies
have an
average particle size of about 250 nm.
In still another embodiment, nanoparticles have an average particle size of
about 120
nm.
In still another embodiment, the nanoparticles have an average particle size
of about
400 nm. In another embodiment of Formulation 1, the amount by weight of the
compound is
less than about 60% by weight of the total volume of the formulation. In still
another
embodiment, the amount by weight of the compound is less than about 40% by
weight of the
total volume of the formulation.
In another embodiment of Formulation 1, the amount by weight of the compound
is at
least about 1% by weight of the total volume of the formulation. In still
another embodiment,
the amount by weight of the compound is at least about 3% by weight of the
total volume of
the formulation. In still another embodiment, the amount by weight of the
compound is at least
about 15% by weight of the total volume of the formulation. In still another
embodiment, the.
amount by weight of the compound is at least about 20% by weight of the total
volume, of the
formulation In still another embodiment, the amount by weight of the compound
is at least
about 40% by weight of the total volume of the formulation.
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In another embodiment of Formulation 1, the amount by weight of the compound
is
from about 1% by weight to about 60% by weight of the total volume of the
formulation. In still
another embodiment, the amount by weight of the compound is from about 3% by
weight to
about 60% by weight of the total volume of the formulation. In still another
embodiment, the
amount by weight of the compound is from about 15% by weight to about 60% by
weight of
the total volume of the formulation. In still another embodiment, the amount
by weight of the
compound is from about 20% by weight to about 60% by weight of the total
volume of the
formulation. In still another embodiment, the amount by weight of the compound
is from about
1% by weight to about 40% by weight of the total volume of the formulation. In
still another
embodiment, wherein the amount by weight of the compound is from about 3% by
weight to
about 40% by weight of the total volume of the formulation. In still another
embodiment, the
amount by weight of the compound is from about 15% by weight to about 40% by
weight of
the total volume of the formulation. In still another embodiment, the amount
by weight of the
compound is from about 20% by weight to about 40% by weight of the total
volume of the
formulation.
In another embodiment of Formulation 1, a first surface stabilizer is a
surfactant. In
another embodiment of Formulation 1, a first surface stabilizer is selected
from the group
consisting of anionic surfactants, cationic surfactants, amphoteric
surfactants, non-ionic
surfactants and polymeric surfactants.
In another embodiment of Formulation 1, a first surface stabilizer is an
anionic
surfactant. In another embodiment, a first surface stabilizer is a cationic
surfactant. In another
embodiment, a first surface stabilizer is an amphoteric surfactant. In another
embodiment, a
first surface stabilizer is a non-ionic surfactant. In another embodiment, a
first surface
stabilizer is a polymeric surfactant.
In another embodiment of Formulation 1, a second surface stabilizer is
selected from
the group consisting of anionic surfactants, cationic surfactants, amphoteric
surfactants, non-
ionic surfactants and polymeric surfactants.
In another embodiment of Formulation 1, a second surface stabilizer is an
anionic
surfactant. In another embodiment, a second surface stabilizer is a cationic
surfactant. In
another embodiment, a second surface stabilizer is an amphoteric surfactant.
In another
embodiment, a second surface stabilizer is a non-ionic surfactant. In another
embodiment, a
second surface stabilizer is a polymeric surfactant.
In another embodiment of Formulation 1, a first surface stabilizer and a
second
surface stabilizer are independently selected from the group consisting of
anionic surfactants,
cationic surfactants, amphoteric surfactants, non-ionic surfactants and
polymeric surfactants.
In another embodiment of Formulation 1, a first surface stabilizer is ' an
anionic
surfactant and a second surface stabilizer .is an anionic surfactant. In yet
another
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embodiment, a first surface stabilizer is an anionic surfactant and a second
surface stabilizer
is a cationic surfactant. In yet another embodiment, a first surface
stabilizer is an anionic
surfactant and a second surface stabilizer is an amphoteric surfactant. In yet
another
embodiment, a first surface stabilizer is an anionic surfactant and a second
surface stabilizer
is a non-ionic surfactant. In yet another embodiment, a first surface
stabilizer is an anionic
surfactant and a second surface stabilizer is a polymeric surfactant.
In another embodiment of Formulation 1, a first surface stabilizer is a
cationic
surfactant and a second surface stabilizer is an anionic surfactant. In yet
another
embodiment, a first surface stabilizer is an cationic surfactant and a second
surface stabilizer
is a cationic surfactant. In yet another embodiment, a first surface
stabilizer is a cationic
surfactant and a second surface stabilizer is an amphoteric surfactant. In yet
another
embodiment, a first surface stabilizer is a cationic surfactant and a second
surface stabilizer is
a non-ionic surfactant. In yet another embodiment, a first surface stabilizer
is a cationic
surfactant and a second surface stabilizer is a polymeric surfactant.
In another embodiment of Formulation 1, a first surface stabilizer is an
amphoteric
surfactant and a second surface stabilizer is an anionic surfactant. In yet
another
embodiment, a first surface stabilizer is an amphoteric surfactant and a
second surface
stabilizer is a cationic surfactant. In yet another embodiment, a first
surface stabilizer is an
amphoteric surfactant and a second surface stabilizer is an amphoteric
surfactant. In yet
another embodiment, a first surface stabilizer is an amphoteric surfactant and
a second
surface stabilizer is a non-ionic surfactant. In yet another embodiment, a
first surface
stabilizer is an amphoteric surfactant and a second surface stabilizer is a
polymeric
surfactant.
In another embodiment of Formulation 1, a first surface stabilizer is a non-
ionic
surfactant and a second surface stabilizer is an anionic surfactant. In yet
another
embodiment, a first surface stabilizer is a non-ionic surfactant and a second
surface stabilizer
is a cationic surfactant. In yet another embodiment, a first surface
stabilizer is a non-ionic
surfactant and a second surface stabilizer is am amphoteric surfactant. In yet
another
embodiment, a first surface stabilizer is a non-ionic surfactant and a second
surface stabilizer
is a non-ionic surfactant. In yet another embodiment, a first surface
stabilizer is a non-ionic
surfactant and a second surface stabilizer is a polymeric surfactant.
In another embodiment of Formulation 1, a first surface stabilizer is a
polymeric
surfactant and a second surface stabilizer is an anionic surfactant. In yet
another
embodiment, a first surface stabilizer is a polymeric surfactant and a second
surface stabilizer
is a cationic surfactant. In yet another embodiment, a first surface
stabilizer is a polymeric
surfactant and a second surface stabilizer is an amphoteric surfactant. In yet
another
embodiment, a first surface stabilizer is a polymeric surfactant and a second
surface stabilizer
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is a non-ionic surfactant. In yet another embodiment, a first surface
stabilizer is a polymeric
surfactant and a second surface stabilizer is a polymeric surfactarit.
In another embodiment of Formulation 1, a first surface stabilizer is selected
from the
group consisting of Pluronic F108 and Tween 80 and a second surface
stabilizer is
selected from the group consisting of Pluronic F108, Tween 80, and SLS. In
another
embodiment of Formulation 1, a first surface stabilizer is PVP and a second
surface stabilizer
is Pluronic F108. In another embodiment a first surface stabilizer is PVP and
a second
surface stabilizer is Pluronic F68. In another embodiment, a first surface
stabilizer is PVP
and a second surface stabilizer is SLS. In another embodiment, a first surface
stabilizer is
Pluronic F108 and a second surface stabilizer is Tween 80. In another
embodiment, a first
surface stabilizer is PVP and a second surface stabilizer is Tween 80.
In another embodiment of Formulation 1, the amount by weight of a first
surface
stabilizer is from about 0.5% to about 3.0% by weight of the total volume of
the formulation. In
another embodiment, the amount by weight of a first surface stabilizer is from
about 0.5% to
about 2.0% by weight of the total volume of the formulation. In yet another
embodiment of
Formulation 1, the amount by weight of a first surface stabilizer is about
0.5% by weight of the
total volume of the formulation. In yet another embodiment of Formulation 1,
the amount by
weight of a first surface stabilizer is about 1.0 % by weight of the total
volume of the
formulation. In yet another embodiment of Formulation 1, the amount by weight
of a first
surface stabilizer is about 2.0 % by weight of the total volume of the
formulation.
In an embodiment of Formulation 1, the amount by weight of a second surface
stabilizer is from about 0.1 % to about 3.0%, preferably about 0.1 % to about
2.0 %, by weight
of the total volume of the formulation. In another embodiment of Formulation
1, the amount by
weight of a second surface stabilizer is from about 0.1 % to about 1.0% by
weight of the total
volume of the formulation. In another embodiment of Formulation 1, the amount
by weight of
a second surface stabilizer is about 2.0 % by weight of the total volume of
the formulation. In
still another embodiment of Formulation 1, the amount by weight of a second
surface
stabilizer is about 0.5% by weight of the total volume of the formulation. In
still another
embodiment of Formulation 1, the amount by weight of a second surface
stabilizer is about
0.1 % by weight of the total volume of the formulation.
In an embodiment of Formulation 1, a third surface stabilizer is present,
wherein the
amount by weight of the third surface stabilizer is from about 0.018% to about
1.0 % by
weight of the total volume of the formulation. In another embodiment of
Formulation 1, the
amount by weight of the third surface stabilizer is about 0.018% by weight of
the total volume
of the formulation. In still another embodiment, the amount by weight of the
third surface
stabilizer is about 0.1% by weight of the total volume of the formulation. In
still another
embodiment, the amount by weight of the third surface stabilizer is about
0.02% by weight of
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the total volume of the formulation. In still another embodiment, the amount
by weight of the
third surface stabilizer is about 0.5% by weight of the total volume of the
formulation. In still
another embodiment, the amount by weight of the third surface stabilizer is
about 1.0% by
weight of the total volume of the formulation.
In another embodiment of Formulation 1, a third surface stabilizer is a
surfactant. In
another embodiment, the third surfactant is selected from the group consisting
of Pluronic
F68, benzalkonium chloride, lecithin and SLS. In another embodiment, a third
surface
stabilizer is Pluronic F68. In another embodiment, a third surface stabilizer
is benzalkonium
chloride. In another embodiment, a third surface stabilizer is lecithin. In
another embodiment,
a third surface stabilizer is SLS.
In another embodiment of the invention, the total amount by weight of surface
stabilizers in a formulation is about 6% or less, more preferably about 5% or
less.
In an embodiment of Formulation 1, a bulking agent is present, wherein the
amount
by weight of the third surface stabilizer is from about 1.0% to about 10.0 %
by weight of the
total volume of the formulation. In another embodiment of Formulation 1, the
amount by
weight of the bulking agent is about 1.0% by weight of the total volume of the
formulation. In
another embodiment, the amount by weight of the third surface stabilizer is
about 5.0% by
weight of the total volume of the formulation. In another embodiment, the
amount by weight of
the third surface stabilizer is about 10.0% by weight of the total volume of
the formulation.
In another embodiment of Formulation 1, a bulking agent is present, the
bulking agent
selected from the group consisting of trehalose, mannitol and PEG400. In
another
embodiment, the bulking agent is trehalose. In another embodiment, the bulking
agent is
mannitol. In another embodiment, the bulking agent is PEG400.
In another embodiment of Formulation 1, the formulation consists essentially
of a
compound, a carrier, a first surface stabilizer and a second surface
stabilizer, as previously
defined herein. In another embodiment, the formulation consists essentially of
a compound, a
carrier, a first surface stabilizer, a second surface stabilizer and a third
surface stabilizer, as
previously defined herein. In yet another embodiment, the formulation consists
essentially of
a compound, a carrier, a first surface stabilizer, a second surface stabilizer
and a bulking
agent, as previously defined herein. These variations are summarized in the
following table:
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Table B-2
parameter Formulation 2 Formulation 3 Formulation 4
first surface stabilizer Yes Yes Yes
second surface Yes Yes Yes
stabilizer
third surface No Yes No
stabilizer
bulking agent No No Yes
Crystalline Yes Yes Yes
Compound?
C. Methods of Preparation and Treatment
The compound nanoparticles can be made using several different methods,
including,
for example, milling, precipitation and high pressure homogenization.
Exemplary methods of
making compound nanoparticles are described in U.S. Patent No. 5,145, 684, the
entire
content of which is incorporated by reference herein. The optimal effective
average particle
size of the invention can be obtained by controlling the process of particle
size reduction,
such as controlling the milling time and the amount of surface stabilizer
added. Crystal growth
and particle aggregation can also be minimized by milling or precipitating the
composition
under colder temperatures, and by storing the final composition at colder
temperatures.
1. Agueous Milling
In one embodiment of the invention, there is provided a method of preparing
the
injectable depot formulation of the compound according to Formulation 1.
Milling of compound
in aqueous solution to obtain a nanoparticulate dispersion comprises
dispersing compound in
water, followed by applying mechanical means in the presence of grinding media
to reduce
the particle size of the compound to the desired effective average particle
size, the optimal
sizes as provided in other embodiments herein. The compound can be effectively
reduced in
size in the presence of two or more surface stabilizers. Alternatively, the
compound can be
contacted with two or more surface stabilizers after attrition. Other
compounds, such as a
bulking agent, can be added to the compound/surface stabilizer mixture during
the size
reduction process. Dispersions can be manufactured continuously or in a batch
mode. The
resultant nanoparticulate drug dispersion can be utilized in solid or liquid
dosage formulations.
In another embodiment, the nanoparticulate dispersion may be utilized in
intramuscular depot
formulations suitable for injection.
Exemplary useful mills include low energy mills, such as a roller mill,
attritor mill,
vibratory mill and ball mill, and high energy mills, such as Dyno mills,
Netzsch mills, DC mills,
and Planetary mills. Media mills include sand ills and bead mills. In media
milling, the
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compound is placed into a reservoir along with a dispersion medium (for
example, water) and
at least two surface stabilizers. The mixture is recirculated through a
chamber containing
media and a rotating shaft/impeller. The rotating shaft agitates the media
which subjects the
compound to impacting and sheer forces, thereby reducing particle size.
2. Grinding Media
Exemplary grinding media comprises particles that are substantially spherical
in
shape, such as beads, consisting essentially of polymeric resin. In another
embodiment, the
grinding media comprises a core having a coating of a polymeric resin adhered
thereon.
Other examples of grinding media comprise essentially spherical particles
comprising glass,
metal oxide, or ceramic.
In general, suitable polymeric resins are chemically and physically inert,
substantially
free of metals, solvent, and monomers, and of sufficient hardness and
friability to enable them
to avoid being chipped or crushed during grinding. Suitable polymeric resins
include, without
limitation: crosslinked polystyrenes, such as polystyrene crosslinked with
divinylbenzene;
styrene copolymers; polycarbonates; polyacetals, for example, Delrin (E.I. du
Pont de
Nemours and Co.); vinyl chloride polymers and copolymers; polyurethanes;
polyamides;
poly(tetrafluoroethylenes), for example, Teflon (E.I. du Pont de Nemours and
Co.), and
other fluoropolymers; high density polyethylenes; polypropylenes; cellulose
etliers and esters
such as cellulose acetate; polyhydroxymethacrylate; polyhydroxyethyl acrylate;
and silicone-
containing polymers such as polysiloxanes. The polymer can be biodegradable.
Exemplary
biodegradable polymers include poly(lactides), poly(glycolide) copolymers of
lactides and
glycolide, polyanhydrides, poly(hydroxyethyl methacylate), poly(imino
carbonates), poly(N-
acylhydroxyproline)esters, poly(N-palmitoyl hydroxyproline) esters, ethylene-
vinyl acetate
copolymers, poly(orthoesters), poly(caprolactones), and poly(phosphazenes).
For
biodegradable polymers, contamination from the media itself advantageously can
metabolize
in vivo into biologically acceptable products that can be eliminated from the
body.
The grinding media preferably ranges in size from about 10 pm to about 3 mm.
For
fine grinding, exemplary grinding media is from about 20 pm to about 2 mm. In
another
embodiment, exemplary grinding media is from about 30 pm to about 1 mm in
size. In another
embodiment, the grinding media is about 500 pm in size. The polymeric resin
can have a
density from about 0.8 to about 3.0 g/ml.
In one exemplary grinding process, the particles are made continuously. Such a
method comprises continuously introducing compound into a milling chamber,
contacting the
compound with grinding media while in the chamber to reduce the compound
particle size,
and continuously removin.g the nanoparticulate compound from the milling
chamber.
The grinding media is separated from the milled nanoparticulate compound using
conventional separation techniques in a secondary process, including, without
limitation,
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simple filtration, sieving through a mesh filter or screen, and the like.
Other separation
techniques such as centrifugation may also be employed.
3. Precipitation
Another method of forming the desired nanoparticulate dispersion is by
microprecipitation. This is a method of preparing stable dispersions of drugs
in the presence
of two or more surface stabilizers and one or-more colloid stability enhancing
surface active
agents free of any trace toxic solvents or solubilized heavy metal impurities.
An exemplary
method comprises: (1) dissolving the compound in a suitable solvent; (2)
adding the
formulation from step (1) to a solution comprising at least two surface
stabilizers to form a
clear solution; and (3) precipitating the formulation from step (2) using an
appropriate non-
solvent. The method can be followed by removal of any formed salt, if present,
by dialysis or
diafiltration and concentration of the dispersion by conventional means. The
resultant
nanoparticulate drug dispersion can be utilized in solid or liquid dosage
formulations. In
another embodiment, the nanoparticulate dispersion may be utilized in
intramuscular depot
formulations suitable for injection.
4. Homogenization
Another method of forming the desired nanoparticulate dispersion is by
homogenization. Like precipitation, this technique does not use milling media.
Instead,
compound, surface stabilizers and carrier - the "mixture" (or, in an
alternative embodiment,
compound and carrier with the surface stabilizers added following reduction in
particle size)
constitute a process stream propelled into a process zone, which in a
Microfluidizer
(Microfluidics Corp.) is called the Interaction Chamber. The mixture to be
treated is inducted
into the pump and then forced out. The priming valve of the Microfluidizer
purges air out of
the pump. Once the pump is filled with the mixture, the priming valve is
closed and the
mixture is forced through the Interaction Chamber. The geometry of the
Interaction Chamber
produces powerful forces of sheer, impact and cavitation which reduce particle
size. Inside
the Interaction Chamber, the pressurized mixture is split into two streams and
accelerated to
extremely high velocities. The formed jets are then directed toward each other
and collide in
the interaction zone. The resulting product has very fine and uniform particle
size.
5. Sterile Product Manufacturing
Development of injectable compositions requires the production of a, sterile
product.
The manufacturing process of the present invention is similar to typical known
manufacturing
processes for sterile suspensions. A typical sterile suspension manufacturing
process
flowchart is as follows:
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(Media conditioning)
Compounding
1
Particle size reduction
1
Vial filling
(lyophilization) and/or (terminal sterilization)
As indicated by the optional steps in parentheses, some of the processing is
dependent upon the method of particle size reduction and/or method of
sterilization. For
example, media conditioning is not required for a milling method that does not
use media. If
terminal sterilization is not feasible due to chemical and/or physical
instability, aseptic
processing can be used. Terminal sterilization can be by steam sterilization
or by high energy
irradiation of the product.
6. Methods of Treatment
Conditions
The conditions that can be treated in accordance with the present invention
include
one or more disorders selected from the group consisting of: arthritis,
including rheumatoid
arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic
lupus erythematosus
and juvenile arthritis, osteoarthritis, and other arthritic conditions;
central nervous system
disorders (including, but not limited to, central nervous system disorders
having an
inflammatory or apoptotic component), such as Alzheimer's disease, Parkinson's
disease,
Huntington's Disease, amyotrophic lateral sclerosis, spinal cord injury, and
peripheral
neuropathy; peripheral nervous system disorders; cardiovascular diseases
including
atherosclerosis, myocardial infarction (including post-myocardial infarction
indications),
thrombosis, congestive heart failure, and cardiac reperfusion injury, as well
as complications
associated with hypertension and/or heart failure such as vascular organ
damage, restenosis;
gastrointestinal conditions such as inflammatory bowel disease, Crohn's
disease, gastritis,
irritable bowel syndrome and ulcerative colitis, parasitic infections,
microbial diseases,
neoplastic disorders, immunological disorders, blood disorders, hormone
deficiencies, skin-
related conditions such as psoriasis, eczema, burns, dermatitis, keloid
formation, scar tissue
formation, and angiogenic disorders; ophthalmological conditions such as
corneal graft
rejection, ocular neovascularization, retinal neovascularization including
neovascularization
following injury or infection, and retrolental fibroplasia; glaucoma including
primary open angle
glaucoma (POAG), juvenile onset primary open-angle glaucoma, angle-closure
glaucoma,
pseudoexfoliative glaucoma, anterior ischemic optic neuropathy (AION), ocular
hypertension,
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Reiger's syndrome, normal tension glaucoma, neovascular glaucoma, ocular
inflammation
and corticosteroid-induced glaucoma; acute injury to the eye tissue and ocular
traumas such
as post-traumatic glaucoma, traumatic optic neuropathy, and central retinal
artery occlusion
(CRAO); ophthalmic diseases such as retinitis, retinopathies (including
diabetic retinopathy),
uveitis, ocular photophobia, nonglaucomatous optic nerve atrophy, and age
related macular
degeneration (ARMD) (including ARMD-atrophic form) and pathological, but non-
malignant,
conditions such as hemaginomas, including infantile hemaginomas, angiofibroma
of the
nasopharynx and avascular necrosis of bone; benign and malignant
tumors/neoplasia
including cancer, such as colorectal cancer, brain cancer, bone cancer,
epithelial cell-derived
neoplasia (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma,
gastrointestinal cancer such as lip cancer, mouth cancer, esophageal cancer,
small bowel
cancer and stomach cancer, colon cancer, liver cancer, bladder cancer,
pancreas cancer,
ovarian cancer, cervical cancer, lung cancer, breast cancer and skin cancer,
such as
squamus cell and basal cell cancers, prostate cancer, renal cell carcinoma,
and other known
cancers that affect epithelial cells throughout the body; leukemia; lymphoma;
systemic lupus
erthrematosis (SLE); angiogenesis including neoplasia; and metastasis;
inflammation;
neuroinflammation; allergy; neuropathic pain; fever; pulmonary disorders or
lung
inflammation, including adult respiratory distress syndrome, pulmonary
sarcoidosis, asthma,
silicosis, chronic pulmonary inflammatory disease, chronic obstructive
pulmonary disease
(COPD), and asthma; cardiomyopathy; stroke including ischemic and hemorrhagic
stroke;
ischemia including brain ischemia and ischemia resulting from cardiac/coronary
bypass;
reperfusion injury; renal reperfusion injury; brain edema; neurotrauma and
brain trauma
including closed head injury; neurodegenerative disorders;.liver disease and
nephritis;ulcerative diseases such as gastric ulcer; periodontal disease;
diabetes; diabetic
nephropathy;viral and bacterial infections, including sepsis, septic shock,
gram negative
sepsis, malaria, meningitis, HIV infection, opportunistic infections, cachexia
secondary to
infection or malignancy, cachexia secondary to acquired immune deficiency
syndrome
(AIDS), AIDS, ARC (AIDS related complex), pneumonia, and herpes virus;
myalgias due to
infection; influenza; endotoxic shock and sepsis; toxic shock syndrome;
autoimmune disease
including graft vs. host reaction and allograft rejections; treatment of bone
resorption
diseases, such as osteoporosis; multiple sclerosis; and disorders of the
female reproductive
system such as endometriosis.
Administration and Dosing
Typically, a formulation described in this specification is administered in an
amount
effective to treat conditions listed herein. The depot formulations of the
present invention are
administered by injection, whether subcutaneously or intramuscularly, and in a
dose effective
for the treatment intended. Therapeutically effective doses of the compounds
required to
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prevent or arrest the progress of or to treat the medical condition are
readily ascertained by
one of ordinary skill in the art using preclinical and clinical approaches
familiar to the
medicinal arts.
An effective dose for injection of a formulation of the invention can be
generally
determined by a physician of ordinary skill in the art. The effective dose can
be determined
taking into consideration factors know to those of skill in the art, such as
the indication being
treated, the weight of the patient, and the duration of treatment (e.g.= days
or weeks) desired.
The percentage of drug present in the formulation is also a factor. An example
of an effective
dose for injection of a formulation of the present invention is from about 0.1
ml to about 2.5 ml
injected once every 1, 2, 3 or 4 weeks. Preferably, the dose for injection is
about 2 ml or less,
for example from about 1 ml to about 2 ml.
7. Use in the Preparation of a Medicament
In one embodiment, the present invention comprises methods for the preparation
of a
formulation (or "medicament') comprising the Formulations of other embodiments
herein
disclosed, in combination with one or more pharmaceutically-acceptable
carriers and at least
two surface stabilizers, wherein at least one surface stabilizer is adsorbed
on to the surface of
the compound nanoparticles and wherein the combined amount of the surface
stabilizers is
effective to maintain the average particle size of the nanoparticles
(Formulation 1), in which
such formulation is suitable in treating one or more conditions selected from
the group
consisting of: The conditions that can be treated in accordance with the
present invention
include one or more disorders selected from the group consisting of:
arthritis, including
rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis,
systemic lupus
erythematosus and juvenile arthritis, osteoarthritis, and other arthritic
conditions; central
nervous system disorders (including, but not limited to, central nervous
system disorders
having an inflammatory or apoptotic component), such as Alzheimer's disease,
Parkinson's
disease, Huntington's Disease, amyotrophic lateral sclerosis, spinal cord
injury, and
peripheral neuropathy; peripheral nervous system disorders; cardiovascular
diseases
including atherosclerosis, myocardial infarction (including post-myocardial
infarction
indications), thrombosis, congestive heart failure, and cardiac reperfusion
injury, as well as
complications associated with hypertension and/or heart failure such as
vascular organ
damage, restenosis; gastrointestinal conditions such as inflammatory bowel
disease, Crohn's
disease, gastritis, irritable bowel syndrome and ulcerative colitis, parasitic
infections, microbial
diseases, neoplastic disorders, immunological disorders, blood disorders,
hormone
deficiencies, skin-related conditions such as psoriasis, eczema, burns,
dermatitis, keloid
formation, scar tissue formation, and angiogenic disorders; ophthalmological
conditions such
as corneal graft rejection, ocular neovascularization, retinal
neovascularization including
neovascularization following injury or infection, and retrolental fibroplasia;
glaucoma including
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primary open angle glaucoma (POAG), juvenile onset primary open-angle
glaucoma, angle-
closure glaucoma, pseudoexfoliative glaucoma, anterior ischemic optic
neuropathy (AION),
ocular hypertension, Reiger's syndrome, normal tension glaucoma, neovascular
glaucoma,
ocular inflammation and corticosteroid-induced glaucoma; acute injury to the
eye tissue and
ocular traumas such as post-traumatic glaucoma, traumatic optic neuropathy,
and central
retinal artery occlusion (CRAO); ophthalmic diseases such as retinitis,
retinopathies (including
diabetic retinopathy), uveitis, ocular photophobia, nonglaucomatous optic
nerve atrophy, and
age related macular degeneration (ARMD) (including ARMD-atrophic form) and
pathological,
but non-malignant, conditions such as hemaginomas, including infantile
hemaginomas,
angiofibroma of the nasopharynx and avascular necrosis of bone; benign and
malignant
tumors/neoplasia including cancer, such as colorectal cancer, brain cancer,
bone cancer,
epithelial cell-derived neoplasia (epithelial carcinoma) such as basal cell
carcinoma,
adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth cancer,
esophageal
cancer, small bowel cancer and stomach cancer, colon cancer, liver cancer,
bladder cancer,
pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer
and skin
cancer, such as squamous cell and basal cell cancers, prostate cancer, renal
cell carcinoma,
and other known cancers that affect epithelial cells throughout the body;
leukemia; lymphoma;
systemic lupus erthrematosis (SLE); angiogenesis including neoplasia; and
metastasis;
inflammation; neuroinflammation; allergy; neuropathic pain; fever; pulmonary
disorders or
lung inflammation, including adult respiratory distress syndrome, pulmonary
sarcoidosis,
asthma, silicosis, chronic pulmonary inflammatory disease, chronic obstructive
pulmonary
disease (COPD), and asthma; cardiomyopathy; stroke including ischemic and
hemorrhagic
stroke; ischemia including brain ischemia and ischemia resulting from
cardiac/cbronary
bypass; reperfusion injury; renal reperfusion injury; brain edema; neurotrauma
and brain
trauma including closed head injury; neurodegenerative disorders;.liver
disease and
nephritis;ulcerative diseases such as gastric ulcer; periodontal disease;
diabetes; diabetic
nephropathy;viral and bacterial infections, including sepsis, septic shock,
gram negative
sepsis, malaria, meningitis, HIV infection, opportunistic infections, cachexia
secondary to
infection or malignancy, cachexia secondary to acquired immune deficiency
syndrome
(AIDS), AIDS, ARC (AIDS related complex), pneumonia, and herpes virus;
myalgias due to
infection; influenza; endotoxic shock and sepsis; toxic shock syndrome;
autoimmune disease
including graft vs. host reaction and allograft rejections; treatment of bone
resorption
diseases, such as osteoporosis; multiple sclerosis; and disorders of the
female reproductive
system such as endometriosis.
D. Working Examples
The following examples illustrate the present invention. Additional
embodiments of
the present invention may be prepared using information presented in these
Working
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Examples, either alone or in combination with techniques generally known in
the art. In these
working examples, percentages, when given to describe components of the
formulation, are
in the unit weight per volume, or w/v.
Example 1
Preparation of Formulation A
A coarse suspension was prepared by placing 8.86 gm of ziprasidone free base
in a
100 ml milling chamber with 48.90 gm of milling media (500 micron polystyrene
beads). To
this, 4.2 ml each of 10% solutions of Pluronic F108 and Tween 80 were added.
In
addition, 27.8 ml of water for injection was added to the milling chamber. The
above mixture
was stirred until uniform suspension was obtained. This suspension was then
milled for 30
minutes at 2100 RPM in a Nanomill-1 (Manufacturer Elan Drug Delivery, Inc.)
and the
temperature during milling was maintained at 4 C. The resulting suspension was
filtered
under vacuum to remove the milling media and the suspension characterized by
microscopy
and light scattering (Brookhaven). For microscopic observation, a drop of
diluted suspension
was placed between a cover slip and slide and observed under both bright and
dark field. For
particle size determination by light scattering, a drop of suspension was
added to a sample
cuvette filled with water and particle size measured. The reported values are
effective
diameter in nm.
The above suspension after milling was free flowing and did not show any large
crystals under the microscope at 400X and dispersed particles could not be
seen individually
due to the rapid Brownian motion. The effective diameter of the 21%
ziprasidone free base
nanosuspension was 235 nm.
Example 2
Preparation of Formulation B
A coarse suspension was prepared by placing 8.84 gm of ziprasidone free base
in a
100 ml milling chamber with 48.90 gm of milling media (500 micron polystyrene
beads). To
this, 4.2 ml of 10% solution of Pluronic F108 was added. In addition, 32 mi
of water for
injection was added to the milling chamber. The above mixture was milled under
identical
conditions as in example 1.
When the milling was stopped at 30 minutes, the above suspension turned into a
paste and thus a uniform non-aggregated free flowing nanosuspension was not
obtained.
Since the paste could not be filtered to separate the milling media,
additional characterization
could not be performed. -
Example 3
Preparation of Formulation C
A coarse suspension was prepared by placing 8.82 gm of ziprasidone free base
in
the 100 ml milling chamber with 48.87 gm of milling media (500 micron
polystyrene beads).
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To this, 4.2 ml of 10% solution of PVP-K30 was added. In addition, 32 ml of
water for
injection was added to the milling chamber. The above mixture was milled under
identical
conditions as in example 1.
When the milling was stopped at 30 minutes, the above suspension turned into a
paste and thus a uniform non-aggregated free flowing nanosuspension was not
obtained.
Since the paste could not be filtered to separate the milling media,
additional characterization
could not be performed.
Example 4
Preparation of Formulation D
A 21% ziprasidone free base coarse suspension was prepared in 2.5% aqueous
solution of Pluronic F108. This suspension was diluted 1:1 v/v with water to
result in 10.5%
ziprasidone free base suspension with 1.25% of Pluronic F108 in water. The
suspension
was milled in a 100 ml milling chamber with milling media (500 micron
polystyrene beads) at
5500 RPM.
When the milling was stopped at 1 hour, the above suspension after filtration
was free
flowing and did not show any large crystals under the microscope and the rapid
Brownian
motion was observed of the particles. The effective diameter of the 10.5%
ziprasidone free
base nanosuspension was 181 nm.
Example 5
Preparation of Formulation E
A coarse suspension was prepared by placing 9.69 gm of ziprasidone
hydrochloride
in a 100 ml milling chamber with 48.96 gm of milling media (500 micron
polystyrene beads).
To this, 4.2 ml each of the 10% PVP and 10% of Pluronic F108 solutions were
added. In
addition, 25.4 ml of water for injection was added to the milling chamber. The
above mixture
was milled under identical conditions for 3 hours as in example 1.
When the milling was stopped at 3 hours, the above suspension after filtration
was
free flowing and did not show any large crystals under the microscope and the
rapid Brownian
motion was observed of the particles. The effective diameter of the 23%
ziprasidone
hydrochloride nanosuspension was 117 nm.
Example 6
Preparation of Formulation F
A coarse suspension was prepared by placing 11.78 gm of ziprasidone mesylate
in a
100 ml milling chamber with 48.89 gm of milling media (500 micron polystyrene
beads). To
this, 8.4 ml of 10% PVP and 2.1 ml of 10% of Pluronic F108 solutions were
added. In
addition, 24.2 ml of water for injection was added to the milling chamber. The
above mixture
was milled under identical conditions for 3 hours as in example 1.
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When the milling was stopped at 3 hours, the above suspension after filtration
was
free flowing and did not show any large crystals under the microscope and the
rapid Brownian
motion was observed of the particles. The effective diameter of the 28%
ziprasidone mesylate
nanosuspension was 406 nm.
Example 7
Preparation of Formulation G
A coarse suspension was prepared by placing 8.85 gm of ziprasidone free base
in
the 100 ml milling chamber with 4$.89 gm of milling media (500 micron
polystyrene beads).
To this, 4.2 ml each of 10% solutions of Pluronic F108, Tween 80 and 5%
Lecithin
solutions were added. In addition, 23.8 ml of water for injection was added to
the milling
chamber. The above mixture was stirred until uniform suspension was obtained.
This
suspension was then milled for 30 minutes at 2100 RPM in a Nanomill-1
(Manufacturer Elan
Drug Delivery, Inc.) and the temperature during milling was maintained at 4 C.
The resulting
suspension was filtered under vacuum to remove the milling media and the
suspension
characterized by microscopy and light scattering as described in example 1.
Example 8
Preparation of Formulation H
A coarse suspension was prepared by placing 8.87 gm of ziprasidone free base
in
the 100 ml milling chamber with 48.9 gm of milling media (500 micron
polystyrene beads). To
this, 4.2 ml of 10% Tween 80 solution and 8.4 ml of 10% Pluronic F108
solution were
added. In addition, 23.6 ml of water for injection was added to the milling
chamber. . The
above mixture was stirred until uniform suspension was obtained. This
suspension was then
milled for 30 minutes at 2100 RPM in a Nanomill-1 (Manufacturer Elan Drug
Delivery, Inc.)
and the temperature during milling was maintained at 4 C. The resulting
suspension was
filtered under vacuum to remove the milling media and the suspension
characterized by
microscopy and light scattering as described in example 1.
Example 9
Stability of an Exemplary Formulation Comprising 21% ziprasidone free base
nanoparticies
The particle size of Formulation A packaged in a vial stored at 5 C was
monitored.
For particle size determination by light scattering a drop of suspension was
added to a
sample cuvette filled with water and particle size measured. The reported
values are effective
diameter in nm. The results are listed in D-1.
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Table D-1: Effective Particle Diameter of Formulation A Stored at 5 C.
Time (days) Effective diameter (nm)
0 233
230
50 233
60 238
92 234
130 245
220 246
339 248
700 256
Example 10
Stability of an Exemplary Formulation Comprising 23% ziprasidone HCI
nanoparticles
5 The particle size of Formulation E packaged in a vial stored at 5 C was
monitored. For
particle size determination by light scattering a drop of suspension was added
to a sample
cuvette filled with water and particle size measured. The reported values are
effective
diameter in nm. The results are listed in the following table.
Table D-2: Effective Particle Diameter of Formulation E Stored at 5 C.
Time (days) Effective diameter (nm)
0 117
4 120
7 126
52 142
85 136
123 142
Example 11
Stability of an Exemplary Formulation Comprising 28% ziprasidone mesylate
nanoparticles
The particle size of Formulation F packaged in a vial stored at 5 C was
monitored.
For particle size determination by light scattering a drop of suspension was
added to a
sample cuvette filled with water and particle size measured. The reported
values are effective
diameter in nm. The results are listed in the following table.
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Table D-3: Effective Particle Diameter of Formulation F Stored at 5 C.
Time (days) Effective diameter (nm)
0 406
444
50 415
60 407
92 518
130 485
339 525
700 609
Example 12
Sterilization and Storage Stability of Formulation G
5 The filtered suspension of Example 7 was filled (3 ml) into flint vials. The
vials were
sealed with a rubber stopper and an aluminum seal was crimped on the stopper.
The filled
vials were sterilized for 15 min at 121 C in a steam sterilizer. The
suspension after
sterilization was characterized and particle size measured by light
scattering. The filled vials
were stored at 5 C and sampled at various times to determine particle size and
stability of the
suspension.
The following table shows particle size stability of Formulation G during
autoclaving
and upon storage of the sterilized formulation.
Table D-4: Effective Particle Diameter of Formulation G after Autoclaving and
upon Storage at
5 C.
Time Effective diameter (nm)
Before Sterilization 235 nm
After Sterilization 267 nm
Storage Time (days) post-sterilization Effective diameter (nm)
0 274
4 281
7 271
16 268
36 274
Example 13
Sterilization and Storage Stability of Formulation H
The filtered suspension of Example 8 was filled (3 ml) into flint vials. The
vials were
sealed with a rubber stopper and an aluminum seal was crimped on the stopper.
The filled
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vials were sterilized for 15 min at 121 C in a steam sterilizer. The
suspension after
sterilization was characterized and particle size measured by light
scattering. The filled vials
were stored at 5 C and sampled at various times to determine particle size and
stability of the
suspension. The following table shows particle size stability of Formulation H
during
autoclaving and upon storage of the sterilized formulation.
Table D-5: Effective Particle Diameter of Formulation H after
Autoclaving and upon Storage at 5 C.
Time Effective diameter (nm)
Before Sterilization 234 nm
After Sterilization 311 nm
Storage Time (days) post-sterilization Effective diameter (nm)
0 319
3 331
6 325
313
35 319
Example 14
10 Stability of Ziprasidone Nanosuspensions: Monitoring of Particle Size Using
Dynamic
Light Scattering
It was surprisingly discovered that use of a single surface stabilizer was not
sufficient
to allow the suspension post-milling to resolve into a uniform free-flowing
suspension without
large crystals. Instead, as shown in Table D-6 and Working Examples 2 and 3,
use of a single
15 surface stabilizer resulted in only an unresolvable paste. However, when
two or more surface
stabilizers were present, a free flowing suspension resolved. Upon closer
examination, the
data shows that a smaller particle size (initial effective diameter) is
achieved, even when the
total volume of the two surfactants is less than the total volume of a single
surfactant. Thus,
similar compounds similar in nature to ziprasidone (low water solubility, logP
about 3 or
greater, e.g.) may also require two surface stabilizers to maintain particle
size in a
nanoparticle formulation.
Without being bound by theory, it may be that the combination of two or more
surface
stabilizers provide enhanced surface stability and improve the ability of the
crystal to maintain
its nanoparticulate size without aggregation. The addition of a different,
second surface
stabilizer may allow for the reduction in total amount of surface stabilizers
by % w/v, which
supports a synergistic interaction between surface stabilizers. That is, the
use of at least two
surface stabilizers in a formulation with a compound of low water solubility
seems to maintain
particle size and, therefore, provide a foundation for an IM depot formulation
of interest.
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Table D-6: Nanosuspensions of Ziprasidone and Particle Size
% other
% % Tween additiv milling Time Initial effective
Z - Com. PVP F108 80 es time (days) diameter (nm)
21%FB 1 30min 0 --
21 % FB 1 1 30 min 0 242
21%FB 1 1 30min 0 312
21 % FB 1 0.5 30 min 0 309
21 % FB I 1 10 min 0 390
21 % FB 1 1 20 min 0 255
21 % FB 1 1 30 min 0 232
21 % FB 1 1 45 min 0 234
21 % FB 1 1 30 min 0 249
21 % FB 1 1 60 min 0 230
21 % FB 1 1 60 min 55 190
21 % FB 1 1 60 min 0 252
21 % FB 1 1 60 min 45 201
21 % FB 1 1 60 min 52 231
21 % FB 1 1 60 min 105 238
21 % FB 1 1 60 min 143 261
21 % FB 1 1 60 min 352 220
21%FB 1 1 30min 0 234
21 % FB 1 90 min 0 --
21 /a FB 1 30 min 0 --
21% FB I 1 30 min 0 220
21 % FB 2 1 30 min 0 234
21 % FB 1 1 30 min 0 233
21 % FB 1 1 30 min 5 230
21% FB 1 1 30 min 50 233
21 % FB 1 1 30 min 60 238
21 % FB 1 1 30 min 92 234
21 % FB 1 1 30 min 130 245
21 % FB 1 1 30 min 220 246
21 % FB 1 1 30 min 339 248
21 % FB 1 1 30 min 700 256
21 % FB 1 1 30 min 0 273
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21%FB 1 1 30min 50 218
21 % FB 1 1 30 min 0 275
21 % FB 1 1 30 min 30 236
0.018%
21 % FB 1 1 SLS 30 min 0 233
0.02%
Benzalk
21 % FB 1 1 CI 30 min 0 237
0.1 %SL
21 % FB I , S 30 min 0 163
0.5%
21% FB 1 1 Lecithin 30 min 0 235
21 % FB 1 1% F68 30 min 0 655
1%
PEG40
21 % FB 1 1 0 30 min 0 308
10%
Trehalo
21 % FB 1 1 se 30 min 0 295
10%
Trehalo
21 % FB I I se 30 min 0 236
10%
Trehalo
21 % FB 1 1 se 30 min 0 237
5%
Mannito
21 % FB 1 1 I 30 min 0 247
5%
Mannito
21 % FB 1 0.5 I 30 min 0 260
5%
Mannito
21%FB 1 1 I 30min 0 247
5%
Mannito
21 % FB 1 1 1 30 min 15 268
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5%
Mannito
21 % FB 1 1 I 30 min 44 278
5%
Mannito
21 % FB I 1 I 30 min 86 310
23% HCI 1 1 3 hr 0 122
23% HCI 1 1 3 hr 0 117
23% HCI 1 1 3 hr 4 120
23% HCI 1 1 3 hr 7 126
23% HCI 1 1 3 hr 52 142
23% HCI 1 1 3 hr 85 136
23% HCI 1 1 3 hr 123 142
23% HCI 1 1 3 hr 0 106
23% HCI 1 1 3 hr 17 113
23% HCI 1 1 3 hr 26 113
23% HCI 1 1 3 hr 48 122
23% HCI 1 1 3 hr 81 129
23% HCI 1 1 3 hr 119 120
23% HCI 1 1 3 hr 328 138
23% HCI 1 1 3 hr 700 160
23% HCI 1 1 3 hr 0 122
23% HCI 1 1 3 hr 0 122
23% HCI 1 1 3 hr 14 133
23% HCI 1 1 3 hr 45 161
23% HCI 1 1 3 hr 78 154
23% HCI 1 1 3 hr 116 144
23% HCI 1 1 3 hr 206 148
23% HCI 1 1 3 hr 325 157
23% HCI 1 1 3 hr 700 175
28% Mes 2 0.5 6 hr 0 376
28% Mes 2 0.5 4 hr 0 339
28% Mes 2 0.5 3 hr 0 406
28% Mes 2 0.5 3 hr 5 444
28% Mes 2 0.5 3 hr 50 415
28% Mes 2 0.5 3 hr 60 407
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28% Mes 2 0.5 3 hr 92 518
28% Mes 2 0.5 3 hr 130 485
28% Mes 2 0.5 3 hr 339 525
28% Mes 2 0.5 3 hr 700 609
28% Mes 2 0.5 6 hr 0 376
28% Mes 2 0.5 6 hr 3 354
28% Mes 2 0.5 120 min 0 481
28% Mes 2 0.5 120 min 40 452
28% Mes 2 0.5 120 min 47 509
* Column I is ziprasidone compound - selected from free base, mesylate salt or
hydrochloride salt
Example 15
Preparation of Formulation I(42% Ziprasidone Free Base)
A coarse suspension was prepared by placing 21.92 gm of ziprasidone free base
in
the 100 ml milling chamber with 38.42 gm of milling media (500 micron
polystyrene beads).
To this, 10.44 ml of 10% Tween 80 solution, 10.44 ml of 10% Pluronic F108
solution and
5.22 ml of Lecithin were added. In addition, 13.8 ml of water for injection
was added to the
milling chamber. The above mixture was stirred until uniform suspension was
obtained. This
suspension was then milled for 80 minutes at 2100 RPM in a Nanomill-1
(Manufacturer Elan
Drug Delivery, Inc.) and the temperature during milling was maintained at 4 C.
The resulting
suspension was filtered under vacuum to remove the milling media and the
suspension
characterized by microscopy and light scattering as described in example 1.
The filtered suspension was filled (2.5 ml) into flint vials. The vials were
sealed with a
rubber stopper and an aluminum seal was crimped on the stopper. The filled
vials were
sterilized for 15 min at 121 C in a steam sterilizer. The suspension after
sterilization was
characterized and particle size measured by light scattering. The following
table shows
particle size stability of the 42% ziprasidone free base formulation after
milling and following
autoclaving.
Table D-7: Mean Particle Size of 42% Formulation I After Milling and Following
Autoclaving.
Mean particle size, D[4,3]
(nm)
After milling 262 nm
After Sterilization 384 nm
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Example 16
Sterilization and Storage Stability of an Exemplary Formulation J Comprising
40%
Ziprasidone Free Base
Formulation J was prepared as described in example 15. The filtered suspension
was
filled (3 ml) into flint vials. The vials were sealed with a rubber stopper
and an aluminum seal
was crimped on the stopper. The filled vials were sterilized for 15 min at 121
C in a steam
sterilizer. The suspension after sterilization was characterized and particle
size measured by
light diffraction. The filled vials were stored at 5, 25, and 40 C and
sampled at various times
to determine particle size and stability of the suspension. The following
table shows particle
size stability of Formulation J during autoclaving and upon storage of the
sterilized
formulation.
Table D-8: Mean Particle Size of Formulation J after Autoclaving and
Upon Storage at 5, 25 and 40 C.
Mean particle size, D[4,3]
(nm)
After milling 291 nm
After Sterilization 279 nm
Storage Time (days) post- Temperature Mean particle size, D[4,3]
sterilization ( C) (nm)
7 5 279
21 5 275
42 5 280
84 -5 273
7= 25 277
21 25 274
42 25 276
84 25 270
7 40 276
21 40 273
42 40 275
84 40 271
Example 17
Preparation of 21% Ziprasidone Free Base Formulation by High Pressure
Homogenization and Storage Stability of the Formulation
A coarse suspension was prepared by placing pre-ground 17.71 gm ziprasidone
'freebase in 250 mL bottle with 8.4 mL of each, 10%w/v Pluronic F108 and
10%w/v Tween 80
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and 55.6 mL of water. The suspension was placed in a cooling bath set to 5 C.
The high
pressure homogenizer (Manufacturer Avestin, Inc.) was cleaned and primed with
water at full
open setting. The suspension was pumped for three minutes under the full open
condition of
the homogenizer during which time it flowed smoothly. The pressure drop across
the gap
was then slowly increased until to 10,000 psi, and held for 5 minutes. The
pressure drop
across the gap was then increased to15,000 psi, and was held here for 22
minutes. A sample
of the homogenized suspension was taken at this point from the recirculation
vessel, and
homogenization was continued. The homogenization was stopped at 68 minutes at
which
time the formulation was pumped out of the homogenizer. The particle size of
the final
product samples was measured by laser diffraction (Malvern Mastersizer). The
mean particle
size (D[4,3]) of 21% ziprasidone free base formulation was 356 nm after
homogenization. 2.7
ml of the above formulation and 0.3 mL of 5%w/v aqueous lecithin were filled
into 5 mL vials
and swirled to mix. All vials were stoppered and crimped and autoclaved for 15
minutes at
121 C. The autoclaved vials were placed in stability ovens and monitored for
particle size.
The particle size stability of the formulation is listed in the following
table D-9.
Table D-9: Particle size stability of autoclaved 21 % ziprasidone free
base nanosuspension prepared by high pressure homogenization.
Mean Particle Size
Temperature Time (nm)
(degree C) (days) D[4,3]
Before sterilization 0 356
After sterilization 0 379
5 14 392
5 28 393
5 56 378
5 84 392
0 379
30 14 383
30 28 384
30 56 380
30 84 379
Example 18
Preparation of a Dry Lyophilized 21 % Ziprasidone Free Base Formulation
Lyophilization Process
The 21%w/v Ziprasidone freebase nanosuspension was prepared by methods
described in examples 7 and 8. Batch of 27%w/v Trehalose, 1%w/v F108, 1%w/v
Tween 80,
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and 0.5%w/v Lecithin in water was used as diluent to prepare the samples for
lyophilization.
The formulation and diluent were combined in a ratio of 3 volumes of diluent
to 1 volume of
21 % formulation and were gently mixed. This resultant suspension was filled
using a 0.5 mL
fill volume into 5 mL and 10 mL glass vials and stoppered at the
lyophilization position. These
vials were then placed into the FTS LyoStar freeze-drying unit, and the
following thermal
program was run:
1) Shelves were cooled at 0.2 C/min (for 300 min) to -40 C and held here for
120
min.
2) Shelves were warmed at 1 C/min (for 10 min) to -30 C and 150 mTorr and
held
for 2000 min.
3) Shelves were warmed at 1 C/min (for 40 min) to 10 C and 150 mTorr and held
for 720 min.
4) Shelves were warmed at 1 C/min (for 20 min) to 30 C and 150 mTorr and held
for 720 min.
5) Shelves were cooled at 1 C/min (for 15 min) to 15 C and 150 mTorr and held
until cycle could be manually ended.
The freeze-drying cycle was manually stopped, and the vials were stoppered and
crimped. They were then placed in the refrigerator for storage.
The dry cake in the vials were reconstituted with the same volume as the
initial fill
with either 0.5 mL of water or 0.5 mL of 1%w/v F108, 1%w/v Tween80, 0.5%w/v
Lecithin in
water (the formulation vehicle). These vials were swirled, upon which the cake
wetted and
reconstituted into a milky white suspension easily.
In order to determine if this lyophile could also be reconstituted to a higher
concentration, the cake was reconstituted with 0.125 mL of water to result in
21%
concentration equivalent to the initial drug level. The cake wetted and
reconstituted into
suspension easily as well. The reconstituted suspensions were then analyzed
for particle size
by Laser Diffraction. The particle size results are listed in the following
Table D-10. A
refrigerated, non-lyophilized suspension served as the control.
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Table D-10: Particle sizing of reconstituted Ziprasidone freebase lyophiles
Volume of vehicle Sonication for
Vehicle for used for p. size Mean Particle Size
Reconstitution reconstitution measurement? (nm)
D[4,3]
Control-none N/A No 292
Water 0.5mL No 467
Water 0.5mL Yes 382
Stabilizer
solution 0.5mL No 464
Stabilizer
solution 0.5mL Yes 385
Water 0.125mL No 471
Water 0.125mL Yes 358
Example 19
Pharmacokinetic Study in Dogs Comparing Unmilled and Micronized Ziprasidone
Free Base and its salts to Ziprasidone Free Base and salt Nanoparticles
Pharmacokinetic studies were conducted with various particle sizes of
ziprasidone
freebase, and its salts in aqueous suspension formulations to determine the
effect of particle
size on PK performance of the drug in-vivo. Ziprasidone free base and salt
formulations with
a mean effective diameter of less than 1000 nm showed significantly higher
exposure
(Average depot levels and Area under the curve) than a formulations with
particle size greater
than 5 pm (higher AUC and average depot levels). See Table D-1 1, presented in
Working
Examples 1-16.
Table D-11. Pharmacokinetics of Ziprasidone in Dog Following IM Administration
of Various
Depot Formulations. Reported values are mean sd of n=4 dogs.
Formulation Effective Dose of AUC o-inf Average Cmax
diameter or Ziprasidon (ng.h/ml) Depot (ng/mi)
mean e active (Cl-3 Wk)
diameter (mg) Levels
(nm) (ng/ml)
42% Ziprasidone 384 840 117408 310 243 86 495 98
Free Base with 2% 97
Pluronic F108, 2%
Tween 80 and 0.5%
Lecithin
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Formulation Effective Dose of AUC o_inf Average Cmax
diameter or Ziprasidon (ng.h/ml) Depot (ng/mi)
mean e active (CI-3Wk)
diameter (mg) Levels
(nm) (ng/ml)
21% Ziprasidone 260 420 58300 6490 110 23 146 35
Free Base with 2%
PVP and 0.1 % SLS
21 % Ziprasidone 231 420 62600 9400 100 15 180 85
Free Base with 1 %
Pluronic F108 and
1 % Tween 80
21 lo Ziprasidone 911 420 64400 7800, 105 19 389 231
Free Base with 1 %
Pluronic F108, 1 %
Tween 80 and 0.5%
Lecithin
23% Ziprasidone 113 420 53800 1100 78 14 211 168
Hydrochloride salt 0
with 1 % Pluronic
F108 and 1 % PVP
28% Ziprasidone 406 420 48700 4400 74 14 116 39
Mesylate Salt 2%
PVP and 0.5%
Pluronic F108
21% Micronized 4660 420 40000 6700 47 8 71 14
Ziprasidone Free
Base, 1.5%
NaCMC and 0.1%
Tween 80 aqueous
suspension
28% Micronized 3610 420 38900 1600 55 27 73 40
Ziprasidone
Mesylate salt, 0.1 %
Tween 80 aqueous
suspension
28% Ziprasidone 10660 420 31400 1100 43 30 60 38
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Formulation Effective Dose of AUC o=inf Average Cmax
diameter or Ziprasidon (ng.h/ml) Depot (ng/ml)
mean e active (C1-3 wk)
diameter (mg) Levels
(nm) (ng/ml)
Mesylate-Nominal 0
size aqueous
suspension
All mentioned documents are incorporated by reference as if here written. When
introducing elements of the present invention or the exemplary embodiment(s)
thereof, the,
articles "a," "an," "the" and "said" are intended to mean that there are one
or more of the
elements. The terms "comprising," "including" and "having" are intended to be
inclusive and
mean that there may be additional elements other than the listed elements.
Although this
invention has been described with respect to specific embodiments, the details
of these
embodiments are not to be construed as limitations.
