U.S. patent application number 13/024315 was filed with the patent office on 2011-08-11 for injectable nanoparticulate olanzapine formulations.
Invention is credited to Scott Jenkins, Elaine Merisko Liversidge, Gary Liversidge.
Application Number | 20110195095 13/024315 |
Document ID | / |
Family ID | 36407708 |
Filed Date | 2011-08-11 |
United States Patent
Application |
20110195095 |
Kind Code |
A1 |
Liversidge; Gary ; et
al. |
August 11, 2011 |
INJECTABLE NANOPARTICULATE OLANZAPINE FORMULATIONS
Abstract
Described are injectable formulations of nanoparticulate
olanzapine that produce a prolonged duration of action upon
administration, and methods of making and using such formulations.
The injectable formulations comprise nanoparticulate
olanzapine.
Inventors: |
Liversidge; Gary; (West
Chester, PA) ; Jenkins; Scott; (Downingtown, PA)
; Liversidge; Elaine Merisko; (West Chester, PA) |
Family ID: |
36407708 |
Appl. No.: |
13/024315 |
Filed: |
February 9, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11274887 |
Nov 16, 2005 |
7910577 |
|
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13024315 |
|
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|
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60628748 |
Nov 16, 2004 |
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Current U.S.
Class: |
424/400 ;
427/2.18; 514/220; 977/773 |
Current CPC
Class: |
Y10S 977/905 20130101;
A61P 25/00 20180101; Y10S 977/904 20130101; Y10S 977/906 20130101;
A61K 9/0019 20130101; A61K 9/146 20130101; A61P 25/24 20180101;
A61P 25/22 20180101; A61K 31/551 20130101; A61P 25/18 20180101;
A61P 25/20 20180101; A61P 25/28 20180101; Y10S 977/915 20130101;
Y10S 977/902 20130101; A61P 25/34 20180101; A61K 9/145 20130101;
A61P 25/08 20180101; A61P 25/04 20180101; A61K 9/148 20130101 |
Class at
Publication: |
424/400 ;
514/220; 427/2.18; 977/773 |
International
Class: |
A61K 31/5513 20060101
A61K031/5513; A61K 9/00 20060101 A61K009/00; A61P 25/00 20060101
A61P025/00; B05D 3/12 20060101 B05D003/12 |
Claims
1-18. (canceled)
19. A method of making an injectable nanoparticulate olanzapine
composition that produces an intramuscular depot upon
administration comprising: contacting particles of olanzapine or a
salt thereof with at least one surface stabilizer for a time and
under conditions sufficient to provide an olanzapine composition
having an effective average particle size that results in a
therapeutic efficacy of about one week or greater, wherein the
effective average particle size is between about 300 nm and about
5000 nm.
20. The method of claim 19, wherein the contacting comprises
grinding, wet grinding, homogenizing, or a combination thereof.
21. (canceled)
22. The composition of claim 19, wherein the effective average
particle size of the olanzapine particles is less than about 4900
nm, less than about 4800 nm, less than about 4700 nm, less than
about 4600 nm, less than about 4500 nm, less than about 4400 nm,
less than about 4300 nm, less than about 4200 nm, less than about
4100 nm, less than about 4000 nm, less than about 3900 nm, less
than about 3800 nm, less than about 3700 nm, less than about 3600
nm, less than about 3500 nm, less than about 3400 nm, less than
about 3300 nm, less than about 3200 nm, less than about 3100 nm,
less than about 3000 nm, less than about 2900 nm, less than about
2800 nm, less than about 2700 nm, less than about 2600 nm, less
than about 2500 nm, less than about 2400 nm, less than about 2300
nm, less than about 2200 nm, less than about 2100 nm, less than
about 2000 nm, less than about 1900 nm, less than less than about
1800 nm, less than about 1700 nm, less than about 1600 nm, less
than about 1500 nm, less than about 1400 nm, less than about 1300
nm, less than about 1200 nm, less than about 1100 nm, less than
about 1000 nm, less than about 900 nm, less than about 800 nm, less
than about 700 nm, less than about 600 nm, less than about 500 nm,
or less than about 400 nm.
23. A method for the treatment of a subject for disorders of the
central nervous system comprising administering to the subject an
effective amount of an injectable composition comprising: (a)
olanzapine nanoparticles having an effective average particle size
that results in a therapeutic efficacy of about one week or
greater; (b) at least one surface stabilizer; and (c) at least one
pharmaceutically acceptable carrier; wherein the effective average
particle size is between about 300 nm and about 5000 nm.
24. (canceled)
25. The method of claim 23, wherein the effective average particle
size of the olanzapine particles is less than about 4900 nm, less
than about 4800 nm, less than about 4700 nm, less than about 4600
nm, less than about 4500 nm, less than about 4400 nm, less than
about 4300 nm, less than about 4200 nm, less than about 4100 nm,
less than about 4000 nm, less than about 3900 nm, less than about
3800 nm, less than about 3700 nm, less than about 3600 nm, less
than about 3500 nm, less than about 3400 nm, less than about 3300
nm, less than about 3200 nm, less than about 3100 nm, less than
about 3000 nm, less than about 2900 nm, less than about 2800 nm,
less than about 2700 nm, less than about 2600 nm, less than about
2500 nm, less than about 2400 nm, less than about 2300 nm, less
than about 2200 nm, less than about 2100 nm, less than about 2000
nm, less than about 1900 nm, less than less than about 1800 nm,
less than about 1700 nm, less than about 1600 nm, less than about
1500 nm, less than about 1400 nm, less than about 1300 nm, less
than about 1200 nm, less than about 1100 nm, less than about 1000
nm, less than about 900 nm, less than about 800 nm, less than about
700 nm, less than about 600 nm, less than about 500 nm, or less
than about 400 nm.
26. The method of claim 23, wherein the depot releases the
olanzapine at therapeutic levels for a period of time from about
two to about six weeks.
27. The method of claim 23, wherein the depot releases the
olanzapine at therapeutic levels for a period of time from about
two to about twelve weeks.
28. The method of claim 23, wherein the depot releases the
olanzapine at therapeutic levels for a period of time selected from
the group consisting of from about one week to about two weeks,
from about one week to about three weeks, from about one week to
about four weeks, from about one week to about five weeks, from
about one week to about six weeks, from about one week to about
seven weeks, from about one week to about eight weeks, from about
one week to about nine weeks, from about one week to about ten
weeks, from about one week to about eleven weeks, from about one
week to about twelve weeks, and combinations thereof.
29. The method of claim 23, wherein the AUC of the olanzapine, when
assayed in the plasma of a mammalian subject following injectable
administration, is greater than the AUC for a non-nanoparticulate
olanzapine formulation, administered at the same dosage.
30. The method of claim 29, wherein the AUC is at least about 25%,
at least about 50%, at least about 75%, at least about 100%, at
least about 125%, at least about 150%, at least about 175%, at
least about 200%, at least about 225%, at least about 250%, at
least about 275%, at least about 300%, at least about 350%, at
least about 400%, at least about 450%, at least about 500%, at
least about 550%, at least about 600%, at least about 750%, at
least about 700%, at least about 750%, at least about 800%, at
least about 850%, at least about 900%, at least about 950%, at
least about 1000%, at least about 1050%, at least about 1100%, at
least about 1150%, or at least about 1200% greater than the AUC
exhibited by the non-nanoparticulate formulation of olanzapine,
administered at the same dosage.
31. The method of claim 23, wherein the method is used to treat an
indication selected from the group consisting of schizophrenia and
related psychoses, bipolar mania, bipolar disorder, seizures,
obsessive/compulsive disorders, generalized anxiety disorder, post
traumatic distress syndrome, extreme shyness, diabetic nerve pain,
smoking cessation, and depression.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a division of U.S. application Ser. No.
11/274,887, filed Nov. 16, 2005, which claims benefit under 35
U.S.C. .sctn.119(e) of U.S. Provisional Application No. 60/628,748,
filed Nov. 16, 2004, the disclosures of which are incorporated
herein by reference in their entireties.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention is directed to novel delivery systems
for psychotropic agents that ensure better patient compliance and
therefore improved therapeutic efficacy and better overall mental
health for the patient. More specifically, the present invention
comprises injectable nanoparticulate olanzapine formulations having
a prolonged duration of action.
[0004] 2. Background of Invention
A. Background Regarding Olanzapine
[0005] Currently there are many drugs available for the treatment
of disorders of the central nervous system. Among these drugs is a
category known as antipsychotics for treating serious mental
conditions such as schizophrenia and schizophreniform illness. The
drugs available for such conditions are often associated with
undesirable side effects, and there is a need for better products
that control or eliminate the symptoms in a safer and more
effective way. Furthermore, many patients do not respond or only
partially respond to present drug treatment, and estimates of such
partial-or-non-responders vary between 40% and 80% of those
treated.
[0006] Since antipsychotics were introduced it has been observed
that patients are liable to suffer from drug-induced extra
pyramidal symptoms, which include drug-induced Parkinsonism, acute
dystonic reactions, akathisia, tardive dyskinesia, and tardive
dystonia. The Simpsons Angus Scale, Barnes Akathisia Rating Scale,
and Abnormal Involuntary Movement Scale (AIMS) are well known
scales for assessing extra pyramidal symptoms. The great majority
of drugs available for treatment of schizophrenia are prone to
produce these extra pyramidal side effects when used at dosages
that yield a beneficial effect on the symptoms of the disease. The
severity of adverse events and/or lack of efficacy in a
considerable number of patients frequently result in poor
compliance or termination of treatment.
[0007] Many of the drugs are associated with a sedative effect and
may also have an undesirable influence on the affective symptoms of
the disease, causing depression. In some instances long term use of
the drug leads to irreversible conditions, such as the tardive
dyskinesia and tardive dystonia referred to above. This, coupled
with the fact that many of the patients in need of such drugs are
not in full control of their mental faculties, often results in
poor patient compliance and diminished therapeutic effect. A dosage
form of such a drug having prolonged activity, and therefore
requiring less frequent administrations, is highly desirable. This
is because such a dosage form would minimize complications caused
by patients missing or failing to take a dose.
[0008] A widely used and popular anti-psychotic drug useful in the
treatment of disorders of the central nervous system is olanzapine,
which is commercially available as Zyprexa.RTM. (Eli Lilly,
Indianapolis, Ind.). Zyprexa.RTM. is available in both orally
administered tablets and intramuscular injection formulations.
[0009] Olanzapine has the chemical name
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine
(C.sub.17H.sub.20N.sub.4S), a molecular weight of 312.439, and the
following chemical structure:
##STR00001##
[0010] Olanzapine is a yellow crystalline solid which is
practically insoluble in water. The compound is disclosed and
claimed in U.S. Pat. No. 5,229,382 to Chakrabarti et al., which is
incorporated herein by reference.
[0011] Olanzapine is an antagonist of dopamine at D-1 and D-2
receptors, and in addition has antimuscarinic, anti-cholinergic
properties, and is an antagonist for 5HT-2 receptor sites. The
compound also has antagonist activity at noradrenergic
alpha-receptors. These properties indicate that the compound is a
potential neuroleptic with relaxant, anxiolytic, or anti-emetic
properties, and is useful in treating psychotic conditions such as
schizophrenia, schizophreniform diseases, and acute mania. At lower
doses the compound is indicated for use in the treatment of mild
anxiety states.
[0012] Olanzapine is a selective monoaminergic antagonist with high
affinity binding to the following receptors serotonin 5HT.sub.2A/2C
(K.sub.1=4 and 11 nM, respectively), dopamine D.sub.1-4
(K.sub.1=11-31.sub.I 25 nM), histamine H.sub.1 (K I=7 nM), and
adrenergic (alpha).sub.1 receptors (K.sub.1=nM) GABA.sub.A, BZD,
and (beta) adrenergic receptors (K.sub.1>10 .mu.M).
[0013] The mechanism of action of olanzapine, as with other drugs
having efficacy in schizophrenia is unknown. However, it has been
proposed that this drug's efficacy in schrizophrenia is mediated
through a combination of dopamine and serotonin type 2 (5HT.sub.2)
antagonism. The mechanism of action of olanzapine in the treatment
of acute manic episodes associated with Bipolar 1 Disorder is
unknown.
[0014] Antagonism at receptor other than dopamine and 5HT.sub.2
with similar receptor affinities may explain some of the other
therapeutic and side effect of olanzapine. Olanzapine's antagonism
of muscorinic M.sub.1-5 receptors explains its anticholinergic
effects. Olanzapine's antagonism of histamine H.sub.1 receptors may
explain somnolence observed with this drug. Olanzapine's antagonism
of adrenergic (alpha) receptors may explain orthostatic hypotension
observed with this drug.
B. Background Regarding Nanoparticulate Drugs
[0015] Bioavailability is the degree to which a drug becomes
available to the target tissue after administration. Many factors
can affect bioavailability including the dosage form and various
properties, e.g., dissolution rate of the drug. Poor
bioavailability is a significant problem encountered in the
development of pharmaceutical compositions, particularly those
containing an active ingredient that is poorly soluble in water.
Poorly water soluble drugs tend to be unsafe for intravenous
administration techniques, which are used primarily in conjunction
with fully soluble drug substances.
[0016] It is known that the rate of dissolution of a particulate
drug can increase with increasing surface area, i.e., decreasing
particle size. Consequently, methods of making finely divided drugs
have been studied and efforts have been made to control the size
and size range of drug particles in pharmaceutical compositions.
U.S. Pat. No. 5,145,684 to Liversidge et. al., which is herein
incorporated by reference, discloses particles of a drug substance
having a non-crosslinked surface stabilizer absorbed on the surface
thereof and methods for the preparation thereof. This patent does
not teach or suggest nanoparticulate compositions of
olanzapine.
[0017] Methods of making nanoparticulate compositions are
described, for example, in U.S. Pat. Nos. 5,518,187 and 5,862,999,
both for "Method of Grinding Pharmaceutical Substances;" U.S. Pat.
No. 5,718,388, for "Continuous Method of Grinding Pharmaceutical
Substances;" and U.S. Pat. No. 5,510,118 for "Process of Preparing
Therapeutic Compositions Containing Nanoparticles." These patents
do not describe methods of making nanoparticulate olanzapine.
[0018] Nanoparticulate compositions are also described, for
example, in U.S. Pat. Nos. 5,298,262 for "Use of Ionic Cloud Point
Modifiers to Prevent Particle Aggregation During Sterilization;"
5,302,401 for "Method to Reduce Particle Size Growth During
Lyophilization;" 5,336,507 for "Use of Charged Phospholipids to
Reduce Nanoparticle Aggregation;" 5,340,564 for "Formulations
Comprising Olin 10-G to Prevent Particle Aggregation and Increase
Stability;" 5,346,702 for "Use of Non-Ionic Cloud Point Modifiers
to Minimize Nanoparticulate Aggregation During Sterilization;"
5,352,459 for "Use of Purified Surface Modifiers to Prevent
Particle Aggregation During Sterilization;" 5,399,363 and
5,494,683, both for "Surface Modified Anticancer Nanoparticles;"
5,429,824 for "Use of Tyloxapol as a Nanoparticulate Stabilizer;"
5,470,583 for "Method of Preparing Nanoparticle Compositions
Containing Charged Phospholipids to Reduce Aggregation;" 5,518,738
for "Nanoparticulate NSAID Formulations;" 5,552,160 for "Surface
Modified NSAID Nanoparticles;" 5,560,931 for "Formulations of
Compounds as Nanoparticulate Dispersions in Digestible Oils or
Fatty Acids;" 5,565,188 for "Polyalkylene Block Copolymers as
Surface Modifiers for Nanoparticles;" 5,569,448 for "Sulfated
Non-ionic Block Copolymer Surfactant as Stabilizer Coatings for
Nanoparticle Compositions;" 5,571,536 for "Formulations of
Compounds as Nanoparticulate Dispersions in Digestible Oils or
Fatty Acids;" 5,573,783 for "Redispersible Nanoparticulate Film
Matrices With Protective Overcoats;" 5,580,579 for "Site-specific
Adhesion Within the GI Tract Using Nanoparticles Stabilized by High
Molecular Weight, Linear Poly(ethylene Oxide) Polymers;" 5,585,108
for "Formulations of Oral Gastrointestinal Therapeutic Agents in
Combination with Pharmaceutically Acceptable Clays;" 5,587,143 for
"Butylene Oxide-Ethylene Oxide Block Copolymers Surfactants as
Stabilizer Coatings for Nanoparticulate Compositions;" 5,591,456
for "Milled Naproxen with Hydroxypropyl Cellulose as Dispersion
Stabilizer;" 5,622,938 for "Sugar Based Surfactant for
Nanocrystals;" 5,718,919 for "Nanoparticles Containing the
R(-)Enantiomer of Ibuprofen;" 5,747,001 for "Aerosols Containing
Beclomethasone Nanoparticle Dispersions;" 5,834,025 for "Reduction
of Intravenously Administered Nanoparticulate Formulation Induced
Adverse Physiological Reactions;" 6,045,829 "Nanocrystalline
Formulations of Human Immunodeficiency Virus (HIV) Protease
Inhibitors Using Cellulosic Surface Stabilizers;" 6,068,858 for
"Methods of Making Nanocrystalline Formulations of Human
Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic
Surface Stabilizers;" 6,153,225 for "Injectable Formulations of
Nanoparticulate Naproxen;" 6,165,506 for "New Solid Dose Form of
Nanoparticulate Naproxen;" 6,221,400 for "Methods of Treating
Mammals Using Nanocrystalline Formulations of Human
Immunodeficiency Virus (HIV) Protease Inhibitors;" 6,264,922 for
"Nebulized Aerosols Containing Nanoparticle Dispersions;" 6,267,989
for "Methods for Preventing Crystal Growth and Particle Aggregation
in Nanoparticle Compositions;" 6,270,806 for "Use of
PEG-Derivatized Lipids as Surface Stabilizers for Nanoparticulate
Compositions;" 6,316,029 for "Rapidly Disintegrating Solid Oral
Dosage Form," 6,375,986 for "Solid Dose Nanoparticulate
Compositions Comprising a Synergistic Combination of a Polymeric
Surface Stabilizer and Dioctyl Sodium Sulfosuccinate," 6,428,814
for "Bioadhesive nanoparticulate compositions having cationic
surface stabilizers;" 6,431,478 for "Small Scale Mill;" 6,432,381
for "Methods for Targeting Drug Delivery to the Upper and/or Lower
Gastrointestinal Tract," 6,592,903 for "Nanoparticulate Dispersions
Comprising a Synergistic Combination of a Polymeric Surface
Stabilizer and Dioctyl Sodium Sulfosuccinate," 6,582,285 for
"Apparatus for sanitary wet milling;" 6,656,504 for
"Nanoparticulate Compositions Comprising Amorphous Cyclosporine;"
6,742,734 for "System and Method for Milling Materials;" 6,745,962
for "Small Scale Mill and Method Thereof;" 6,811,767 for "Liquid
droplet aerosols of nanoparticulate drugs;" and 6,908,626 for
"Compositions having a combination of immediate release and
controlled release characteristics;" all of which are specifically
incorporated by reference. In addition, U.S. Patent Application No.
20020012675 A1, published on Jan. 31, 2002, for "Controlled Release
Nanoparticulate Compositions," and WO 02/098565 for "System and
Method for Milling Materials," describe nanoparticulate active
agent compositions, and are specifically incorporated by reference.
None of these references describe nanoparticulate compositions of
olanzapine.
[0019] Amorphous small particle compositions are described, for
example, in U.S. Pat. Nos. 4,783,484 for "Particulate Composition
and Use Thereof as Antimicrobial Agent;" 4,826,689 for "Method for
Making Uniformly Sized Particles from Water-Insoluble Organic
Compounds;" 4,997,454 for "Method for Making Uniformly-Sized
Particles From Insoluble Compounds;" 5,741,522 for "Ultrasmall,
Non-aggregated Porous Particles of Uniform Size for Entrapping Gas
Bubbles Within and Methods;" and 5,776,496, for "Ultrasmall Porous
Particles for Enhancing Ultrasound Back Scatter." These references
do not describe nanoparticulate olanzapine.
[0020] There is a need in the art for nanoparticulate olanzapine
formulations which overcome these and other problems associated
with prior conventional olanzapine formulations. The present
invention satisfies these needs.
SUMMARY OF THE INVENTION
[0021] The present invention relates to injectable nanoparticulate
olanzapine compositions. The compositions comprise olanzapine and
at least one surface stabilizer, which is preferably adsorbed on or
associated with the surface of the olanzapine particles. The
nanoparticulate olanzapine particles have an effective average
particle size of less than about 5 microns. The surface stabilizer
is present in an amount sufficient to maintain the olazapine at an
effective average particle size that maintains the efficacy of the
drug over a period of time, such as about one week or greater than
about one week. The nanoparticle size of the olanzapine particles
can be manipulated to give the desirable blood profile and duration
of action when administered by either intramuscular (IM) or
subcutaneous (SC) routes.
[0022] Long acting anti-psychotics are preferred, as the patient
population treated with such drugs can suffer from poor patient
compliance, resulting in diminished therapeutic effect for the
administered drug. Drugs requiring multiple daily administration,
or even daily administration, are not preferred for this patient
population. A simpler dosage form, such as a once-weekly dosage
form, can result in dramatically improved patient compliance, and
consequently improved quality of life. Advantages and properties of
the compositions of the invention are described herein.
[0023] Another aspect of the invention is directed to
pharmaceutical compositions comprising a nanoparticulate olanzapine
composition of the invention. The pharmaceutical compositions
preferably comprise olanzapine, at least one surface stabilizer,
and at least one pharmaceutically acceptable carrier, as well as
any desired excipients.
[0024] The invention further discloses a method of making a
nanoparticulate olanzapine composition. Such a method comprises
contacting olanzapine and at least one surface stabilizer for a
time and under conditions sufficient to provide a nanoparticulate
olanzapine composition. The one or more surface stabilizers can be
contacted with olanzapine either before, preferably during, or
after size reduction of the olanzapine.
[0025] The present invention is also directed to methods of
treatment using the injectable nanoparticulate olanzapine
compositions of the invention for, for example, psychotropic
therapy and the treatment of central nervous system disorders. In
one embodiment of the invention, intramuscular or subcutaneous
injection of olanzapine is utilized. The administration of the drug
in this manner allows for the formation of an intramuscular or
subcutaneous depot of olanzapine which slowly releases the drug
into the patient's system over a longer period of time than if
administered orally. The period of time over which the drug is
released is preferably up to about one week, from about two weeks
to about six weeks, and from about two weeks to about twelve weeks.
Additional time periods of efficacy are described herein. This
allows for improved patient compliance with enhanced therapeutic
outcomes. Moreover, injectable formulations of olanzapine result in
a significantly shorter response time as compared to oral
administration. While current conventional formulations of
olanzapine can be formulated for injection (i.e., Zyprexa.RTM.),
such conventional injectable olanzapine formulations are difficult
to prepare due to the low water solubility of the drug.
[0026] In psychotropic therapy and the treatment of central nervous
system disorders, it is important to provide an olanzapine dosage
form that delivers the required therapeutic amount of the drug in
vivo and renders the drug bioavailable in a rapid and consistent
manner. The nanoparticulate olanzapine formulations of the present
invention achieve those goals through the formation of a drug
depot, preferably following intramuscular injection. The depot
slowly releases the drug into the bloodstream at almost zero order
kinetics for about one (1) to about twelve (12) weeks through
control of the nanoparticle size of the drug. Different
nanoparticle sizes will dissolve at different rates, and will
therefore release the drug to the bloodstream from the depot at
different release rates.
[0027] Both the foregoing general description and the following
brief description of the drawings and detailed description are
exemplary and explanatory and are intended to provide further
explanation of the invention as claimed. Other objects, advantages,
and novel features will be readily apparent to those skilled in the
art from the following detailed description of the invention.
BRIEF DESCRIPTION OF THE FIGURE
[0028] FIG. 1: Shows an electron micrograph of unmilled
olanzapine.
[0029] FIG. 2: Shows an electron micrograph of a milled
nanoparticulate olanzapine formulation.
[0030] FIG. 3: Shows an electron micrograph of a milled
nanoparticulate olanzapine formulation.
[0031] FIG. 4: Graphically shows the plasma concentration (ng/mL)
of olanazpine over a six hour time period following intramuscular
administration to six male dogs of a nanoparticulate olanzapine
formulation.
[0032] FIG. 5: Graphically shows the plasma concentration (ng/mL)
of olanazpine over a six hour time period following intramuscular
administration to six male dogs of a nanoparticulate olanzapine
formulation.
DETAILED DESCRIPTION OF INVENTION
[0033] The invention provides injectable nanoparticulate olanzapine
formulations that can comprise high drug concentrations in low
injection volumes, with durations of action that can be controlled
to give efficacious blood levels through manipulation of particle
size and hence dissolution for periods of about one week or
greater.
[0034] In other embodiments of the invention, compositions of the
invention provide efficacious levels of drug from about one week to
about two weeks, from about one week to about three weeks, from
about one week to about four weeks, from about one week to about
five weeks, from about one week to about six weeks, from about one
week to about seven weeks, from about one week to about eight
weeks, from about one week to about nine weeks, from about one week
to about ten weeks, from about one week to about eleven weeks, from
about one week to about twelve weeks, and any combination thereof,
such as from about two weeks to about six weeks, from about three
weeks to about four weeks, from about three weeks to about seven
weeks, etc.
[0035] The composition of the invention is administered via
injection, such as by intramuscular or subcutaneously, to form a
drug depot. The drug depot results in efficacious levels of drug up
to about one week or greater.
[0036] As taught in U.S. Pat. No. 5,145,684, not every combination
of surface stabilizer and active agent will result in a stable
nanoparticulate composition. It was surprisingly discovered that
stable, injectable, nanoparticulate olanzapine formulations can be
made.
[0037] The current formulations of olanzapine suffer from the
following problems: (1) the poor solubility of the drug results in
a relatively low bioavailability; (2) dosing must be repeated
several times each day; and (3) a wide variety of side effects are
associated with the current dosage forms of the drug.
[0038] The present invention overcomes problems encountered with
the prior art olanzapine formulations. Specifically, the
nanoparticulate olanzapine formulations of the invention may offer
the following advantages: (1) a decrease in the frequency of dosing
and/or prolonged therapeutic levels of drug following dosing; (2)
faster onset of action; (3) smaller doses of olanzapine required to
obtain the same pharmacological effect; (4) increased
bioavailability; (5) improved performance characteristics for
intravenous, subcutaneous, or intramuscular injection, such as
higher dose loading and smaller liquid dose volumes; (6) improved
pharmacokinetic profiles, such as improved C.sub.max and AUC
profiles; (7) substantially similar or bioequivalent
pharmacokinetic profiles of the nanoparticulate olanzapine
compositions when administered in the fed versus the fasted state;
(8) bioadhesive olanzapine formulations, which can coat the desired
site of application and be retained for a period of time, thereby
increasing the efficacy of the drug as well as eliminating or
decreasing the frequency of dosing; (9) high redispersibility of
the nanoparticulate olanzapine particles present in the
compositions of the invention following administration; (10) low
viscosity liquid nanoparticulate olanzapine dosage forms can be
made; (11) the nanoparticulate olanzapine compositions can be used
in conjunction with other active agents; (12) the nanoparticulate
olanzapine compositions can be sterile filtered; (13) the
nanoparticulate olanzapine compositions are suitable for parenteral
administration; and (14) the nanoparticulate olanzapine
compositions do not require organic solvents or pH extremes.
[0039] A preferred dosage form of the invention is a liquid
injectable formulation. However, the composition may also be
formulated in a powder or solid for reconstitution prior to
injectable administration, such as by lyophilization. The dosage
form can be, for example, controlled release dosage form, delayed
release dosage form, extended release dosage form, pulsatile
release dosage form, mixed immediate release and controlled release
dosage form, or a combination thereof.
[0040] The present invention is described herein using several
definitions, as set forth below and throughout the application.
[0041] As used herein, "about" will be understood by persons of
ordinary skill in the art and will vary to some extent on the
context in which it is used. If there are uses of the term which
are not clear to persons of ordinary skill in the art given the
context in which it is used, "about" will mean up to plus or minus
10% of the particular term.
[0042] "Conventional" or "non-nanoparticulate active agent" shall
mean an active agent which is solubilized or which has an effective
average particle size of greater than about 5 microns.
Nanoparticulate active agents as defined herein have an effective
average particle size of less than about 5 microns.
[0043] "Poorly water soluble drugs" as used herein means those
having a solubility of less than about 30 mg/ml, preferably less
than about 20 mg/ml, preferably less than about 10 mg/ml, or
preferably less than about 1 mg/ml.
[0044] As used herein with reference to stable drug particles,
`stable` includes, but is not limited to, one or more of the
following parameters: (1) that the olanzapine particles do not
appreciably flocculate or agglomerate due to interparticle
attractive forces, or otherwise significantly increase in particle
size over time; (2) that the physical structure of the olanzapine
particles is not altered over time, such as by conversion from an
amorphous phase to crystalline phase; (3) that the olanzapine
particles are chemically stable; and/or (4) where the olanzapine
has not been subject to a heating step at or above the melting
point of the olanzapine in the preparation of the nanoparticles of
the invention.
[0045] `Therapeutically effective amount` as used herein with
respect to a drug dosage, shall mean that dosage that provides the
specific pharmacological response for which the drug is
administered in a significant number of subjects in need of such
treatment. It is emphasized that `therapeutically effective
amount,` administered to a particular subject in a particular
instance will not always be effective in treating the diseases
described herein, even though such dosage is deemed a
`therapeutically effective amount` by those skilled in the art. It
is to be further understood that drug dosages are, in particular
instances, measured as injectable dosages.
[0046] Enhanced pK Profiles
[0047] The invention also preferably provides olanzapine
compositions having a desirable pharmacokinetic profile when
administered to mammalian subjects. The desirable pharmacokinetic
profile of the olanzapine compositions preferably includes, but is
not limited to: (1) a C.sub.max for olanzapine, when assayed in the
plasma of a mammalian subject following administration, that is
preferably greater than the C.sub.max for a non-nanoparticulate
olanzapine formulation (e.g., Zyprexa.RTM.), administered at the
same dosage; and/or (2) an AUC for olanzapine, when assayed in the
plasma of a mammalian subject following administration, that is
preferably greater than the AUC for a non-nanoparticulate
olanzapine formulation (e.g., Zyprexa.RTM.), administered at the
same dosage. The desirable pharmacokinetic profile, as used herein,
is the pharmacokinetic profile measured after the initial
injectable dose of olanzapine.
[0048] Conventional olanzapine (e.g., Zyprexa.RTM.), reaches peak
plasma levels in 5-8 hours, and has a half-life of about 35 hours,
depending on metabolism.
[0049] A preferred injectable olanzapine composition of the
invention exhibits in comparative pharmacokinetic testing with a
non-nanoparticulate olanzapine formulation of (e.g., Zyprexa.RTM.),
administered at the same dosage, a C.sub.max which is at least
about 50%, at least about 100%, at least about 200%, at least about
300%, at least about 400%, at least about 500%, at least about
600%, at least about 700%, at least about 800%, at least about
900%, at least about 1000%, at least about 1100%, at least about
1200%, at least about 1300%, at least about 1400%, at least about
1500%, at least about 1600%, at least about 1700%, at least about
1800%, or at least about 1900% greater than the C.sub.max exhibited
by the non-nanoparticulate olanzapine formulation.
[0050] A preferred injectable olanzapine composition of the
invention exhibits in comparative pharmacokinetic testing with a
non-nanoparticulate olanzapine formulation (e.g., Zyprexa.RTM.),
administered at the same dosage, an AUC which is at least about
25%, at least about 50%, at least about 75%, at least about 100%,
at least about 125%, at least about 150%, at least about 175%, at
least about 200%, at least about 225%, at least about 250%, at
least about 275%, at least about 300%, at least about 350%, at
least about 400%, at least about 450%, at least about 500%, at
least about 550%, at least about 600%, at least about 750%, at
least about 700%, at least about 750%, at least about 800%, at
least about 850%, at least about 900%, at least about 950%, at
least about 1000%, at least about 1050%, at least about 1100%, at
least about 1150%, or at least about 1200% greater than the AUC
exhibited by the non-nanoparticulate olanzapine formulation.
[0051] Combination Pharmacokinetic Profile Compositions
[0052] In yet another embodiment of the invention, a first
nanoparticulate olanzapine composition providing a desired
pharmacokinetic profile is co-administered, sequentially
administered, or combined with at least one other olanzapine
composition that generates a desired different pharmacokinetic
profile. More than two olanzapine compositions can be
co-administered, sequentially administered, or combined. While the
first olanzapine composition has a nanoparticulate particle size,
the additional one or more olanzapine compositions can be
nanoparticulate, solubilized, or have a microparticulate particle
size.
[0053] The second, third, fourth, etc., olanzapine compositions can
differ from the first, and from each other, for example: (1) in the
effective average particle sizes of olanzapine; or (2) in the
dosage of olanzapine. Such a combination composition can reduce the
dose frequency required.
[0054] If the second olanzapine composition has a nanoparticulate
particle size, then preferably the olanzapine particles of the
second composition have at least one surface stabilizer associated
with the surface of the drug particles. The one or more surface
stabilizers can be the same as or different from the surface
stabilizer(s) present in the first olanzapine composition.
[0055] Preferably where co-administration of a "fast-acting"
formulation and a "longer-lasting" formulation is desired, the two
formulations are combined within a single composition, for example
a dual-release composition.
A. Olanazpine Compositions
[0056] The invention provides compositions comprising
nanoparticulate olanzapine particles and at least one surface
stabilizer. The surface stabilizers are preferably adsorbed to or
associated with the surface of the olanzapine particles. Surface
stabilizers useful herein do not chemically react with the
olanzapine particles or itself. Preferably, individual molecules of
the surface stabilizer are essentially free of intermolecular
cross-linkages. The compositions can comprise two or more surface
stabilizers.
[0057] The present invention also includes nanoparticulate
olanzapine compositions together with one or more non-toxic
physiologically acceptable carriers, adjuvants, or vehicles,
collectively referred to as carriers. The compositions can be
formulated for parenteral injection (e.g., intravenous,
intramuscular, or subcutaneous).
[0058] Olanzapine can be in a crystalline phase, an amorphous
phase, a semi-crystalline phase, a semi-amorphous phase, or a
mixtures thereof.
[0059] Illustrative but not limiting compositions comprise, based
on % w/w:
TABLE-US-00001 Olanzapine 5-50% Surface stabilizer 0.1-50%
preservatives (Optional) 0.05-0.25% pH adjusting agent pH about 6
to about 7 water for injection q.s.
[0060] 1. Surface Stabilizers
[0061] The choice of a surface stabilizer for olanzapine is
non-trivial and required experimentation to realize a desirable
formulation. Combinations of more than one surface stabilizer can
be used in the invention. Useful surface stabilizers which can be
employed in the invention include, but are not limited to, known
organic and inorganic pharmaceutical excipients. Such excipients
include various polymers, low molecular weight oligomers, natural
products, and surfactants. Surface stabilizers include nonionic,
ionic, anionic, cationic, and zwitterionic surfactants.
[0062] Preferred surface stabilizers include, but are not limited
to, a polysorbate, such as Tween 80, benzalkonium chloride, and
combinations thereof.
[0063] Representative examples of useful surface stabilizers
include but are not limited to Low viscosity hydroxypropyl
cellulose (HPC or HPC-SL); hydroxypropyl methyl cellulose (HPMC);
hydroxymethyl cellulose (HMC); ethycellulose; povidone; Pluronics;
sodium deoxycholate; PEG-Phospholipids; Tyloxapol and other
approved tritons, polyvinylpyrrolidone, sodium lauryl sulfate,
dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides),
dextran, gum acacia, cholesterol, tragacanth, stearic acid,
benzalkonium chloride, calcium stearate, glycerol monostearate,
cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters,
polyoxyethylene alkyl ethers (e.g., macrogol ethers such as
cetomacrogol 1000), polyoxyethylene castor oil derivatives,
polyoxyethylene sorbitan fatty acid esters (e.g., the commercially
available Tweens.RTM. such as e.g., Tween 20.RTM. and Tween 80.RTM.
(ICI Speciality Chemicals)); polyethylene glycols (e.g., Carbowaxs
3550.RTM. and 934.RTM. (Union Carbide)), polyoxyethylene stearates,
colloidal silicon dioxide, phosphates, carboxymethylcellulose
calcium, carboxymethylcellulose sodium, methylcellulose,
hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate,
noncrystalline cellulose, magnesium aluminium silicate,
triethanolamine, polyvinyl alcohol (PVA),
4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and
formaldehyde (also known as tyloxapol, superione, and triton),
poloxamers (e.g., Pluronics F68.RTM. and F108.RTM., which are block
copolymers of ethylene oxide and propylene oxide); poloxamines
(e.g., Tetronic 908.RTM., also known as Poloxamine 908.RTM., which
is a tetrafunctional block copolymer derived from sequential
addition of propylene oxide and ethylene oxide to ethylenediamine
(BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic 1508.RTM.
(T-1508) (BASF Wyandotte Corporation), Tritons X-200.RTM., which is
an alkyl aryl polyether sulfonate (Rohm and Haas); Crodestas
F-110.RTM., which is a mixture of sucrose stearate and sucrose
distearate (Croda Inc.); p-isononylphenoxypoly-(glycidol), also
known as Olin-IOG.RTM. or Surfactant 10-G.RTM. (Olin Chemicals,
Stamford, Conn.); Crodestas SL-40.RTM. (Croda, Inc.); and SA9OHCO,
which is
C.sub.18H.sub.37CH.sub.2(CON(CH.sub.3)--CH.sub.2(CHOH).sub.4(CH.sub.20H).-
sub.2 (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl
.beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside;
n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside;
n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl
.beta.-D-thioglucopyranoside; PEG-derivatized phospholipid,
PEG-derivatized cholesterol, PEG-derivatized cholesterol
derivative, PEG-derivatized vitamin A, PEG-derivatized vitamin E,
lysozyme, random copolymers of vinyl pyrrolidone and vinyl acetate,
and the like.
[0064] Povidone Polymers
[0065] In one embodiment of the invention, a povidone polymer is
utilized as a surface stabilizer. Povidone polymers for injectable
compositions preferably have a molecular weight of less than about
40,000 daltons. Povidone polymers, also known as polyvidon(e),
povidonum, PVP, and polyvinylpyrrolidone, are sold under the trade
names Kollidon.RTM. (BASF Corp.) and Plasdone.RTM. (ISP
Technologies, Inc.). They are polydisperse macromolecular
molecules, with a chemical name of 1-ethenyl-2-pyrrolidinone
polymers and 1-vinyl-2-pyrrolidinone polymers. Povidone polymers
are produced commercially as a series of products having mean
molecular weights ranging from about 10,000 to about 700,000
daltons. To be useful as a surface modifier for a drug compound to
be administered to a mammal, the povidone polymer must have a
molecular weight of less than about 40,000 daltons, as a molecular
weight of greater than 40,000 daltons would have difficulty
clearing the body.
[0066] Povidone polymers are prepared by, for example, Reppe's
process, comprising: (1) obtaining 1,4-butanediol from acetylene
and formaldehyde by the Reppe butadiene synthesis; (2)
dehydrogenating the 1,4-butanediol over copper at 200.degree. to
form .gamma.-butyrolactone; and (3) reacting .gamma.-butyrolactone
with ammonia to yield pyrrolidone. Subsequent treatment with
acetylene gives the vinyl pyrrolidone monomer. Polymerization is
carried out by heating in the presence of H.sub.2O and NH.sub.3.
See The Merck Index, 10.sup.th Edition, page 1106 (Merck & Co.,
Rahway, N.J., 1983).
[0067] The manufacturing process for povidone polymers produces
polymers containing molecules of unequal chain length, and thus
different molecular weights. The molecular weights of the molecules
vary about a mean or average for each particular commercially
available grade. Because it is difficult to determine the polymer's
molecular weight directly, the most widely used method of
classifying various molecular weight grades is by K-values, based
on viscosity measurements. The K-values of various grades of
povidone polymers represent a function of the average molecular
weight, and are derived from viscosity measurements and calculated
according to Fikentscher's formula.
[0068] The weight-average of the molecular weight, Mw, is
determined by methods that measure the weights of the individual
molecules, such as by light scattering. Table 1 provides molecular
weight data for several commercially available povidone polymers,
all of which are soluble.
TABLE-US-00002 TABLE 1 Mv Mw Mn Povidone K-Value (Daltons)**
(Daltons)** (Daltons)** Plasdone 17 .+-. 1 7,000 10,500 3,000 C-15
.RTM. Plasdone 30.5 .+-. 1.5 38,000 62,500* 16,500 C-30 .RTM.
Kollidon 12 11-14 3,900 2,000-3,000 1,300 PF .RTM. Kollidon 17
16-18 9,300 7,000-11,000 2,500 PF .RTM. Kollidon 24-32 25,700
28,000-34,000 6,000 25 .RTM. *Because the molecular weight is
greater than 40,000 daltons, this povidone polymer is not useful as
a surface stabilizer for a drug compound to be administered
parenterally (i.e., injected). **Mv is the viscosity-average
molecular weight, Mn is the number-average molecular weight, and Mw
is the weight average molecular weight. Mw and Mn were determined
by light scattering and ultra-centrifugation, and Mv was determined
by viscosity measurements.
[0069] Based on the data provided in Table 1, exemplary preferred
commercially available povidone polymers for injectable
compositions include, but are not limited to, Plasdone C-15.RTM.,
Kollidon 12 PF.RTM., Kollidon 17 PF.RTM., and Kollidon 25.RTM..
[0070] Cationic Surface Stabilizers
[0071] Depending upon the desired method of administration,
bioadhesive formulations of nanoparticulate olanzapine can be
prepared by selecting one or more cationic surface stabilizers that
impart bioadhesive properties to the resultant composition. Useful
cationic surface stabilizers are described below.
[0072] Examples of useful cationic surface stabilizers include, but
are not limited to, polymers, biopolymers, polysaccharides,
cellulosics, alginates, phospholipids, and nonpolymeric compounds,
such as zwitterionic stabilizers, poly-n-methylpyridinium, anthryul
pyridinium chloride, cationic phospholipids, chitosan, polylysine,
polyvinylimidazole, polybrene, polymethylmethacrylate
trimethylammoniumbromide bromide (PMMTMABr),
hexyldesyltrimethylammonium bromide (HDMAB),
polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl
sulfate, 1,2
Dipalmitoyl-sn-Glycero-3-Phosphoethanolamine-N-[Amino(Polyethylene
Glycol)2000] (sodium salt) (also known as DPPE-PEG(2000)-Amine Na)
(Avanti Polar Lipids, Alabaster, Ala.), Poly(2-methacryloxyethyl
trimethylammonium bromide) (Polysciences, Inc., Warrington, Pa.)
(also known as S1001), poloxamines such as Tetronic 908.RTM., also
known as Poloxamine 908.RTM., which is a tetrafunctional block
copolymer derived from sequential addition of propylene oxide and
ethylene oxide to ethylenediamine (BASF Wyandotte Corporation,
Parsippany, N.J.), lysozyme, long-chain polymers such as alginic
acid, carrageenan (FMC Corp.), and POLYOX (Dow, Midland,
Mich.).
[0073] Other useful cationic stabilizers include, but are not
limited to, cationic lipids, sulfonium, phosphonium, and
quarternary ammonium compounds, such as stearyltrimethylammonium
chloride, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut
trimethyl ammonium chloride or bromide, coconut methyl
dihydroxyethyl ammonium chloride or bromide, decyl triethyl
ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or
bromide, C.sub.12-15dimethyl hydroxyethyl ammonium chloride or
bromide, coconut dimethyl hydroxyethyl ammonium chloride or
bromide, myristyl trimethyl ammonium methyl sulphate, lauryl
dimethyl benzyl ammonium chloride or bromide, lauryl
dimethyl(ethenoxy).sub.4 ammonium chloride or bromide, N-alkyl
(C.sub.12-18)dimethylbenzyl ammonium chloride, N-alkyl
(C.sub.14-18)dimethyl-benzyl ammonium chloride,
N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl
didecyl ammonium chloride, N-alkyl and (C.sub.12-14) dimethyl
1-napthylmethyl ammonium chloride, trimethylammonium halide,
alkyl-trimethylammonium salts and dialkyl-dimethylammonium salts,
lauryl trimethyl ammonium chloride, ethoxylated
alkyamidoalkyldialkylammonium salt and/or an ethoxylated trialkyl
ammonium salt, dialkylbenzene dialkylammonium chloride,
N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl
ammonium, chloride monohydrate, N-alkyl(C.sub.12-14) dimethyl
1-naphthylmethyl ammonium chloride and dodecyldimethylbenzyl
ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl
trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride,
alkyl benzyl dimethyl ammonium bromide, C.sub.12, C.sub.15,
C.sub.17 trimethyl ammonium bromides, dodecylbenzyl triethyl
ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC),
dimethyl ammonium chlorides, alkyldimethylammonium halogenides,
tricetyl methyl ammonium chloride, decyltrimethylammonium bromide,
dodecyltriethylammonium bromide, tetradecyltrimethylammonium
bromide, methyl trioctylammonium chloride (ALIQUAT 336.TM.),
POLYQUAT 10.TM., tetrabutylammonium bromide, benzyl
trimethylammonium bromide, choline esters (such as choline esters
of fatty acids), benzalkonium chloride, stearalkonium chloride
compounds (such as stearyltrimonium chloride and Di-stearyldimonium
chloride), cetyl pyridinium bromide or chloride, halide salts of
quaternized polyoxyethylalkylamines, MIRAPOL.TM. and ALKAQUAT.TM.
(Alkaril Chemical Company), alkyl pyridinium salts; amines, such as
alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines,
N,N-dialkylaminoalkyl acrylates, and vinyl pyridine, amine salts,
such as lauryl amine acetate, stearyl amine acetate,
alkylpyridinium salt, and alkylimidazolium salt, and amine oxides;
imide azolinium salts; protonated quaternary acrylamides;
methylated quaternary polymers, such as
poly[diallyldimethylammonium chloride] and poly-[N-methyl vinyl
pyridinium chloride]; and cationic guar.
[0074] Such exemplary cationic surface stabilizers and other useful
cationic surface stabilizers are described in J. Cross and E.
Singer, Cationic Surfactants: Analytical and Biological Evaluation
(Marcel Dekker, 1994); P. and D. Rubingh (Editor), Cationic
Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J.
Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker,
1990).
[0075] Nonpolymeric cationic surface stabilizers are any
nonpolymeric compound, such as benzalkonium chloride, a carbonium
compound, a phosphonium compound, an oxonium compound, a halonium
compound, a cationic organometallic compound, a quarternary
phosphorous compound, a pyridinium compound, an anilinium compound,
an ammonium compound, a hydroxylanunonium compound, a primary
ammonium compound, a secondary ammonium compound, a tertiary
ammonium compound, and quarternary ammonium compounds of the
formula NR.sub.1R.sub.2R.sub.3R.sub.4.sup.(+). For compounds of the
formula NR.sub.1R.sub.2R.sub.3R.sub.4.sup.(+): [0076] (i) none of
R.sub.1-R.sub.4 are CH.sub.3; [0077] (ii) one of R.sub.1-R.sub.4 is
CH.sub.3; [0078] (iii) three of R.sub.1-R.sub.4 are CH.sub.3;
[0079] (iv) all of R.sub.1-R.sub.4 are CH.sub.3; [0080] (v) two of
R.sub.1-R.sub.4 are CH.sub.3, one of R.sub.1-R.sub.4 is
C.sub.6H.sub.5CH.sub.2, and one of R.sub.1-R.sub.4 is an alkyl
chain of seven carbon atoms or less; [0081] (vi) two of
R.sub.1-R.sub.4 are CH.sub.3, one of R.sub.1-R.sub.4 is
C.sub.6H.sub.5CH.sub.2, and one of R.sub.1-R.sub.4 is an alkyl
chain of nineteen carbon atoms or more; [0082] (vii) two of
R.sub.1-R.sub.4 are CH.sub.3 and one of R.sub.1-R.sub.4 is the
group C.sub.6H.sub.5(CH.sub.2).sub.n, where n>1; [0083] (viii)
two of R.sub.1-R.sub.4 are CH.sub.3, one of R.sub.1-R.sub.4 is
C.sub.6H.sub.5CH.sub.2, and one of R.sub.1-R.sub.4 comprises at
least one heteroatom; [0084] (ix) two of R.sub.1-R.sub.4 are
CH.sub.3, one of R.sub.1-R.sub.4 is C.sub.6H.sub.5CH.sub.2, and one
of R.sub.1-R.sub.4 comprises at least one halogen; [0085] (x) two
of R.sub.1-R.sub.4 are CH.sub.3, one of R.sub.1-R.sub.4 is
C.sub.6H.sub.5CH.sub.2, and one of R.sub.1-R.sub.4 comprises at
least one cyclic fragment; [0086] (xi) two of R.sub.1-R.sub.4 are
CH.sub.3 and one of R.sub.1-R.sub.4 is a phenyl ring; or [0087]
(xii) two of R.sub.1-R.sub.4 are CH.sub.3 and two of
R.sub.1-R.sub.4 are purely aliphatic fragments.
[0088] Such compounds include, but are not limited to,
behenalkonium chloride, benzethonium chloride, cetylpyridinium
chloride, behentrimonium chloride, lauralkonium chloride,
cetalkonium chloride, cetrimonium bromide, cetrimonium chloride,
cethylamine hydrofluoride, chlorallylmethenamine chloride
(Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyl
dimethyl ethylbenzyl ammonium chloride (Quaternium-14),
Quaternium-22, Quaternium-26, Quaternium-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 HCl, iofetamine hydrochloride,
meglumine hydrochloride, methylbenzethonium chloride, myrtrimonium
bromide, oleyltrimonium chloride, polyquaternium-1,
procainehydrochloride, cocobetaine, stearalkonium bentonite,
stearalkoniumhectonite, stearyl trihydroxyethyl propylenediamine
dihydrofluoride, tallowtrimonium chloride, and hexadecyltrimethyl
ammonium bromide.
[0089] Most of these surface stabilizers are known pharmaceutical
excipients and 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), specifically incorporated
by reference.
[0090] The surface stabilizers are commercially available and/or
can be prepared by techniques known in the art.
[0091] While applicants do not wish to be bound by theoretical
mechanisms, it is believed that the stabilizer hinders the
flocculation and/or agglomeration of the olanzapine particles by
functioning as a mechanical or steric barrier between the
particles, minimizing the close, interparticle approach necessary
for agglomeration and flocculation.
[0092] 2. Excipients
[0093] Exemplary preservatives include methylparaben (about 0.18%
based on % w/w), propylparaben (about 0.02% based on % w/w), phenol
(about 0.5% based on % w/w), and benzyl alcohol (up to 2% v/v). An
exemplary pH adjusting agent is sodium hydroxide, and an exemplary
liquid carrier is sterile water for injection. Other useful
preservatives, pH adjusting agents, and liquid carriers are
well-known in the art.
[0094] 3. Nanoparticulate Olanzapine Particle Size
[0095] As used herein, particle size is determined on the basis of
the weight average particle size as measured by conventional
particle size measuring techniques well known to those skilled in
the art. Such techniques include, for example, sedimentation field
flow fractionation, photon correlation spectroscopy, light
scattering, and disk centrifugation.
[0096] The compositions of the invention comprise olanzapine
nanoparticles which have an effective average particle size of less
than about 5 microns. In other embodiments of the invention, the
olanzapine particles have a size of less than about 4900 nm, less
than about 4800 nm, less than about 4700 nm, less than about 4600
nm, less than about 4500 nm, less than about 4400 nm, less than
about 4300 nm, less than about 4200 nm, less than about 4100 nm,
less than about 4 microns, less than about 3900 nm, less than about
3800 nm, less than about 3700 nm, less than about 3600 nm, less
than about 3500 nm, less than about 3400 nm, less than about 3300
nm, less than about 3200 nm, less than about 3100 nm, less than
about 3 microns, less than about 2900 nm, less than about 2800 nm,
less than about 2700 nm, less than about 2600 nm, less than about
2500 nm, less than about 2400 nm, less than about 2300 nm, less
than about 2200 nm, less than about 2100 nm, less than about 2000
nm, less than about 1900 nm, less than less than about 1800 nm,
less than about 1700 nm, less than about 1600 nm, less than about
1500 nm, less than about 1400 nm, less than about 1300 nm, less
than about 1200 nm, less than about 1100 nm, less than about 1000
nm, less than about 900 nm, less than about 800 nm, less than about
700 nm, less than about 600 nm, less than about 500 nm, less than
about 400 nm, less than about 300 nm, less than about 250 nm, less
than about 200 nm, less than about 150 nm, less than about 140 nm,
less than about 130 nm, less than about 120 nm, less than about 110
nm, less than about 100 nm, less than about 90 nm, less than about
80 nm, less than about 70 nm, less than about 60 nm, or less than
about 50 nm, when measured by the above-noted techniques.
[0097] By "an effective average particle size of less than about 5
microns" it is meant that at least 50% of the nanoparticulate
olanzapine particles have a weight average particle size of less
than about 5 microns, when measured by the above-noted techniques.
In other embodiments of the invention, at least about 70%, at least
about 90%, at least about 95%, or at least about 99% of the
nanoparticulate olanzapine particles have a particle size of less
than the effective average, by weight, i.e., less than about 5
microns, less than about 4900 nm, less than less than about 4800
nm, less than about 4700 nm, etc. (as listed in the paragraph
above).
[0098] If the nanoparticulate olanzapine composition is combined
with a microparticulate olanzapine or non-olanzapine active agent
composition, then such a composition is either solubilized or has
an effective average particle size of greater than about 5 microns.
By "an effective average particle size of greater than about 5
microns" it is meant that at least 50% of the microparticulate
olanzapine or non-olanzapine active agent particles have a particle
size of greater than about 5 microns, by weight, when measured by
the above-noted techniques. In other embodiments of the invention,
at least about 70%, at least about 90%, at least about 95%, or at
least about 99%, by weight, of the microparticulate olanzapine or
non-olanzapine active agent particles have a particle size greater
than about 5 microns.
[0099] In the present invention, the value for D50 of a
nanoparticulate olanzapine composition is the particle size below
which 50% of the olanzapine particles fall, by weight. Similarly,
D90 and D99 are the particle sizes below which 90% and 99%,
respectively, of the olanzapine particles fall, by weight.
[0100] 4. Concentration of Nanoparticulate Olanzapine and Surface
Stabilizers
[0101] The relative amounts of olanzapine and one or more surface
stabilizers can vary widely. The optimal amount of the individual
components can depend, for example, upon the hydrophilic lipophilic
balance (HLB), melting point, and the surface tension of water
solutions of the stabilizer, etc.
[0102] The concentration of olanzapine can vary from about 99.5% to
about 0.001%, from about 95% to about 0.1%, from about 90% to about
0.5%, or from about 5.0% to about 50%, by weight, based on the
total combined dry weight of the olanzapine and at least one
surface stabilizer, not including other excipients.
[0103] The concentration of the at least one surface stabilizer can
vary from about 0.5% to about 99.999%, from about 5.0% to about
99.9%, from about 10% to about 99.5%, or from about 0.1 to about
50%, by weight, based on the total combined dry weight of the
olanzapine and at least one surface stabilizer, not including other
excipients.
[0104] 5. Additional Active Agents
[0105] The invention encompasses the nanoparticulate olanzapine
compositions of the invention formulated or co-administered with
one or more non-olanzapine active agents. Methods of using such
combination compositions are also encompassed by the invention. The
non-olanzapine active agents can be present in a crystalline phase,
an amorphous phase, a semi-crystalline phase, a semi-amorphous
phase, or a mixture thereof.
[0106] The compound to be administered in combination with a
nanoparticulate olanzapine composition of the invention can be
formulated separately from the nanoparticulate olanzapine
composition or co-formulated with the nanoparticulate olanzapine
composition. Where a nanoparticulate olanzapine composition is
co-formulated with a second active agent, the second active agent
can be formulated in any suitable manner, such as
immediate-release, rapid-onset, sustained-release, or dual-release
form.
[0107] Such non-olanzapine active agents can be, for example, a
therapeutic agent. A therapeutic agent can be a pharmaceutical
agent, including a biologic. The active agent can be selected from
a variety of known classes of drugs, including, for example, amino
acids, proteins, peptides, nucleotides, anti-obesity drugs, central
nervous system stimulants, carotenoids, corticosteroids, elastase
inhibitors, anti-fungals, oncology therapies, anti-emetics,
analgesics, cardiovascular agents, anti-inflammatory agents, such
as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic
agents, antibiotics (including penicillins), anticoagulants,
antidepressants, antidiabetic agents, antiepileptics,
antihistamines, antihypertensive agents, antimuscarinic agents,
antimycobacterial agents, antineoplastic agents,
immunosuppressants, antithyroid agents, antiviral agents,
anxiolytics, sedatives (hypnotics and neuroleptics), astringents,
alpha-adrenergic receptor blocking agents, beta-adrenoceptor
blocking agents, blood products and substitutes, cardiac inotropic
agents, contrast media, corticosteroids, cough suppressants
(expectorants and mucolytics), diagnostic agents, diagnostic
imaging agents, diuretics, dopaminergics (antiparkinsonian agents),
haemostatics, immunological agents, lipid regulating agents, muscle
relaxants, parasympathomimetics, parathyroid calcitonin and
biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones
(including steroids), anti-allergic agents, stimulants and
anoretics, sympathomimetics, thyroid agents, vasodilators, and
xanthines.
[0108] Examples of secondary active agents particularly useful in
the compositions of the invention include, but are not limited to,
antidepressants. Examples of classes of useful antidepressants
include, but are not limited to, selective serotonin reuptake
inhibitors (SSRIs), tricyclic antidepressants, and monoamine
oxidase Inhibitors (MAOI's). Examples of antidepressants include,
but are not limited to, citalopram (Celexa.RTM.), escitalopram HB
(Lexapro.RTM.), fluoxetine hydrochloride (Prozac.RTM.), paroxetine
(Paxil.RTM.), fluvoxamine (Luvox.RTM.), sertraline (Zoloft.RTM.),
venlafaxine (Effexor.RTM.), amitriptyline (Elavil.RTM.),
desipramine, nortriptyline, duloxetine (Cymbalta.RTM.), mirtazepine
(Remeron.RTM.), phenelzine (Nardil.RTM.), tranylcypromine
(Parnate.RTM.), nefazodone (Serzone.RTM.), trazodone, and bupropion
(Wellbutrin.RTM.). A particularly useful antidepressant is
fluoxetine (Prozac.RTM.).
B. Methods of Making Injectable Olanzapine Formulations
[0109] In another aspect of the invention there is provided a
method of preparing the injectable nanoparticulate olanzapine
formulations of the invention. The method comprises of one of the
following methods: attrition, precipitation, evaporation, or
combinations of these. Exemplary methods of making nanoparticulate
compositions are described in U.S. Pat. No. 5,145,684. Methods of
making nanoparticulate compositions are also described in U.S. Pat.
No. 5,518,187 for "Method of Grinding Pharmaceutical Substances;"
U.S. Pat. No. 5,718,388 for "Continuous Method of Grinding
Pharmaceutical Substances;" U.S. Pat. No. 5,862,999 for "Method of
Grinding Pharmaceutical Substances;" U.S. Pat. No. 5,665,331 for
"Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents
with Crystal Growth Modifiers;" U.S. Pat. No. 5,662,883 for
"Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents
with Crystal Growth Modifiers;" U.S. Pat. No. 5,560,932 for
"Microprecipitation of Nanoparticulate Pharmaceutical Agents;" U.S.
Pat. No. 5,543,133 for "Process of Preparing X-Ray Contrast
Compositions Containing Nanoparticles;" U.S. Pat. No. 5,534,270 for
"Method of Preparing Stable Drug Nanoparticles;" U.S. Pat. No.
5,510,118 for "Process of Preparing Therapeutic Compositions
Containing Nanoparticles;" and U.S. Pat. No. 5,470,583 for "Method
of Preparing Nanoparticle Compositions Containing Charged
Phospholipids to Reduce Aggregation," all of which are specifically
incorporated by reference.
[0110] Following milling, homogenization, precipitation, etc., the
resultant nanoparticulate olanzapine composition can be utilized a
liquid dosage formulation for injectable administration.
[0111] In one embodiment of the invention, the olanzapine particles
are reduced to an effective average particle size of less than
about 600 nm. Preferably, the effective average particle size of
the nanoparticulate olanzapine is less than about 450 nm, more
preferably less than about 300 nm, even more preferably less than
about 250 nm, and most preferably less than about 100 nm. The pH of
the liquid dispersion media is preferably maintained within the
range of from about 3.0 to about 8.0, or about 5.0 to about 7.5,
more preferably, at a pH of about 7.4, during the size reduction
process. Preferably, the dispersion media used for the size
reduction process is aqueous. However, any media in which
olanzapine is poorly soluble and dispersible can be used as a
dispersion media. Non-aqueous examples of dispersion media include,
but are not limited to, aqueous salt solutions, safflower oil and
solvents such as ethanol, t-butanol, hexane, and glycol.
[0112] Effective methods of providing mechanical force for particle
size reduction of olanzapine include ball milling, media milling,
and homogenization, for example, with a Microfluidizer.RTM.
(Microfluidics Corp.). Ball milling is a low energy milling process
that uses milling media, drug, stabilizer, and liquid. The
materials are placed in a milling vessel that is rotated at optimal
speed such that the media cascades and reduces the drug particle
size by impaction. The media used must have a high density as the
energy for the particle reduction is provided by gravity and the
mass of the attrition media.
[0113] Media milling is a high energy milling process. Drug,
stabilizer, and liquid are placed in a reservoir and recirculated
in a chamber containing media and a rotating shaft/impeller. The
rotating shaft agitates the media which subjects the drug to
impaction and sheer forces, thereby reducing the drug particle
size.
[0114] Homogenization is a technique that does not use milling
media. Drug, stabilizer, and liquid (or drug and liquid with the
stabilizer added after particle size reduction) constitute a
process stream propelled into a process zone, which in the
Microfluidizer.RTM. is called the Interaction Chamber. The product
to be treated is inducted into the pump, and then forced out. The
priming valve of the Microfluidizer.RTM. purges air out of the
pump. Once the pump is filled with product, the priming valve is
closed and the product is forced through the interaction chamber.
The geometry of the interaction chamber produces powerful forces of
sheer, impact, and cavitation which are responsible for particle
size reduction. Specifically, inside the interaction chamber, the
pressurized product 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 or droplet size. The
Microfluidizer.RTM. also provides a heat exchanger to allow cooling
of the product. U.S. Pat. No. 5,510,118, which is specifically
incorporated by reference, refers to a process using a
Microfluidizer.RTM. resulting in nanoparticulate particles.
[0115] Olanzapine can be added to a liquid medium in which it is
essentially insoluble to form a premix. The concentration of the
olanzapine in the liquid medium can vary from about 5 to about 60%,
and preferably is from about 15 to about 50% (w/v), and more
preferably about 20 to about 40%. The surface stabilizer can be
present in the premix, it can be during particle size reduction, or
it can be added to the drug dispersion following particle size
reduction. The concentration of the surface stabilizer can vary
from about 0.1 to about 50%, and preferably is from about 0.5 to
about 20%, and more preferably from about 1 to about 10%, by
weight.
[0116] The premix can be used directly by subjecting it to
mechanical means to reduce the average olanzapine particle size in
the dispersion to the desired size, preferably less than about 5
microns. It is preferred that the premix be used directly when a
ball mill is used for attrition. Alternatively, olanzapine and the
surface stabilizer can be dispersed in the liquid media using
suitable agitation, e.g., a Cowles type mixer, until a homogeneous
dispersion is observed in which there are no large agglomerates
visible to the naked eye. It is preferred that the premix be
subjected to such a premilling dispersion step when a recirculating
media mill is used for attrition.
[0117] The mechanical means applied to reduce the olanzapine
particle size conveniently can take the form of a dispersion mill.
Suitable dispersion mills include a ball mill, an attritor mill, a
vibratory mill, and media mills such as a sand mill and a bead
mill. A media mill is preferred due to the relatively shorter
milling time required to provide the desired reduction in particle
size. For media milling, the apparent viscosity of the premix is
preferably from about 100 to about 1000 centipoise, and for ball
milling the apparent viscosity of the premix is preferably from
about 1 up to about 100 centipoise. Such ranges tend to afford an
optimal balance between efficient particle size reduction and media
erosion but are in no way limiting
[0118] The attrition time can vary widely and depends primarily
upon the particular mechanical means and processing conditions
selected. For ball mills, processing times of up to five days or
longer may be required. Alternatively, processing times of less
than 1 day (residence times of one minute up to several hours) are
possible with the use of a high shear media mill.
[0119] The olanzapine particles must be reduced in size at a
temperature which does not significantly degrade olanzapine.
Processing temperatures of less than about 30.degree. to less than
about 40.degree. C. are ordinarily preferred. If desired, the
processing equipment can be cooled with conventional cooling
equipment. Control of the temperature, e.g., by jacketing or
immersion of the milling chamber with a cooling liquid, is
contemplated. Generally, the method of the invention is
conveniently carried out under conditions of ambient temperature
and at processing pressures which are safe and effective for the
milling process. Ambient processing pressures are typical of ball
mills, attritor mills, and vibratory mills.
[0120] Grinding Media
[0121] The grinding media can comprise particles that are
preferably substantially spherical in shape, e.g., beads,
consisting essentially of polymeric resin or glass or Zirconium
Silicate or other suitable compositions. Alternatively, the
grinding media can comprise a core having a coating of a polymeric
resin adhered thereon.
[0122] 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 crosslinked polystyrenes, such as
polystyrene crosslinked with divinylbenzene; styrene copolymers;
polycarbonates; polyacetals, such as Delrin.RTM. (E.I. du Pont de
Nemours and Co.); vinyl chloride polymers and copolymers;
polyurethanes; polyamides; poly(tetrafluoroethylenes), e.g.,
Teflon.RTM. (E.I. du Pont de Nemours and Co.), and other
fluoropolymers; high density polyethylenes; polypropylenes;
cellulose ethers and esters such as cellulose acetate;
polyhydroxymethacrylate; polyhydroxyethyl acrylate; and
silicone-containing polymers such as polysiloxanes and the like.
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.
[0123] The grinding media preferably ranges in size from about 0.01
to about 3 mm. For fine grinding, the grinding media is preferably
from about 0.02 to about 2 mm, and more preferably from about 0.03
to about 1 mm in size.
[0124] The polymeric resin can have a density from about 0.8 to
about 3.0 g/cm.sup.3.
[0125] In one embodiment of the invention, the olanzapine particles
are made continuously. Such a method comprises continuously
introducing olanzapine into a milling chamber, contacting the
olanzapine with grinding media while in the chamber to reduce the
olanzapine particle size, and continuously removing the
nanoparticulate olanzapine from the milling chamber.
[0126] The grinding media can be separated from the milled
nanoparticulate olanzapine using conventional separation
techniques, in a secondary process such as by simple filtration,
sieving through a mesh filter or screen, and the like. Other
separation techniques such as centrifugation may also be employed.
Alternatively, a screen can be utilized during the milling process
to remove the grinding media following completion of particle size
reduction.
[0127] Sterile Product Manufacturing
[0128] 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:
##STR00002##
[0129] 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.
C. Method of Treatment
[0130] Yet another aspect of the present invention provides a
method of treating a mammal, including a human, of disorders of the
central nervous system including, but not limited to psychiatric
treatment. Such treatment comprises administering to the subject
the injectable nanoparticulate olanzapine formulation of the
invention. As used herein, the term "subject" is used to mean an
animal, preferably a mammal, including a human or non-human. The
terms patient and subject may be used interchangeably.
[0131] Examples of disorders that can be treated with olanzapine
include, but are not limited to, schizophrenia and related
psychoses, bipolar mania and/or bipolar disorder, seizures,
obsessive/compulsive disorders, generalized anxiety disorder, post
traumatic distress syndrome, extreme shyness, diabetic nerve pain,
smoking cessation, and depression.
[0132] Particularly advantageous features of the present invention
include that the pharmaceutical formulation of the invention
exhibits a prolonged duration of action that can be controlled upon
administration, and produces minimal or no pain or irritation upon
administration. For example, compositions of the invention can
provide efficacious levels of drug for up to about one week, from
about two to about six weeks, or from about two to about twelve
weeks. In addition, the injectable formulation of the invention can
provide a high olanzapine concentration in a small volume to be
injected. A general protocol for administration thereof comprises
an intramuscular or subcutaneous bolus injection of olanzapine.
[0133] Conventional olanzapine (Zyprexa.RTM.) has a starting single
evening dose of 10 mg. The usual maximum dose should be 20 mg. For
treatment of psychoses, such as schizophrenia, the adult dosage is
5-10 mg/day initially, with a target dose of 10 mg/day within
several days.
[0134] Olanzapine shows mesolimbic sensitivity, blocks conditioned
avoidance at lower doses than those inducing catalepsy, substitutes
for clozapine in a drug discrimination assay, produces a modest
rise in prolactin, produces few extrapyramidal side effects, and
reduces positive and negative symptoms of schizophrenia as
efficaciously as clozapine. However, despite this `atypical`
profile, olanzapine has a weaker alpha-2 blockade than clozapine or
risperidone. It has relatively high affinity for muscarinic, 5HT-2,
and D1, D2 and D4 receptors. Trials suggest a good response in
schizophrenia with few extrapyramidal side effects (EPSEs).
[0135] Compositions suitable for parenteral injection may comprise
physiologically acceptable sterile aqueous or nonaqueous solutions,
dispersions, suspensions or emulsions, and sterile powders for
reconstitution into sterile injectable solutions or dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents,
solvents, or vehicles including water, ethanol, polyols
(propyleneglycol, polyethylene-glycol, glycerol, and the like),
suitable mixtures thereof, vegetable oils (such as olive oil) and
injectable organic esters such as ethyl oleate. Proper fluidity can
be maintained, for example, by the use of a coating such as
lecithin, by the maintenance of the required particle size in the
case of dispersions, and by the use of surfactants.
[0136] The nanoparticulate compositions may also contain adjuvants
such as preserving, wetting, emulsifying, and dispensing agents.
Prevention of the growth of microorganisms can be ensured by
various antibacterial and antifungal agents, such as parabens,
chlorobutanol, phenol, sorbic acid, and the like. It may also be
desirable to include isotonic agents, such as sugars, sodium
chloride, and the like. Prolonged absorption of the injectable
pharmaceutical form can be brought about by the use of agents
delaying absorption, such as aluminum monostearate and gelatin.
[0137] One of ordinary skill will appreciate that effective amounts
of olanzapine can be determined empirically and can be employed in
pure form or, where such forms exist, in pharmaceutically
acceptable salt, ester, or prodrug form. Actual dosage levels of
olanzapine in the nanoparticulate compositions of the invention may
be varied to obtain an amount of olanzapine that is effective to
obtain a desired therapeutic response for a particular composition
and method of administration. The selected dosage level therefore
depends upon the desired therapeutic effect, the route of
administration, the potency of the administered olanzapine, the
desired duration of treatment, and other factors.
[0138] Dosage unit compositions may contain such amounts of such
submultiples thereof as may be used to make up the daily dose. It
will be understood, however, that the specific dose level for any
particular patient will depend upon a variety of factors: the type
and degree of the cellular or physiological response to be
achieved; activity of the specific agent or composition employed;
the specific agents or composition employed; the age, body weight,
general health, sex, and diet of the patient; the time of
administration, route of administration, and rate of excretion of
the agent; the duration of the treatment; drugs used in combination
or coincidental with the specific agent; and like factors well
known in the medical arts.
[0139] The following examples are given to illustrate the present
invention. It should be understood, however, that the spirit and
scope of the invention is not to be limited to the specific
conditions or details described in these examples but should only
be limited by the scope of the claims that follow. All references
identified herein, including U.S. patents, are hereby expressly
incorporated by reference.
Example 1
[0140] The purpose of this example is to illustrate the procedure
for identifying a suitable nanoparticulate formulation of
olanzapine.
[0141] The study can be conducted by screening eleven surface
stabilizers to identify the most suitable stabilizer for parenteral
administration of olanzapine. The dispersions can be formulated at
40% solids to 2.4% surface stabilizer.
TABLE-US-00003 TABLE 2 Surface Stabilizer Plasdone C15 .RTM.
(polyvinylpyrrolidone) Kollidon 17PF .RTM. (a polyvinylpyrrolidone
polymer) Povidone K30 .RTM. (a polyvinylpyrrolidone polymer)
Tyloxapol Pluronic F68 .RTM. (a high molecular weight
polyoxyalkylene ether) Pluronic F108 .RTM. (a high molecular weight
polyoxyalkylene ether) Tween 80 .RTM. (a polyoxyethylene sorbitan
fatty acid ester) dioctylsulfosuccinate (CAS No. 577-11-7; aka
Docusate Sodium) B20-5000 .RTM. (a triblock copolymer surface
modifier) B20-5000-sulfonated (a triblock copolymer surface
modifier) lecithin (CAS No. 8002-43-5) Povidone K30 .RTM. and
Pluronic F108 .RTM.
[0142] Such combinations may produce stable dispersions of
differing nanoparticulate size that will have differing durations
of action when administered. Preclinical and clinical studies will
identify the optimum formulation and size associated with the
desired prolonged duration of action.
Example 2
[0143] The purpose of this example was to prepare a nanoparticulate
formulation of olanzapine.
[0144] The particle size of olanzapine drug crystals was first
measured prior to incorporation into a nanoparticulate formulation.
The particle size, as measured using a Horiba LA 910 particle size
analyzer (Horiba Instruments, Irvine, Calif.), was a mean of 137.08
microns, and a D90 of less than 335.59 microns. See FIG. 1.
[0145] An aqueous dispersion of 10% olanzapine (Camida LLC, Newark,
N.J.), combined with 1% Tween 80, 0.1% benzalkonium chloride, and
20% dextrose, was milled in a NanoMing 0.01 (Elan Drug Delivery),
along with 500 micron PolyMill.RTM. grinding media (Dow Chemical)
(50-89% media load). The mixture was milled at a speed of 1009-5500
rpms, at a temperature of 5-10.degree. C., for about 30 min.
[0146] Following milling, the particle size of the milled
olanzapine particles was measured, in deionized distilled water,
using a Horiba LA 910 particle size analyzer. The median milled
olanzapine particle size was 347 nm, with a mean size of 606 nm, a
D90 of 1.28 microns, and a D83 of less than 1 micron. See FIG.
2.
Example 3
[0147] The purpose of this example was to prepare a nanoparticulate
formulation of olanzapine.
[0148] An aqueous dispersion of 30% olanzapine (Camida LLC, Newark,
N.J.), combined with 2.5% Tween 80, was milled in a NanoMill.RTM.
0.01 (Elan Drug Delivery), along with 500 micron PolyMill.RTM.
grinding media (Dow Chemical) (50-89% media load). The mixture was
milled at a speed of 1009-5500 rpms, at a temperature of
5-10.degree. C., for about 30 min.
[0149] Following milling, the particle size of the milled
olanzapine particles was measured, in deionized distilled water,
using a Horiba LA 910 particle size analyzer. The median milled
olanzapine particle size was 990 nm, with a mean size of 1.136 nm,
a D90 of 2.07 microns, and a D50 of less than 1 micron. See FIG.
3.
Example 4
[0150] The purpose of this example was to determine the in vivo
characteristics of the nanoparticulate olanzapine formulation
prepared in Example 2.
[0151] An in vivo study, utilizing male beagle dogs, was conducted
to determine the therapeutic levels of olanazapine present in vivo
over a period of time following intramuscular (IM) administration
of the nanoparticulate olanazapine formulation prepared in Example
2. Six dogs were given a single intramuscular dose of 10 mg/kg
(about 100 mg/animal), which is about 10.times. the daily dose in
humans. Blood samples were taken at t=0, 0.5, 1, 2, 4, 8, 24, and
49 hours post administration, and 4, 7, 14, and 28 days post
administration. The plasma concentration (ng/ml) over a 168 hr
period is shown in FIG. 4. As shown in FIG. 4, therapeutic levels
of olanzapine, of 5 to 22 ng/ml, were present in vivo for over a
168 hr period. FIG. 5 further demonstrates that for all animals
dosed, therapeutic levels of olanzapine, of 5 to 22 ng/ml, were
present in vivo for over a 168 hr period.
[0152] In addition to demonstrating that the injectable olazapine
formulations of the invention produce measurable and detectable
levels of drug in the plasma for more than seven days following
administration, this example further demonstrates: (1) that the
olanzapine formulation prepared as in Example 2 is syringeable with
a 23 gauge needle; and (2) that the olanzapine formulation prepared
as in Example 2 is well tolerated by mammals.
[0153] It will be apparent to those skilled in the art that various
modifications and variations can be made in the methods and
compositions of the present invention without departing from the
spirit or scope of the invention. Thus, it is intended that the
present invention cover the modifications and variations of this
invention provided they come within the scope of the appended
claims and their equivalents.
* * * * *