U.S. patent number RE41,884 [Application Number 12/027,100] was granted by the patent office on 2010-10-26 for reduction of intravenously administered nanoparticulate-formulation-induced adverse physiological reactions.
This patent grant is currently assigned to Elan Pharma International Limited. Invention is credited to Lawrence de Garavilla, Elaine Liversidge, Gary G. Liversidge.
United States Patent |
RE41,884 |
de Garavilla , et
al. |
October 26, 2010 |
Reduction of intravenously administered
nanoparticulate-formulation-induced adverse physiological
reactions
Abstract
Disclosed are methods of intravenous administration of
nanoparticulate drug formulations to a mammal to avoid adverse
hemodynamic effects: by reducing the rate and concentration of the
nanoparticles in the formulations; or by pre-treating the subject
with histamine; or by pretreating the subject with a desensitizing
amount of the nanoparticulate drug formulations.
Inventors: |
de Garavilla; Lawrence
(Downington, PA), Liversidge; Elaine (West Chester, PA),
Liversidge; Gary G. (West Chester, PA) |
Assignee: |
Elan Pharma International
Limited (Co. Clare, IR)
|
Family
ID: |
26673068 |
Appl.
No.: |
12/027,100 |
Filed: |
February 6, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60004488 |
Sep 29, 1995 |
|
|
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Reissue of: |
08696754 |
Aug 14, 1996 |
05834025 |
Nov 10, 1998 |
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Current U.S.
Class: |
424/501; 264/4.3;
977/904; 428/402.21; 977/700; 424/502 |
Current CPC
Class: |
A61K
9/0019 (20130101); B82Y 5/00 (20130101); A61K
9/146 (20130101); A61K 45/06 (20130101); Y10T
428/2985 (20150115) |
Current International
Class: |
A61K
9/50 (20060101); B01J 13/02 (20060101); B32B
5/16 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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3722837 |
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Jan 1989 |
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DE |
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0233559 |
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May 1992 |
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EP |
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|
Primary Examiner: Azpuru; Carlos A
Attorney, Agent or Firm: Wenderoth, Lind & Ponack,
L.L.P.
Parent Case Text
BACKGROUND OF THE INVENTION
This application claims the benefit under 35 USC 119(e) of
Provisional Application Number 60/004,488 filed Sep. 29, 1995.
Claims
What is claimed is:
1. A method of administering a nanoparticulate composition to a
mammal without eliciting adverse hemodynamic effects comprising
intravenously administering to said mammal an effective amount of a
nanoparticulate drug composition at .[.an infusion rate not
exceeding.]. .Iadd.a solids dose rate of less than .Iaddend.10
mg/min, wherein said drug composition comprises: (a) particles
consisting essentially of from about 0.1 to about 99.9% by weight
of a crystalline organic drug substance having a solubility in
water of less than 10 mg/ml; (b) a surface modifier adsorbed on the
surface of the drug substance in an amount of from about 0.1 to
about 99.9% by weight and sufficient to maintain an effective
average particle size of from about 50 nm to about 1000 nm; and (c)
a pharmaceutically acceptable carrier therefor.
2. The method of claim 1 wherein the effective average particle
size of said drug is from about 50 to about 400 nm.
3. The method of claim 1 wherein said drug is an organic
therapeutic substance.
4. The method of claim 1 wherein said drug is a diagnostic
agent.
5. A method of administering a nanoparticulate composition to a
mammal without eliciting adverse hemodynamic effects comprising:
(a) intravenously administering to said mammal an antihistamine in
the amount of from about 5 to about 10 mg/kg of body weight; and
(b) subsequently intravenously administering to said mammal an
effective amount of a nanoparticulate drug composition comprising:
(1) particles consisting essentially of from about 0.1 to about
99.9% by weight of a crystalline drug substance having a solubility
in water of less than 10 mg/ml; and (b 2) a surface modifier
adsorbed on the surface of the drug substance in an amount of from
about 99.9 to about 0.1% by weight and sufficient to maintain an
effective average particle size of less than about 1000 nm.
6. The method of claim 5 wherein the effective average particle
size of said drug is .[.of.]. from about 50 to about 400 nm.
7. The method of claim 5 wherein said drug is an organic
therapeutic substance.
8. The method of claim 5 wherein said drug is a diagnostic
agent.
9. A method of administering a nanoparticulate composition to a
mammal without eliciting adverse hemodynamic effects comprising:
(a) intravenously administering to said mammal a desensitizing
amount of a nanoparticulate drug composition at .[.an infusion rate
not exceeding.]. .Iadd.a solids dose rate of less than .Iaddend.10
mg/min; and (b) intravenously administering an effective amount of
said nanoparticulate composition comprising: (1) particles
consisting essentially of from about 0.1 to about 99.9% by weight
of a crystalline organic drug substance having a solubility in
water of less than 10 mg/ml; (2) a surface modifier adsorbed on the
surface of the drug substance in an amount sufficient to maintain
an effective average particle size of from about 100 to about 1000
nm; and (3) a pharmaceutically acceptable carrier therefor.
10. The method of claim 9 wherein said drug is an organic
therapeutic substance.
11. The method of claim 9 wherein said drug is a diagnostic
agent.
12. The method of claim 9 wherein the effective average particle
size of said drug is .[.of.]. from about 100 to about 400 nm.
13. A method of administering a nanoparticulate composition to a
mammal without eliciting adverse hemodynamic effects comprising
intravenously administering to said mammal an effective amount of a
nanoparticulate drug composition at .[.an infusion rate not
exceeding.]. .Iadd.a solids dose rate of less than .Iaddend.10
mg/min, wherein said drug composition comprises: (a) particles
having an effective average particle size of from about 50 to about
1000 nm and consisting essentially of from about 0.1 to about 99.9%
by weight of an organic drug substance entrapped in from about 99.9
to about 0.1% by weight of liposome or a colloidal polymeric
material; and (b) a pharmaceutically acceptable carrier
therefor.
14. The method of claim 13 wherein the effective average particle
size of said drug is .[.of.]. from about 50 to about 400 nm.
15. The method of claim 13 wherein said drug is an organic
therapeutic substance.
16. The method of claim 13 wherein said drug is a diagnostic
agent.
17. A method of administering a nanoparticulate composition to a
mammal without eliciting adverse hemodynamic effects comprising:
(a) intravenously administering to said mammal an antihistamine in
the amount of from about 5 to about 10 mg/kg of body weight; and
(b) subsequently intravenously administering to said mammal an
effective amount of a nanoparticulate drug composition comprising:
(1) particles having an effective average particle size of from
about 50 to .[.bout.]. .Iadd.about .Iaddend.1000 nm and consisting
essentially of from about 0.1 to about 99.9% by weight of an
organic drug substance entrapped in from about 99.9 to about 0.1%
by weight of liposome or a colloidal polymeric material; and (2) a
pharmaceutically acceptable carrier therefor.
18. The method of claim 17 wherein the effective average particle
size of said drug is .[.of.]. from about 50 to about 400 nm.
19. The method of claim 17 wherein said drug is an organic
therapeutic substance.
20. The method of claim 17 wherein said drug is a diagnostic
agent.
.Iadd.21. The method of claim 13 wherein the organic drug substance
is in crystalline phase. .Iaddend.
.Iadd.22. The method of claim 17 wherein the organic drug substance
is in crystalline phase. .Iaddend.
.Iadd.23. The method of claim 1 wherein the solids dose rate is 5
mg/min. .Iaddend.
.Iadd.24. The method of claim 9 wherein the solids dose rate is 5
mg/min. .Iaddend.
.Iadd.25. The method of claim 13 wherein the solids dose rate is 5
mg/min. .Iaddend.
.Iadd.26. The method of claim 1 wherein said drug is selected from
the group consisting of anti-inflammatory agents, anti-arrhythmic
agents, antibiotics, anticoagulants, antidepressants, antidiabetic
agents, antiepileptics, antihistamines, antihypertensive agents,
antimuscarinic agents, antimycobactehal agents, antineoplastic
agents, immunosuppressants, antithyroid agents, antiviral agents,
anxiolytic sedatives, beta-adrenoceptor blocking agents, cardiac
inotropic agents, contrast media, corticosteroids, dopaminergics,
haemostatics, lipid regulation agents, muscle relaxants,
parasympathomimetics, parathyroid calcitonin and biphosphonates
prostaglandins, anti-allergic agents, anoretics, thyroid agents,
vasodilators and xanthines. .Iaddend.
.Iadd.27. The method of claim 5 wherein said drug is selected from
the group consisting of anti-inflammatory agents, anti-arrhythmic
agents, antibiotics, anticoagulants, antidepressants, antidiabetic
agents, antiepileptics, antihistamines, antihypertensive agents,
antimuscarinic agents, antimycobactehal agents, antineoplastic
agents, immunosuppressants, antithyroid agents, antiviral agents,
anxiolytic sedatives, beta-adrenoceptor blocking agents, cardiac
inotropic agents, contrast media, corticosteroids, dopaminergics,
haemostatics, lipid regulation agents, muscle relaxants,
parasympathomimetics, parathyroid calcitonin and biphosphonates
prostaglandins, anti-allergic agents, anoretics, thyroid agents,
vasodilators and xanthines. .Iaddend.
.Iadd.28. The method of claim 9 wherein said drug is selected from
the group consisting of anti-inflammatory agents, anti-arrhythmic
agents, antibiotics, anticoagulants, antidepressants, antidiabetic
agents, antiepileptics, antihistamines, antihypertensive agents,
antimuscarinic agents, antimycobacterial agents, antineoplastic
agents, immunosuppressants, antithyroid agents, antiviral agents,
anxiolytic sedatives, beta-adrenoceptor blocking agents, cardiac
inotropic agents, contrast media, corticosteroids, dopaminergics,
haemostatics, lipid regulation agents, muscle relaxants,
parasympathomimetics, parathyroid calcitonin and biphosphonates,
prostaglandins, anti-allergic agents, anoretics, thyroid agents,
vasodilators and xanthines. .Iaddend.
.Iadd.29. The method of claim 13 wherein said drug is selected from
the group consisting of anti-inflammatory agents, anti-arrhythmic
agents, antibiotics, anticoagulants, antidepressants, antidiabetic
agents, antiepileptics, antihistamines, antihypertensive agents,
antimuscarinic agents, antimycobacterial agents, antineoplastic
agents, immunosuppressants, antithyroid agents, antiviral agents,
anxiolytic sedatives, beta-adrenoceptor blocking agents, cardiac
inotropic agents, contrast media, corticosteroids, dopaminergics,
haemostatics, lipid regulation agents, muscle relaxants,
parasympathomimetics, parathyroid calcitonin and biphosphonates,
prostaglandins, anti-allergic agents, anoretics, thyroid agents,
vasodilators and xanthines. .Iaddend.
.Iadd.30. The method of claim 17 wherein said drug is selected from
the group consisting of anti-inflammatory agents, anti-arrhythmic
agents, antibiotics, anticoagulants, antidepressants, antidiabetic
agents, antiepileptics, antihistamines, antihypertensive agents,
antimuscarinic agents, antimycobacterial agents, antineoplastic
agents, immunosuppressants, antithyroid agents, antiviral agents,
anxiolytic sedatives, beta-adrenoceptor blocking agents, cardiac
inotropic agents, contrast media, corticosteroids, dopaminergics,
haemostatics, lipid regulation agents, muscle relaxants,
parasympathomimetics, parathyroid calcitonin and biphosphonates,
prostaglandins, anti-allergic agents, anoretics, thyroid agents,
vasodilators and xanthines. .Iaddend.
.Iadd.31. The method of claim 26 wherein said drug is selected from
the group consisting of antibiotics, antimicrobials,
antineoplastics and immunosuppresants. .Iaddend.
.Iadd.32. The method of claim 27 wherein said drug is selected from
the group consisting of antibiotics, antimicrobials,
antineoplastics and immunosuppresants..Iaddend.
.Iadd.33. The method of claim 28 wherein said drug is selected from
the group consisting of antibiotics, antimicrobials,
antineoplastics and immunosuppresants..Iaddend.
.Iadd.34. The method of claim 29 wherein said drug is selected from
the group consisting of antibiotics, antimicrobials,
antineoplastics and immunosuppresants..Iaddend.
.Iadd.35. The method of claim 30 wherein said drug is selected from
the group consisting of antibiotics, antimicrobials,
antineoplastics and immunosuppresants. .Iaddend.
Description
FIELD OF THE INVENTION
The present invention is directed to nanoparticulate, liposome,
emulsion and polymeric colloidal drug formulations for intravenous
administration, the delivery of which to a mammal,
reduces/eliminates the adverse physiological effects. More
particularly, the invention relates to a method of intravenous
nanoparticulate, liposome, emulsion and polymeric colloidal drug
formulations to a mammal, wherein the rate of infusion and
concentration of the drug is controlled.
Reported Developments
Nanoparticles are well know in the prior art, having been
described, for example, in U.S. Pat. No. 5,145,684. These particles
consist of a crystalline drug substance having a surface modifier
adsorbed on the surface of the particles such that the average
particle size is less than about 400 mm. Low solubility of solid
drugs prompted the pharmaceutical industry to create nanoparticles
of such drugs which then can be administered systematically to
provide bioavailability. Drug substances disclosed which can be
made into nanoparticles include a variety of known classes of
drugs.
In order to provide nanometer-size particles, the drug substance is
comminuted in the presence of a surface active agent or,
alternatively, the surface active agent is allowed to be adsorbed
to the nanoparticulate drug substance after the process of
comminution. The surface active agent prevents flocculation or
congregation of the nanoparticles. The achievements of
nanoparticulate technology in the pharmaceutical industry affords
the opportunity to prepare parenteral formulations of
water-insoluble or poorly water-soluble drugs. These formulations
by their nature are suspensions rather than solutions since the
particles are dispersed/suspended in a pharmaceutically acceptable
vehicle. Liposomes, emulsions and colloids when used as carriers
for an active drug are also suspensions rather than solutions.
We have observed that intravascular adminstration of a suspensions
to dogs causes significant cardiovascular dysfunction, such as
reduction in arterial blood pressure and cardiac function,
including heart rate cardiac output and ventricular
contractility.
Other investigators have reported similar findings, for example:
Slack et al., Acute Hemadynamic Effects and Blood Pool Kinetics of
Polystyrene Microspheres Following Intravenous Administration, J.
Pharm. Sci., 660, 1981; Faithfull et al., Cardiorespiratory
Consequences of Flurocarbon Reactions in Dogs, Bio. Art. Organs, 1,
1988; and Lorenz et al, Histamine Release in Dogs by Cremophore EL
and its Derivatives, Agents and Actions, 63, 1977.
It has now been discovered that hemodynamic effects of suspensions
can be eliminated or at least substantially reduced by controlling
the rate of infusion and/or the concentration of the active drug in
the suspensions.
The present invention will be described particularly in reference
to nanoparticulate crystalline drug formulations, however, the
invention encompasses the use of other carriers for active drugs
that do not form a solution but rather a suspension or dispersion
having nanoparticulates in the range of less than 1000 nm.
SUMMARY OF THE INVENTION
This invention provides a method of administering a nanoparticulate
composition to a mammal such as a dog or other sensitive species
without eliciting adverse hemodynamic effects comprising:
intravenously administering to said dog an effective amount of a
nanoparticulate drug composition at .[.an infusion.]. .Iadd.a
solids dose .Iaddend.rate not exceeding 10 mg/min comprising
particles consisting essentially of from about 0.1 to about 99.9%
by weight of a crystalline organic drug substance having a
solubility in water of less than 10 mg/ml, said drug substance
having a surface modifier adsorbed on the surface thereof in an
amount of 0.1-99.9% by weight and sufficient to maintain an
effective average particle size of from about 50 to about 1000 nm,
and a pharmaceutically acceptable carrier therefor.
In another embodiment, the present invention provides a method of
administering a nanoparticulate composition to a mammal such as a
dog or other sensitive species without eliciting adverse
hemodynamic effects comprising:
intravenously administering to said dog an antihistamine including
H1, H2 and H3 receptor antagonists in the amount of form about 5 to
about 10 mg/kg of body weight, such as diphenhydramine, cimetidine
or thioperamide or a combination thereof followed by intravenously
administering to said dog an effective amount of a nanoparticulate
drug composition comprising particles consisting essentially of
from about 0.1 to about 99.9% by weight of a crystalline drug
substance having a solubility in water of less than 10 mg/ml, said
drug substance having a surface modifier adsorbed on the surface
thereof in an amount of 0.1-99.0% by weight and sufficient to
maintain an effective average particle size of less than 1000 nm,
and preferably less than about 400 nm, and a pharmaceutically
acceptable carrier thereof.
In still another embodiment the present invention provides a method
of administering a nanoparticulate composition to a mammal, such as
a dog or other sensitive species without eliciting adverse
hemodynamic effects comprising: intravenously administering to said
mammal a desensitizing amount of a nanoparticulate drug composition
at .[.an infusion.]. .Iadd.a solids dose .Iaddend.rate not
exceeding 10 mg/min, followed by intravenous administration of an
effective amount of said nanoparticulate composition comprising
particles consisting essentially of from about 0.1 to about 99.9%
by weight of a crystalline organic drug substance having a
solubility in water of less than 10 mg/ml, said drug substance
having a surface modifier adsorbed on the surface thereof in an
amount sufficient to maintain an effective average particle size of
from 50 to 1000 nm, and a pharamceutically acceptable carrier
therefor.
In a liposome- or colloidal-drug delivery system, the bioactive
drug is entrapped in the liposome or colloidal particles in an
amount of from about 0.1 to about 99.9 to about 99.1 to about 0.1%
by weight liposome or colloidal particles, such particles having a
particle size of less than 1000 mm, and then administered to the
patient to be treated.
As used herein, the term "desensitizing amount" means a dose low
enough so as not to elicit a response but still acutely
precondition the mammal so that a subsequent injection of a full
dose will now be without effect.
Also, as used herein, mammal preferably means a dog and other
sensitive species including human species.
DETAILED DESCRIPTION OF THE INVENTION
Nanoparticulate formulations cause a significant transient decrease
in arterial blood pressure immediately following intravenous
injection in anesthetized dogs. Extensive studies were conducted to
evaluate the acute hemodynamic effects of intravenously
administered nanoparticles. To eliminate effects which may be
caused by an active drug, inert polystyrene nanoparticles were used
in the studies. Parameters were monitored throughout the studies
including mean arterial pressure, heart rate, mean pulmonary
arterial pressure, left ventricular systolic pressure, temperature,
blood chemistry and hematology. In order to distinguish and
separate the effects arising from components of nanoparticulate
formulations, the effects of intravenous injections of: inert
polystyrene nanoparticles, surfactant-coated polystyrene
nanoparticles and surfactant alone were used in separate groups of
dogs in the studies.
STUDY DESIGN/METHODS
A. Animals
Mongrel dogs of either sex weighing between 13 and 16 kg were used
in these studies. Dogs were acquired form Butler Farms (Clyde,
N.Y.) and allowed at least a two week acclimation period following
shipment and prior to conducting these studies.
B. Anesthesia and Surgical Preparation
Dogs were anesthetized with sodium pentobarbital (30 mg/kg, i.v.).
Following surgical preparation, the dogs were placed on an infusion
of sodium pentobarbital (4 mg/kg/hr) to maintain an adequate,
constant level of anesthesia throughout the experimental protocol.
All anesthetic injections were administered via a 20 gauge
percutaneous venicatheter placed in the right cephalic vein.
Following induction of anesthesia, dogs were placed in dorsal
recumbency and intubated with a 7 French endotracheal tube and
allowed to breathe room air. (Core temperature, as measured using a
thermistor probe inserted 6 cm into the colon, was maintained
between 37.5.degree. and 38.5.degree. C. using a thermostatically
controlled heating pad (Harvard Homeothermic Heating Blanket,
Harvard Instruments, Natick, Mass.).
The right carotid artery, right femoral artery, and the right and
left femoral veins were surgically isolated via percutaneous
incisions and blunt dissection. A high fidelity, solid state, dual
sensor pressure transducer catheter (Model SPC 784A, Millar
Instruments, Houston, Tex.) was advanced retrograde from the
carotid artery and placed into the left ventricular chamber of the
heart The distal pressure sensor, positioned in the left ventricle,
was used to measure intraventricular pressure and the proximal
sensor, positioned at the root of the aorta, measured intra-aortic
pressure. The pulsatile left ventricular pressure (LVP) signal was
electronically differentiated (dP/dt) to acquire an estimate of
cardiac contractility (LV dP/dt). Heart rate (HR) was also derived
from the pulsatile LVP signal. Mean arterial blood pressure (MAP)
was derived form the pulsatile signal of intraaortic pressure.
Another fluid-filled catheter was placed in the right femoral
artery for acquisition of arterial blood samples for blood gas
measurements. Arterial blood pH, PCO.sub.2 and .sub.pO.sub.2 were
measured on freshly drawn samples using an automated blood gas
analyzer (Model ABL30, Radiometer Corp., Westlake, Ohio). Platinum
pin electrodes were inserted subcutaneously to monitor lead II
electrocardiogram. All particles were injected in the left cephalic
vein via a 20 gauge percutaneous venicatheter.
Following surgical preparation and instrumentation, the dogs were
allowed a 30 minute acclimation period prior to initiation of the
test.
C. Data Acquisition and Analysis
The following variables were continuously recorded on a pc-based
automated data acquisition system (Modular Instruments, Inc.,
Malvern, Pa.): Mean arterial blood pressure (MAP; mmHg) Heart rate
(HR; min.sup.-1) Mean pulmonary arterial blood pressure (PAP; mmHg)
Left ventricular systolic blood pressure (LVP.sub.sys; mmHg)
Maximum left ventricular dP/dt (+LV dP/dt mmHg sec.sup.-1) Maximum
left ventricular dP/dt (-LV dP/dt mmHg sec.sup.-1)
The following variable were mathematically derived from the above
variables and cardiac output (CO; L min.sup.-1): Systemic arterial
vascular resistance (SVR; calculated as MAP/CO; mmHg L.sup.-1 min)
Pulmonary vascular resistance (PVR; calculated as PAP/CO; mmHg
L.sup.-1 min) Stroke volume (SV; calculated as CO/HR.1000; cc).
Data were down-loaded onto a PC-based statistical package CRUNCH
(Crunch Software Corporation, Oakland, Calif.). An analysis of
variance followed by a Dunnett's comparison was used to test the
effect of dose within each group. Between group effects (WIN 8883
vs. vehicle) were analyzed using a t-test. In all cases, data are
expressed as mean.+-.s.c.
D. Drugs and Solutions
Polystyrene Particles (Surfactant Coated)
Polystyrene particles having a diameter of 200 nm were obtained
form Polysciences, Inc.
1) The Vehicle (Placebo)
A 10% solution of F108 was made by weighing out 1 g of F108 in a 50
ml plastic beaker and then adding 8 ml of water (Sterile water for
injection--SWFI) to the surfactant. The beaker was placed in the
refrigerator until the surfactant had gone into solution. SWIF was
added to bring the final volume to 10 mls which was then filtered
with a 0.1 .mu.m syringe filter before use.
2) 5% Polystyrene Particles (PSP)+5% F108
To prepare 20 mls of 5% PSP+5% F108, 10 mls of the 200 nm particles
were added to 10 mls of 10% F108 in a 50 ml centrifuge tube. The
tube was placed on a mutator and the suspension was allowed to mix
for 1 hour. Solutions were also prepared with 100 and 50 nm
particle size polystyrene particles.
3) 5% WIN 8883+5% P108
The suspension of 5% WIN 8883+5% F108 was prepared analogously to
the 5% Polystyrene+5% F108 suspension shown in #2.
4) Supernatant of 5% WIN 8883
Supernatant of WIN 8883 was prepared by centrifugation of a sample
of WIN 8883 at 20,000 g for 1 hour, followed by recentrifugation of
the decanted supernatant 5% WIN 8883. No WIN 8883 was found in the
decanted solution.
5) Supernatant of 5% Polystyrene+5% F108
The supernatant was prepared analogously to that shown in #4. No
polystyrene was found in the supernatant.
The preparations of #1, #2, #3, #4 and #5 were administered to
groups of dogs subcutaneously and intravenously at various dose
levels described below. Baseline hemodynamics were recorded for a
10 minute period just prior to administration of the preparations.
Following administration of the preparation each dog was monitored
60 minutes.
E. Results
Results of testing are shown in the following tables.
TABLE-US-00001 TABLE 1 Effect of the vehicle 5% F108 and a
particulate-free supernatant on the hemodynamic and hematological
response in dogs when infused at a rate of 5 ml/min and a dose of
0.1 ml/kg. Values listed as means .+-. S.E. % Change from Baseline
Treatment N MAP #5% F108 4 -1 .+-. 1 #5 Supernatant 3 -1 .+-. 1
wherein: N = no. of dogs MAP = Mean Arterial Blood Pressure
TABLE-US-00002 TABLE 2 Effect of uncoated and F108 (5%) coated 200
.[.nM.]. .Iadd.nm.Iaddend. diameter polystyrene nanospheres, 5%
suspension, infused at a rate of 1 ml/min and a dose of 0.1 ml/kg
on the hemodynamic and a hematological response in dogs. Values
listed as means .+-. S.E. % Change from Baseline Treatment N MAP #4
Uncoated 3 -1 .+-. 1 #3 Coated 4 -50 .+-. 7 wherein: N = no. of
dogs MAP = Mean Arterial Blood Pressure
TABLE-US-00003 TABLE 3 Effect of rate of infusion of 200 .[.nM.].
.Iadd.nm.Iaddend. diameter polystyrene nanospheres on the
hemodynamic and hematological response in dogs. Each formulation
was prepared as a 1% (w:v) suspension in a solution of 5% F108 and
administered intravenously at a dose of 0.1 ml/kg. Values listed as
means .+-. S.E. Rate % Change from Baseline (ml/min) N MAP 5 3 -39
.+-. 15 1 4 -26 .+-. 5 0.5 3 -5 .+-. 1 wherein: N = no. of dogs MAP
= Mean Arterial Blood Pressure
TABLE-US-00004 TABLE 4 Effect of rate of infusion of 200 .[.nM.].
.Iadd.nm.Iaddend. diameter polystyrene nanospheres on the
hemodynamic and hematological response in dogs. Each formulation
was prepared as a 5% (w:v) suspension in a solution of 5% F108 and
administered intravenously at a dose of 0.1 ml/kg. Values listed as
means .+-. S.E. Rate % Change from Baseline (ml/min) N MAP 1 4 -50
.+-. 7 0.1 3 -1 .+-. 1 wherein: N = no. of dogs MAP = Mean Arterial
Blood Pressure
TABLE-US-00005 TABLE 5 Effect of pretreatment with antihistamines
on the hemodynamic and hematological response in dogs following
ontravenous administration of a 1% (w:v) suspension of polystyrene
nanospheres, 200 .[.nM.]. .Iadd.nm.Iaddend. in diameter in a 5%
solution of F108 at a dose of 0.1 ml/kg and a rate of 5 ml/min.
Values listed as means .+-. S.E. % Change from Baseline
Antihistamine N MAP None 3 -39 .+-. 15 Diphenhydramine 10 mg/kg 4
-7 .+-. 1 Cirnetidine 5 mg/kg Diaphenhydramine 10 mg/kg 3 -4 .+-. 2
Cimetifine 5 mg/kg Thioperamide 5 mg/kg wherein: N = no. of dogs
MAP = Mean Arterial Blood Pressure
TABLE-US-00006 TABLE 6 Effect of particle size on the hemodynamic
and hematological response in dogs. Each formulation was prepared
as a 1% (w:v) suspension in a 5% solution of F108 and administered
intravenously at a dose of 0.1 ml/kg and a rate of 5 ml/min. Values
listed as means .+-. S.E. Diameter % Change from Baseline .[.nM.].
.Iadd.nm.Iaddend. N MAP 200 3 -39 .+-. 15 100 4 -26 .+-. 14 50 3 -8
.+-. 5 wherein: N = no. of dogs MAP = Mean Arterial Blood
Pressure
TABLE-US-00007 TABLE 7 % Solids Infusion Rate Solids Dose Rate
Response (w/v) (ml/min) .[.(mg/ml/min).]. .Iadd.(mg/min).Iaddend. Y
or N 5 (50 mg/ml) 1 50 Y 1 (10 mg/ml) 10 100 Y 1 (10 mg/ml) 5 50 Y
1 (10 mg/ml) 1 10 Y 5 (50 mg/ml) 0.1 5 N .[.10 ng/ml.]. 0.5 5 N
.Iadd.1 (10 mg/ml).Iaddend.
The studies indicate that there is a critical set of parameters
which control hemodynamic effects in dogs. To avoid overt
deleterious hemodynamic effects the following parameters should be
controlled:
1) The vehicle-surfactant administered alone does not initiate a
hemodynamic response.
2) "uncoated" polystyrene nanoparticles administered at a dose of
0.1 ml/kg of body weight and a rate of 1 ml/min does not induce
hemodynamic effect. However, "uncoated" nano-particle drugs cannot
be administered safely, since they coagulate/flocculate causing
deleterious side effects. Accordingly, active drugs must be
surfactant coated to circumvent coagulation/flocculation of the
nanoparticles.
3) Hemodynamic effect is associated with the surfactant-particle
combination. While the inventors would not want to be limited to a
theory of mechanism in the practice of their invention, it appears
that the particles act as carrier for the surfactant, delivering it
to its site of action in the blood stream. Theoretically, the
uncoated particle also accesses the site of action but cannot
initiate the response in the absence of the surfactant. Conversely,
in the absence of particles, the surfactant also cannot access the
site of action and does not initiate the response.
4) At a concentration of 1% solids, at 0.1 ml/kg and at infusion
rate of 10 ml/min hemodynamic effects occur. At 5 ml/min delivery
of the hemodynamic effect was about half of that of the 10 ml/min
infusion.
5) At particle size of less than about 100 nm no hemodynamic effect
occurs, while hemodynamic effect increases from 100 nm to 200 nm
particle size and above 200 nm particle size.
6) Pretreatment with antihistamines to avoid hemodynamic effects.
Plasma histamine levels appear to be elevated during the response.
Thus the ability to block the effects of histamine at its receptor
site can block the response or at least mitigate it.
Based on these and other studies the present invention provides
methods which can be utilized to deliver effective amounts of drugs
without eliciting adverse hemodynamic effects in dogs. The drug
formulations and their methods of preparations will now be
described.
Drugs
The particles comprise a therapeutic or diagnostic agent,
(therapeutic agents are sometimes referred to as drugs or
pharmaceuticals. The diagnostic agent referred to is typically a
contrast agent such as an x-ray contrast agent but can also be
other diagnostic materials.) The therapeutic or diagnostic agent
exists as a discrete, crystalline phase. The crystalline phase
differs from a non-crystalline or amorphous phase which results
from precipitation techniques, such as described in EPO
275,796.
The invention can be practiced with a wide variety of therapeutic
or diagnostic agents. The therapeutic or diagnostic agent
preferably is present in an essentially pure form. The therapeutic
or diagnostic agent must be poorly soluble and dispersible in at
least one liquid medium. By "poorly soluble" it is meant that the
therapeutic or diagnostic agent has a solubility in the liquid
dispersion medium of less than about 10 mg/ml, and preferably of
less than about 1 mg/ml. A preferred liquid dispersion medium is
water. However, the invention can be practiced with other liquid
media in which a therapeutic or diagnostic agent is poorly soluble
and dispersible including, for example, aqueous salt solutions,
safflower oil and solvents such as ethanol, t-butanol, hexane and
glycol. The pH of the aqueous dispersion media can be adjusted by
techniques known in the art.
Suitable therapeutic or diagnostic agents can be selected from a
variety of known classes of therapeutic or diagnostic agents
including, for example, anti-inflammatory agents, 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,
anxiolytic sedatives (hypnotics and neuroleptics),
beta-adrenoceptor blocking agents, cardiac inotropic agents,
contrast media, corticosteroids, diagnostic agents, diagnostic
imaging agents, dopaminergics (antiparkinsonian agents),
haemostatics, immuniological 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. A description of these classes of therapeutic agents and
diagnostic agents and a listing of species within each class can be
found in Martindale, The Extra Pharmacopoeia, Twenty-ninth Edition,
The Pharmaceutical Press, London, 1989. The therapeutic or
diagnostic agents are commercially available and/or can be prepared
by techniques known in the art.
Preferred diagnostic agents include the x-ray imaging agent
WIN-8883 (ethyl 3,5-diacetamido-2,4,6triiodobenzoate) also known as
the ethyl ester of diatrazoic acid (EEDA), WIN 67722, i.e.,
(6-ethoxy-6-oxohexyl-3,5-bis(acetamido)- 2,4,6-triiodobenzoate;
ethyl-2-(3,5-bis (acetamido)-2,4,6-triiodobenzoyloxy)butyrate (WIN
16318); ethyl diatrizoxyacetate (WIN 12901); ethyl
2-(3,5bis(acetamido)-2,4,6-triiodobenzoyloxypropionate (WIN 16923);
N-ethyl 2-(3,5-bis(acetamido)-2,4,6triiodobenzoyloxy acetamide (WIN
65312); isopropyl 2(3,5-bis(acetamido)-2,4,6-triiodobenzoyloxy)
acetamide (WIN 12855); diethyl
2-(3,5-bis(acetamido)-2,4,6triiodobenzoyloxy malonate (WIN 67721);
ethyl 2-(3,5bis (acetamido)-2,4,6-triiodobenzoyloxy) phenylacetate
(WIN 67585); propanedioic acid,
3,5-bis(acetylamino)2,4,5-triodobenzoyl]oxy]-,bis(1-methyl)ester
(WIN 68165); and benzoic acid, 3,5-bis(acetylamino) 2,4,6triodo-,
4-(ethyl-3ethoxy-2-butenoate) ester (WIN 68209). Suitable
diagnostic agents are also disclosed in U.S. Pat. No. 5,260,478;
U.S. Pat. No. 5,264,610; U.S. Pat. No. 5,322,679 and U.S. Pat. No.
5,300,739.
Preferred contrast agents include those which are expected to
disintegrate relatively rapidly under physiological conditions,
thus minimizing any particle associated inflammatory response.
Surface Modifiers
Suitable surface modifiers can preferably be selected from known
organic and inorganic pharmaceutical excipients. Such excipients
include various polymers, low molecular weight oligomers, natural
products and surfactants. Preferred surface modifiers include
nonionic and ionic surfactants.
Representative examples of surface modifiers include gelatin,
casein, lecithin (phosphatides), 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.TM., polyethylene glycols,
polyoxyethylene stearates, colloidal silicon dioxide, phosphates,
sodium dodecylsulfate, carboxymethylcellulose calcium,
carboxymethyl cellulose sodium, methylcellulose,
hydroxyethylcellulose, hydroxy propylcellulose,
hydroxypropylmethylcellulose phthalate, noncrystalline cellulose,
magnesium aluminum silicate, triethanolamine, polyvinyl alcohol,
and polyvinylpyrrolidone (PVP). Most of these surface modifiers 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, 1986.
Particularly preferred surface modifiers include
polyvinylpyrrolidone, tyloxapol, poloxamers such as Pluronics.TM.
F68 and F108, which are block copolymers of ethylene oxide and
propylene oxide, and polyxamines such as Tetronics.TM. 908 (also
known as Poloxamine.TM. 908), which is a tetrafunctional block
copolymer derived from sequential addition of propylene oxide and
ethylene oxide to ethylenediamine, available from BASF, dextran,
lecithin, dialkylesters of sodium sulfosuccinic acid, such as
Aerosol OTs.TM., which is a dioctyl ester of sodium sulfosuccinic
acid, available from American Cyanimid, Duponols.TM. P, which is a
sodium lauryl sulfate, available from DuPont, Tritons.TM. X-200,
which is an alkyl aryl polyether sulfonate, available from Rohn and
Haas, Tween.TM. 20 and Tweens.TM. 80, which are polyoxyethylene
sorbitan fatty acid esters, available from ICI Specialty Chemicals;
Carbowaxs.TM. 3550 and 934, which are polyethylene glycols
available from Union Carbide; Crodestas.TM. F-110, which is a
mixture of sucrose stearate and sucrose distearate, available from
Croda Inc., Crodestas.TM. SL-40, which is available from 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.2OH).sub.2. Surface modifiers which have been found to be
particularly useful include Tetronics.TM. 908, the Tweenss.TM.,
Pluronics.TM. F-68 and polyvinylpyrrolidone. Other useful surface
modifiers include: 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; and the like.
Another useful surface modifier is tyloxapol (a nonionic liquid
polymer of the alkyl aryl polyether alcohol type; also known as
superinone or triton). This surface modifier is commercially
available and/or can be prepared by techniques known in the
art.
Another preferred surface modifier is
p-isononylphenoxypoly(glycidol) also known as Olin-10G.TM. or
Surfactant 10-G, is commercially available as 10G.TM. from Olin
Chemicals, Stamford, Conn.
Non-Ionic Surface Modifiers
Preferred surface modifiers can be selected from known non-ionic
surfactants, including the poloxamines such as Tetronic.TM.908
(also known as Poloxanmine.TM.908), which is a tetrafunctional
block copolymer derived from sequential addition of propylene oxide
and ethylene oxide to ethylenediamine, available from BASF, or
Tetronic.TM. 1508 (T-1508), or a polymer of the alkyl aryl
polyether alcohol type, such as tyloxapol.
The surface modifiers are commercially available and/or can be
prepared by techniques known in the art. Two-or more surface
modifiers can be used in combination.
Auxiliary Surface Modifiers
Particularly preferred auxiliary surface modifiers are those which
impart resistance to particle aggregation during sterilization and
include dioctylsulfosuccinate (DOSS), polyethylene glycol,
glycerol, sodium dodecyl sulfate, dodecyl trimethyl ammonium
bromide and a charged phospholipid such as dimyristoyl phophatidyl
glycerol. The surface modifiers are commercially available and/or
can be prepared by techniques known in the art. Two or more surface
modifiers can be used in combination.
Block Copolvmer Surface Modifiers
One preferred surface modifier is a block copolymer linked to at
least one anionic group. The polymers contain at least one, and
preferably two, three, four or more anionic groups per
molecule.
Preferred anionic groups include sulfate, sulfonate, phosphonate,
phosphate and carboxylate groups. The anionic groups are covalently
attached to the nonionic block copolymer. The nonionic sulfated
polymeric surfactant has a molecular weight of 1,000-50,000,
preferably 2,000-40,000 and more preferably 3,000-30,000. In
preferred embodiments, the polymer comprises at least about 50%,
and more preferably, at least about 60% by weight of hydrophilic
units, e.g., alkylene oxide units. The reason for this is that the
presence of a major weight proportion of hydrophilic units confers
aqueous solubility to the polymer.
A preferred class of block copolymers useful as surface modifiers
herein includes sulfated block copolymers of ethylene oxide and
propylene oxide. These block copolymers in an unsulfated form are
commercially available as Pluronics.TM.. Specific examples of the
unsulfated block copolymers include F68, F108 and F127.
Another preferred class of block copolymers useful herein include
tetrafunctional block copolymers derived from sequential addition
of ethylene oxide and propylene oxide to ethylene diamine. These
polymers, in an unsulfated form, are commercially available as
Tetronics.TM..
Another preferred class of surface modifiers contain at least one
polyethylene oxide (PEO) block as the hydrophilic portion of the
molecule and at least one polybutylene oxide (PBO) block as the
hydrophobic portion. Particularly preferred surface modifiers of
this class are diblock, triblock, and higher block copolymers of
ethylene oxide and butylene oxide, such as are represented, for
example, by the following structural formula: POEPBOPEOPBOPEO; and
PEOPBOPEOPBO. The block copolymers useful herein are known
compounds and/or can be readily prepared by techniques well known
in the art.
Highly preferred surface modifiers include triblock copolymers of
the PEOPBOPEOhaving molecular weights of 3800 and 5000 which are
commercially available from Dow Chemical, Midland, Michigan, and
are referred to as B20-3800 and B20-5000. These surface modifiers
contain about 80% by weight PEO. In a preferred embodiment, the
surface modifier is a triblock polymer having the structure:
##STR00001## Q is an anionic group wherein R is H or a metal cation
such as Na+, K+ and the like, x is 15-700, Y is 5-200 and z is
15-700.
Grinding
The described particles can be prepared in a method comprising the
steps of dispersing a therapeutic or diagnostic agent in a liquid
dispersion medium and applying mechanical means in the presence of
grinding media to reduce the particle size of the therapeutic or
diagnostic agent to an effective average particle size of less than
about 1000 nm, and preferably of less than about 400 nm. The
particles can be reduced in size in the presence of a surface
modifier. Alternatively, the particles can be contacted with a
surface modifier after attrition.
The therapeutic or diagnostic agent selected is obtained
commercially and/or prepared by techniques known in the art in a
conventional coarse form. It is preferred, but not essential, that
the particle size of the coarse therapeutic or diagnostic agent
selected be less than about 10 mm as determined by sieve analysis.
If the coarse particle size of the therapeutic or diagnostic agent
is greater than about 100 mm, then it is preferred that the
particles of the therapeutic or diagnostic agent be reduced in size
to less than 100 mm using a conventional milling method such as
airjet or fragmentation milling.
The coarse therapeutic or diagnostic agent selected can then be
added to a liquid medium in which it is essentially insoluble to
form a premix. The concentration of the therapeutic or diagnostic
agent in the liquid medium can vary from about 0.1-60%, and
preferably is from 5-30% (w/w). It is preferred, but not essential,
that the surface modifier be present in the premix. The
concentration of the surface modifier can vary from about 0.1 to
about 90%, and preferably is 1-75%, more preferably 20-60%, by
weight based on the total combined weight of the therapeutic or
diagnostic agent and surface modifier. The apparent viscosity of
the premix suspension is preferably less than about 1000
centipoise.
The premix can be used directly by subjecting it to mechanical
means to reduce the average particle size in the dispersion to less
than 1000 nm. It is preferred that the premix be used directly when
a ball mill is used for attrition. Alternatively, the therapeutic
or diagnostic agent and, optionally, the surface modifier, can be
dispersed in the liquid medium using suitable agitation, e.g., a
roller mill or 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. Alternatively, the therapeutic or diagnostic agnet
and, optionally, the surface modifier, can be dispersed in the
iquid medium using suitable agitiation, e.g., a roller mill or 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.
The mechanical means applied to reduce the particle size of the
therapeutic or diagnostic agent 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 intended
result, desired reduction in particle size. For media milling, the
apparent viscosity of the premix preferably is from about 100 to
about 1000 centipoise. For ball milling, the apparent viscosity of
the premix preferably is from about 1 up to about 100 centipoise.
Such ranges tend to afford an optimal balance between efficient
particle fragmentation and media erosion.
Preparation Conditions
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. On the other hand, processing times of less than 1 day
(residence times of one minute up to several hours) have provided
the desired results using a high shear media mill.
The particles must be reduced in size at a temperature which does
not significantly degrade the therapeutic or diagnostic agent.
Processing temperatures of less than about 30.degree.-40.degree. C.
are ordinarily preferred. If desired, the processing equipment can
be cooled with conventional cooling equipment. The method is
conveniently carried out under conditions of ambient temperature
and at processing pressures which are safe and effective for the
milling process. For example, ambient processing pressures are
typical of ball mills, attritor mills and vibratory mills. Control
of the temperature, e.g., by jacketing or immersion of the milling
chamber in ice water are contemplated. Processing pressures from
about 1 psi (0.07 kg/cm2) up to about 50 psi (3.5 kg/cm2) are
contemplated. Processing pressures from about 10 psi (0.7 kg/cm2)
to about 20 psi 1.4 kg/cm2)
The surface modifier, if it was not present in the premix, must be
added to the dispersion after attrition in an amount as described
for the premix above. Thereafter, the dispersion can be mixed,
e.g., by shaking vigorously. Optionally, the dispersion can be
subjected to a sonication step, e.g., using an ultrasonic power
supply. For example, the dispersion can be subjected to ultrasonic
energy having a frequency of 20-80 kHz for a time of about 1 to 120
seconds.
After attrition is completed, the grinding media is separated from
the milled particulate product (in either a dry or liquid
dispersion form) using conventional separation techniques, such as
by filtration, sieving through a mesh screen, and the like.
Grinding Media
The grinding media for the particle size reduction step can be
selected from rigid media preferably spherical or particulate in
form having an average size less than about 3 mm and, more
preferably, less than about 1 mm. Such media desirably can provide
the particles with shorter processing times and impart less wear to
the milling equipment. The selection of material for the grinding
media is not believed to be critical. We have found that zirconium
oxide, such as 95% ZrO2 stabilized with magnesia, zirconium
silicate, and glass grinding media provide particles having levels
of contamination which are believed to be acceptable for the
preparation of pharmaceutical compositions. However, other media,
such as stainless steel, titania, alumina, and 95% ZrO2 stabilized
with yttrium, are expected to be useful. Preferred media have a
density greater than about 3 g/cm3.
Polymeric Grinding Media
The grinding media can comprise particles, preferably substantially
spherical in shape, e.g., beads, consisting essentially of
polymeric resin. Alternatively, the grinding media can comprise
particles comprising a core having a coating of the polymeric resin
adhered thereon.
In general, polymeric resins suitable for use herein 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.TM., vinyl chloride
polymers and copolymers, polyurethanes, polyamides, poly
(tetrafluoroethylenes), e.g., Teflon.TM., and other fluoropolymers,
high density polyethylenes, polypropylenes, cellulose ethers and
esters such as cellulose acetate, polyhydroxymethacrylate,
polyhydroxyethyl acrylate, 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). In the case of
biodegradable polymers, contamination from the media itself
advantageously can metabolize in vivo into biologically acceptable
products which can be eliminated from the body.
The polymeric resin can have a density from 0.8 to 3.0 g/cm3.
Higher density resins are preferred inasmuch as it is believed that
these provide more efficient particle size reduction.
The media can range in size from about 0.1 to 3 mm. For fine
grinding, the particles preferably are from 0.2 to 2 mm, more
preferably, 0.25 to 1 mm in size.
In a particularly preferred method, a therapeutic or diagnostic
agent is prepared in the form of submicron particles by grinding
the agent in the presence of a grinding media having a mean
particle size of less than about 75 microns.
The core material of the grinding media preferably can be selected
from materials known to be useful as grinding media when fabricated
as spheres or particles. Suitable core materials include zirconium
oxides (such as 95% zirconium oxide stabilized with magnesia or
yttrium), zirconium silicate, glass, stainless steel, titania,
alumina, ferrite and the like. Preferred core materials have a
density greater than about 2.5 g/cm.sup.3. The selection of high
density core materials is believed to facilitate efficient particle
size reduction.
Useful thicknesses of the polymer coating on the core are believed
to range from about 1 to about 500 microns, although other
thicknesses outside this range may be useful in some applications.
The thickness of the polymer coating preferably is less than the
diameter of the core.
The cores can be coated with the polymeric resin by techniques
known in the art. Suitable techniques include spray coating,
fluidized bed coating, and melt coating. Adhesion promoting or tie
layers can optionally be provided to improve the adhesion between
the core material and the resin coating. The adhesion of the
polymer coating to the core material can be enhanced by treating
the core material to adhesion promoting procedures, such as
roughening of the core surface, corona discharge treatment, and the
like.
Continuous Grinding
In a preferred grinding process, the particles are made
continuously rather than in a batch mode. The continuous method
comprises the steps of continuously introducing the therapeutic or
diagnostic agent and rigid grinding media into a milling chamber,
contacting the agent with the grinding media while in the chamber
to reduce the particle size of the agent, continuously removing the
agent and the grinding media from the milling chamber, and
thereafter separating the agent from the grinding media.
The therapeutic or diagnostic agent and the grinding media are
continuously removed from the milling chamber. Thereafter, the
grinding media is separated from the milled particulate agent (in
either a dry or liquid dispersion form) 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.
In a preferred embodiment, the agent and grinding media are
recirculated through the milling chamber. Examples of suitable
means to effect such recirculation include conventional pumps such
as peristaltic pumps, diaphragm pumps, piston pumps, centrifugal
pumps and other positive displacement pumps which do not use
sufficiently close tolerances to damage the grinding media.
Peristaltic pumps are generally preferred.
Another variation of the continuous process includes the use of
mixed media sizes. For example, larger media may be employed in a
conventional manner where such media is restricted to the milling
chamber. Smaller grinding media may be continuously recirculated
through the system and permitted to pass through the agitated bed
of larger grinding media. In this embodiment, the smaller media is
preferably between about 1 and 300 mm in mean particle size and the
larger grinding media is between about 300 and 1000 mm in mean
particle size.
Precipitation Method
Another method of forming the desired nanoparticle dispersion is by
microprecipitation. This is a method of preparing stable
dispersions of therapeutic and diagnostic agents in the presence of
a surface modifying and colloid stability enhancing surface active
agent free of trace of any toxic solvents or solubilized heavy
metal inpurities by the following procedural steps:
1.Dissolving the therapeutic or diagnostic agent in aqueous base
with stirring,
2. Adding above #1 formulation with stirring to a surface active
surfactant (or surface modifiers) solution to form a clear
solution, and
3. Neutralizing above formulation #2 with stirring with an
appropriate acid solution. The procedure can be followed by:
4. Removal of formed salt by dialysis or diafiltration and
5. Concentration of dispersion by conventional means.
This microprecipitation process produces dispersion of therapeutic
or diagnostic agents with Z-average particle diameter less than 400
nm (as measured by photon correlation spectroscopy) that are stable
in particle size upon keeping under room temperature or
refrigerated conditions. Such dispersions also demonstrate limited
particle size growth upon autoclave-decontamination conditions used
for standard blood-pool pharmaceutical agents.
Step 3 can be carried out in semicontinuous, continuous batch, or
continuous methods at constant flow rates of the reacting
components in computercontrolled reactors or in tubular reactors
where reaction pH can be kept constant using pH-stat systems.
Advantages of such modifications are that they provide cheaper
manufacturing procedures for large-scale production of
nanoparticulate dispersion systems.
Additional surface modifier may be added to the dispersion after
precipitation. Thereafter, the dispersion can be mixed, e.g., by
shaking vigorously. Optionally, the dispersion can be subjected to
a sonicationstep, e.g., using an ultrasonic power supply. For
example, the dispersion can be subjected to ultrasonic energy
having a frequency of 20-80 kHz for a time of about 1 to 120
seconds.
In a preferred embodiment, the above procedure is followed with
step 4 which comprises removing the formed salts by diafiltration
or dialysis. This is done in the case of dialysis by standard
dialysis equipment and by diafiltration using standard
diafiltration equipment known in the art. Preferably, the final
step is concentration to a desired concentration of the agent
dispersion. This is done either by diafiltration or evaporation
using standard equipment known in this art
An advantage of microprecipitation is that unlike milled
dispersion, the final product is free of heavy metal contaminants
arising from the milling media that must be removed due to their
toxicity before product is formulated.
A further advantage of the microprecipitation method is that unlike
solvent precipitation, the final product is free of any trace of
trace solvents that may be toxic and must be removed by expensive
treatments prior to final product formulation.
In another preferred embodiment of the microprecipitation process,
a crystal growth modifier is used. A crystal growth modifier is
defined as a compound that in the co-precipitation process
incorporates into the crystal structure of the microprecipitated
crystals of the pharmaceutical agent, thereby hindering growth or
enlargement of the microcrystalline precipitate, by the so called
Ostwald ripening process. A crystal growth modifier (or a CGM) is a
chemical that is at least 75% identical in chemical structure to
the pharmaceuticl agent. By "identical" is meant that the
structures are identical atom for atom and their connectivity.
Structural identity is charactarized as having 75% of the chemical
structure, on a molecular weight basis, identical to the
therapeutic or diagnostic agent. The remaining 25% of the structure
may be absent or replaced by different chemical structure in the
CGM. The crystal growth modifier is dissolved in step #1 with the
therapeutic or diagnostic agent.
Particle Size
As used herein, particle size refers to a number average particle
size as measured by conventional particle size measuring techniques
well known to those skilled in the art, such as sedimentation field
flow fractionation, photon correlation spectroscopy, or disk
centrifugation. When photon correlation spectroscopy (PCS) is used
as the method of particle sizing the average particle diameter is
the Z-average particle diameter known to those skilled in the art.
By "an effective average particle size of less than about 1000 nm"
it is meant that at least 90% of the particles have a weight
average particle size of less than about 1000 nm when measured by
the above-noted techniques. In preferred embodiments, the effective
average particle size is less than about 400 nm and more
preferrably less than about 300 nm. In some embodiments, an
effective average particle size of less than about 100 nm has been
achieved. With reference to the effective average particle size, it
is preferred that at least 95% and, more preferably, at least 99%
of the particles have a particle size less than the effective
average, e.g., 1000 nm. In particularly preferred embodiments
essentially all of the particles have a size less than 1000 nm. In
some embodiments, essentially all of the particles have a size less
than 400 nm.
Ratios
The relative amount of therapeutic or diagnostic agent and surface
modifier can vary widely and the optimal amount of the surface
modifier can depend, for example, upon the particular therapeutic
or diagnostic agent and surface modifier selected, the critical
micelle concentration of the surface modifier if it forms micelles,
the hydrophilic lipophilic balance (HLB) of the stabilizer, the
melting point of the stabilizer, its water solubility, the surface
tension of water solutions of the stabilizer, etc. The surface
modifier preferably is present in an amount of about 0.1-10 mg per
square meter surface area of the therapeutic or diagnostic agent.
The surface modifier can be present in an amount of 0.1-90%,
preferably 20-60% by weight based on the total weight of the dry
particle.
Diagnosis
A method for diagnostic imaging for use in medical procedures in
accordance with this invention comprises intravenously
administering to the body of a test subject in need of a diagnostic
image an effective contrast producing amount of the diagnostic
image contrast composition. Thereafter, at least a portion of the
body containing the administered contrast agent is exposed to
x-rays or a magnetic field to produce an x-ray or magnetic
resonance image pattern corresponding to the presence of the
contrast agent. The image pattern can then be visualized.
Any x-ray visualization technique, preferably, a high contrast
technique such as computed tomography, can be applied in a
conventional manner. Alternatively, the image pattern can be
observed directly on an x-ray sensitive phosphor screen-silver
halide photographic film combination or by use of a storage
phosphor screen.
Visualization with a magnetic resonance imaging system can be
accomplished with commercially available magnetic imaging systems
such as a General Electric 1.5 T Sigma imaging system [1H resonant
frequency 63.9 megahertz (MHz)]. Commercially available magnetic
resonance imaging systems are typically characterized by the
magnetic field strength used, with a field strength of 2.0 Tesla as
the current maximum and 0.2 Tesla as the current minimum. For a
given field strength, each detected nucleus has a characteristic
frequency. For example, at a field strength of 1.0 Tesla, the
resonance frequency for hydrogen is 42.57 10 MHz; for phosphorus-31
it is 17.24 MHz; and for sodium23 it is 11.26 Mhz.
A contrast effective amount of the diagnostic agent containing
composition is that amount necessary to provide tissue
visualization with, for example, magnetic resonance imaging or
x-ray imaging. Means for determining a contrast effective amount in
a particular subject will depend, as is well known in the art, on
the nature of the magnetically reactive material used, the mass of
the subject being imaged, the sensitivity of the magnetic resonance
or x-ray imaging system and the like.
After administration of the compositions, the subject is maintained
for a time period sufficient for the administered compositions to
be distributed throughout the subject and enter the tissues of the
mammal. Typically, a sufficient time period is from about 20
minutes to about 90 minutes and, preferably from about 20 minutes
to about 60 minutes.
The invention has been described with particular reference to
preferred embodiments thereof, but it will be understood that
variations and modifications can be effected within the spirit and
scope of the invention.
* * * * *
References