U.S. patent application number 11/283397 was filed with the patent office on 2006-06-22 for submicron suspensions with polymorph control.
Invention is credited to Mark J. Doty, James E. Kipp, Rajaram Sriram, Jane Werling.
Application Number | 20060134150 11/283397 |
Document ID | / |
Family ID | 46280130 |
Filed Date | 2006-06-22 |
United States Patent
Application |
20060134150 |
Kind Code |
A1 |
Werling; Jane ; et
al. |
June 22, 2006 |
Submicron suspensions with polymorph control
Abstract
The present invention provides a method for preparing a
suspension of a pharmaceutically active compound, the solubility of
which is greater in a water miscible first organic solvent than in
a second solvent which is aqueous, The process includes the steps
of: (i) dissolving a first quantity of the pharmaceutically active
compound in the water miscible first organic solvent to form a
first solution; (ii) mixing the first solution with the second
solvent to precipitate the pharmaceutically active compound; and
(iii) seeding the first solution or the second solvent or the
presuspension.
Inventors: |
Werling; Jane; (Arlington
Heights, IL) ; Kipp; James E.; (Wauconda, IL)
; Sriram; Rajaram; (Glenview, IL) ; Doty; Mark
J.; (Grayslake, IL) |
Correspondence
Address: |
BAXTER HEALTHCARE CORPORATION
ONE BAXTER PARKWAY
DF2-2E
DEERFIELD
IL
60015
US
|
Family ID: |
46280130 |
Appl. No.: |
11/283397 |
Filed: |
February 27, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10035821 |
Oct 19, 2001 |
6977085 |
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11283397 |
Feb 27, 2006 |
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09953979 |
Sep 17, 2001 |
6951656 |
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10035821 |
Oct 19, 2001 |
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09874637 |
Jun 5, 2001 |
6869617 |
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09953979 |
Sep 17, 2001 |
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60258160 |
Dec 22, 2000 |
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Current U.S.
Class: |
424/400 |
Current CPC
Class: |
A61K 9/146 20130101;
A61K 31/495 20130101; A61K 31/496 20130101; A61K 9/1688 20130101;
A61K 9/145 20130101; A61K 9/14 20130101; A61K 9/10 20130101 |
Class at
Publication: |
424/400 |
International
Class: |
A61K 9/00 20060101
A61K009/00 |
Claims
1. A method for preparing a suspension of a pharmaceutically-active
compound, the solubility of which is greater in a water miscible
first organic solvent than in a second solvent which is aqueous,
the process comprising the steps of: (i) dissolving a first
quantity of the pharmaceutically-active compound in the
water-miscible first organic solvent to form a first solution; (ii)
mixing the first solution with the second solvent to precipitate
the pharmaceutically-active compound to create a presuspension; and
(iii) seeding the first solution or the second solvent prior to the
or the presuspension after the mixing step.
2. The method of claim 1 wherein the step of precipitating the
pharmaceutically-active compound comprises the step of
precipitating the compound in a form selected from the group
consisting of a supercooled liquid, an amorphous particle, a
semicrystalline particle and a crystalline particle.
3. The method of claim 2 further comprising the step of adding
energy to the presuspension.
4. The method of claim 3 wherein the adding-energy step comprises
the step of subjecting the presuspension to high energy
agitation.
5. The method of claim 3 wherein the adding energy step comprises
the step of adding heat to the presuspension.
6. The method of claim 3 wherein the energy addition step comprises
the step of exposing the presuspension to electromagnetic
energy.
7. The method of claim 6 wherein the step of exposing the
presuspension to electromagnetic energy comprises the step of
exposing the presuspension to a laser beam.
8. The method of claim 1 further comprising the step of forming a
desired polymorph of the pharmaceutically active compound.
9. The method of claim 8 wherein the step of seeding comprises the
step of using a seed compound.
10. The method of claim 9 wherein the seed compound is the desired
polymorph of the pharmaceutically-active compound.
11. The method of claim 9 wherein the seed compound is a compound
other than the desired polymorph of the pharmaceutically-active
compound.
12. The method of claim 11 wherein the seed compound is selected
from the group consisting of: an inert impurity; and an organic
compound with a structure similar to that of the desired
polymorph.
13. The method of claim 9 wherein the seed compound is added to the
first solution.
14. The method of claim 9 wherein the seed compound is added to the
second solvent.
15. The method of claim 9 wherein the seed compound is added to the
presuspension.
16. The method of claim 8 wherein the step of forming a desired
polymorph comprises the step of forming a seed compound in the
first solution.
17. The method of claim 16 wherein the step of forming the seed
compound in the first solution comprises the step of adding the
pharmaceutically-active compound in sufficient quantity to exceed
the solubility of the pharmaceutically-active compound in the first
solvent to create a supersaturated solution.
18. The method of claim 17 wherein the step of forming the seed
compound in the first solution further comprises the step of
treating the supersaturated solution.
19. The method of claim 18 wherein the step of treating the
supersaturated solution comprises the step of aging the
supersaturated solution.
20. The method of claim 1 wherein the seeding step comprises the
step of using electromagnetic energy.
21. The method of claim 20 wherein the electromagnetic energy is
dynamic electromagnetic energy.
22. The method of claim 20 wherein the electromagnetic energy is a
laser beam.
23. The method of claim 20 wherein the electromagnetic energy is
radiation.
24. The method of claim 1 wherein the step of seeding comprises the
step of using a particle beam.
25. The method of claim 1 wherein the step of seeding comprises the
step of using an electron beam.
26. The method of claim 1 wherein the step of seeding comprises
using ultrasound.
27. The method of claim 1 wherein the step of seeding comprises
using a static electrical field.
28. The method of claim 1 wherein the step of seeding comprises
using a static magnetic field.
29. The method of claim 1 further comprising the steps of forming
particles having an average effective particle size less than about
2 .mu.m.
30. A method for preparing a suspension of a
pharmaceutically-active compound, the solubility of which is
greater in a water-miscible first organic solvent than in a second
solvent which is aqueous, the process comprising the steps of: (i)
dissolving a first quantity of the pharmaceutically-active compound
in the water-miscible first organic solvent to form a first
solution; (ii) mixing the first solution with the second solvent to
precipitate the pharmaceutically active compound to create a
presuspension; and (iii) providing a seed compound to the first
solution or the second solvent or the presuspension.
31. The method of claim 30 further comprising the step of adding
energy to the presuspension to provide particles having an average
effective particle size of less than about 2 .mu.m.
32. The method of claim 30 further comprising the step of forming a
desired polymorph of the pharmaceutically active compound.
33. The method of claim 32 wherein the step of seeding comprises
the step of providing a seed compound.
34. The method of claim 33 wherein the seed compound is the desired
polymorph of the pharmaceutically-active compound.
35. The method of claim 33 wherein the seed compound is a compound
other than the desired polymorph of the pharmaceutically-active
compound.
36. The method of claim 35 wherein the seed compound is selected
from the group consisting of: an inert impurity; and an organic
compound with a structure similar to that of the desired
polymorph.
37. The method of claim 33 wherein the seed compound is added to
the first solution.
38. The method of claim 33 wherein the seed compound is added to
the second solvent.
39. The method of claim 33 wherein the seed compound is added to
the presuspension.
40. The method of claim 32 wherein the step of forming a desired
polymorph comprises the step of forming a seed compound in the
first solution.
41. The method of claim 40 wherein the step of forming the seed
compound in the first solution comprises the step of adding the
pharmaceutically-active compound in sufficient quantity to exceed
the solubility of the pharmaceutically-active compound in the first
solvent to create a supersaturated solution.
42. The method of claim 41 wherein the step of forming the seed
compound in the first solution further comprises the step of
treating the supersaturated solution.
43. The method of claim 41 wherein the step of treating the
supersaturated solution comprises the step of aging the
supersaturated solution.
44. A method for preparing a suspension of a
pharmaceutically-active compound, the solubility of which is
greater in a water-miscible first organic solvent than in a second
solvent which is aqueous, the process comprising the steps of: (i)
adding a quantity of the pharmaceutically-active compound to the
first organic solvent to create a supersaturated solution; (ii)
aging the supersaturated solution to form detectable crystals to
create a seeding mixture; and (iii) mixing the seeding mixture with
the second solvent to precipitate the pharmaceutically-active
compound to create a presuspension.
45. The method of claim 44 wherein the pharmaceutically-active
compound of the presuspension is in a form selected from the group
consisting of a supercooled liquid, an amorphous particle, a
semicrystalline particle and a crystalline particle.
46. The method of claim 45 further comprising the step of
converting the compound in the presuspension to a desired
polymorph.
47. The method of claim 46 wherein the step of converting the
compound of the presuspension comprises the step of adding energy
to the presuspension.
48. The method of claim 47 wherein the adding-energy step comprises
the step of subjecting the presuspension to high energy
agitation.
49. The method of claim 47 wherein the adding-energy step comprises
the step of adding heat to the presuspension.
50. The method of claim 47 wherein the adding-energy step comprises
the step of exposing the presuspension to electromagnetic
energy.
51. The method of claim 47 wherein the step of exposing the
presuspension to electromagnetic energy comprises the step of
exposing the presuspension to a laser beam.
52. The method of claim 44 further comprising the steps of: adding
energy to the pre-suspension to form particles having an average
effective particle size of less than about 2 .mu.m.
53. A method for preparing a suspension of a
pharmaceutically-active compound, the solubility of which is
greater in a water-miscible first organic solvent than in a second
solvent which is aqueous, the process comprising the steps of: (i)
adding a quantity of the pharmaceutically-active compound to the
first organic solvent to create a supersaturated solution; (ii)
treating the supersaturated solution to form a detectable crystal
to create a seeding mixture; and (iii) mixing the seeding mixture
with the second solvent to precipitate the pharmaceutically-active
compound.
54. The method of claim 53, wherein the treating step comprises
aging.
55. The method of claim 53, wherein the treating step comprises
adding a surfactant.
56. The method of claim 53, wherein the treating step comprises
adding a crystallization modifier.
57. The method of claim 53, wherein the treating step comprises
dropping the temperature.
58. The method of claim 53, wherein the treating step comprises
using a laser beam.
59. The method of claim 53, wherein the treating step comprises
using radiation.
60. The method of claim 53, wherein the treating step comprises
using a particle beam.
61. The method of claim 53, wherein the treating step comprises
using an electron beam.
62. The method of claim 53 wherein the treating step comprises
using ultrasound.
63. The method of claim 53 wherein the treating step comprises
using a static electrical field.
64. The method of claim 53, wherein the treating step comprises
using a static magnetic field.
65. A composition of matter of a polymorphic
pharmaceutically-active compound in a desired polymorphic form
essentially free of an unspecified polymorphic form.
66. The composition of claim 65 wherein the pharmaceutically-active
compound is itraconazole.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation in part of application
Ser. No. 09/953,979 filed Sep. 17, 2001 which is a continuation in
part of application Ser. No. 09/874,637 filed on Jun. 5, 2001,
which claims priority from provisional application Ser. No.
60/258,160 filed Dec. 22, 2000, each of which is incorporated
herein by reference and made a part hereof.
FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not Applicable.
BACKGROUND OF THE INVENTION
[0003] 1. Technical Field
[0004] The present invention relates to the preparation of a
pharmaceutically active compound. More particularly the invention
relates to the manufacture of nanosuspensions of the
pharmaceutically active compound in a desired polymorph.
[0005] 2. Background Art
[0006] There is an ever increasing number of pharmaceutical drugs
being formulated that are poorly soluble or insoluble in aqueous
solutions. Such drugs provide challenges to delivering them in an
injectable form such as through parenteral administration. Drugs
that are insoluble in water can have significant benefits when
formulated as a stable suspension of sub-micron particles. Accurate
control of particle size is essential for safe and efficacious use
of these formulations. Particles must be less than seven microns in
diameter to safely pass through capillaries without causing emboli
(Allen et al., 1987; Davis and Taube, 1978; Schroeder et al., 1978;
Yokel et al., 1981).
[0007] One approach to delivering an insoluble drug is disclosed in
U.S. Pat. No. 2,745,785. This patent discloses a method for
preparing crystals of penicillin G suitable for parenteral
administration. The method includes the step of recrystallizing the
penicillin G from a formamide solution by adding water to reduce
the solubility of the penicillin G. The '785 patent further
provides that the penicillin G particles can be coated with wetting
agents such as lecithin, or emulsifiers, surface-active and
defoaming agents, or partial higher fatty acid esters of sorbitan
or polyoxyalkyklene derivatives thereof, or aryl alkyl polyether
alcohols or salts thereof. The '785 patent further discloses
micronizing the penicillin G with an air blast under pressure to
form crystals ranging from about 5 to 20 microns.
[0008] Another approach is disclosed in U.S. Pat. No. 5,118,528
which discloses a process for preparing nanoparticles. The process
includes the steps of: (1) preparing a liquid phase of a substance
in a solvent or a mixture of solvents to which may be added one or
more surfactants, (2) preparing a second liquid phase of a
non-solvent or a mixture of non-solvents, the non-solvent is
miscible with the solvent or mixture of solvents for the substance,
(3) adding together the solutions of (1) and (2) with stirring; and
(4) removing of unwanted solvents to produce a colloidal suspension
of nanoparticles. The '528 patent discloses that it produces
particles of the substance smaller than 500 nm without the supply
of energy. In particular the '528 patent states that it is
undesirable to use high energy equipment such as sonicators and
homogenizers.
[0009] U.S. Pat. No. 4,826,689 discloses a method for making
uniformly sized particles from water-insoluble drugs or other
organic compounds. First, a suitable solid organic compound is
dissolved in an organic solvent, and the solution can be diluted
with a non-solvent. Then, an aqueous precipitating liquid is
infused, precipitating non-aggregated particles with substantially
uniform mean diameter. The particles are then separated from the
organic solvent. Depending on the organic compound and the desired
particle size, the parameters of temperature, ratio of non-solvent
to organic solvent, infusion rate, stir rate, and volume can be
varied according to the invention. The '689 patent discloses this
process forms a drug in a metastable state which is
thermodynamically unstable and which eventually converts to a more
stable crystalline state. The '689 patent discloses trapping the
drug in a metastable state in which the free energy lies between
that of the starting drug solution and the stable crystalline form.
The '689 patent discloses utilizing crystallization inhibitors
(e.g. polyvinylpyrrolidinone) and surface-active agents (e.g.
poly(oxyethylene)-co-oxypropylene)) to render the precipitate
stable enough to be isolated by centrifugation, membrane filtration
or reverse osmosis.
[0010] In U.S. Pat. Nos. 5,091,188; 5,091,187 and 4,725,442 which
disclose (a) either coating small drug particles with natural or
synthetic phospholipids or (b) dissolving the drug in a suitable
lipophilic carrier and forming an emulsion stabilized with natural
or semisynthetic phospholipids. One of the disadvantages of these
approaches is they rely on the quality of the raw material of the
drug and do not disclose steps of changing the morphology of the
raw material to render the material in a friable, more easily
processed form.
[0011] Another approach to providing insoluble drugs for parenteral
delivery is disclosed in U.S. Pat. No. 5,145,684. The '684 patent
discloses the wet milling of an insoluble drug in the presence of a
surface modifier to provide a drug particle having an average
effective particle size of less than 400 nm. The '684 patent
emphasizes the desirability of not using any solvents in its
process. The '684 patent discloses the surface modifier is adsorbed
on the surface of the drug particle in an amount sufficient to
prevent agglomeration into larger particles.
[0012] Yet another attempt to provide insoluble drugs for
parenteral delivery is disclosed in U.S. Pat. No. 5,922,355. The
'355 patent discloses providing submicron sized particles of
insoluble drugs using a combination of surface modifiers and a
phospholipid followed by particle size reduction using techniques
such as sonication, homogenization, milling, microfluidization,
precipitation or recrystallization. There is no disclosure in the
'355 patent of changing process conditions to make crystals in a
more friable form.
[0013] U.S. Pat. No. 5,780,062 discloses a method of preparing
small particles of insoluble drugs by (1) dissolving the drug in a
water-miscible first solvent, (2) preparing a second solution of a
polymer and an amphiphile in an aqueous second solvent in which the
drug is substantially insoluble whereby a polymer/amphiphile
complex is formed and (3) mixing the solutions from the first and
second steps to precipitate an aggregate of the drug and
polymer/amphiphile complex.
[0014] U.S. Pat. No. 5,858,410 discloses a pharmaceutical
nanosuspension suitable for parenteral administration. The '410
patent discloses subjecting at least one solid therapeutically
active compound dispersed in a solvent to high pressure
homogenization in a piston-gap homogenizer to form particles having
an average diameter, determined by photon correlation spectroscopy
(PCS) of 10 nm to 1000 nm, the proportion of particles larger than
5 .mu.m in the total population being less than 0.1% (number
distribution determined with a Coulter counter), without prior
conversion into a melt, wherein the active compound is solid at
room temperature and is insoluble, only sparingly soluble or
moderately soluble in water, aqueous media and/or organic solvents.
The Examples in the '410 patent disclose jet milling prior to
homogenization.
[0015] U.S. Pat. No. 4,997,454 discloses a method for making
uniformly sized particles from solid compounds. The method of the
'454 patent includes the steps of dissolving the solid compound in
a suitable solvent followed by infusing precipitating liquid
thereby precipitating non-aggregated particles with substantially
uniform mean diameter. The particles are then separated from the
solvent. The '454 patent discourages forming particles in a
crystalline state because during the precipitating procedure the
crystal can dissolve and recrystallize thereby broadening the
particle size distribution range. The '454 patent encourages during
the precipitating procedure to trap the particles in a metastable
particle state.
[0016] U.S. Pat. No. 5,605,785 discloses a process for forming
nanoamorphous dispersions of photographically useful compounds. The
process of forming nanoamorphous dispersions include any known
process of emulsification that produces a disperse phase having
amorphous particulates.
SUMMARY OF THE INVENTION
[0017] The present invention provides a method for preparing a
suspension of a pharmaceutically-active compound, the solubility of
which is greater in a water-miscible first organic solvent than in
a second solvent which is aqueous. The process includes the steps
of: (i) dissolving a first quantity of the pharmaceutically-active
compound in the water-miscible first organic solvent to form a
first solution; (ii) mixing the first solution with the second
solvent to precipitate the pharmaceutically-active compound; and
(iii) seeding the first solution or the second solvent or the
presuspension. The method further includes the step of forming a
desired polymorph of the pharmaceutically active compound. In a
preferred form of the invention the step of seeding includes the
step of adding a seed compound to the first solution, to the second
solvent and/or to the presuspension.
[0018] The present invention further provides a method for
preparing a suspension of a pharmaceutically-active compound, the
solubility of which is greater in a water-miscible first organic
solvent than in a second solvent which is aqueous. The method
includes the steps of: (i) adding a quantity of the
pharmaceutically-active compound to the first organic solvent to
create a supersaturated solution, (ii) aging the supersaturated
solution to form detectable crystals to create a seeding mixture;
and (iii) mixing the seeding mixture with the second solvent to
precipitate the pharmaceutically-active compound to create a
presuspension.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 shows a diagrammatic representation of Method A, a
subcategory of the process categories of the present invention.
[0020] FIG. 2 shows a diagrammatic representation of Method B,
another subcategory of the process categories of the present
invention.
[0021] FIG. 3 shows amorphous particles prior to homogenization.
(Example 1).
[0022] FIG. 4 shows particles after annealing by
homogenization.
[0023] FIG. 5 is an X-Ray diffractogram of microprecipitated
itraconazole with polyethylene glycol-660 12-hydroxystearate before
and after homogenization. (Example 5).
[0024] FIG. 6 shows carbamazepine crystals before homogenization.
(Example 6).
[0025] FIG. 7 shows carbamazepine microparticulate after
homogenization. (Avestin C-50).
[0026] FIG. 8 is a diagram showing the microprecipitation process
for prednisolone. (Examples 9-12).
[0027] FIG. 9 is a photomicrograph of prednisolone suspension
before homogenization. (Hoffman Modulation Contrast, 1250.times.
magnification).
[0028] FIG. 10 is a photomicrograph of prednisolone suspension
after homogenization. (Hoffman Modulation Contrast, 1250.times.
magnification).
[0029] FIG. 11 is a comparison of size distributions of
nanosuspensions (this invention) and a commercial fat emulsion.
(Example 13).
[0030] FIG. 12 shows the X-ray powder diffraction patterns for raw
material itraconazole (top) and SMP-2-PRE (bottom). The raw
material pattern has been shifted upward for clarity. (Example 16).
Scanning parameters included [wh0601.raw] raw matl itra, SCAN:
5.0/40.0/0.02/4.8 (sec), Cu(17026 kV, 10486 mA), I(max)=22339,
08/06/01 19:33, and [WH 1601.RAW] SMP 2PRE, SCAN: 5.0/40.0/0.02/4.8
(sec), Cu(17026 kV, 10486 mA), I(max)=25502, 08/16/01 12:51.
[0031] FIG. 13a shows the DSC trace for raw material itraconazole.
(Example 16).
[0032] FIG. 13b shows the DSC trace for SMP-2-PRE. (Example
16).
[0033] FIG. 14 is the DSC trace for SMP-2-PRE showing the melt of
the less stable polymorph upon heating to 160.degree. C., a
recrystallization event upon cooling, and the subsequent melting of
the more stable polymorph upon reheating to 180.degree. C. (Example
16).
[0034] FIG. 15 shows a comparison of SMP-2-PRE samples after
homogenization. Solid line is the sample seeded with raw material
itraconazole. Dashed line is the unseeded sample. The solid line
has been shifted by 1 W/g for clarity. (Example 16).
[0035] FIG. 16 shows the effect of seeding during precipitation.
Dashed line is the unseeded sample, and solid line is the sample
seeded with raw material itraconazole. The unseeded trace (dashed
line) has been shifted upward by 1.5 W/g for clarity. (Example
17).
[0036] FIG. 17 shows the effect of seeding the drug concentrate
through aging. Top x-ray diffraction pattern is for crystals
prepared from fresh drug concentrate, and is consistent with the
stable polymorph (see FIG. 12, top). Bottom pattern is for crystals
prepared from aged (seeded) drug concentrate, and is consistent
with the metastable polymorph (see FIG. 12, bottom). The top
pattern has been shifted upward for clarity. (Example 18).
Collection parameters included [WJ0301B.RAW] 1092701-0.1, SCAN:
5.0/40.0/0.02/4.8(sec), Cu(17026 kV, 10486 mA), I(max)=19600,
10/03/01 18:58, and [WJ1501B.RAW] 1100901-2, SCAN:
5.0/40.0/0.02/4.8(sec), Cu(17026 kV, 10486 mA), I(max)=22108,
10/15/01 19:01.
DETAILED DESCRIPTION OF THE INVENTION
[0037] The present invention is susceptible of embodiments in many
different forms. Preferred embodiments of the invention are
disclosed with the understanding that the present disclosure is to
be considered as exemplifications of the principles of the
invention and are not intended to limit the broad aspects of the
invention to the embodiments illustrated.
[0038] The present invention provides methods or processes for
forming particles of an organic compound having an average
effective particle size suitable for parenteral administration and,
in a most preferred form of the invention, is less than about 2
.mu.m.
[0039] The processes can be separated into three general
categories. Each of the categories of processes share the steps of:
(1) dissolving an organic compound in a water miscible first
organic solvent to create a first solution, (2) mixing the first
solution with a second solvent of water to precipitate the organic
compound to create a pre-suspension, and (3) adding energy to the
presuspension in the form of high-shear mixing or heat to provide a
stable form of the organic compound having the desired size ranges
defined above.
[0040] The three categories of processes are distinguished based
upon the physical properties of the organic compound as determined
through x-ray diffraction studies, differential scanning
calorimetry (DSC) studies or other suitable study conducted prior
to the energy-addition step and after the energy-addition step. In
the first process category, prior to the energy-addition step the
organic compound in the presuspension takes an amorphous form, a
semi-crystalline form or a supercooled liquid form and has an
average effective particle size. After the energy-addition step the
organic compound is in a crystalline form having an average
effective particle size essentially the same as that of the
presuspension (i.e., from less than about 2 .mu.m).
[0041] In the second process category, prior to the energy-addition
step the organic compound is in a crystalline form and has an
average effective particle size. After the energy-addition step the
organic compound is in a crystalline form having essentially the
same average effective particle size as prior to the
energy-addition step but the crystals after the energy-addition
step are less likely to aggregate.
[0042] The lower tendency of the organic compound to aggregate is
observed by laser dynamic light scattering and light
microscopy.
[0043] In the third process category, prior to the energy-addition
step the organic compound is in a crystalline form that is friable
and has an average effective particle size. What is meant by the
term "friable" is that the particles are fragile and are more
easily broken down into smaller particles. After the
energy-addition step the organic compound is in a crystalline form
having an average effective particle size smaller than the crystals
of the pre-suspension. By taking the steps necessary to place the
organic compound in a crystalline form that is friable, the
subsequent energy-addition step can be carried out more quickly and
efficiently when compared to an organic compound in a less friable
crystalline morphology.
[0044] The energy-addition step can be carried out in any fashion
wherein the pre-suspension is exposed to cavitation, shearing or
impact forces. In one preferred form of the invention, the
energy-addition step is an annealing step. Annealing is defined in
this invention as the process of converting matter that is
thermodynamically unstable into a more stable form by single or
repeated application of energy (direct heat or mechanical stress),
followed by thermal relaxation. This lowering of energy may be
achieved by conversion of the solid form from a less ordered to a
more ordered lattice structure. Alternatively, this stabilization
may occur by a reordering of the surfactant molecules at the
solid-liquid interface.
[0045] These three process categories will be discussed separately
below. It should be understood, however, that the process
conditions such as choice of surfactants or combination of
surfactants, amount of surfactant used, temperature of reaction,
rate of mixing of solutions, rate of precipitation and the like can
be selected to allow for any drug to be processed under any one of
the categories discussed next.
[0046] The first process category, as well as the second and third
process categories, can be further divided into two subcategories,
Method A, and B shown in FIGS. 1 and 2 respectively.
[0047] An organic compound for use in the process of this invention
is any organic chemical entity whose solubility decreases from one
solvent to another. This organic compound might be a
pharmaceutically active compound from various groups such as, but
not limited to: antihyperlipidemics; antimicrobials, e.g.,
antibacterials such as sulfadiazine, antifingals such as
itraconazole; non-steroidal anti-inflammatory drugs, e.g.,
indomethacin; antihypercholesteremic agents, e.g., probucol; and
steroidal compounds, e.g., dexamethasone; immunosuppresants, e.g.,
cyclosporin A, tacrolimus, and mycophenolate mofetil. Or the
organic compound might be from the group used as adjuvants or
excipients in pharmaceutical preparations and cosmetics, such as,
but not limited to, preservatives, e.g., propylparaben.
[0048] The first solvent according to the present invention is a
solvent or mixture of solvents in which the organic compound of
interest is relatively soluble and which is miscible with the
second solvent. Examples of such solvents include, but are not
limited to: polyvinylpyrrolidone, N-methyl-2-pyrrolidinone (also
called N-methyl-2-pyrrolidone), 2-pyrrolidone, dimethyl sulfoxide,
dimethylacetamide, lactic acid, methanol, ethanol, isopropanol,
3-pentanol, n-propanol, glycerol, butylene glycol (butanediol),
ethylene glycol, propylene glycol, mono- and diacylated
monoglycerides (such as glyceryl caprylate), dimethyl isosorbide,
acetone, dimethylformamide, 1,4-dioxane, polyethylene glycol (for
example, PEG-4, PEG-8, PEG-9, PEG-12, PEG-14, PEG-16, PEG-120,
PEG-75, PEG-150, polyethylene glycol esters (examples such as PEG-4
dilaurate, PEG-20 dilaurate, PEG-6 isostearate, PEG-8
palmitostearate, PEG-150 palmitostearate), polyethylene glycol
sorbitans (such as PEG-20 sorbitan isostearate), polyethylene
glycol monoalkyl ethers (examples such as PEG-3 dimethyl ether,
PEG-4 dimethyl ether), polypropylene glycol (PPG), polypropylene
alginate, PPG-10 butanediol, PPG-10 methyl glucose ether, PPG-20
methyl glucose ether, PPG-15 stearyl ether, propylene glycol
dicaprylate/dicaprate, propylene glycol laurate.
Method A
[0049] In Method A (see FIG. 1), the organic compound ("drug") is
first dissolved in the first solvent to create a first solution.
The organic compound can be added from about 0.1% (w/v) to about
50% (w/v) depending on the solubility of the organic compound in
the first solvent. Heating of the concentrate from about 30.degree.
C. to about 100.degree. C. may be necessary to ensure total
dissolution of the compound in the first solvent.
[0050] A second aqueous solution is provided with one or more
optional surface modifiers such as an anionic surfactant, a
cationic surfactant, a nonionic surfactant or a biological surface
active molecule added thereto. Suitable anionic surfactants include
but are not limited to potassium laurate, sodium lauryl sulfate,
sodium dodecylsulfate, alkyl polyoxyethylene sulfates, sodium
alginate, dioctyl sodium sulfosuccinate, phosphatidyl choline,
phosphatidyl glycerol, phosphatidyl inosine, phosphatidylserine,
phosphatidic acid and their salts, glyceryl esters, sodium
carboxymethylcellulose, cholic acid and other bile acids (e.g.,
cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid,
glycodeoxycholic acid) and salts thereof (e.g., sodium
deoxycholate, etc.). Suitable cationic surfactants include but are
not limited to quaternary ammonium compounds, such as benzalkonium
chloride, cetyltrimethylammonium bromide,
lauryldimethylbenzylammonium chloride, acyl carnitine
hydrochlorides, or alkyl pyridinium halides. As anionic
surfactants, phospholipids may be used. Suitable phospholipids
include, for example phosphatidylcholine, phosphatidylethanolamine,
phosphatidylserine, phosphatidylinositol, phosphatidylglycerol,
phosphatidic acid, lysophospholipids, egg or soybean phospholipid
or a combination thereof. The phospholipid may be salted or
desalted, hydrogenated or partially hydrogenated or natural
semisynthetic or synthetic.
[0051] Suitable nonionic surfactants include: polyoxyethylene fatty
alcohol ethers (Macrogol and Brij), polyoxyethylene sorbitan fatty
acid esters (Polysorbates), polyoxyethylene fatty acid esters
(Myrj), sorbitan esters (Span), glycerol monostearate, polyethylene
glycols, polypropylene glycols, cetyl alcohol, cetostearyl alcohol,
stearyl alcohol, aryl alkyl polyether alcohols,
polyoxyethytene-polyoxypropylene copolymers (poloxomers),
polaxamines, methylcellulose, hydroxycellulose, hydroxy
propylcellulose, hydroxy propylmethylcellulose, noncrystalline
cellulose, polysaccharides including starch and starch derivatives
such as hydroxyethylstarch (HES), polyvinyl alcohol, and
polyvinylpyrrolidone. In a preferred form of the invention the
nonionic surfactant is a polyoxyethylene and polyoxypropylene
copolymer and preferably a block copolymer of propylene glycol and
ethylene glycol. Such polymers are sold under the tradename
POLOXAMER also sometimes referred to as PLURONIC.RTM., and sold by
several suppliers including Spectrum Chemical and Ruger. Among
polyoxyethylene fatty acid esters is included those having short
alkyl chains. One example of such a surfactant is SOLUTOL.RTM. HS
15, polyethylene-660-hydroxystearate, manufactured by BASF
Aktiengesellschaft.
[0052] Surface active biological molecules include such molecules
as albumin, casein, heparin, hirudin or other appropriate
proteins.
[0053] It may also be desirable to add a pH adjusting agent to the
second solution such as sodium hydroxide, hydrochloric acid, tris
buffer or citrate, acetate, lactate, meglumine, or the like. The
second solution should have a pH within the range of from about 3
to about 11.
[0054] In a preferred form of the invention, the method for
preparing submicron sized particles of an organic compound includes
the steps of adding the first solution to the second solution. The
addition rate is dependent on the batch size, and precipitation
kinetics for the organic compound. Typically, for a small-scale
laboratory process (preparation of 1 liter), the addition rate is
from about 0.05 cc per minute to about 10 cc per minute. During the
addition, the solutions should be under constant agitation. It has
been observed using light microscopy that amorphous particles,
semi-crystalline solids, or a supercooled liquid are formed to
create a pre-suspension. The method further includes the step of
subjecting the pre-suspension to an annealing step to convert the
amorphous particles, supercooled liquid or semicrystalline solid to
a crystalline more stable solid state. The resulting particles will
have an average effective paticles size as measured by dynamic
light scattering methods (e.g., photocorrelation spectroscopy,
laser diffraction, low-angle laser light scattering (LALLS),
medium-angle laser light scattering (MALLS), light obscuration
methods (Coulter method, for example), rheology, or microscopy
(light or electron) within the ranges set forth above).
[0055] The energy-addition step involves' adding energy through
sonication, homogenization, counter current flow homogenization,
microfluidization, or other methods of providing impact, shear or
cavitation forces. The sample may be cooled or heated during this
stage. In one preferred form of the invention the annealing step is
effected by a piston gap homogenizer such as the one sold by
Avestin Inc. under the product designation EmulsiFlex-C160. In
another preferred form of the invention the annealing may be
accomplished by ultrasonication using an ultrasonic processor such
as the Vibra-Cell Ultrasonic Processor (600 W), manufactured by
Sonics and Materials, Inc. In yet another preferred form of the
invention the annealing may be accomplished by use of an
emulsification apparatus as described in U.S. Pat. No. 5,720,551
which is incorporated herein by reference and made a part
hereof.
[0056] Depending upon the rate of annealing, it may be desirable to
adjust the temperature of the processed sample to within the range
of from approximately -30.degree. C. to 30.degree. C.
Alternatively, in order to effect a desired phase change in the
processed solid, it may also be necessary to heat the
pre-suspension to a temperature within the range of from about
30.degree. C. to about 100.degree. C. during the annealing
step.
Method B
[0057] Method B differs from Method A in the following respects.
The first difference is a surfactant or combination of surfactants
is added to the first solution. The surfactants may be selected
from the groups of anionic, nonionic and cationinc surfactants set
forth above.
Comparative Example of Method A and Method B and U.S. Pat. No.
5,780,062
[0058] U.S. Pat. No. 5,780,062 discloses a process for preparing
small particles of an organic compound by first dissolving the
compound in a suitable water-miscible first solvent. A second
solution is prepared by dissolving a polymer and an amphiphile in
aqueous solution. The first solution is then added to the second
solution to form a precipitate that consists of the organic
compound and a polymer-amphiphile complex. The '062 patent does not
disclose utilizing the energy-addition step of this invention in
Methods A and B. Lack of stability is typically evidenced by rapid
aggregation and particle growth. In some instances, amorphous
particles recrystallize as large crystals. Adding energy to the
pre-suspension in the manner disclosed above typically affords
particles that show decreased rates of particle aggregation and
growth, as well as the absence of recrystallization upon product
storage.
[0059] Methods A and B are further distinguished from the process
of the '062 patent by the absence of a step of forming a
polymer-amphiphile complex prior to precipitation. In Method A,
such a complex cannot be formed as no polymer is added to the
diluent (aqueous) phase. In Method B, the surfactant, which may
also act as an amphiphile, or polymer, is dissolved with the
organic compound in the first solvent. This precludes the formation
of any amphiphile-polymer complexes prior to precipitation. In the
'062 patent, successful precipitation of small particles relies
upon the formation of an amphiphile-polymer complex prior to
precipitation. The '062 patent discloses the amphiphile-polymer
complex forms aggregates in the aqueous second solution. The '062
patent explains the hydrophobic organic compound interacts with the
amphiphile-polymer complex, thereby reducing solubility of these
aggregates and causing precipitation. In the present invention it
has been demonstrated that the inclusion of the surfactant or
polymer in the first solvent (Method B) leads, upon subsequent
addition to second solvent, to formation of a more uniform, finer
particulate than is afforded by the process outlined by the '062
patent.
[0060] To this end, two formulations were prepared and analyzed.
Each of the formulations have two solutions, a concentrate and an
aqueous diluent, which are mixed together and then sonicated. The
concentrate in each formulation has an organic compound
(itraconazole), a water miscible solvent (N-methyl-2-pyrrolidinone
or NMP) and possibly a polymer (poloxamer 188). The aqueous diluent
has water, a tris buffer and possibly a polymer (poloxamer 188)
and/or a surfactant (sodium deoxycholate). The average particle
diameter of the organic particle is measured prior to sonication
and after sonication.
[0061] The first formulation A has as the concentrate itraconazole
and NMP. The aqueous diluent includes water, poloxamer 188, tris
buffer and sodium deoxycholate. Thus the aqueous diluent includes a
polymer (poloxamer 188), and an amphiphile (sodium deoxycholate),
which may form a polymer/amphiphile complex, and, therefore, is in
accordance with the disclosure of the '062 patent. (However, again
the '062 patent does not disclose an energy addition step.)
[0062] The second formulation B has as the concentrate
itraconazole, NMP and poloxamer 188. The aqueous diluent includes
water, tris buffer and sodium deoxycholate. This formulation is
made in accordance with the present invention. Since the aqueous
diluent does not contain a combination of a polymer (poloxamer) and
an amphiphile (sodium deoxycholate), a polymer/amphiphile complex
cannot form prior to the mixing step.
[0063] Table I shows the average particle diameters measured by
laser diffraction on three replicate suspension preparations. An
initial size determination was made, after which the sample was
sonicated for 1 minute. The size determination was then repeated.
The large size reduction upon sonication of Method A was indicative
of particle aggregation. TABLE-US-00001 TABLE 1 Average particle
After diameter sonication Method Concentrate Aqueous Diluent
(microns) (1 minute) A itraconazole poloxamer 188 18.7 2.36 (18%),
N- (2.3%), sodium 10.7 2.46 methyl-2- deoxycholate 12.1 1.93
pyrrolidinone (0.3%)tris buffer (6 mL) (5 mM, pH 8)water (qs to 94
mL) B itraconazole sodium 0.194 0.198 (18%)poloxamer deoxycholate
0.178 0.179 188 (37%)N- (0.3%)tris buffer 0.181 0.177 methyl-2- (5
mM, pH 8)water pyrrolidinone (qs to 94 mL) (6 mL)
[0064] A drug suspension resulting from application of the
processes described in this invention may be administered directly
as an injectable solution, provided Water for Injection is used in
formulation and an appropriate means for solution sterilization is
applied. Sterilization may be accomplished by separate
sterilization of the drug concentrate (drug, solvent, and optional
surfactant) and the diluent medium (water, and optional buffers and
surfactants) prior to mixing to form the pre-suspension.
Sterilization methods would include pre-filtration first through a
3.0 micron filter followed by filtration through a 0.45-micron
particle filter, followed by steam or heat sterilization or sterile
filtration through two redundant 0.2-micron membrane filters.
[0065] Optionally, a solvent-free suspension may be produced by
solvent removal after precipitation. This can be accomplished by
centrifugation, dialysis, diafiltration, force-field fractionation,
high-pressure filtration or other separation techniques well known
in the art. Complete removal of N-methyl-2-pyrrolidinone was
typically carried out by one to three successive centrifugation
runs; after each centrifugation (18,000 rpm for 30 minutes) the
supernatant was decanted and discarded. A fresh volume of the
suspension vehicle without the organic solvent was added to the
remaining solids and the mixture was dispersed by homogenization.
It will be recognized by others skilled in the art that other
high-shear mixing techniques could be applied in this
reconstitution step.
[0066] Furthermore, any undesired excipients such as surfactants
may be replaced by a more desirable excipient by use of the
separation methods described in the above paragraph. The solvent
and first excipient may be discarded with the supernatant after
centrifugation or filtration. A fresh volume of the suspension
vehicle without the solvent and without the first excipient may
then be added. Alternatively, a new surfactant may be added. For
example, a suspension consisting of drug, N-methyl-2-pyrrolidinone
(solvent), poloxamer 188 (first excipient), sodium deoxycholate,
glycerol and water may be replaced with phospholipids (new
surfactant), glycerol and water after centrifugation and removal of
the superatant.
I. First Process Category
[0067] The methods of the first process category generally include
the step of dissolving the organic compound in a water miscible
first solvent followed by the step of mixing this solution with an
aqueous solution to form a presuspension wherein the organic
compound is in an amorphous form, a semicrystalline form or in a
supercooled liquid form as determined by x-ray diffraction studies,
DSC, light microscopy or other analytical techniques and has an
average effective particle size within one of the effective
particle size ranges set forth above. The mixing step is followed
by an energy-addition step and, in a preferred form of the
invention an annealing step.
II. Second Process Category
[0068] The methods of the second processes category include
essentially the same steps as in the steps of the first processes
category but differ in the following respect. An x-ray diffraction,
DSC or other suitable analytical techniques of the presuspension
shows the organic compound in a crystalline form and having an
average effective particle size. The organic compound after the
energy-addition step has essentially the same average effective
particle size as prior to the energy-addition step but has less of
a tendency to aggregate into larger particles when compared to that
of the particles of the presuspension. Without being bound to a
theory, it is believed the differences in the particle stability
may be due to a reordering of the surfactant molecules at the
solid-liquid interface.
III. Third Process Category
[0069] The methods of the third category modify the first two steps
of those of the first and second processes categories to ensure the
organic compound in the presuspension is in a friable form having
an average effective particle size (e.g., such as slender needles
and thin plates). Friable particles can be formed by selecting
suitable solvents, surfactants or combination of surfactants, the
temperature of the individual solutions, the rate of mixing and
rate of precipitation and the like. Friability may also be enhanced
by the introduction of lattice defects (e.g., cleavage planes)
during the steps of mixing the first solution with the aqueous
solution. This would arise by rapid crystallization such as that
afforded in the precipitation step. In the energy-addition step
these friable crystals are converted to crystals that are
kinetically stabilized and having an average effective particle
size smaller than those of the presuspension. Kinetically
stabilized means particles have a reduced tendency to aggregate
when compared to particles that are not kineticalty stabilized. In
such instance the energy-addition step results in a breaking up of
the friable particles. By ensuring the particles of the
presuspension are in a friable state, the organic compound can more
easily and more quickly be prepared into a particle within the
desired size ranges when compared to processing an organic compound
where the steps have not been taken to render it in a friable
form.
Polymorph Control
[0070] The present invention further provides additional steps for
controlling the crystal structure of the pharmaceutically-active
compound to ultimately produce a suspension of the compound in the
desired size range and a desired crystal structure. What is meant
by the term "crystal structure" is the arrangement of the atoms
within the unit cell of the crystal. Pharmaceutically-active
compounds that can be crystallized into different crystal
structures are said to be polymorphic. Identification of polymorphs
is important step in drug formulation since different polymorphs of
the same drug can show differences in solubility, therapeutic
activity, bioavailabilty, and suspension stability. Accordingly, it
is important to control the polymorphic form of the compound for
ensuring product purity and batch-to-batch reproducibility.
[0071] The steps to control the polymorphic form of the compound
includes seeding the first solution, the second solvent or the
presuspension to ensure the formation of the desired polymorph.
Seeding includes using a seed compound or adding energy. In a
preferred form of the invention the seed compound is the
pharmaceutically-active compound in the desired polymorphic form.
Alternatively, the seed compound can also be an inert impurity or
an organic compound with a structure similar to that of the desired
polymorph such as a bile salt.
[0072] The seed compound can be precipitated from the first
solution. This method includes the steps of adding the
pharmaceutically-active compound in sufficient quantity to exceed
the solubility of the pharmaceutically-active compound in the first
solvent to create a supersaturated solution. The supersaturated
solution is treated to precipitate the pharmaceutically-active
compound in the desired polymorphic form. Treating the
supersaturated solution includes aging the solution for a time
period until the formation of a crystal or crystals is observed to
create a seeding mixture. It is also possible to add energy to the
supersaturated solution to cause the pharmaceutically-active
compound to precipitate out of the solution in the desired
polymorph. The energy can be added in a variety of ways including
the energy addition steps described above. Further energy can be
added by heating or exposing the presuspension to electromagnetic
energy, particle beam or electron beam sources. The electromagnetic
energy includes using a laser beam, dynamic electromagnetic energy,
or other radiation sources. It is further contemplated utilizing
ultrasound, static electric field and a static magnetic field as
the energy addition source.
[0073] In a preferred form of the invention the method for
producing seed crystals from an aged supersaturated solution
includes the steps of: (i) adding a quantity of the
pharmaceutically-active compound to the first organic solvent to
create a supersaturated solution; (ii) aging the supersaturated
solution to form detectable crystals to create a seeding mixture;
and (iii) mixing the seeding mixture with the second solvent to
precipitate the pharmaceutically-active compound to create a
presuspension. The presuspension can then be further processed as
described in detail above to provide an aqueous suspension of the
pharmaceutically-active compound in the desired polymorph and in
the desired size range.
[0074] Seeding can also be accomplished by adding energy to the
first solution, the second solvent or the presuspension provided
that the exposed liquid or liquids contain the pharmaceutically
active compound or a seed material. The energy can be added in the
same fashion as described above for the supersaturated
solution.
[0075] Accordingly, the present invention provides a composition of
matter of a pharmaceutically active compound in a desired
polymorphic form essentially free of the unspecified polymorph or
polymorphs. One such example is set forth in example 16 below where
seeding during microprecipitation provides a polymorph of
itraconazole essentially free of the polymorph of the raw material.
It is contemplated the methods of this invention can apply used to
selectively produce a desired polymorph for numerous
pharmaceutically active compounds.
EXAMPLES
Examples of Process Category 1
Example 1
Preparation of Itraconazole Suspension by Use of Process Category
1, Method A with Homogenization
[0076] To a 3-L flask add 1680 mL of Water for Injection. Heat
liquid to 60-65.degree. C., and then slowly add 44 grams of
Pluronic F-68 (poloxamer 188), and 12 grams of sodium deoxycholate,
stirring after each addition to dissolve the solids. After addition
of solids is complete, stir for another 15 minutes at 60-65.degree.
C. to ensure complete dissolution. Prepare a 50 mM tris
(tromethamine) buffer by dissolving 6.06 grams of tris in 800 mL of
Water for Injection. Titrate this solution to pH 8.0 with 0.1 M
hydrochloric acid. Dilute the resulting solution to 1 liter with
additional Water for Injection. Add 200 mL of the tris buffer to
the poloxamer/deoxycholate solution. Stir thoroughly to mix
solutions.
[0077] In a 150-mL beaker add 20 grams of itraconazole and 120 mL
of N-methyl-2-pyrrolidinone. Heat mixture to 50-60.degree. C., and
stir to dissolve solids. After total dissolution is visually
apparent, stir another 15 minutes to ensure complete dissolution.
Cool itraconazole-NMP solution to room temperature.
[0078] Charge a syringe pump (two 60-mL glass syringes) with the
120-mL of itraconazole solution prepared previously. Meanwhile pour
all of the surfactant solution into a homogenizer hopper which has
been cooled to 0-5.degree. C. (this may either by accomplished by
use of a jacketed hopper through which refrigerant is circulated,
or by surrounding the hopper with ice). Position a mechanical
stirrer into the surfactant solution so that the blades are fully
immersed. Using the syringe pump, slowly (1-3 mL/min) add all of
the itraconazole solution to the stirred, cooled surfactant
solution. A stirring rate of at least 700 rpm is recommended. An
aliquot of the resulting suspension (Suspension A) is analyzed by
light microscopy (Hoffman Modulation Contrast) and by laser
diffraction (Horiba). Suspension A is observed by light microscopy
to consist of roughly spherical amorphous particles (under 1
micron), either bound to each other in aggregates or freely moving
by Brownian motion. See FIG. 3. Dynamic light scattering
measurements typically afford a bimodal distribution pattern
signifying the presence of aggregates (10-100 microns in size) and
the presence of single amorphous particles ranging 200-700 nm in
median particle diameter.
[0079] The suspension is immediately homogenized (at 10,000 to
30,000 psi) for 10-30 minutes. At the end of homogenization, the
temperature of the suspension in the hopper does not exceed
75.degree. C. The homogenized suspension is collected in 500-mL
bottles, which are cooled immediately in the refrigerator
(2-8.degree. C.). This suspension (Suspension B) is analyzed by
light microscopy and is found to consist of small elongated plates
with a length of 0.5 to 2 microns and a width in the 0.2-1 micron
range. See FIG. 4. Dynamic light scattering measurements typically
indicate a median diameter of 200-700 nm.
Stability of Suspension A ("Pre-suspension") (Example 1)
[0080] During microscopic examination of the aliquot of Suspension
A, crystallization of the amorphous solid was directly observed.
Suspension A was stored at 2-8.degree. C. for 12 hours and examined
by light microscopy. Gross visual inspection of the sample revealed
severe flocculation, with some of the contents settling to the
bottom of the container. Microscopic examination indicated the
presence of large, elongated, plate-like crystals over 10 microns
in length.
Stability of Suspension B
[0081] As opposed to the instability of Suspension A, Suspension B
was stable at 2-8.degree. C. for the duration of the preliminary
stability study (1 month). Microscopy on the aged sample clearly
demonstrated that no significant change in the morphology or size
of the particles had occurred. This was confirmed by light
scattering measurement.
Example 2
Preparation of itraconazole suspension by use of Process Category
1, Method A with Ultrasonication
[0082] To a 500-mL stainless steel vessel add 252 mL of Water for
Injection. Heat liquid to 60-65.degree. C., and then slowly add 6.6
grams of Pluronic F-68 (poloxamer 188), and 0.9 grams of sodium
deoxycholate, stirring after each addition to dissolve the solids.
After addition of solids is complete, stir for another 15 minutes
at 60-65.degree. C. to ensure complete dissolution. Prepare a 50 mM
tris (tromethamine) buffer by dissolving 6.06 grams of tris in 800
mL of Water for Injection. Titrate this solution to pH 8.0 with 0.1
M hydrochloric acid. Dilute the resulting solution to 1 liter with
additional Water for Injection. Add 30 mL of the tris buffer to the
poloxamer/deoxycholate solution. Stir thoroughly to mix
solutions.
[0083] In a 30-mL container add 3 grams of itraconazole and 18 mL
of N-methyl-2-pyrrolidinone. Heat mixture to 50-60.degree. C., and
stir to dissolve solids. After total dissolution is visually
apparent, stir another 15 minutes to ensure complete dissolution.
Cool itraconazole-NMP solution to room temperature.
[0084] Charge a syringe pump with 18-mL of itraconazole solution
prepared in a previous step. Position a mechanical stirrer into the
surfactant solution so that the blades are fully immersed. Cool the
container to 0-5.degree. C. by immersion in an ice bath. Using the
syringe pump, slowly (1-3 mL/min) add all of the itraconazole
solution to the stirred, cooled surfactant solution. A stirring
rate of at least 700 rpm is recommended. Immerse an ultrasonicator
horn in the resulting suspension so that the probe is approximately
1 cm above the bottom of the stainless steel vessel. Sonicate
(10,000 to 25,000 Hz, at least 400 W) for 15 to 20 minute in
5-minute intervals. After the first 5-minute sonication, remove the
ice bath and proceed with further sonication. At the end of
ultrasonication, the temperature of the suspension in the vessel
does not exceed 75.degree. C.
[0085] The suspension is collected in a 500-mL Type I glass bottle,
which is cooled immediately in the refrigerator (2-8.degree. C.).
Characteristics of particle morphology of the suspension before and
after sonication were very similar to that seen in Method A before
and after homogenization (see Example 1).
Example 3
Preparation of Itraconazole Suspension by Use of Process Category
1, Method B with Homogenization
[0086] Prepare a 50 mM tris (tromethamine) buffer by dissolving
6.06 grams of tris in 800 mL of Water for Injection. Titrate this
solution to pH 8.0 with 0.1 M hydrochloric acid. Dilute the
resulting solution to 1 liter with additional Water for Injection.
To a 3-L flask add 1680 mL of Water for Injection. Add 200 mL of
the tris buffer to the 1680 mL of water. Stir thoroughly to mix
solutions.
[0087] In a 150-mL beaker add 44 grams of Pluronic F-68 (poloxamer
188) and 12 grams of sodium deoxycholate to 120 mL of
N-methyl-2-pyrrolidinone. Heat the mixture to 50-60.degree. C., and
stir to dissolve solids. After total dissolution is visually
apparent, stir another 15 minutes to ensure complete dissolution.
To this solution, add 20 grams of itraconazole, and stir until
totally dissolved. Cool the itraconazole-surfactant-NMP solution to
room temperature.
[0088] Charge a syringe pump (two 60-mL glass syringes) with the
120-mL of the concentrated itraconazole solution prepared
previously. Meanwhile pour the diluted tris buffer solution
prepared above into a homogenizer hopper which has been cooled to
0-5.degree. C. (this may either by accomplished by use of a
jacketed hopper through which refrigerant is circulated, or by
surrounding the hopper with ice). Position a mechanical stirrer
into the buffer solution so that the blades are fully immersed.
Using the syringe pump, slowly (1-3 mL/min) add all of the
itraconazole-surfactant concentrate to the stirred, cooled buffer
solution. A stirring rate of at least 700 rpm is recommended. The
resulting cooled suspension is immediately homogenized (at 10,000
to 30,000 psi) for 10-30 minutes. At the end of homogenization, the
temperature of the suspension in the hopper does not exceed
75.degree. C.
[0089] The homogenized suspension is collected in 500-mL bottles,
which are cooled immediately in the refrigerator (2-8.degree. C.).
Characteristics of particle morphology of the suspension before and
after homogenization were very similar to that seen in Example 1,
except that in process category 1 B, the pre-homogenized material
tended to form fewer and smaller aggregates which resulted in a
much smaller overall particle size as measured by laser
diffraction. After homogenization, dynamic light scattering results
were typically identical to those presented in Example 1.
Example 4
Preparation of Itraconazole Suspension by Use of Process Category
1, Method B with Ultrasonication
[0090] To a 500-mL flask add 252 mL of Water for Iniection. Prepare
a 50 mM tris (tromethamine) buffer by dissolving 6.06 grams of tris
in 800 mL of Water for Injection. Titrate this solution to pH 8.0
with 0.1 M hydrochloric acid. Dilute the resulting solution to 1
liter with additional Water for Injection. Add 30 mL of the tris
buffer to the water. Stir thoroughly to mix solutions.
[0091] In a 30-mL beaker add 6.6 grams of Pluronic F-68 (poloxamer
188) and 0.9 grams of sodium deoxycholate to 18 mL of
N-methyl-2-pyrrolidinone. Heat the mixture to 50-60.degree. C., and
stir to dissolve solids. After total dissolution is visually
apparent, stir another 15 minutes to ensure complete dissolution.
To this solution, add 3.0 grams of itraconazole, and stir until
totally dissolved. Cool the itraconazole-surfactant-NMP solution to
room temperature.
[0092] Charge a syringe pump (one 30-mL glass syringe with the
18-mL of the concentrated itraconazole solution prepared
previously. Position a mechanical stirrer into the buffer solution
so that the blades are fully immersed. Cool the container to
0-5.degree. C. by immersion in an ice bath. Using the syringe pump,
slowly (1-3 mL/min) add all of the itraconazole-surfactant
concentrate to the stirred, cooled buffer solution. A stirring rate
of at least 700 rpm is recommended. The resulting cooled suspension
is immediately sonicated (10,000 to 25,000 Hz, at least 400 W) for
15-20 minutes, in 5 minute intervals. After the first 5-minute
sonication, remove the ice bath and proceed with further
sonication. At the end of ultrasonication, the temperature of the
suspension in the hopper does not exceed 75.degree. C.
[0093] The resultant suspension is collected in a 500-mL bottle,
which is cooled immediately in the refrigerator (2-8.degree. C.).
Characteristics of particle morphology of the suspension before and
after sonication were very similar to that seen in Example 1,
except that in Process Category 1, Method B, the pre-sonicated
material tended to form fewer and smaller aggregates which resulted
in a much smaller overall particle size as measured by laser
diffraction. After ultrasonication, dynamic light scattering
results were typically identical to those presented in Example
1
B. Examples of Process Category 2
Example 5
Preparation of Itraconazole Suspension (1%) with 0.75% Solutol.RTM.
HR (PEG-660-12-hydroxystearate) Process Category 2, Method B
[0094] Solutol (2.25 g) and itraconazole (3.0 g) were weighed into
a beaker and 36 mL of filtered N-methyl-2-pyrrolidinone (NMP) was
added. This mixture was stirred under low heat (up to 40.degree.
C.) for approximately 15 minutes until the solution ingredients
were dissolved. The solution was cooled to room temperature and was
filtered through a 0.2-micron filter under vacuum. Two 60-mL
syringes were filled with the filtered drug concentrate and were
placed in a syringe pump. The pump was set to deliver approximately
1 mL/min of concentrate to a rapidly stirred (400 rpm) aqueous
buffer solution. The buffer solution consisted of 22 g/L of
glycerol in 5 mM tris buffer. Throughout concentrate addition, the
buffer solution was kept in an ice bath at 2-3.degree. C. At the
end of the precipitation, after complete addition of concentrate to
the buffer solution, about 100 mL of the suspension was centrifuged
for 1 hour, the supernatant was discarded. The precipitate was
resuspended in a 20% NMP solution in water, and again centrifuged
for 1 hour. The material was dried overnight in a vacuum oven at
25.degree. C. The dried material was transferred to a vial and
analyzed by X-ray diffractometry using chromium radiation (see FIG.
5).
[0095] Another 100 mL-aliquot of the microprecipitated suspension
was sonicated for 30 minutes at 20,000 Hz, 80% full amplitute (full
amplitude=600 W). The sonicated sample was homogenized in 3 equal
aliquots each for 45 minutes (Avestin C5, 2-5.degree. C.,
15,000-20,000 psi). The combined fractions were centrifuged for
about 3 hours, the supernatant removed, the precipitate resuspended
in 20% NMP. The resuspended mixture was centrifuged again (15,000
rpm at 5.degree. C.). The supernatant was decanted off and the
precipitate was vacuum dried overnight at 25.degree. C. The
precipitate was submitted for analysis by X-ray diffractometry (see
FIG. 5). As seen in FIG. 5, the X-ray diffraction patterns of
processed samples, before and after homogenization, are essentially
identical, yet show a significantly different pattern as compared
with the starting raw material. The unhomogenized suspension is
unstable and agglomerates upon storage at room temperature. The
stabilization that occurs as a result of homogenization is believed
to arise from rearrangement of surfactant on the surface of the
particle. This rearrangement should result in a lower propensity
for particle aggregation.
C. Examples of Process Category
Example 6
Preparation of Carbamazepine Suspension by Use of Process Category
3, Method A with Homogenization
[0096] 2.08 g of carbamazepine was dissolved into 10 mL of NMP. 1.0
mL of this concentrate was subsequently dripped at 0.1 mL/min into
20 mL of a stirred solution of 1.2% lecithin and 2.25% glycerin.
The temperature of the lecithin system was held at 2-5.degree. C.
during the entire addition. The predispersion was next homogenized
cold (5-15.degree. C.) for 35 minutes at 15,000 psi, The pressure
was increased to 23,000 psi and the homogenization was continued
for another 20 minutes. The particles produced by the process had a
mean diameter of 0.881 .mu.m with 99% of the particles being less
than 2.44 .mu.m.
Example 7
Preparation of 1% Carbamazepine Suspension with 0.125% Solutol.RTM.
by Use of Process Category 3, Method B with Homogenization
[0097] A drug concentrate of 20% carbamazepine and 5%
glycodeoxycholic acid (Sigma Chemical Co.) in
N-methyl-2-pyrrolidinone was prepared. The microprecipitation step
involved adding the drug concentrate to the receiving solution
(distilled water) at a rate of 0.1 mL/min. The receiving solution
was stirred and maintained at approximately 5.degree. C. during
precipitation. After precipitation, the final ingredient
concentrations were 1% carbamazepine and 0.125% Solutol.RTM.. The
drug crystals were examined under a light microscope using positive
phase contrast (400.times.). The precipitate consisted of fine
needles approximately 2 microns in diameter and ranging from 50-150
microns in length.
[0098] Homogenization (Avestin C-50 piston-gap homogenizer) at
approximately 20,000 psi for approximately 15 minutes results in
small particles, less than 1 micron in size and largely
unaggregated. Laser diffraction analysis (Horiba) of the
homogenized material showed that the particles had a mean size of
0.4 micron with 99% of the particles less than 0.8 micron. Low
energy sonication, suitable for breaking agglomerated particles,
but not with sufficient energy to cause a cominution of individual
particles, of the sample before Horiba analysis had no effect on
the results (numbers were the same with and without sonication).
This result was consistent with the absence of particle
agglomeration.
[0099] Samples prepared by the above process were centrifuged and
the supernatant solutions replaced with a replacement solution
consisting of 0.125% Solutol.RTM.. After centrifugation and
supernatant replacement, the suspension ingredient concentrations
were 1% carbamazepine and 0.125% Solutol.RTM.. The samples were
re-homogenized by piston-gap homogenizer and stored at 5.degree. C.
After 4 weeks storage, the suspension had a mean particle size of
0.751 with 99% less than 1.729. Numbers reported are from Horiba
analysis on unsonicated samples.
Example 8
Preparation of 1% Carbamazepine Suspension with 0.06% Sodium
Glycodeoxycholate and 0.06% Poloxamer 188 by Use of Process
Category 3, Method B with Homogenization
[0100] A drug concentrate comprising 20% carbamazepine and 5%
glycodeoxycholate in N-methyl-2-pyrrolidinone was prepared. The
microprecipitation step involved adding the drug concentrate to the
receiving solution (distilled water) at a rate of 0.1 mL/min. Thus,
this and the following examples demonstrate that adding a
surfactant or other excipient to the aqueous precipitating solution
in Methods A and B above is optional. The receiving solution was
stirred and maintained at approximately 5.degree. C. during
precipitation. After precipitation, the final ingredient
concentrations were 1% carbamazepine and 0.125% Solutol.RTM.. The
drug crystals were examined under a light microscope using positive
phase contrast (400.times.). The precipitate consisted of fine
needles approximately 2 microns in diameter and ranging from 50-150
microns in length. Comparison of the precipitate with the raw
material before precipitation reveals that the precipitation step
in the presence of surface modifier (glycodeoxycholic acid) results
in very slender crystals that are much thinner than the starting
raw material (see FIG. 6).
[0101] Homogenization (Avestin C-50 piston-gap homogenizer) at
approximately 20,000 psi for approximately 15 minutes results in
small particles, less than 1 micron in size and largely
unaggregated. See FIG. 7. Laser diffraction analysis (Horiba) of
the homogenized material showed that the particles had a mean size
of 0.4 micron with 99% of the particles less than 0.8 micron.
Sonication of the sample before Horiba analysis had no effect on
the results (numbers were the same with and without sonication).
This result was consistent with the absence of particle
agglomeration.
[0102] Samples prepared by the above process were centrifuged and
the supernatant solutions replaced with a replacement solution
consisting of 0.06% glycodeoxycholic acid (Sigma Chemical Co.) and
0.06% Poloxamer 188. The samples were re-homogenized by piston-gap
homogenizer and stored at 5.degree. C. After 2 weeks storage, the
suspension had a mean particle size of 0.531 micron with 99% less
than 1.14 micron. Numbers reported are from Horiba analysis on
unsonicated samples.
Mathematical Analysis (Example 8) of Force Required to Break
Precipitated Particles as Compared to Force Required to Break
Particles of the Starting Raw Material (Carbamazepine):
[0103] The width of the largest crystals seen in the carbamazepine
raw material (FIG. 6, picture on left) are roughly 10-fold greater
than the width of crystals in the microprecipitated material (FIG.
6, picture on right). On the assumption that the ratio of crystal
thickness (1:10) is proportional to the ratio of crystal width
(1:10), then the moment of force required to cleave the larger
crystal in the raw material should be approximately 1,000-times
greater than the force needed to break the microprecipitated
material, since: e.sub.L=6PL/Ewx.sup.2) Eq. 1 where,
[0104] e.sub.L=longitudinal strain required to break the crystal
("yield value")
[0105] P=load on beam
[0106] L=distance from load to fulcrum
[0107] E=elasticity modulus
[0108] w=width of crystal
[0109] x=thickness of crystal
[0110] Let us assume that L and E are the same for the raw material
and the precipitated material. Additionally, let us assume that
w/w.sub.0=x/x.sub.0=10. Then,
(e.sub.L)0=6P.sub.0L/(Ew.sub.0x.sub.0.sup.2), where the `0`
subscripts refer to raw material e.sub.L=6PL/(Ewx.sup.2), for the
microprecipitate Equating (e.sub.L).sub.0 and e.sub.L,
6PL/(Ewx.sup.2)=6P.sub.0L/(Ew.sub.0x.sub.0.sup.2) After
simplification,
P=P.sub.0(w/w.sub.0)(x/x.sub.0).sup.2=P.sub.0(0.1)(0.1).sup.2=0.001
P.sub.0
[0111] Thus, the yield force, P, required to break the
microprecipitated solid is one-thousandth the required force
necessary to break the starting crystalline solid. If, because of
rapid precipitation, lattice defects or amorphic properties are
introduced, then the modulus (E) should decrease, making the
microprecipitate even easier to cleave.
Example 9
Preparation of 1.6% (w/v) Prednisolone Suspension with 0.05% Sodium
Deoxycholate and 3% N-methyl-2-pyrrolidinone Process Category 3,
Method B
[0112] A schematic of the overall manufacturing process is
presented in FIG. 8. A concentrated solution of prednisolone and
sodium deoxycholate was prepared. Prednisolone (32 g) and sodium
deoxycholate (1 g) were added to a sufficient volume of 1-methyl
2-pyrrolidinone (NMP) to produce a final volume of 60 mL. The
resulting prednisolone concentration was approximately 533.3 mg/mL
and the sodium deoxycholate concentration was approximately 16.67
mg/mL. 60 mL of NMP concentrate was added to 2 L of water cooled to
5.degree. C. at an addition rate of 2.5 mL/min while stirring at
approximately 400 rpm. The resulting suspension contained slender
needle-shaped crystals less than 2 .mu.m in width (FIG. 9). The
concentration contained in the precipitated suspension was 1.6%
(w/v) prednisolone, 0.05% sodium deoxycholate, and 3% NMP.
[0113] The precipitated suspension was pH adjusted to 7.5-8.5 using
sodium hydroxide and hydrochloric acid then homogenized (Avestin
C-50 piston-gap homogenizer) for 10 passes at 10,000 psi. The NMP
was removed by performing 2 successive centrifugation steps
replacing the supernatant each time with a fresh surfactant
solution, which contained the desired concentrations of surfactants
needed to stabilize the suspension (see Table 2). The suspension
was homogenized for another 10 passes at 10,000 psi. The final
suspension contained particles with a mean particle size of less
than 1 .mu.m, and 99% of particles less than 2 .mu.m. FIG. 10 is a
photomicrograph of the final prednisolone suspension after
homogenization.
[0114] A variety of different surfactants at varying concentrations
were used in the centrifugation/surfactant replacement step (see
Table 2). Table 2 lists combinations of surfactants that were
stable with respect to particle size (mean<1 .mu.m, 99%<2
.mu.m), pH (6-8), drug concentration (less than 2% loss) and
re-suspendability (resuspended in 60 seconds or less).
[0115] Notably this process allows for adding the active compound
to an aqueous diluent without the presence of a surfactant or other
additive. This is a modification of process Method B in FIG. 2.
TABLE-US-00002 TABLE 2 List of stable prednisolone suspensions
prepared by microprecipitation process of FIG. 8 (Example 9) 2
Weeks 2 Months Initial 40.degree. C. 5.degree. C. 25.degree. C.
40.degree. C. Formulation Mean >99% Mean >99% Mean >99%
Mean >99% Mean >99% % Loss* 1.6% prednisolone, 0.79 1.65 0.84
1.79 0.83 1.86 0.82 1.78 0.82 1.93 <2% 0.6% phospholipids, 0.5%
sodium deoxycholate, 5 mM TRIS, 2.2% glycerol** 1.6% prednisolone,
0.77 1.52 0.79 1.67 0.805 1.763 0.796 1.693 0.81 1.633 <2% 0.6%
Solutol .RTM., 0.5% sodium deoxycholate, 2.2% glycerol 1.6%
prednisolone, 0.64 1.16 0.82 1.78 0.696 1.385 0.758 1.698 0.719
1.473 <2% 0.1% poloxamer 188, 0.5% sodium deoxycholate, 2.2%
glycerol 1.6% prednisolone, 0.824 1.77 0.87 1.93 0.88 1.95 0.869
1.778 0.909 1.993 <2% 5% phospholipids, 5 mM TRIS, 2.2% glycerol
*Difference in itraconazole concentration between samples stored
for 2 months at 5 and 25.degree. C. **Stable through at least 6
months.
[0116] Particle sizes (by laser light scattering), in microns:
[0117] 5.degree. C.: 0.80 (mean), 1.7 (99%) [0118] 25.degree. C.:
0.90 (mean); 2.51 (99%) [0119] 40.degree. C.: 0.99 (mean); 2.03
(99%)
[0120] Difference in itraconazole concentration between samples
stored at 5 and 25.degree. C.: <2%
Example 10
Preparation of Prednisolone Suspension by Use of Process Category
3, Method A with Homogenization
[0121] 32 g of prednisolone was dissolved into 40 mL of NMP. Gentle
heating at 40-50.degree. C. was required to effect dissolution. The
drug NMP concentrate was subsequently dripped at 2.5 mL/min into 2
liters of a stirred solution that consisted of 0.1.2% lecithin and
2.2% glycerin. No other surface modifiers were added. The
surfactant system was buffered at pH=8.0 with 5 mM tris buffer and
the temperature was held at 0.degree. to 5.degree. C. during the
entire precipitation process. The post-precipitated dispersion was
next homogenized cold (5-15.degree. C.) for 20 passes at 10,000
psi. Following homogenization, the NMP was removed by centrifuging
the suspension, removing the supernatant, and replacing the
supernatant with fresh surfactant solution. This post-centrifuged
suspension was then rehomogenized cold (5-15.degree. C.) for
another 20 passes at 10,000 psi. The particles produced by this
process had a mean diameter of 0.927 .mu.m with 99% of the
particles being less than 2.36 .mu.m.
Example 11
Preparation of Nabumetone Suspension by Use of Process Category 3,
Method B with Homogenization
[0122] Surfactant (2.2 g of poloxamer 188) was dissolved in 6 mL of
N-methyl-2-pyrrolidinone. This solution was stirred at 45.degree.
C. for 15 minutes, after which 1.0 g of nabumetone was added. The
drug dissolved rapidly. Diluent was prepared which consisted of 5
mM tris buffer with 2.2% glycerol, and adjusted to pH 8, A 100-mL
portion of diluent was cooled in an ice bath. The drug concentrate
was slowly added (approximately 0.8 mL/min) to the diluent with
vigorous stirring.
[0123] This crude suspension was homogenized at 15,000 psi for 30
minutes and then at 20,000 psi for 30 minutes
(temperature=5.degree. C.). The final nanosuspension was found to
be 930 nm in effective mean diameter (analyzed by laser
diffraction). 99% of the particles were less than approximately 2.6
microns.
Example 12
Preparation of Nabumetone Suspension by use of Process Category 3,
Method B with Homogenization and the use of Solutol.RTM. HS 15 as
the Surfactant. Replacement of Supernatant Liquid with a
Phospholipid Medium
[0124] Nabumetone (0.987 grams) was dissolved in 8 mL of
N-methyl-2-pyrmlidinone. To this solution was added 2.2 grams of
Solutol.RTM. HS 15. This mixture was stirred until complete
dissolution of the surfactant in the drug concentrate. Diluent was
prepared, which consisted of 5 mM tris buffer with 2.2% glycerol,
and which was adjusted to pH 8. The diluent was cooled in an ice
bath, and the drug concentrate was slowly added (approximately 0.5
mL/min) to the diluent with vigorous stirring. This crude
suspension was homogenized for 20 minutes at 15,000 psi, and for 30
minutes at 20,000 psi.
[0125] The suspension was centrifuged at 15,000 rpm for 15 minutes
and the supernatant was removed and discarded. The remaining solid
pellet was resuspended in a diluent consisting of 1.2%
phospholipids. This medium was equal in volume to the amount of
supernatant removed in the previous step. The resulting suspension
was then homogenized at approximately 21,000 psi for 30 minutes.
The final suspension was analyzed by laser diffraction and was
found to contain particles with a mean diameter of 542 nm, and a
99% cumulative particle distribution sized less than 1 micron.
Example 13
Preparation of 1% Itraconazole Suspension with Poloxamer with
Particles of a Mean Diameter of Approximately 220 nm
[0126] Itraconazole concentrate was prepared by dissolving 10.02
grams of itraconazole in 60 mL of N-methyl-2-pyrrolidinone. Heating
to 70.degree. C. was required to dissolve the drug. The solution
was then cooled to room temperature. A portion of 50 mM
tris(hydroxymethyl)aminomethane buffer (tris buffer) was prepared
and was pH adjusted to 8.0 with SM hydrochloric acid. An aqueous
surfactant solution was prepared by combining 22 g/L poloxamer 407,
3.0 g/L egg phosphatides, 22 g/L glycerol, and 3.0 g/L sodium
cholate dihydrate. 90.degree. mL of the surfactant solution was
mixed with 100 mL of the tris buffer to provide 1000 mL of aqueous
diluent.
[0127] The aqueous diluent was added to the hopper of the
homogenizer (APV Gaulin Model 15MR-8TA), which was cooled by using
an ice jacket. The solution was rapidly stirred (4700 rpm) and the
temperature was monitored. The itraconazole concentrate was slowly
added, by use of a syringe pump, at a rate of approximately 2
mL/min. Addition was complete after approximately 30 minute. The
resulting suspension was stirred for another 30 minutes while the
hopper was still being cooled in an ice jacket, and an aliquot was
removed for analysis by light microscopy any dynamic light
scatting. The remaining suspension was subsequently homogenized for
15 minutes at 10,000 psi. By the end of the homogenization the
temperature had risen to 74.degree. C. The homogenized suspension
was collected in a 1-L Type I glass bottle and sealed with a robber
closure. The bottle containing suspension was stored in a
refrigerator at 5.degree. C.
[0128] A sample of the suspension before homogenization showed the
sample to consist of both free particles, clumps of particles, and
multilamellar lipid bodies. The free particles could not be clearly
visualized due to Brownian motion; however, many of the aggregates
appeared to consist of amorphous, non-crystalline material.
[0129] The homogenized sample contained free submicron particles
having excellent size homogeneity without visible lipid vesicles.
Dynamic light scattering showed a monodisperse logarithmic size
distribution with a median diameter of approximately 220 nm. The
upper 99% cumulative size cutoff was approximately 500 nm. FIG. 11
shows a comparison of the size distribution of the prepared
nanosuspension with that of a typical parenteral fat emulsion
product (10% Intralipid.RTM., Pharmacia).
Example 14
Preparation of 1% Itraconazole Nanosuspension with
Hydroxyethylstarch
[0130] Preparation of Solution A: Hydroxyethylstarch (1 g,
Ajinomoto) was dissolved in 3 mL of N-methyl-2-pyrrolidinone (NMP).
This solution was heated in a water bath to 70-80.degree. C. for 1
hour. In another container was added 1 g of itraconazole (Wyckoff).
Three mL of NMP were added and the mixture heated to 70-80.degree.
C. to effect dissolution (approximately 30 minutes). Phospholipid
(Lipoid S-100) was added to this hot solution. Heating was
continued at 70-90.degree. C. for 30 minutes until all of the
phospholipid was dissolved. The hydroxyethylstach solution was
combined with the itraconazole/phospholipid solution. This mixture
was heated for another 30 minutes at 80-95.degree. C. to dissolve
the mixture.
[0131] Addition of Solution A to Tris Buffer: Ninety-four (94) mL
of 50 mM tris(hydroxymethyl)aminomethane buffer was cooled in an
ice bath. As the tris solution was being rapidly stirred, the hot
Solution A (see above) was slowly added dropwise (less than 2
cc/minute).
[0132] After complete addition, the resulting suspension was
sonicated (Cole-Panner Ultrasonic Processor-20,000 Hz, 80%
amplitude setting) while still being cooled in the ice bath. A
one-inch solid probe was utilized. Sonication was continued for 5
minutes. The ice bath was removed, the probe was removed and
retuned, and the probe was again immersed in the suspension. The
suspension was sonicated again for another 5 minutes without the
ice bath. The sonicater probe was once again removed and retuned,
and after immersion of the probe the sample was sonicated for
another 5 minutes. At this point, the temperature of the suspension
had risen to 82.degree. C. The suspension was quickly cooled again
in an ice bath and when it was found to be below room temperature
it was poured into a Type I glass bottle and sealed. Microscopic
visualization of the particles indicated individual particle sizes
on the order of one micron or less.
[0133] After one year of storage at room temperature, the
suspension was reevaluated for particle size and found to have a
mean diameter of approximately 300 nm.
Example 15
Prophetic Example of Method A using HES
[0134] The present invention contemplates preparing a 1%
itraconazole nanosuspension with hydroxyethylstarch utilizing
Method A by following the steps of Example 14 with the exception
the HES would be added to the tris buffer solution instead of to
the NMP solution. The aqueous solution may have to be heated to
dissolve the HES.
Example 16
Seeding During Homogenization to Convert a Mixture of Polymorphs to
the More Stable Polymorph
[0135] Sample preparation. An itraconazole nanosuspension was
prepared by a microprecipitation-homogenization method as follows.
Itraconazole (3 g) and Solutol HR (2.25 g) were dissolved in 36 mL
of N-methyl-2-pyrrolidinone (NMP) with low heat and stirring to
form a drug concentrate solution. The solution was cooled to room
temperature and filtered through a 0.2 .mu.m nylon filter under,
vacuum to remove undissolved drug or particulate matter. The
solution was viewed under polarized light to ensure that no
crystalline material was present after filtering. The drug
concentrate solution was then added at 1.0 mL/minute to
approximately 264 mL of an aqueous buffer solution (22 g/L glycerol
in 5 mM tris buffer). The aqueous solution was kept at 2-3.degree.
C. and was continuously stirred at approximately 400 rpm during the
drug concentrate addition. Approximately 100 mL of the resulting
suspension was centrifuged and the solids resuspended in a
pre-filtered solution of 20% NMP in water. This suspension was
re-centrifuged and the solids were transferred to a vacuum oven for
overnight drying at 25.degree. C. The resulting solid sample was
labeled SMP 2 PRE.
[0136] Sample characterization. The sample SMP 2 PRE and a sample
of the raw material itraconazdle were analyzed using powder x-ray
diffractometry. The measurements were performed using a Rigaku
MiniFlex+instrument with copper radiation, a step size of
0.02.degree. 2.theta.and scan speed of 0.25.degree.
2.theta./minute. The resulting powder diffraction patterns are
shown in FIG. 12. The patterns show that SMP-2-PRE is significantly
different from the raw material, suggesting the presence of a
different polymorph or a pseudopolymorph.
[0137] Differential scanning calorimetry (DSC) traces for the
samples are shown in FIGS. 13 a and b. Both samples were heated at
2'/min to 180.degree. C. in hermetically sealed aluminum pans.
[0138] The trace for the raw material itraconazle (FIG. 13a) shows
a sharp endotherm at approximately 165.degree. C.
[0139] The trace for SMP 2 PRE (FIG. 13b) exhibits two endotherms
at approximately 159.degree. C. and 153.degree. C. This result, in
combination with the powder x-ray diffraction patterns, suggests
that SMP 2 PRE consists of a mixture of polymorphs, and that the
predominant form is a polymorph that is less stable than polymorph
present in the raw material.
[0140] Further evidence for this conclusion is provided by the DSC
trace in FIG. 14, which shows that upon heating SMP 2 PRE through
the first transition, then cooling and reheating, the less stable
polymorph melts and recrystallizes to form the more stable
polymorph.
[0141] Seeding. A suspension was prepared by combining 0.2 g of the
solid SMP 2 PRE and 0.2 g of raw material itraconazole with
distilled water to a final volume of 20 mL (seeded sample). The
suspension was stirred until all the solids were wetted. A second
suspension was prepared in the same manner but without adding the
raw material itraconazole (unseeded sample). Both suspensions were
homogenized at approximately 18,000 psi for 30 minutes. Final
temperature of the suspensions after homogenization was
approximately 30.degree. C. The suspensions were then centrifuged
and the solids dried for approximately 16 hours at 30.degree.
C.
[0142] FIG. 15 shows the DSC traces of the seeded and unseeded
samples. The heating rate for both samples was 2.sup.0/min to
180.degree. C. in hermetically sealed aluminum pans. The trace for
the unseeded sample shows two endotherms, indicating that a mixture
of polymorphs is still present after homogenization. The trace for
the seeded sample shows that seeding and homogenization causes the
conversion of the solids to the stable polymorph. Therefore,
seeding appears to influence the kinetics of the transition from
the less stable to the more stable polymorphic form.
Example 17
Seeding During Precipitation to Preferentially Form a Stable
Polymorph
[0143] Sample preparation. An itraconazole-NMP drug concentrate was
prepared by dissolving 1.67 g of itraconazole in 10 mL of NMP with
stirring and gentle heating. The solution was filtered twice using
0.2 .mu.m syringe filters. Itraconazole nanosuspensions were then
prepared by adding 1.2 mL of the drug concentrate to 20 mL of an
aqueous receiving solution at approx. 3.degree. C. and stirring at
approx. 500 rpm. A seeded nanosuspension was prepared by using a
mixture of approx. 0.02 g of raw material itraconazole in distilled
water as the receiving solution. An unseeded nanosuspension was
prepared by using distilled water only as the receiving solution.
Both suspensions were centrifuged, the supernatants decanted, and
the solids dried in a vacuum oven at 30.degree. C. for
approximately 16 hours.
[0144] Sample characterization. FIG. 16 shows a comparison of the
DSC traces for the solids from the seeded and unseeded suspensions.
The samples were heated at 2.degree./min to 180.degree. C. in
hermetically sealed aluminum pans. The dashed line represents the
unseeded sample, which shows two endotherms, indicating the
presence of a polymorphic mixture. The solid line represents the
seeded sample, which shows only one endotherm near the expected
melting temperature of the raw material, indicating that the seed
material induced the exclusive formation of the more stable
polymorph.
Example 18
Polymorph Control by Seeding the Drug Concentrate
[0145] Sample preparation. The solubility of itraconazole in NMP at
room temperature (approximately 22.degree. C.) was experimentally
determined to be 0.16 g/mL. A 0.20 g/mL drug concentrate solution
was prepared by dissolving 2.0 g of itraconazole and 0.2 g
Poloxamer 188 in 10 mL NMP with heat and stirring. This solution
was then allowed to cool to room temperature to yield a
supersaturated solution. A microprecipitation experiment was
immediately performed in which 1.5 mL of the drug concentrate was
added to 30 mL of an aqueous solution containing 0.1% deoxycholate,
2.2% glycerol. The aqueous solution was maintained at
.about.2.degree. C. and a stir rate of 350 rpm during the addition
step. The resulting presuspension was homogenized at .about.13,000
psi for approx. 10 minutes at 50.degree. C. The suspension was then
centrifuged, the supernatant decanted, and the solid crystals dried
in a vacuum oven at 30.degree. C. for 135 hours.
[0146] The supersaturated drug concentrate was subsequently aged by
storing at room temperature in order to induce crystallization.
After 12 days, the drug concentrate was hazy, indicating that
crystal formation had occurred. An itraconazole suspension was
prepared from the drug concentrate, in the same manner as in the
first experiment, by adding 1.5 mL to 30 mL of an aqueous solution
containing 0.1% deoxycholate, 2.2% glycerol. The aqueous solution
was maintained at .about.5.degree. C. and a stir rate of 350 rpm
during the addition step. The resulting presuspension was
homogenized at .about.13,000 psi for approx. 10 minutes at
50.degree. C. The suspension was then centrifuged, the supernatant
decanted, and the solid crystals dried in a vacuum oven at
30.degree. C. for 135 hours.
[0147] Sample characterization. X-ray powder diffraction analysis
was used to determine the morphology of the dried crystals. The
resulting patterns are shown in FIG. 17. The crystals from the
first experiment (using fresh drug concentrate) were determined to
consist of the more stable polymorph. In contrast, the crystals
from the second experiment (aged drug concentrate) were
predominantly composed of the less stable polymorph, with a small
amount of the more stable polymorph also present. Therefore, it is
believed that aging induced the formation of crystals of the less
stable polymorph in the drug concentrate, which then acted as seed
material during the microprecipitation and homogenization steps
such that the less stable polymorph was preferentially formed.
[0148] While specific embodiments have been illustrated and
described, numerous modifications come to mind without departing
from the spirit of the invention and the scope of protection is
only limited by the scope of the accompanying claims.
* * * * *