U.S. patent application number 10/175883 was filed with the patent office on 2003-05-08 for pharmaceutical compositions for poorly soluble drugs.
Invention is credited to Hayes, David, Morella, Angelo Mario.
Application Number | 20030086976 10/175883 |
Document ID | / |
Family ID | 25646230 |
Filed Date | 2003-05-08 |
United States Patent
Application |
20030086976 |
Kind Code |
A1 |
Hayes, David ; et
al. |
May 8, 2003 |
Pharmaceutical compositions for poorly soluble drugs
Abstract
The present invention provides a pharmaceutical composition of a
practically insoluble drug, wherein the composition may be
administered with food or without food. The composition may be in
the form of a solid dispersion of the practically insoluble drug
and a polymer having acidic functional groups, and the composition
may in vitro form a suspension.
Inventors: |
Hayes, David; (Rostrevor,
AU) ; Morella, Angelo Mario; (Athelstone,
AU) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Family ID: |
25646230 |
Appl. No.: |
10/175883 |
Filed: |
June 21, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10175883 |
Jun 21, 2002 |
|
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PCT/AU00/01592 |
Dec 22, 2000 |
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Current U.S.
Class: |
424/486 ;
424/501 |
Current CPC
Class: |
A61K 31/496 20130101;
A61P 43/00 20180101; A61K 9/1652 20130101; A61P 31/10 20180101;
A61K 9/146 20130101; A61K 9/4866 20130101 |
Class at
Publication: |
424/486 ;
424/501 |
International
Class: |
A61K 009/14; A61K
009/50 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 23, 1999 |
AU |
PQ4854 |
May 12, 2000 |
AU |
PQ7450 |
Claims
1. A pharmaceutical composition in the form of a solid dispersion
of a practically insoluble drug and a polymer having acidic
functional groups, wherein in vitro the composition forms a
suspension.
2. A pharmaceutical composition according to claim 1, wherein the
pharmaceutical composition is such that, upon administration, a
suspension is formed in vivo, the suspension being a homogeneous
dispersion of particles.
3. A pharmaceutical composition according to claim 2, wherein the
particles of the suspension, formed in vitro, are at least of a
size where they in vitro diffract light such that the suspension
presents as a cloudy suspension.
4. A pharmaceutical composition according to claim 2 wherein the
particles of the suspension are of a size less than 10 micrometer
but greater than 1 nm.
5. A pharmaceutical composition according to claim 3 wherein the
particles of the suspension are of a size less than 10 micrometer
but greater than 1 nm.
6. A pharmaceutical composition according to claim 2 wherein a
portion of the particles is in microparticulate form and a portion
of the particles is in nanoparticulate form.
7. A pharmaceutical composition according to claim 3 wherein a
portion of the particles is in microparticulate form and a portion
of the particles is in nanoparticulate form.
8. A pharmaceutical composition according to claim 2 wherein at
least a portion of the particles of the suspension are of a size
less than 450 nm but greater than 1 nm, such that after passing the
cloudy suspension through a 450 nm filter, the suspension remains
cloudy.
9. A pharmaceutical composition according to claim 3 wherein at
least a portion of the particles of the suspension are of a size
less than 450 nm but greater than 1 nm, such that after passing the
cloudy suspension through a 450 nm filter, the suspension remains
cloudy.
10. A pharmaceutical composition according to any one of claims 1
to 9 wherein the suspension is present during in vitro dissolution
testing at a pH in the range of 4.0 to 8.0.
11. A pharmaceutical composition according to any one of claims 1
to 9 wherein the suspension is present during in vitro dissolution
testing at a pH in the range of 5.5 to 7.5.
12. A pharmaceutical composition according to claim 10 wherein the
in vitro dissolution testing includes an acidic pre-treatment
step.
13. A pharmaceutical composition according to claim 11 wherein the
in vitro dissolution testing includes an acidic pre-treatment
step.
14. A pharmaceutical composition according to claim 12 wherein the
acidic pre-treatment step is suspension in a dissolution medium at
a pH of about 1.2 for a period of about 20 minutes.
15. A pharmaceutical composition according to claim 13 wherein the
acidic pre-treatment step is suspension in a dissolution medium at
a pH of about 1.2 for a period of about 20 minutes.
16. A pharmaceutical composition according to any one of claims 1
to 9 wherein the drug is an azole antifungal drug.
17. A pharmaceutical composition according to claim 16 wherein the
azole antifungal drug is itraconazole.
18. A pharmaceutical composition according to claim 16 wherein the
azole antifungal drug is saperconazole.
19. A pharmaceutical composition according to any one of claims 1
to 9 wherein the polymer is one or more of the group comprising
hydroxypropyl methylcellulose phthalate, polyvinyl acetate
phthalate, hydroxypropylmethylcellulose acetate succinate,
alginate, carbomer, carboxymethyl cellulose, methacrylic acid
copolymer, shellac, cellulose acetate phthalate, starch glycolate,
polacrylin, cellulose acetate phthalate, methyl cellulose acetate
phthalate, hydroxypropylcellulose acetate phthalate, cellulose
acetate terephthalate, cellulose acetate isophthalate and cellulose
acetate trimellitate.
20. A pharmaceutical composition according to claim 16 wherein the
polymer is one or more of the group comprising hydroxypropyl
methylcellulose phthalate, polyvinyl acetate phthalate,
hydroxypropylmethylcellulose acetate succinate, alginate, carbomer,
carboxymethyl cellulose, methacrylic acid copolymer, shellac,
cellulose acetate phthalate, starch glycolate, polacrylin,
cellulose acetate phthalate, methyl cellulose acetate phthalate,
hydroxypropylcellulose acetate phthalate, cellulose acetate
terephthalate, cellulose acetate isophthalate and cellulose acetate
trimellitate.
21. A pharmaceutical composition according to claim 17 wherein the
polymer is one or more of the group comprising hydroxypropyl
methylcellulose phthalate, polyvinyl acetate phthalate,
hydroxypropylmethylcellulose acetate succinate, alginate, carbomer,
carboxymethyl cellulose, methacrylic acid copolymer, shellac,
cellulose acetate phthalate, starch glycolate, polacrylin,
cellulose acetate phthalate, methyl cellulose acetate phthalate,
hydroxypropylcellulose acetate phthalate, cellulose acetate
terephthalate, cellulose acetate isophthalate and cellulose acetate
trimellitate.
22. A pharmaceutical composition according to claim 18 wherein the
polymer is one or more of the group comprising hydroxypropyl
methylcellulose phthalate, polyvinyl acetate phthalate,
hydroxypropylmethylcellulose acetate succinate, alginate, carbomer,
carboxymethyl cellulose, methacrylic acid copolymer, shellac,
cellulose acetate phthalate, starch glycolate, polacrylin,
cellulose acetate phthalate, methyl cellulose acetate phthalate,
hydroxypropylcellulose acetate phthalate, cellulose acetate
terephthalate, cellulose acetate isophthalate and cellulose acetate
trimellitate.
23. A pharmaceutical composition according to claim 19 wherein the
polymer is a hydroxypropyl methylcellulose phthalate.
24. A pharmaceutical composition according to any one of claims 20
to 22 wherein the polymer is a hydroxypropyl methylcellulose
phthalate.
25. A pharmaceutical composition according to any one of claims 1
to 9 wherein the ratio of drug to polymer is in the range of from
3:1 to 1:20.
26. A pharmaceutical composition according to any one of claims 1
to 9 wherein the ratio of drug to polymer is in the range of from
1:1 to 1:3.
27. A pharmaceutical composition according to any one of claims 1
to 9 wherein the solid dispersion is formed by spray drying
techniques.
28. A pharmaceutical composition according to claim 27 wherein the
polymer is dispersed within a solvent prior to dispersion of the
drug, wherein the solvent is one or more of the group comprising
methylene chloride, chloroform, ethanol, methanol, propan-2-ol,
ethylacetate, acetone and water.
29. A pharmaceutical composition according to any one of claims 1
to 9 wherein the bioavailability of the drug in the pharmaceutical
composition is at least twice the bioavailability of the drug per
se.
30. A pharmaceutical composition according to claim 16 wherein the
bioavailability of the drug in the pharmaceutical composition is at
least twice the bioavailability of the drug per se.
31. A pharmaceutical composition according to claim 17 wherein the
bioavailability of the drug in the pharmaceutical composition is at
least twice the bioavailability of the drug per se.
32. A pharmaceutical composition according to claim 18 wherein the
bioavailability of the drug in the pharmaceutical composition is at
least twice the bioavailability of the drug per se.
33. A pharmaceutical composition according to any one of claims 1
to 9 wherein the composition has an AUC under fed conditions that
is 80 to 125% of the composition's AUC under fasted conditions.
34. A pharmaceutical composition according to claim 16 wherein the
composition has an AUC under fed conditions that is 80 to 125% of
the composition's AUC under fasted conditions.
35. A pharmaceutical composition according to claim 17 wherein the
composition has an AUC under fed conditions that is 80 to 125% of
the composition's AUC under fasted conditions.
36. A pharmaceutical composition according to claim 18 wherein the
composition has an AUC under fed conditions that is 80 to 125% of
the composition's AUC under fasted conditions.
37. A pharmaceutical dosage form according to any of claims 1 to 9
wherein the composition has a reduced food effect compared to the
drug per se.
38. A pharmaceutical dosage form according to claim 16 wherein the
composition has a reduced food effect compared to the drug per
se.
39. A pharmaceutical dosage form according to claim 17 wherein the
composition has a reduced food effect compared to the drug per
se.
40. A pharmaceutical dosage form according to claim 18 wherein the
composition has a reduced food effect compared to the drug per
se.
41. A pharmaceutical dosage form containing a therapeutically
effective amount of the pharmaceutical composition of any one of
claims 1 to 9.
42. A pharmaceutical dosage form containing a therapeutically
effective amount of the pharmaceutical composition of claim 16.
43. A pharmaceutical dosage form containing a therapeutically
effective amount of the pharmaceutical composition of claim 17.
44. A pharmaceutical dosage form containing a therapeutically
effective amount of the pharmaceutical composition of claim 18.
45. A pharmaceutical dosage form according to claim 41 including
one or more excipients such as disintegrants, diluents, fillers,
lubricants, glidants, colourants and flavours.
46. A pharmaceutical dosage form according to claim 41 wherein the
dosage form is a capsule or a tablet.
47. A pharmaceutical composition in the form of a solid dispersion
of an azole antifungal drug and a polymer having acidic functional
groups, wherein in vitro the composition forms a suspension.
48. A pharmaceutical composition according to claim 47 wherein the
suspension is present during in vitro dissolution testing at a pH
in the range of 4.0 to 8.0.
49. A pharmaceutical composition according to claim 47 wherein the
suspension is present during in vitro dissolution testing at a pH
in the range of 5.5 to 7.5.
50. A pharmaceutical composition according to any one of claims 47
to 49 wherein the polymer is a hydroxypropyl methylcellulose
phthalate.
51. A pharmaceutical composition according to any one of claims 47
to 49 wherein the drug is itraconazole.
52. A pharmaceutical composition according to any one of claims 47
to 49 wherein in vivo the composition provides a mean C.sub.max of
at least 100 ng/ml, after administration of a 100 mg dose of the
azole antifungal drug in the fasted state.
53. A pharmaceutical composition according to claim 50 wherein in
vivo the composition provides a mean C.sub.max of at least 100
ng/ml, after administration of a 100 mg dose of the azole
antifungal drug in the fasted state.
54. A pharmaceutical composition according to claim 51 wherein in
vivo the composition provides a mean C.sub.max of at least 100
ng/ml, after administration of a 100 mg dose of the azole
antifungal drug in the fasted state.
55. A pharmaceutical composition according to any one of claims 47
to 49 wherein in vivo the composition provides a mean C.sub.max of
at least 150 to 250 ng/ml, after administration of a 100 mg dose of
the azole antifungal drug in the fasted state.
56. A pharmaceutical composition according to claim 50 wherein in
vivo the composition provides a mean C.sub.max of at least 150 to
250 ng/ml, after administration of a 100 mg dose of the azole
antifungal drug in the fasted state.
57. A pharmaceutical composition according claim 51 wherein in vivo
the composition provides a mean C.sub.max of at least 150 to 250
ng/ml, after administration of a 100 mg dose of the azole
antifungal drug in the fasted state.
58. A pharmaceutical composition according to any one of claims 47
to 49 wherein the composition provides a mean AUC of at least 800
ng.h/ml, after administration of a 100 mg dose of the azole
antifungal drug in the fasted state.
59. A pharmaceutical composition according to claims 50 wherein the
composition provides a mean AUC of at least 800 ng.h/ml, after
administration of a 100 mg dose of the azole antifungal drug in the
fasted state.
60. A pharmaceutical composition according to claim 51 wherein the
composition provides a mean AUC of at least 800 ng.h/ml, after
administration of a 100 mg dose of the azole antifungal drug in the
fasted state.
61. A pharmaceutical composition according to any one of claims 47
to 49 wherein the composition provides a mean AUC of 1300 to 2300
ng.h/ml, after administration of a 100 mg dose of the azole
antifungal drug in the fasted state.
62. A pharmaceutical composition according to claim 50 wherein the
composition provides a mean AUC of 1300 to 2300 ng.h/ml, after
administration of a 100 mg dose of the azole antifungal drug in the
fasted state.
63. A pharmaceutical composition according to claim 51 wherein the
composition provides a mean AUC of 1300 to 2300 ng.h/ml, after
administration of a 100 mg dose of the azole antifungal drug in the
fasted state.
64. A pharmaceutical composition according to any one of claims 47
to 49 wherein the composition has a reduced food effect compared to
the drug per se.
65. A pharmaceutical composition according to claim 50 wherein the
composition has a reduced food effect compared to the drug per
se.
66. A pharmaceutical composition according to claim 51 wherein the
composition has a reduced food effect compared to the drug per
se.
67. A pharmaceutical composition including about 100 mg of an azole
antifungal drug -wherein in vivo the composition provides a mean
C.sub.max of at least 100 ng/ml, after administration in the fasted
state.
68. A pharmaceutical composition according to claim 67 wherein in
vivo the composition provides a mean C.sub.max of at least 150 to
250 ng/ml, after administration of the azole antifungal drug in the
fasted state.
69. A pharmaceutical composition including about 100 mg of an azole
antifungal drug wherein the composition provides a mean AUC of at
least 800 ng.h/ml, after administration in the fasted state.
70. A pharmaceutical composition according to claim 69 wherein the
composition provides a mean AUC of 1300 to 2300 ng.h/ml, after
administration of the azole antifungal drug in the fasted
state.
71. A pharmaceutical composition according to claim 61 wherein the
azole antifungal drug is itraconazole.
72. A pharmaceutical composition according to claim 62 wherein the
azole antifungal drug is itraconazole.
73. A pharmaceutical composition according to claim 63 wherein the
azole antifungal drug is itraconazole.
74. A pharmaceutical composition according to claim 64 wherein the
azole antifungal drug is itraconazole.
75. A pharmaceutical composition according to claim 65 wherein the
azole antifungal drug is itraconazole.
76. A pharmaceutical composition according to claim 66 wherein the
azole antifungal drug is itraconazole.
77. A pharmaceutical composition according to claim 67 wherein the
azole antifungal drug is itraconazole.
78. A pharmaceutical composition according to claim 68 wherein the
azole antifungal drug is itraconazole.
79. A pharmaceutical composition in the form of a solid dispersion
of a hydroxypropyl methylcellulose phthalate and a practically
insoluble drug, wherein the composition forms a suspension in vitro
in the pH range of 4.0 to 8.0 and provides acceptable absorption in
the intestines.
80. A pharmaceutical composition according to claim 79 wherein the
drug is itraconazole.
81. A pharmaceutical composition according to claim 79 wherein the
suspension is present during in vitro dissolution testing at a pH
in the range of 5.5 to 7.5.
82. A pharmaceutical composition according to claim 80 wherein the
suspension is present during in vitro dissolution testing at a pH
in the range of 5.5 to 7.5.
83. A pharmaceutical composition according to any one of claims 67
to 70 wherein the composition has a reduced food effect compared to
the drug per se.
84. A process for preparing a pharmaceutical composition of a
practically insoluble drug, the process including the steps of: (a)
adding a polymer having acidic functional groups to a solvent to
form a dispersion; (b) adding the drug to the dispersion to form a
suspension or solution; and (c) spray drying the suspension or
solution to form the pharmaceutical composition in the form of a
solid dispersion.
85. A process according to claim 84 wherein step (a) is conducted
so as not to dissolve the polymer acid.
86. A process according to claim 84 wherein the polymer is a
hydroxypropyl methylcellulose phthalate.
87. A process according to claim 85 wherein the polymer is a
hydroxypropyl methylcellulose phthalate.
88. A process according to any one of claims 84 to 87 wherein the
solvent is methylene chloride.
89. A process according to any one of claims 84 to 87 wherein the
drug is itraconazole.
90. A process according to any one of claims 84 to 87 wherein the
solid dispersion is subsequently blended with one or more
excipients to produce a powder for use in a pharmaceutical dosage
form.
91. A process according to claim 90 wherein the blending occurs
with grinding.
92. A process for preparing a pharmaceutical composition of a
practically insoluble drug, the process including dispersing in a
solvent the drug and a polymer having acidic functional groups, and
spray drying the dispersion to form a solid dispersion.
93. A pharmaceutical composition of a practically insoluble drug,
the composition having an AUC under fed conditions that is 80 to
125% of the composition's AUC under fasted conditions.
94. A pharmaceutical composition according to claim 93 wherein the
composition is a solid dispersion of the practically insoluble drug
and a polymer having acidic functional groups.
95. A pharmaceutical composition according to claim 94 wherein the
polymer is a hydroxypropyl methylcellulose phthalate.
96. A pharmaceutical composition according to claim 94 wherein in
vitro the composition forms a suspension.
97. A pharmaceutical composition according to claim 95 wherein in
vitro the composition forms a suspension.
98. A pharmaceutical composition according to any one of claims 93
to 97 wherein the drug is an azole antifungal drug.
99. A pharmaceutical composition according to claim 98 wherein the
drug is itraconazole.
100. A pharmaceutical composition according to claim 98 wherein the
drug is saperconazole.
101. A pharmaceutical composition of a practically insoluble drug,
wherein in vitro the composition forms a suspension.
102. A pharmaceutical composition according to claim 101 wherein
the drug is an azole antifungal drug.
103. A pharmaceutical composition according to claim 102 wherein
the drug is itraconazole.
104. A pharmaceutical composition according to claim 102 wherein
the drug is saperconazole.
105. A pharmaceutical composition according to any one of claims 93
to 97 wherein the composition has a reduced food effect compared to
the drug per se.
106. A pharmaceutical composition according to claim 98 wherein the
composition has a reduced food effect compared to the drug per
se.
107. A pharmaceutical composition according to any one of claims 99
to 104 wherein the composition has a reduced food effect compared
to the drug per se.
108. A process for preparing a pharmaceutical composition of a
practically insoluble drug, the process including the steps of: (a)
adding the drug to a solvent to form a dispersion; (b) adding a
polymer having acidic functional groups to the dispersion to form a
suspension or solution; and (c) spray drying the suspension or
solution to form the pharmaceutical composition in the form of a
solid dispersion.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to improved pharmaceutical
compositions of drugs that are practically insoluble in aqueous
media. The present invention also relates to a process for
preparing the compositions. Furthermore, the present invention
relates to improved dosage forms for the administration of the
compositions.
BACKGROUND OF THE INVENTION
[0002] Drugs that are totally water-insoluble, or are at least
poorly water-soluble, are usually characterised by low absorption
and poor bioavailability, and present special difficulties when
formulating dosage forms therefor. For the purposes of this
specification, such drugs will be referred to as being "practically
insoluble".
[0003] Indeed, it has been reported that the bioavailability of
many practically insoluble drugs is limited by their dissolution
rates and solubility, which in turn are understood to be controlled
by the surface area that they present for dissolution. As such,
attempts to improve the bioavailability of these practically
insoluble drugs have often focussed on particle size reduction.
[0004] Examples of attempts to improve the bioavailability of such
drugs are illustrated in international patent applications
PCT/EP93/02327 and PCT/EP98/01773 both to Janssen Pharmaceutica
N.V. These applications both relate to dosage forms of azole
antifungals, such as itraconazole and saperconazole, which are said
to be only very sparingly soluble in water, and both describe the
incorporation of the drug with water-soluble polymers and the
subsequent coating of the mixture on small beads. In PCT/EP93/02327
the beads are 600 to 700 micrometer in diameter, whereas in
PCT/EP98/01773 the beads are 250 to 355 micrometer in diameter.
[0005] The dosage forms in both applications are said to have good
bioavailability in a form suitable for oral administration, and are
both designed for dissolution in the stomach.
[0006] Janssen adopted a different approach in international patent
application PCT/EP97/02507, again for azole antifungals such as
itraconazole and saperconazole. In this patent application, the
proposed solution to the bioavailability problem is to form a solid
dispersion of the practically insoluble drug and a water soluble
polymer, with ratios of drug to polymer that aim to dissolve the
drug to ensure that the required bioavailability is obtained.
[0007] Another approach is reported in the article "Oral Absorption
Improvement of Poorly Soluble Drug Using Solid Dispersion
Technique" by T. Kai et al (Chem. Pharm. Bull. 44(3) 568-571(1996))
in relation to another antifungal agent, again said to be of low
solubility and exhibiting poor oral absorption characteristics. In
this article, a solid dispersion of the drug is formed with an
enteric polymer and the dissolution characteristics of the solid
dispersion are tested in suitable media at pH 1.2 and pH 6.8, with
a view to determining the dissolution state of the drug. The
article verifies that the drug at pH 6.8 is fully dissolved
(supersaturated) and is thus bioavailable, whereas at pH 1.2 the
enteric polymers had not dissolved, preventing dissolution of the
drug. The article thus promotes as important the supersaturation
(complete dissolution) of the drug to ensure adequate
bioavailability.
[0008] A final attempt to be illustrated is that of European patent
application 98305960.1 to Pfizer Products Inc. This application is
again aimed at improving the bioavailability of low-solubility
drugs such as glycogen phosphorylase inhibitors, 5-lipoxygenase
inhibitors, corticotropic releasing hormone inhibitors and
antipsychotics.
[0009] The Pfizer patent application suggests the use of a solid
dispersion of an enteric polymer (namely,
hydroxypropylmethylcellulose acetate succinate [HPMCAS]) with the
low-solubility drug, again to produce a supersaturated solution in
vivo to ensure adequate bioavailability. Indeed, this application
specifically aims to produce a supersaturated solution of the drug
in order to keep the drug dissolved for as long as possible after
administration.
[0010] Further in relation to practically insoluble drugs, it has
been reported that many such drugs are formulated into dosage forms
that should only be administered with food. For example, a
commercially available itraconazole dosage form (Sporanox.TM.) is
only prescribed for use with food because of relatively poor
bioavailability results when administered under fasted
conditions.
[0011] It is an aim of the present invention to provide a
pharmaceutical composition with improved bioavailability for drugs
that are considered to be practically insoluble.
[0012] However, before turning to discuss the invention, it should
be appreciated that the above discussion of documents, acts,
materials, devices, articles and the like is included in this
specification solely for the purpose of providing a context for the
present invention. It is not suggested or represented that any or
all of these matters formed part of the prior art base or were
common general knowledge in the field relevant to the present
invention as it existed in Australia or elsewhere before the
priority date of each claim of this application.
SUMMARY OF THE INVENTION
[0013] The present invention provides a pharmaceutical composition
of a practically insoluble drug, wherein the composition may be
administered with food or without food. In this form of the
invention, the composition may be in the form of a solid dispersion
of the practically insoluble drug and a polymer having acidic
functional groups, and the composition may in vitro form a
suspension.
[0014] The present invention also provides a pharmaceutical
composition of a practically insoluble drug, the composition having
an AUC under fed conditions that is 80% to 125% of the
composition's AUC under fasted conditions. In this form of the
invention, the composition may be in the form of a solid dispersion
of the practically insoluble drug and a polymer having acidic
functional groups, and the composition may in vitro form a
suspension.
[0015] Further, the present invention provides a pharmaceutical
composition of a practically insoluble drug, wherein in vitro the
composition forms a suspension. In a preferred form, the
composition may be in the form of a solid dispersion of the
practically insoluble drug and a polymer having acidic functional
groups.
[0016] Of course, in all forms of the present invention, and as
will be explained below, it will be appreciated that the
pharmaceutical composition may include other components within it,
such as disintegrants, diluents, fillers and the like.
[0017] Various terms that will be used throughout this
specification have meanings that will be well understood by a
skilled addressee. However, for ease of reference, some of these
terms will now be defined.
[0018] The term "practically insoluble" as used herein applies to
drugs that are essentially totally water-insoluble or are at least
poorly water-soluble. More specifically, the term is applied to any
drug that has a dose (mg) to aqueous solubility (mg/ml) ratio
greater than 100 ml, where the drug solubility is that of the
neutral (for example, free base or free acid) form in unbuffered
water. This meaning is to include, but is not to be limited to,
drugs that have essentially no aqueous solubility (less than 1.0
mg/ml).
[0019] The term "drug" will be widely understood and denotes a
compound having beneficial prophylactic and/or therapeutic
properties when administered to, for example, humans. Further, the
term "drug per se" is used throughout this specification for the
purposes of comparison, and means the drug when in an aqueous
solution/suspension without the addition of any excipients.
[0020] The term "a solid dispersion" in general means a system in
solid state comprising at least two components, wherein one
component is dispersed more or less evenly throughout the other
component or components. In particular, and with reference to a
widely accepted definition from the early 1970's, "solid
dispersions" are the dispersion of one or more active ingredients
in an inert carrier or matrix at solid state, prepared by the
melting, solvent, or melting-solvent methods.
[0021] The term "in vivo" in general means in the living body of a
plant or animal, whereas the term "in vitro" generally means
outside the body and in an artificial environment.
[0022] Reference throughout this specification will be made to the
administration of a pharmaceutical composition under fed conditions
or fasted conditions. It is well understood in the art that the
pharmacokinetic performance of some compositions is affected by the
presence or not of food in the gastrointestinal system. Other
compositions are not so affected. These references thus relate to
the normally accepted administration circumstances that are
referred to in the art as `fed` or `fasted`.
[0023] Reference will also be made to the pharmacokinetic parameter
AUC. This is a widely accepted parameter determined from the
graphical presentation of actual or theoretical plasma profiles
(concentration vs time), and represents the area under the curve
(AUC) of such a profile.
GENERAL DESCRIPTION OF THE INVENTION
[0024] Returning now to a general description of the present
invention, in one form of the invention the pharmaceutical
composition is such that, upon administration, a suspension is
formed in vivo. Preferably, the suspension is a homogeneous
dispersion of particles (containing the drug), the particles at
least being of a size where, in vitro, they diffract light such
that the suspension presents as a cloudy suspension. Thus, evidence
of the presence of such a cloudy suspension can be seen during in
vitro dissolution testing of the solid dispersion of the inventive
composition.
[0025] The particles in the cloudy suspension in vitro will
generally be particles of a size greater than about 1 nm but less
than about 10 micrometer. In vitro dissolution testing of a
pharmaceutical composition according to this form of the present
invention reveals that particles in this size range are present
when tested at a pH in the range of 5.5 to 7.5. Additionally, when
pretreated at acidic pH (namely, when suspended in a dissolution
medium at a pH of about 1.2 for a period of about 20 minutes), in
vitro dissolution testing of a pharmaceutical composition according
to this form of the present invention again reveals that particles
in this size range are present when subsequently tested at a pH in
the range of 5.5 to 7.5. This pre-treatment may be conducted to
simulate in vivo conditions.
[0026] In one form of the present invention, it may be preferred
for a portion of the particles to be present in nanoparticulate
form, such as in the range of 1 nm to 450 nm, and a portion to be
present in microparticulate form (such as in the range of 0.45
micrometer to 10 micrometer). The presence of such nanoparticles in
vivo may be determined by testing for them in vitro, such as by
passing the cloudy suspension through a 450 nm filter and having
the suspension remain cloudy. Such nanoparticles are preferably
present regardless of whether the acidic pre-treatment step
described above is utilised in the testing procedure.
[0027] Therefore, the present invention additionally provides a
pharmaceutical composition of a practically insoluble drug, wherein
the composition forms a suspension in vitro at a pH in the range of
5.5 to 7.5, the suspension having particles in the size range of 1
nm to 10 micrometer, with or without a pre-treatment at acidic pH.
Preferably, the suspension has at least a portion of its particles
in the size range of 1 nm to 450 nm in vitro at a pH in the range
of 5.5 to 7.5, again with or without a pre-treatment at acidic
pH.
[0028] In this preferred form, the pharmaceutical composition may
therefore provide for acceptable absorption of the practically
insoluble drug (where acceptable absorption is indicated by the
extent of the absorption being greater than that of the
crystallised form of the drug per se), in the intestines where the
pH is expected to be in the range of 5.5 to 7.5.
[0029] In another form of the present invention (as mentioned
above), the pharmaceutical composition may be administered with
food or without food. This is beneficial as many practically
insoluble drugs are unable to be formulated in a manner that allows
administration without food, particularly those typically
formulated as solid dosage forms. This makes administration of
these dosage forms cumbersome and quite inflexible for the patient.
Indeed, the pharmaceutical composition of the present invention is
preferably bioequivalent when administered under fed conditions
compared to administration under fasted conditions. In particular,
the AUC for a composition administered under fed conditions is
preferably within the range of 80 to 125% of the AUC under fasted
conditions, when considering the 90% confidence interval for the
ratio of the fed value to the fasted value (using natural log
transformed data).
[0030] Any practically insoluble drug may be beneficially used in
the pharmaceutical composition of the present invention. In this
respect, it should be appreciated that while the specification will
here list various drugs that are typically considered to be
practically insoluble, many drugs (whether considered practically
insoluble or not) will have versions (crystalline forms,
polymorphs, etc) that are in fact practically insoluble. Also, it
is to be appreciated that drugs developed in the future that are
also considered to be practically insoluble, are also to be
included within the scope of the present invention.
[0031] While the specific benefits of the pharmaceutical
composition of the present invention have been established by the
inventors for azole antifungal drugs, such as itraconazole and
saperconazole, similar benefits will be available for other classes
of drugs such as anti-hypertensives, immunosuppressants,
anti-inflammatories, diuretics, antiepileptics, cholesterol
lowering drugs, hormonals, hypoglycemics, antiviral drugs, nasal
decongestants, antimicrobials, anti-arrthrytics, analgesics,
anti-cancer drugs, anti-parasitics, proteins, peptides, CNS
stimulants, CNS depressants, 5 HT inhibitors, anti-schizophrenics,
anti-Alzheimer drugs, anti-psoriatics, steroidals,
oligonucleotides, anti-ulcer drugs, proton pump inhibitors,
anti-asthmatics, thrombolyitics and vitamins.
[0032] Indeed, even though the following description will mainly
describe embodiments of the invention with respect to azole
antifungal drugs, it is to be appreciated that the invention is not
to be so limited.
[0033] The polymers useful for forming the solid dispersion of the
pharmaceutical composition of the present invention are those
having acidic functional groups. In a preferred form, such polymers
will be polycarboxylic acids. Such polycarboxylic acids may be any
polycarboxylic acid which, when in a solid dispersion with a
practically insoluble drug, results in the formation of the
abovementioned suspension, ideally in the preferred pH ranges, and
preferably to provide acceptable absorption in the intestines.
[0034] Such polymers may be one or more of the group comprising
hydroxypropyl methylcellulose phthalate, polyvinyl acetate
phthalate (PVAP), hydroxypropylmethylcellulose acetate succinate
(HPMCAS), alginate, carbomer, carboxymethyl cellulose, methacrylic
acid copolymer, shellac, cellulose acetate phthalate (CAP), starch
glycolate, polacrylin, methyl cellulose acetate phthalate,
hydroxypropylcellulose acetate phthalate, cellulose acetate
terephthalate, cellulose acetate isophthalate and cellulose acetate
trimellitate, and includes the various grades of each polymer such
as HPMCAS-LF, HPMCAS-MF and HPMCAS-HG.
[0035] In a particularly preferred form of the present invention,
the polymer is a polycarboxylic acid such as a hydroxypropyl
methylcellulose phthalate such as that available from Shin-Etsu
Chemical Industry Co Ltd as HP-50, HP-55 or HP-55S. However, it is
envisaged that alternatives such as the use of an aqueous based
enteric polymer, such as the dispersion Eudragit L30D, or enteric
polymers dissolved in water with the addition of ammonia or
alkaline agents, may be useful.
[0036] In relation to amounts of drug and the polymer in the solid
dispersion, the ratio of drug to polymer may be in the range of
from 3:1 to 1:20. However, ratios in the narrower range of 3:1 to
1:5 are preferred. An even more preferred range is 1:1 to 1:3, with
the most preferred ratio being about 1:1.5 (or 2:3).
[0037] The solid dispersion of the composition of the present
invention is preferably formed by spray drying techniques, although
it will be understood that suitable solid dispersions may be formed
by a skilled addressee utilising other conventional techniques,
such as co-grinding, melt extrusion, freeze drying, rotary
evaporation or any solvent removal process.
[0038] In the preferred spray drying technique, the solid
dispersion is formed by dispersing or dissolving the drug and the
polymer in a suitable solvent, and subsequently spray drying to
form the solid dispersion in the form of a powder. Suitable
solvents or dispersion media include methylene chloride,
chloroform, ethanol, methanol, propan-2-ol, ethylacetate, acetone,
water or mixtures thereof.
[0039] Other excipients may then be blended into the powder (with
or without milling or grinding) to form a composition suitable for
use in dosage forms such as tablets and capsules.
[0040] The present invention therefore also provides a process for
preparing a pharmaceutical composition of a practically insoluble
drug, the process including dispersing in a solvent the drug and a
polymer having acidic functional groups, and spray drying the
dispersion to form a solid dispersion.
[0041] The present invention may thus provide a process for
preparing a pharmaceutical composition of a practically insoluble
drug, where the process includes the steps of:
[0042] (a) adding a polymer having acidic functional groups to a
solvent to form a dispersion;
[0043] (b) adding the drug to the dispersion to form a suspension
or solution; and
[0044] (c) spray drying the suspension or solution to form the
pharmaceutical composition in the form of a solid dispersion.
[0045] Alternatively, the present invention may provide a process
for preparing a pharmaceutical composition of a practically
insoluble drug, where the process includes the steps of:
[0046] (a) adding the drug to a solvent to form a dispersion;
[0047] (b) adding a polymer having acidic functional groups drug to
the dispersion to form a suspension or solution; and
[0048] (c) spray drying the suspension or solution to form the
pharmaceutical composition in the form of a solid dispersion.
[0049] The composition of the present invention may be formulated
into pharmaceutical dosage forms comprising a therapeutically
effective amount of the composition. Although pharmaceutical dosage
forms for oral administration, such as tablets and capsules, are
envisaged, the composition of the present invention can also be
used to prepare other pharmaceutical dosage forms, such as for
rectal, vaginal, ocular or buccal administration, or the like. It
should also be appreciated that the solid dispersions of the
composition of the invention may be spray coated (or the like) onto
cores to produce particles suitable for use in any of these dosage
forms.
[0050] It will also be appreciated that various of these dosage
forms may include a range of traditional excipients such as
disintegrants, diluents, fillers, lubricants, glidants, colourants
and flavours.
[0051] For example, suitable disintegrants may be those that have a
large coefficient of expansion, and examples may include
crosslinked polymers such as crospovidone (crosslinked
polyvinylpyrrolidone), croscarmellose (crosslinked sodium
carboxymethylcellulose), and sodium starch glycolate.
[0052] Also, it will be appreciated that it may be advantageous to
add to a dosage form an inert substance such as a diluent or a
filler. A variety of materials may be used as diluents or fillers,
and examples may be sucrose, dextrose, mannitol, sorbitol, starch,
micro-crystalline cellulose, and others known in the art, and
mixtures thereof.
[0053] Lubricants and glidants may be employed in the manufacture
of certain dosage forms, and will usually be employed when
producing tablets. Examples of lubricants and glidants are
hydrogenated vegetable oils, magnesium stearate, stearic acid,
sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silica,
talc, mixtures thereof, and others known in the art. A preferred
lubricant is magnesium stearate, or mixtures of magnesium stearate
with colloidal silica.
[0054] Excipients such as colouring agents and pigments may also be
added to dosage forms in accordance with the present invention, and
suitable colouring agents and pigments may include titanium dioxide
and dyes suitable for food.
[0055] Flavours may be chosen from synthetic flavour oils and
flavouring aromatics or natural oils, extracts from plants, leaves,
flowers, fruits and so forth and combinations thereof. These may
include cinnamon oil, oil of wintergreen, peppermint oils, bay oil,
anise oil, eucalyptus, thyme oil. Also useful as flavours are
vanilla, citrus oil, including lemon, orange, grape, lime and
grapefruit, and fruit essences including apple, banana, pear,
peach, strawberry, raspberry, cherry, plum, pineapple, apricot and
so forth.
[0056] With reference to the pharmocokinetic performance of
pharmaceutical compositions in accordance with the present
invention, it will be appreciated that the parameters that are
commonly used in the art to describe the in vivo performance of a
formulation (or the bioavailability) are C.sub.max (the maximum
concentration of the active in the blood) and, as mentioned
previously, AUC (area under the curve--a measure of the total
amount of drug absorbed by the patient). These are also the
parameters used by regulatory agencies around the world to assess
bioequivalence of different formulations. For instance, to be
considered bioequivalent, the 90% confidence interval for the ratio
of the test to reference product (using natural log-transformed
data) for C.sub.max and AUC are within the range of 80 to 125%.
[0057] By utilising compositions in accordance with the present
invention, it has been found that drugs previously considered to
present bioavailability problems may be presented in dosage forms
with superior bioavailability. For instance, and as will be
described in more detail below with respect to two examples, where
the drug is itraconazole the inventive compositions have produced
formulations that are not considered bioequivalents to, but have at
least twice the bioavailability of, a commercially available
itraconazole product (Sporanox.TM.). Additionally, and again in
comparison with Sporanox.TM., the inventive compositions have
produced formulations that have reduced food effect and thus need
not be administered with food (unlike Sporanox.TM.).
[0058] Furthermore, the present invention also provides a
pharmaceutical composition in the form of a solid dispersion of a
polymer with acidic functional groups (preferably a polycarboxylic
acid such as a hydroxypropyl methylcellulose phthalate) and an
azole antifungal drug (such as itraconazole), wherein in vitro the
composition forms a suspension. Preferably, the composition upon
administration forms a suspension at a pH in the range of 4.0 to
8.0, but more preferably in the range 5.5 to 7.5, and may provide
acceptable absorption in the intestines.
[0059] The present invention further provides a pharmaceutical
composition in the form of a solid dispersion of a hydroxypropyl
methylcellulose phthalate and a practically insoluble drug, wherein
the composition forms a suspension in vitro in the pH range of 4.0
to 8.0 (preferably 5.5 to 7.5) and preferably provides acceptable
absorption in the intestines.
[0060] Finally, in a preferred form the present invention is a
pharmaceutical composition in the form of a solid dispersion of
itraconazole that provides a mean C.sub.max of at least 100 ng/ml
when a dose of 100 mg of itraconazole is given in the fasted state.
A more preferred form is such a formulation of itraconazole that
provides a mean Cmax of 150 to 250 ng/ml, when a dose of 100 mg of
itraconazole is given in the fasted state.
[0061] A further form of the present invention is a pharmaceutical
composition in the form of a solid dispersion of itraconazole that
provides a mean AUC at least 800 ng.h/ml when a dosage of 100 mg of
itraconazole is given in the fasted state. A more preferred form is
such a solid dispersion of itraconazole that provides a mean AUC of
1300 to 2300 ng.h/ml, when a dose of 100 mg of itraconazole is
given in the fasted state.
[0062] For formulations in accordance with the present invention
containing drugs other than itraconazole it is preferred that the
bioavailability of the drug as compared to the drug per se is
improved by at least 50% and more preferably 100%, in terms of
AUC.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0063] Reference will now be made to examples that embody the above
general principles of the present invention. However, it is to be
understood that the following description is not to limit the
generality of the above description.
EXAMPLE 1
[0064] To produce the solid dispersion, a solution was prepared by
dispersing HP-50 (60 g) in methylene chloride (1200 g) and then
adding itraconazole (40 g) and stirring to form a pale brown
solution. This solution was then spray dried to form a powder.
[0065] A portion (38.96 g) of this spray dried powder was then
blended with sodium starch glycolate (14.87 g) and colloidal
silicon dioxide (Aerosil 200)(0.75 g) in a mortar and pestle for 5
minutes. Magnesium stearate (1.11 g) was added to the blend from
the mortar and the mixture tumble blended until uniform.
[0066] This powder blend was then filled into size 0 gelatin
capsules by hand. Each capsule was filled with 364 to 378 mg of
powder, containing nominally 98 to 102 mg of itraconazole.
[0067] These capsules were tested in a standard USP type 11
dissolution bath (paddle method). A capsule was weighted with
stainless steel wire and then dropped into 900 ml of dissolution
media consisting of 0.05 M phosphate buffer solution adjusted to pH
6.0. Samples of this media were extracted at appropriate time
intervals through a 10 micrometer filter and the content of
itraconazole in the sample assayed using a HPLC method. Both the
media in the dissolution bath and the extracted, filtered samples
were cloudy in appearance. This test was also formed using 900 ml
of hydrochloric acid acidic media (pH 1.2, 0.06 M HCl). In this
case both the media and the samples were clear.
[0068] The measured amount of itraconazole present in the samples,
as a percentage of the total possible amount, after various times
in the test described above is presented in the table below. For
comparison the results of the same tests performed on a marketed
itraconazole capsule (Sporanox.TM.) are also tabulated.
Sporanox.TM. produced clear solutions in both media.
1 pH 1.2 media, 75 rpm, paddles pH 6.0 media, 100 rpm, paddles Time
Sporanox .TM. Test Time Sporanox .TM. Test (min) 98P0800E Example 1
(min) 98P0800E Example 1 0 0 0 0 0 5 1.9 4 5 1.1 4 10 5.2 6.4 10
1.2 20.2 30 42.3 9.9 30 2.2 58.5 45 56.1 11.6 45 2.8 69.7 60 64 13
60 3.2 76.4 120 76.2 16.6 120 3.7 77.6 180 18.8 180 82.3 240 21.1
240 81.1
EXAMPLE 2
[0069] To produce the solid dispersion, a solution was prepared by
dispersing HP-50 (420 g) in methylene chloride (8400 g) and then
adding itraconazole (280 g) and stirring to form a pale brown
solution. This solution was then spray dried to form a powder.
[0070] A portion (292 g) of this spray dried powder was then
blended with sodium starch glycolate (93.6 g) and colloidal silicon
dioxide (Aerosil 200)(5.6 g) in a Collette mixer at high speed for
5 minutes. Magnesium stearate (8.8 g) was added to the blend from
the Collette mixer and the mixture tumble blended until
uniform.
[0071] This powder blend was then filled into size 0 gelatin
capsules by hand. Each capsule was filled with 345 to 359 mg of
powder, containing nominally 98 to 102 mg of itraconazole.
[0072] These test capsules were utilised in a pharmacokinetic
study. 8 male volunteers were dosed with one 100 mg capsule after
an overnight (10 hour) fast. The capsules were dosed with 240 ml
water. At appropriate time intervals blood samples were taken from
the subjects and the concentration of itraconazole in the plasma
determined. The study was performed in a randomised 2 way crossover
fashion with subjects receiving 100 mg itraconazole as a marketed
capsule (Sporanox.TM.) or as the test formulation described in
example 2 above. The alternate dose was taken after a 2 week
washout period.
[0073] A plot of the mean blood levels measured is as follows:
[0074] The data was analysed and the following standard mean
pharmacokinetic parameters were obtained.
2 Sporanox .TM. capsule Parameter Example capsule (Lot 98P0800E)
Ratio C.sub.max (ng/ml) 182.6 56.0 326% T.sub.max (h) 2.94 3.44
85.5% AUC (ng .multidot. h/ml) 1776 622 285% AUC.sub.inf (ng
.multidot. h/ml) 1875 664 282%
[0075] It can be seen from these results that significantly higher
plasma itraconazole levels are obtained from the formulation
described in the example than the marketed capsule form under these
conditions.
[0076] Indeed, it was expected that the itraconazole formulation of
this invention would have a later T.sub.max (time to maximum blood
concentration of active) than Sporanox.TM., due to the use of an
enteric polymer, which should not have solublised until after
passing through the stomach. This is in comparison to the
water-soluble polymers used in Sporanox.TM. that would solublise in
the stomach.
[0077] However, it can be seen from the above data that the
T.sub.max of the formulation of the present invention is at least
similar to the T.sub.max of Sporanox.TM., if not shorter than it.
Together with the greatly increased C.sub.max, this result was
surprising.
EXAMPLE 3
[0078] Test capsules from Example 2 containing 100 mg of
itraconazole were also utilised in a pharmacokinetic study under
fed conditions, primarily for comparison with the pharmacokinetic
results of Example 2 to determine whether there was any food
effect.
[0079] The study was again conducted as a single dose, crossover
study in 8 health male adult subjects, but under fed conditions.
The subjects commenced eating a standard high fat breakfast 20
minutes prior to dose administration, having fasted for at least 10
hours prior to that.
[0080] A two week washout period between administration of the dose
for each of the two treatments was again used, and the comparative
product was again two 100 mg itraconazole capsules marketed as
Sporanox.TM..
[0081] At appropriate time intervals blood samples were taken from
the subjects and the concentration of itraconazole in the plasma
determined. A plot of the mean blood levels from the fasted study
of example 2 (Fasted Study CM4799) and the fed study of Example 3
(Fed Study CM6000) is as follows:
[0082] The data from the fed study of Example 3 was analysed and
the following mean standard pharmacokinetic parameters were
obtained:
3 Example 3 Capsule Example 2 Capsule Parameter (Fed) (Fasted)
C.sub.max (ng/ml) 148.20 182.6 T.sub.max (h) 10.25 2.94 AUC (ng
.multidot. h/ml) 1806 1776 AUC.sub.inf (ng .multidot. h/ml) 1997
1875
[0083] It can be seen from these results that the example
formulation produces plasma profiles considered bioequivalent in
terms of AUC under fasting and fed conditions, due to the AUC under
fed conditions being about 102% of the AUC under fasted conditions,
which is well within the range of 80 to 120%. This is an indication
that the total amount of drug absorbed over time is essentially
equivalent under fed and fasted conditions.
[0084] Finally, it will be appreciated that there may be other
variations and modifications to the compositions described herein
that are also within the scope of the present invention.
* * * * *