U.S. patent application number 11/031527 was filed with the patent office on 2005-08-04 for pharmaceutical compositions and dosage forms for administration of hydrophobic drugs.
This patent application is currently assigned to Lipocine, Inc.. Invention is credited to Chen, Feng-Jing, Patel, Mahesh V..
Application Number | 20050171193 11/031527 |
Document ID | / |
Family ID | 24876432 |
Filed Date | 2005-08-04 |
United States Patent
Application |
20050171193 |
Kind Code |
A1 |
Chen, Feng-Jing ; et
al. |
August 4, 2005 |
Pharmaceutical compositions and dosage forms for administration of
hydrophobic drugs
Abstract
Pharmaceutical compositions and dosage forms for administration
of hydrophobic drugs, particularly fenofibrate, are provided. The
compositions comprise a therapeutically effective amount of an
active agent and a solubilizer. The solubilizer is selected to
effectively solubilize active agent in the composition. The
solubilizers employed as part of the invention include: a vitamin E
substance; monohydric alcohol esters such as trialkyl citrates,
lactones and lower alcohol fatty acid esters; nitrogen-containing
solvents; phospholipids; glycerol acetates such as acetin, diacetin
and triacetin; glycerol fatty acid esters such as mono-, di- and
triglycerides and acetylated mono- and diglycerides; propylene
glycol esters; ethylene glycol esters; and combinations thereof.
The pharmaceutical dosage forms contain the compositions in a
suitable dosage form unit such as a capsule. Methods of treating
patients comprising administering the compositions are also
provided.
Inventors: |
Chen, Feng-Jing; (Salt Lake
City, UT) ; Patel, Mahesh V.; (Salt Lake City,
UT) |
Correspondence
Address: |
THORPE NORTH & WESTERN, LLP.
8180 SOUTH 700 EAST, SUITE 200
P.O. BOX 1219
SANDY
UT
84070
US
|
Assignee: |
Lipocine, Inc.
|
Family ID: |
24876432 |
Appl. No.: |
11/031527 |
Filed: |
January 6, 2005 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11031527 |
Jan 6, 2005 |
|
|
|
09716029 |
Nov 17, 2000 |
|
|
|
Current U.S.
Class: |
514/458 ;
514/571 |
Current CPC
Class: |
B82Y 5/00 20130101; A61K
31/216 20130101; A61K 9/1075 20130101; A61K 47/22 20130101; A61K
9/0095 20130101; A61K 9/4858 20130101 |
Class at
Publication: |
514/458 ;
514/571 |
International
Class: |
A61K 031/194; A61K
031/355 |
Claims
1-98. (canceled)
99. A pharmaceutical composition for oral administration of
fenofibrate, comprising: a therapeutically effective amount of
fenofibrate, which is not co-micronized with a solid surfactant;
and a solubilizer admixed with the fenofibrate, said solubilizer
comprising tocopherol and a member selected from the group
consisting of glycerol fatty acid esters; Vitamin E substances;
propylene glycol esters; ethylene glycol esters; lower alcohol
fatty acid esters; glycerol acetates and acetylated glycerol fatty
acid esters; and mixtures thereof.
100. The composition of claim 99, wherein the ethylene glycol ester
is a transesterification product of polyethylene glycol with a
triglyceride.
101. The composition of claim 99, wherein the ethylene glycol ester
is a transesterification product of polyethylene glycol with a
vegetable oil.
102. The composition of claim 99, wherein the Vitamin E substance
is alpha-tocopheryl polyethylene glycol 1000 succinate.
103. The composition of claim 99, wherein the glycerol fatty acid
ester is a mono-, di-, or triglyceride.
104. The composition of claim 103, wherein the glycerol fatty acid
ester is a monoglyceride formed by esterification of glycerol and a
fatty acid having about 6-22 carbons.
105. The composition of claim 103, wherein the glycerol fatty acid
ester is a diglyceride formed by esterification of glycerol and
fatty acids having about 6-22 carbons.
106. The composition of claim 103, wherein the glycerol fatty acid
ester is a triglyceride formed by esterification of glycerol and
fatty acids having about 6-22 carbons.
107. The composition of any of claims 103 to 106, wherein the fatty
acids have about 6-12 carbons.
108. The composition of claim 99, wherein the propylene glycol
ester is a propylene glycol monoester with a fatty acid having
about 6-22 carbons.
109. The composition of claim 99, wherein the propylene glycol
ester is a propylene glycol diester with a fatty acid having about
6-22 carbons.
110. The composition of claim 99, wherein the lower alcohol fatty
acid ester is a polyethoxylated sorbitan monooleate.
111. The composition of claim 99, wherein the acetylated glycerol
fatty acid ester is an acetylated monoglyceride.
112. The composition of claim 99, wherein the acetylated glycerol
fatty acid ester is an acetylated diglyceride.
113. The composition of claim 99, wherein the tocopherol is
alpha-tocopherol.
114. The composition of claim 99, wherein the tocopherol is
dl-alpha-tocopherol.
115. The composition of claim 99, wherein the fenofibrate is
solubilized in the composition.
116. The composition of claim 99, wherein the fenofibrate is about
75% solubilized in the composition.
117. The composition of claim 99, wherein the fenofibrate is about
50% solubilized in the composition.
118. A pharmaceutical composition for oral administration of
fenofibrate, comprising: a therapeutically effective amount of
fenofibrate; and a solubilizer comprising a tocopherol, wherein the
composition provides in-vivo absorption of fenofibrate that is
substantially independent of lipolysis.
119. The composition of claim 118, wherein the fenofibrate is not
co-micronized with a solid surfactant.
120. The composition of claim 118, wherein the solubilizer further
comprises at least one member selected from the group consisting of
glycerol fatty acid esters; Vitamin E substances; propylene glycol
esters; ethylene glycol esters; lower alcohol fatty acid esters;
glycerol acetates and acetylated glycerol fatty acid esters; and
mixtures thereof.
121. The composition of claim 120, wherein the ethylene glycol
ester is a transesterification product of polyethylene glycol with
a triglyceride.
122. The composition of claim 120, wherein the ethylene glycol
ester is a transesterification product of polyethylene glycol with
a vegetable oil.
123. The composition of claim 120, wherein the Vitamin E substance
is alpha-tocopheryl polyethylene glycol 1000 succinate.
124. The composition of claim 120, wherein the glycerol fatty acid
ester is a mono-, di-, or triglyceride.
125. The composition of claim 124, wherein the glycerol fatty acid
ester is a monoglyceride formed by esterification of glycerol and a
fatty acid having about 6-22 carbons.
126. The composition of claim 124, wherein the glycerol fatty acid
ester is a diglyceride formed by esterification of glycerol and
fatty acids having about 6-22 carbons.
127. The composition of claim 124, wherein the glycerol fatty acid
ester is a triglyceride formed by esterification of glycerol and
fatty acids having about 6-22 carbons.
128. The composition of any of claims 124 to 127, wherein the fatty
acids have about 6-12 carbons.
129. The composition of claim 120, wherein the propylene glycol
ester is a propylene glycol monoester with a fatty acid having
about 6-22 carbons.
130. The composition of claim 120, wherein the propylene glycol
ester is a propylene glycol diester with a fatty acid having about
6-22 carbons.
131. The composition of claim 120, wherein the lower alcohol fatty
acid ester is a polyethoxylated sorbitan monooleate.
132. The composition of claim 120, wherein the acetylated glycerol
fatty acid ester is an acetylated monoglyceride.
133. The composition of claim 120, wherein the acetylated glycerol
fatty acid ester is an acetylated diglyceride.
134. The composition of claim 118, wherein the tocopherol increases
solubilization of the fenofibrate upon contact with an aqueous
medium.
135. A pharmaceutical composition for oral administration of
fenofibrate, comprising: a therapeutically effective amount of
fenofibrate; and a solubilizer comprising a tocopherol which
increases solubilization of the fenofibrate upon contact with an
aqueous medium.
136. The composition of claim 135, wherein the fenofibrate not
co-micronized with a solid surfactant.
137. The composition of claim 135, wherein the solubilizer further
comprises at least one member selected from the group consisting of
glycerol fatty acid esters; Vitamin E substances; propylene glycol
esters; ethylene glycol esters; lower alcohol fatty acid esters;
glycerol acetates and acetylated glycerol fatty acid esters; and
mixtures thereof.
138. The composition of claim 137, wherein the ethylene glycol
ester is a transesterification product of polyethylene glycol with
a triglyceride.
139. The composition of claim 137, wherein the ethylene glycol
ester is a transesterification product of polyethylene glycol with
a vegetable oil.
140. The composition of claim 137, wherein the Vitamin E substance
is alpha-tocopheryl polyethylene glycol 1000 succinate.
141. The composition of claim 137, wherein the glycerol fatty acid
ester is a mono-, di-, or triglyceride.
142. The composition of claim 141, wherein the glycerol fatty acid
ester is a monoglyceride formed by esterification of glycerol and a
fatty acid having about 6-22 carbons.
143. The composition of claim 141, wherein the glycerol fatty acid
ester is a diglyceride formed by esterification of glycerol and
fatty acids having about 6-22 carbons.
144. The composition of claim 141, wherein the glycerol fatty acid
ester is a triglyceride formed by esterification of glycerol and
fatty acids having about 6-22 carbons.
145. The composition of any of claims 141 to 144, wherein the fatty
acids have about 6-12 carbons.
146. The composition of claim 137, wherein the propylene glycol
ester is a propylene glycol monoester with a fatty acid having
about 6-22 carbons.
147. The composition of claim 137, wherein the propylene glycol
ester is a propylene glycol diester with a fatty acid having about
6-22 carbons.
148. The composition of claim 137, wherein the lower alcohol fatty
acid ester is a polyethoxylated sorbitan monooleate.
149. The composition of claim 137, wherein the acetylated glycerol
fatty acid ester is an acetylated monoglyceride.
150. The composition of claim 137, wherein the acetylated glycerol
fatty acid ester is an acetylated diglyceride.
151. A pharmaceutical composition, comprising a preconcentrate in a
capsule having included therein: a therapeutically effective amount
of fenofibrate, which is not co-micronized with a solid surfactant;
and a solubilizer admixed with the fenofibrate, said solubilizer
comprising tocopherol and a member selected from the group
consisting of glycerol fatty acid esters; Vitamin E substances;
propylene glycol esters; ethylene glycol esters; lower alcohol
fatty acid esters; glycerol acetates and acetylated glycerol fatty
acid esters; and mixtures thereof, wherein the solubilizer
increases solubilization of the fenofibrate upon contact with an
aqueous medium, and the preconcentrate being substantially free of
water.
152. The pharmaceutical composition of claim 151, wherein the
composition provides in vivo absorption of fenofibrate that is
substantially independent of lipolysis.
153. The pharmaceutical composition of claim 151, wherein the
capsule is a hard capsule.
154. The pharmaceutical composition of claim 151, wherein the
capsule is a soft capsule.
155. The pharmaceutical composition of claim 151, wherein the
capsule is comprised of a member selected from the group consisting
of a gelatin, a starch, a cellulosic material, or mixtures thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates generally to the delivery of
hydrophobic drugs, and more specifically relates to novel
pharmaceutical compositions in which a hydrophobic drug,
particularly fenofibrate, is formulated to improve patient
compliance and/or bioavailability following oral administration.
The invention has utility in the fields of pharmaceutical
formulation, pharmacology and medicine.
BACKGROUND
[0002] Numerous therapeutic agents are poorly soluble in an aqueous
medium. Conventional formulations that incorporate unmilled or
non-micronized forms of these therapeutic agents suffer from
several disadvantages such as incomplete dissolution, slow
dissolution and/or highly variable dissolution profiles.
Furthermore, following oral administration, these conventional
formulations exhibit low and/or variable bioavailability. To
compensate for low bioavailability, the dose is often increased in
these formulations. Dosage increases, however, still do not address
the problems associated with highly variable inter- and/or
intra-subject bioavailability. Thus, conventional formulations of
hydrophobic drugs are frequently required to be taken with meals in
order to address poor bioavailability, in addition to the
variability associated with the bioavailability encountered with
these drugs. As a result, however, patient compliance is often low
as patients may forget to administer these formulations with meals
or decide to skip a dose when the patient is not willing to consume
an entire meal. Poor patient compliance, in turn, requires frequent
monitoring and dosage adjustments by the treating clinician. In
particular, these disadvantages are evidenced with several families
of lipid-regulating agents, such as fibrates and statins.
[0003] Fenofibrate
(2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,
1-methylethylester) is a well known lipid-regulating agent from the
fibrate family. The active metabolite of fenofibrate, fenofibric
acid, produces reductions in total cholesterol, low density
lipoprotein (LDL), apolipoprotein B, total triglycerides and very
low density lipoprotein (VLDL). In addition, treatment with
fenofibrate results in increases in high density lipoprotein (HDL).
1
[0004] Fenofibrate is hydrophobic in nature (see structure shown
above) and is practically insoluble in water. Fenofibrate has been
commercially available under the names Lipanthyl, Lipidil.RTM. and
Lipantil. Although the usual daily dose is as high as 300-400 mg,
the product is nonetheless poorly absorbed in the gastrointestinal
tract of patients. As a result, it is poorly and variably
bioavailable and must be taken with food.
[0005] One approach in producing pharmaceutically acceptable
fenofibrate hydrophobic formulations involves the use of
micronization. U.S. Pat. No. 4,895,726 to Curtet et al. discloses a
composition and method of improving the dissolution, and
consequently, the bioavailability, of fenofibrate by using a solid
surfactant that is co-micronized with fenofibrate. U.S. Pat. No.
5,880,148 to Edgar et al. also discloses a combination of a
micronized mixture of fenofibrate with a solid surfactant and a
vitamin E substance. This combination is stated to be useful as an
antiatheromatous drug and to exhibit a synergistic effect by
protecting plasma LDL from oxidation. U.S. Pat. No. 4,800,079 to
Boyer et al. discloses a controlled-release formulation of
fenofibrate based on specially designed granules. Each granule
contains an inert core, a fenofibrate layer and a protective layer.
The formulation is characterized in that fenofibrate is present in
the form of crystalline microparticles of dimensions not greater
than 30 microns. The microparticles are included within the pores
of an inert matrix. U.S. Pat. No. 6,074,670 to Stamm et al.
discloses an immediate-release fenofibrate composition comprising
an inert hydrosoluble carrier covered with at least one layer
containing fenofibrate in a micronized form having a size less than
20 microns.
[0006] In the United States, fenofibrate is currently available
under the name Tricor.RTM.. This fenofibrate formulation is
available in capsule form and contains 67 mg of micronized
fenofibrate. Each capsule also contains lactose, pregelatinized
starch, sodium lauryl sulfate, crospovidone and magnesium stearate.
The bioavailability of fenofibrate is significantly improved over
the non-micronized forms, thus reducing the daily maximum dose of
fenofibrate in this formulation to 200 mg. However, it still
requires administration of three capsules daily, which can result
in patient inconvenience. Furthermore, the absorption of
fenofibrate from Tricor.RTM. is heavily influenced by the presence
of food, thus requiring Tricor.RTM. to be administered with meals
to optimize bioavailability. The number of capsules per day, meal
requirements and variability in bioavailability all present
significant patient compliance challenges in the management of
lipid disorders.
[0007] The preparation of fenofibrate in the form of crystalline
microparticles or that of co-micronizing fenofibrate with a solid
surfactant is a time consuming and costly process. An inherent
drawback of micronization is that the material obtained must comply
with stringent particle size specifications for quality and
performance. In addition, processes that require the production of
coating layers and inert matrixes are also complex, time consuming
and costly. Furthermore, the handling and filling of capsules with
a micronized powder present challenges with regard to safety and
ensuring uniformity of the active agent throughout the formulation.
Most importantly, a micronized microparticle or a co-micronized
mixture containing fenofibrate requires complete and consistent
dissolution of the drug as a prerequisite for the effective
absorption of fenofibrate and to obtain a satisfactory
bioavailability profile.
[0008] Other approaches for producing fenofibrate formulations have
been described. U.S. Pat. No. 5,827,536 to Laruelle discloses a
fenofibrate formulation containing fenofibrate in solution of a
solubilizing agent consisting of a non-ionic surfactant, diethylene
glycol monoethyl ether (DGME).
[0009] U.S. Pat. No. 5,545,628 to Deboeck et al. discloses
pharmaceutical compositions for treating hyperlipidemia or
hypercholesterolemia or both in a mammal. The compositions contain
fenofibrate and an excipient containing one or more polyglycolyzed
glycerides. The polyglycolzed glycerides are generally mixtures of
known monoesters, diesters and triesters of glycerols and known
monoesters and diesters of polyethylene glycol with a mean relative
molecular mass between 200 and 6000. They may be obtained by
partial transesterification of triglycerides with polyethylene
glycol or by esterification of glycerol and polyethylene glycol
with fatty acids.
[0010] U.S. Pat. No. 6,096,338 to Lacy et al. discloses a carrier
for hydrophobic drugs, e.g., fenofibrate, that contains a
digestible oil and a pharmaceutically acceptable surfactant for
dispersing the oil in vivo upon administration of the carrier. The
surfactant comprises a hydrophilic surfactant component which
substantially inhibits the in vivo lipolysis of the digestible oil
and a lipophilic surfactant component capable of at least
substantially reducing the inhibitory effect of the hydrophilic
surfactant component. The lipophilic surfactant component is
present in an amount sufficient to achieve the required
counteracting of the lipolysis-inhibiting properties of the
hydrophilic surfactant component.
[0011] WO 99/29300A1 discloses a self-emulsifying preconcentrate
containing fenofibrate dissolved in a carrier system comprising a
hydrophobic component, a surfactant and a hydrophilic component.
Each of these approaches, however, has individual drawbacks.
[0012] Therefore, for more effective and economic disease
management, there is an ongoing need for improved fenofibrate
formulations. In particular, there is a need for fenofibrate
formulations that are not dependent on the micronization of
fenofibrate or the co-micronization of fenofibrate with a solid
surfactant for effective absorption. Such formulations are more
easily administered, e.g., administered without regard to meals (to
enhance patient compliance), adequately bioavailable and less
costly to manufacture and commercialize.
SUMMARY OF THE INVENTION
[0013] Accordingly, it is a primary object of the invention to
address the above-mentioned need in the art by providing a
pharmaceutical composition and dosage form for orally administering
hydrophobic therapeutic agents, particularly fenofibrate.
[0014] It is another object of the invention to provide such a
composition and dosage form comprising a therapeutically effective
amount of fenofibrate and a solubilizer.
[0015] It is another object of the invention to provide such a
composition and dosage form wherein the solubilizer comprises a
vitamin E substance, a trialkyl citrate, a lactone, a
nitrogen-containing solvent or a combination thereof.
[0016] It is still another object of the invention to provide such
a composition and dosage form wherein the solubilizer comprises a
phospholipid.
[0017] It is yet another object of the invention to provide such a
composition and dosage form wherein the solubilizer comprises a
glyceryl acetate, a fatty acid ester of an acetylated glyceride or
a combination thereof.
[0018] It is a further object of the invention to provide such a
composition and dosage form wherein the solubilizer comprises a
lower alcohol fatty acid ester.
[0019] It is a further object of the invention to provide such a
composition and dosage form wherein the solubilizer consists
essentially of a lower alcohol fatty acid ester.
[0020] It is still another object of the invention to provide a
composition and dosage form wherein the solubilizer consists
essentially of a glycerol fatty acid ester.
[0021] It is yet another object of the invention to provide a
composition and dosage form wherein the solubilizer consists
essentially of a propylene glycol ester.
[0022] It is still another object of the invention to provide a
composition and dosage form wherein the solubilizer consists
essentially of an ethylene glycol ester.
[0023] It is yet another object of the invention to provide a
composition and dosage form wherein the solubilizer consists
essentially of a glycerol fatty acid ester, a propylene glycol
ester, an ethylene glycol ester, a lower alcohol fatty acid ester
or a combination thereof.
[0024] It is still another object of the invention to provide a
pharmaceutical composition and dosage form comprising a
therapeutically effective amount of a hydrophobic drug and a
vitamin E substance.
[0025] It is yet another object of the invention to provide a
method for treating a patient who would benefit from administration
of a fenofibrate-containing composition comprising administering to
the patient a therapeutically acceptable amount of the
fenofibrate-containing compositions described herein.
[0026] Additional objects, advantages and novel features of the
invention will be set forth in part in the description which
follows, and in part will become apparent to those skilled in the
art upon examination of the following, or may be learned by
practice of the invention.
[0027] In one embodiment, then, the invention is directed to a
pharmaceutical composition for oral administration of fenofibrate,
wherein the composition comprises a therapeutically effective
amount of fenofibrate and a solubilizer. The solubilizer is
selected to effectively solubilize fenofibrate in the composition.
Suitable solubilizers include, but are not limited to: a vitamin E
substance such as vitamin E and derivatives thereof; monohydric
alcohol esters such as trialkyl citrates, lactones and lower
alcohol fatty acid esters; nitrogen-containing solvents;
phospholipids; glycerol acetates such as acetin, diacetin and
triacetin; glycerol fatty acid esters such as mono-, di- and
triglycerides and acetylated mono- and diglycerides; propylene
glycol esters; ethylene glycol esters; and combinations
thereof.
[0028] The pharmaceutical compositions and dosage forms described
herein may optionally comprise one or more additives. Preferred
additives include surfactants and polymers. In addition, the
composition is not limited with regard to its form, but it is
preferred that the formulation is in liquid or semi-solid form.
Furthermore, the fenofibrate in the aforementioned pharmaceutical
composition may be completely solubilized or partially solubilized
and partially suspended in the composition.
[0029] In another embodiment, a dosage form is provided comprising
the aforementioned pharmaceutical composition. The dosage form
contains a therapeutically effective amount of fenofibrate,
preferably in an amount of about 40 to about 250 mg, and more
preferably in an amount of about 67 to about 200 mg. The dosage
form contains fenofibrate solubilized in the composition,
preferably in an amount of at least about 40 mg, more preferably in
an amount of at least about 67 mg, and most preferably in an amount
of at least about 100 mg. Although the dosage form may be any
suitable dosage form, the dosage form is preferably a capsule
containing the pharmaceutical composition having a therapeutically
effective amount of fenofibrate contained therein.
[0030] In still another embodiment, a pharmaceutical composition is
provided comprising a therapeutically effective amount of a
hydrophobic drug and a vitamin E substance. The hydrophobic drug is
present in an amount of from about 0.1 to 30% w/w of the
composition. Furthermore, the hydrophobic drug is at least about
50% solubilized in the composition. The vitamin E substance in the
composition is present in an amount of from about 1 to 99% w/w of
said composition.
[0031] In yet another embodiment, a method is provided for treating
a patient who would benefit from administration of a
fenofibrate-containing composition. The method comprises orally
administering to the patient a therapeutically acceptable amount of
the fenofibrate-containing compositions described herein.
DETAILED DESCRIPTION OF THE INVENTION
[0032] I. Definitions and Nomenclature:
[0033] Before the present formulations and dosage forms are
disclosed and described, it is to be understood that unless
otherwise indicated this invention is not limited to specific
dosage forms, solubilizers, or the like, as such may vary. It is
also to be understood that the terminology used herein is for the
purpose of describing particular embodiments only and is not
intended to be limiting.
[0034] It must be noted that, as used in the specification and the
appended claims, the singular forms "a," "an" and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a solubilizer" includes a single
solubilizer or mixtures of two or more solubilizers, reference to
"an additive" refers to a single additive or mixtures of different
additives, reference to "an additional active agent" includes a
single additional active agent or combinations of two or more
additional active agents, and the like.
[0035] In this specification and in the claims that follow,
reference will be made to a number of terms which shall be defined
to have the following meanings:
[0036] "Optional" or "optionally" means that the subsequently
described circumstance may or may not occur, so that the
description includes instances where the circumstance occurs and
instances where it does not.
[0037] The terms "active agent," "drug" and "pharmacologically
active agent" are used interchangeably herein to refer to a
chemical material or compound which, when administered to an
organism (human or animal, generally human) induces a desired
pharmacologic effect. In the context of the present invention, the
terms generally refer to a hydrophobic therapeutic active agent,
preferably fenofibrate, unless the context clearly indicates
otherwise.
[0038] By "pharmaceutically acceptable" is meant a carrier
comprised of a material that is not biologically or otherwise
undesirable.
[0039] "Carrier" or "vehicle" as used herein refer to carrier
materials suitable for drug administration. Carriers and vehicles
useful herein include any such materials known in the art, e.g.,
any liquid, gel, solvent, liquid diluent, solubilizer, surfactant,
or the like, which is nontoxic and which does not interact with
other components of the composition in a deleterious manner.
[0040] The terms "treating" and "treatment" as used herein refer to
reduction in severity and/or frequency of symptoms, elimination of
symptoms and/or underlying cause, prevention of the occurrence of
symptoms and/or their underlying cause, and improvement or
remediation of damage. Thus, for example, "treating" a lipid
disorder, as the term "treating" is used herein, encompasses both
prevention of lipid disorders in a predisposed individual and
treatment of lipid disorders in a clinically symptomatic
individual.
[0041] "Patient" as used herein refers to a mammalian, preferably
human, individual who can benefit from the pharmaceutical
compositions and dosage forms of the present invention.
[0042] The term "vitamin E substance" refers to both vitamin E and
derivatives thereof.
[0043] By the terms "effective amount" or "therapeutically
effective amount" of an agent as provided herein are meant a
nontoxic but sufficient amount of the agent to provide the desired
therapeutic effect. The exact amount required will vary from
subject to subject, depending on the age, weight and general
condition of the subject, the severity of the condition being
treated, the judgment of the clinician, and the like. Thus, it is
not possible to specify an exact "effective amount." However, an
appropriate "effective amount" in any individual case may be
determined by one of ordinary skill in the art using only routine
experimentation.
[0044] The term "lipid disorder" refers to a condition wherein the
level of one or more lipids in the blood of a patient deviates from
normal. Thus, "lipid disorders" include above normal levels of
lipids such as cholesterol (including low density lipoproteins),
triglycerides and apolipoprotein B and below normal levels of
lipids such as high density lipoproteins. When administered, the
fenofibrate-containing compositions described herein are effective
in treating patients suffering from a "lipid disorder" by reducing
one or more lipid levels. Preferably, although not necessarily,
each lipid level will return to a normal level.
[0045] II. The Pharmaceutical Composition:
[0046] The pharmaceutical compositions described herein contain a
hydrophobic therapeutic agent in substantially solubilized form.
The compositions improve the bioavailability of the active agent
after oral administration and/or improve patient compliance through
an easily followed dosing regimen. The compositions described
herein preferably contain the active agent, i.e., fenofibrate, in a
substantially solubilized form and the effective absorption of the
active agent is not dependent on the dissolution of crystalline
material of the active agent.
[0047] In the art of pharmaceutical formulation, vitamin E
substances have been known for their reducing potential and
exclusively used as antioxidant in pharmaceutical compositions. The
inventors have found, however, that vitamin E substances have
unexpected solubilization power toward fenofibrate and other
hydrophobic therapeutic agents.
[0048] The inventors also have surprisingly found that
nitrogen-containing solvents have unexpected solubilization power
toward fenofibrate and other hydrophobic therapeutic agents
relative to other commonly used non-nitrogen containing solvents
such as glycerol, propylene glycol, and polyethylene glycols. With
additional research, the inventors have further surprisingly found
that replacing one or more of the hydroxyl groups of glycerol and
propylene glycol with, for example, a lower alkyl ester, results in
a propylene glycol or glycerol fatty acid ester with an
unexpectedly high solubilizing power for fenofibrate. Similarly,
additional research has yielded other unexpectedly effective
solubilizers for fenofibrate including esters of monohydric
alcohols such as ethanol and ethylene glycols such as polyethylene
glycols with an organic acid such as acetic acid, fatty acids and
citric acids. In contrast to most conventional fenofibrate
compositions, the present compositions do not require a separate
step for the dissolution of crystalline fenofibrate since a
significant fraction of fenofibrate is already solubilized in the
compositions. In addition, the present compositions are not
dependent on lipolysis for the absorption of fenofibrate since the
compositions do not require triglycerides or vegetable oils.
[0049] A. Active Agent
[0050] The active agent in the present invention is generally
hydrophobic in nature (log P greater than 2, P is the intrinsic
octanol partition coefficient). Preferred classes of active agents
from which the hydrophobic drug may be selected include the
following: analgesics, anti-inflammatory agents, anti-helminthics,
anti-arrhythmic agents, anti-asthma agents, anti-bacterial agents,
anti-viral agents, anti-coagulants, anti-depressants,
anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout
agents, anti-hypertensive agents, anti-malarials, anti-migraine
agents, anti-muscarinic agents, anti-neoplastic agents,
immunosuppressants, anti-protozoal agents, anti-thyroid agents,
anti-tussives, anxiolytics, sedatives, hypnotics, neuroleptics,
.beta.-blockers, cardic inotropic agents, cell adhesion inhibitors,
corticosteroids, cytokine receptor activity modulators, diuretics,
anti-parkinsonian agents, gastro-intestinal agents, histamine
H-receptor antagonists, keratolytics, lipid regulating agents,
muscle relaxants, nitrates and other anti-anginal agents,
non-steroid anti-asthma agents, nutritional agents, opioid
analgesics, sex hormones, stimulants and anti-erectile dysfunction
agents.
[0051] A preferred class of hydrophobic drugs in the present
invention is a lipid regulation agent such as a statin compound, a
squalene synthesis inhibitor, a fibrate compound, a LDL (low
density lipoprotein) catabolism enhancer or combinations
thereof.
[0052] Statin compounds are drugs that lower blood cholesterol
levels by inhibiting hydroxymethylglutalyl CoA (HMG-CoA) reductase.
Examples of preferred statin compounds include pravastatin,
simvastatin, lovastatin, atorvastatin, fluvastatin and salts
thereof.
[0053] Squalene synthesis inhibitors are drugs that lower blood
cholesterol levels by inhibiting the synthesis of squalene. An
examples of a preferred squalene synthesis inhibitor includes
(S)-alpha-Bis(2,2-dimethyl-1-oxopropoxy)methoxy-phosphinyl-3-phenoxybenze-
nebutanesulfonic acid mono potassium salt (BMS-188494).
[0054] Fibrate compounds are drugs that lower blood cholesterol
levels by inhibiting the synthesis and secretion of triglycerides
in the liver and activate a lipoprotein lipase. Examples of
preferred fibrate compounds include bezafibrate, beclobrate,
binifibrate, ciplofibrate, clinofibrate, clofibrate, clofibric
acid, etofibrate, fenofibrate, fenofibric acid gemfibrozil,
nicofibrate, pirifibrate, ronifibrate, simfibrate, theofibrate and
combinations thereof.
[0055] LDL catabolism enhancers are drugs that lower blood
cholesterol levels by increasing the number of LDL (low-density
lipoprotein) receptors.
[0056] The above-mentioned statin compounds, squalene synthesis
inhibitors, fibrate compounds and LDL catabolism enhancers can be
substituted with other drugs that can lower blood cholesterol and
triglyceride levels. Examples of these drugs include: nicotinic
acid derivatives such as nicomol and niceritrol; antioxidants such
as probucol; and ion-exchange resins such as cholestyramine and
cholestipol.
[0057] A particularly preferred active agent in the present
invention is fenofibrate. Fenofibrate is commercially available
from Sigma.RTM., St. Louis, Mo. (product number F6020). The
pharmaceutical compositions and dosage forms contain a
therapeutically effective amount of fenofibrate.
[0058] The absorption of fenofibrate in the composition is not
dependent on the dissolution of fenofibrate from the composition in
the patient's gastrointestinal tract since a substantial fraction
of the fenofibrate in the composition itself is already
solubilized. Thus, fenofibrate is not required to be micronized
prior to incorporation in the composition. To the extent that
fenofibrate is micronized in the present compositions, e.g., to
further enhance solubility, it is preferred that the fenofibrate is
micronized in the absence of any other components, particularly
solid surfactants.
[0059] An additional active agent may be administered with the
active agent included in the compositions and dosage forms of the
present invention. It is preferred, however, that the additional
active agent is contained within the composition and dosage form.
It is particularly preferred that the active agent, i.e., primary
active agent, and the additional active agent are both from the
lipid regulating class. The weight ratio of the primary active
agent to the additional active agent may be varied and will depend
upon the effective dose of each ingredient. Each active agent
contained in the composition or dosage form will be present in a
therapeutically effective amount.
[0060] Additional active agents may be solubilized or suspended
with or without the presence of an additional solubilizer. For
those additional active agents that are ionized or ionizable, the
formulations described herein may include a buffer to facilitate or
maintain the presence of a preferred ionized form of the additional
active agent in the formulation.
[0061] A wide range of additional active agents may be
co-administered with fenofibrate including agents that bind
cholesterol, e.g., cholestyramine, to synergistically treat certain
lipid disorders. Other preferred additional active agents include
acipimox, acifran, p-aminosalicylic acid, aspirin, atorvastatin,
bezafibrate, cerivastatin, ciprofibrate, clinofibrate, clofibrate,
colestipol, fluindostatin, fluvastatin, gemfibrozil, imanixil,
istigmastanylphosphorylcholine, lipostabil, lovastatin, melinamide,
mevastatin, neomycin, nicotinic acid, pravastatin, probucol,
simvistatin, tetrahydrolipstatin, rapamycin, progesterone,
estrodial, velostatin, captopril, pivopril, enalopril, fosinopril,
ramipril, cetapril, cilazapril, delapril, indolapril, spirapril,
quinapril and mixtures thereof.
[0062] Other examples of the additional active agents include:
insulin sensitivity enhancers, insulin secretion enhancers and/or
an insulin preparation; an alpha-glucosidase inhibitor; an aldose
reductase inhibitor; a biguanide; and an angiotensin converting
enzyme inhibitor. Insulin sensitivity enhancers are agents that
substantially increase insulin sensitivity in muscle, liver and
adipose tissue resulting in the correction of elevated plasma
levels of glucose, triglycerides and nonesterified fatty acids
without the occurrence of hypoglycemia. Examples of insulin
sensitivity enhancers include, but are not limited to the
glitazones (thiazolidinediones such as pioglitazone, troglitazone,
rosiglitazone, MCC-555, and BRL49653).
[0063] Insulin secretion enhancers are drugs that promote the
secretion of insulin from pancreatic beta-cells. The group of drugs
known as sulfonylureas represents a preferred class of insulin
secretion enhancers. The sulfonylureas are drugs that promote the
secretion of insulin from pancreatic beta-cells by transmitting
signals of insulin secretion via sulfonylurea receptors in cell
membranes. Examples of the sulfonylureas include, but are not
limited to: tolbutamide; chlorpropamide; tolazamide; acetohexamide;
4-chloro-N (1-pyrolidinylamino)carbonyl-benzenesulfonamide (generic
name: glycopyramide) or its ammonium salt;
glibenclamide(glyburide); gliclazide; 1-butyl-3-metanilylurea;
carbutamide; glibonuride; glipizide; gliquidone; glisoxepid;
glybuthiazole; glibuzole; glyhexamide; glymidine; glypinamide;
phenbutamide; tolcyclamide and combinations thereof.
[0064] Other insulin secretion enhancers include
N-(4-(1-methylethyl)cyclo- hexyl)carbonyl-D-phenylalanine
(AY-4166), calcium(2S)-2-benzyl-3-(cis-hexa-
hydro-2-isoindolinylcarbonyl)propionate dihydrate (KAD-1229), and
glimepiride (Hoe 490). The insulin secretion enhancer is especially
preferably glibenclamide.
[0065] Examples of the insulin preparations include animal insulin
preparations typically extracted from bovine or porcine pancreas
and human insulin preparations synthesized by genetic engineering
techniques typically using Escherichia coli or yeasts. Each of
these types of insulin is readily available commercially from, for
example, Eli Lilly and Co., Indianapolis, Ind. While insulin
preparations are available in a variety of types, e.g.
immediate-acting, bimodal-acting, intermediate-acting, and
long-acting, these types of preparations can be selectively
administered according to the patient's condition.
[0066] .alpha.-Glucosidase inhibitors are drugs that inhibit
digestive enzymes such as amylase, maltase, .alpha.-dextrinase,
sucrase, etc. to retard digestion of starch and sugars. Examples
preferred .alpha.-glucosidase inhibitors include acarbose,
N-(1,3-dihydroxy-2-propy- l)valiolamine (generic name; voglibose),
miglitol and combinations thereof. Voglibose is a particularly
preferred .alpha.-glucosidase inhibitor.
[0067] Aldose reductase inhibitors are drugs that inhibit the
first-stage rate-limiting enzyme in the polyol pathway to prevent
or arrest diabetic complications. In the hyperglycemic state of
diabetes, the utilization of glucose in the polyol pathway is
increased and the excess sorbitol accumulated intracellularly acts
as a tissue toxin. The toxicity triggers the onset of complications
such as diabetic neuropathy, retinopathy and nephropathy. Examples
of aldose reductase inhibitors include, but are not limited to,
tolurestat; epalrestat, imirestat, zenarestat, zopolrestat,
sorbinil; 1-(3-bromo-2-benzofuranyl)sulfonyl-2,4-imidazolidinedione
(M-16209) and combinations thereof.
[0068] Biguanides are drugs that stimulate anaerobic glycolysis,
increase the sensitivity to insulin in the peripheral tissues,
inhibit glucose absorption from the intestine, suppress hepatic
gluconeogenesis, and inhibit fatty acid oxidation. Examples of the
biguanides include, but are not limited to phenformin, metformin,
buformin and combinations thereof.
[0069] Angiotensin converting enzyme inhibitors are drugs that
partially lower blood glucose levels in addition to lowering blood
pressure by inhibiting angiotensin converting enzymes. Examples of
angiotensin converting enzyme inhibitors include, for example,
captopril, enalapril, alacepril, delapril, ramipril, lisinopril,
imidapril, benazepril, ceronapril, cilazapril, enalaprilat,
fosinopril, moveltopril, perindopril, quinapril, spirapril,
temocapril, trandolapril and combinations thereof.
[0070] B. Solubilizer
[0071] In addition to fenofibrate, the pharmaceutical compositions
of the invention also contain a carrier. At a minimum, the carrier
must contain a solubilizer. In some instances, the carrier may only
contain one solubilizer without any additional components, i.e.,
additives. Alternatively, the carrier may contain one or more
pharmaceutically acceptable additives in addition to the
solubilizer.
[0072] In the context of the present invention, a solubilizer is
any material that has a solubility for fenofibrate of at least
about 45 mg per gram of the solubilizer, more preferably at least
about 67 mg per gram of the solubilizer and most preferably at
least about 100 mg per gram of the solubilizer. The solubilizer is
preferably present in an amount such that a significant fraction of
fenofibrate is solubilized in the composition and is capable of
providing an immediate and therapeutically effective amount of
fenofibrate to a patient in a readily absorbable form upon
administration. As a consequence of the solubilizer in the
composition, micronization of fenofibrate or the co-micronization
of fenofibrate with a solid surfactant is not necessary in order to
achieve pharmaceutically acceptable compositions. Preferably, the
solubilizers of the present invention can also increase the
solubilization of fenofibrate when the composition contacts an
aqueous medium including water, and particularly gastro-intestinal
fluids upon administration of the dosage form containing the
composition. Thus, the solubilizers as provided herein improve the
dissolution profile of fenofibrate and thereby the bioavailability
of fenofibrate.
[0073] One type of solubilizer that may be used is a vitamin E
substance. This group of solubilizers includes a substance
belonging to the group of .alpha.-, .beta.-, .gamma.-, .delta.-,
.zeta..sub.1-, .zeta..sub.2- and .eta.-tocopherols, their dl, d and
l forms and their structural analogues, such as tocotrienols; the
corresponding derivatives, e.g., esters, produced with organic
acids; and mixtures thereof. As will be appreciated by those of
skill in the art, only those vitamin E substances that effectively
solubilize fenofibrate may be included in the present compositions
as solubilizers. One skilled in the art can easily identify vitamin
E substances that may serve as effective solubilizers by, for
example, mixing a particular vitamin E substance with fenofibrate
and determining the extent of solubility. Preferred vitamin E
substance solubilizers include tocopherols, tocotrienols and
tocopherol derivatives with organic acids such as acetic acid,
propionic acid, bile acid, lactic acid, pyruvic acid, oxalic acid,
malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,
tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic
acid, polyethylene glycol succinate and salicylic acid.
Particularly preferred vitamin E substances include
alpha-tocopherol, alpha-tocopheryl acetate, alpha-tocopheryl acid
succinate, alpha-tocopheryl polyethylene glycol 1000 succinate and
mixtures thereof.
[0074] Another group of solubilizers are monohydric alcohol esters
of organic acids. The monohydric alcohol can be, for example,
ethanol, isopropanol, t-butanol, a fatty alcohol, phenol, cresol,
benzyl alcohol or a cycloalkyl alcohol. The organic acid can be,
for example, acetic acid, propionic acid, butyric acid, a fatty
acid of 6-22 carbon atoms, bile acid, lactic acid, pyruvic acid,
oxalic acid, malic acid, malonic acid, succinic acid, maleic acid,
fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic
acid, mandelic acid and salicylic acid. Preferred solubilizers in
this group include trialkyl citrates, lower alcohol fatty acid
esters and lactones. Preferred trialkyl citrates include triethyl
citrate, acetyltriethyl citrate, tributyl citrate, acetyltributyl
citrate and mixtures thereof with triethyl citrate being
particularly preferred. Lower alcohol fatty acid esters, as the
name implies, comprise a lower alcohol moiety, i.e., containing 2-4
carbon atoms, and a fatty acid moiety of about 6-22 carbon atoms.
Particularly preferred lower alcohol fatty acid esters include
ethyl oleate, ethyl linoleate, ethyl caprylate, ethyl caprate,
isopropyl myristate, isopropyl palmitate and mixtures thereof.
Lactones may also serve as a solubilizer. Examples include
.epsilon.-caprolactone, .delta.-valerolactone,
.beta.-butyrolactone, isomers thereof and mixtures thereof.
[0075] The solubilizer may be a nitrogen-containing solvent.
Preferred nitrogen-containing solvents include dimethylformamide,
dimethylacetamide, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone,
N-alkylpiperidone, N-alkylcaprolactam and mixtures thereof wherein
alkyl is a C.sub.1-12 branched or straight chain alkyl.
Particularly preferred nitrogen-containing solvents include
N-methyl 2-pyrrolidone, N-ethyl 2-pyrrolidone or a mixture thereof.
Alternatively, the nitrogen-containing solvent may be in the form
of a polymer such as polyvinylpyrrolidone.
[0076] Another group of solubilizers includes phospholipids.
Preferred phospholipids include phosphatidylcholine,
phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol,
lecithins, lysolecithins, lysophosphatidylcholine, polyethylene
glycolated phospholipids/lysophosph- olipids,
lecithins/lysolecithins and mixtures thereof.
[0077] Another group of preferred solubilizers are glycerol
acetates and acetylated glycerol fatty acid esters. Preferred
glycerol acetates include acetin, diacetin, triacetin and mixtures
thereof, with triacetin being particularly preferred. Preferred
acetylated glycerol fatty acid esters include acetylated
monoglycerides, acetylated diglycerides and mixtures thereof. In a
most preferred embodiment, the acetylated monoglyceride is a
distilled acetylated monoglyceride.
[0078] In addition, the solubilizer may be a glycerol fatty acid
ester. The fatty acid component is about 6-22 carbon atoms. The
glycerol fatty acid ester can be a monoglyceride, diglyceride,
triglyceride or mixtures thereof. Preferred glycerol fatty acid
esters include monoglycerides, diglycerides, medium chain
triglycerides with fatty acids having about 6-12 carbons and
mixtures thereof. Particularly preferred glycerol fatty acid esters
include medium chain monoglycerides with fatty acids having about
6-12 carbons, medium chain diglycerides with fatty acids having
about 6-12 carbons and mixtures thereof.
[0079] The solubilizer may be a propylene glycol ester. Preferred
propylene glycol esters include propylene carbonate, propylene
glycol monoacetate, propylene glycol diacetate, propylene glycol
fatty acid esters, acetylated propylene glycol fatty acid esters
and mixtures thereof. Alternatively, the propylene glycol fatty
acid ester may be a propylene glycol fatty acid monoester,
propylene glycol fatty acid diester or mixture thereof. The fatty
acid has about 6-22 carbon atoms. It is particularly preferred that
the propylene glycol ester is propylene glycol monocaprylate. Other
preferred propylene glycol esters include propylene glycol
dicaprylate, propylene glycol dicaprate, propylene glycol
dicaprylate/dicaprate and mixtures thereof.
[0080] Another group of solubilizers are ethylene glycol esters.
Ethylene glycol esters include monoethylene glycol monoacetates,
diethylene glycol esters, polyethylene glycol esters and mixtures
thereof. Additional examples include ethylene glycol monoacetates,
ethylene glycol diacetates, ethylene glycol fatty acid monoesters,
ethylene glycol fatty acid diesters, and mixtures thereof.
Alternatively, the ethylene glycol ester may be a polyethylene
glycol fatty acid monoesters, polyethylene glycol fatty acid
diesters or mixtures thereof. Again, the fatty acid component will
contain about 6-22 carbon atoms. Particularly preferred ethylene
glycol esters are those obtained from the transesterification of
polyethylene glycol with a triglyceride or a vegetable oil or
mixture thereof and include, for example, those marketed under the
Labrafil.RTM. and Labrasol.RTM. names.
[0081] C. Additives
[0082] Although not always necessary, the compositions of the
present invention may also include one or more additional
components, i.e., additives. When present, however, the additional
components do not act as solubilizers per se, but rather as an
adjuvant to facilitate the formation and maintenance of a
pharmaceutically acceptable composition. Classes of additives that
may be present in the compositions, include, but are not limited
to, absorbents, acids, adjuvants, anticaking agent, glidants,
antitacking agents, antifoamers, anticoagulants, antimicrobials,
antioxidants, antiphlogistics, astringents, antiseptics, bases,
binders, chelating agents, sequestrants, coagulants, coating
agents, colorants, dyes, pigments, compatiblizers, complexing
agents, softeners, crystal growth regulators, denaturants,
dessicants, drying agents, dehydrating agents, diluents,
dispersants, emollients, emulsifiers, encapsulants, enzymes,
fillers, extenders, flavor masking agents, flavorants, fragrances,
gelling agents, hardeners, stiffening agents, humectants,
lubricants, moisturizers, bufferants, pH control agents,
plasticizers, soothing agents, demulcents, retarding agents,
spreading agents, stabilizers, suspending agents, sweeteners,
disintegrants, thickening agents, consistency regulators,
surfactants, opacifiers, polymers, preservatives, antigellants,
rheology control agents, UV absorbers, tonicifiers and
viscomodulators. One or more additives from any particular class,
as well as one or more different classes of additives, may be
present in the compositions. Specific examples of additives are
well known in the art.
[0083] III. Determination of Component Amounts and Preparation of
Compositions:
[0084] As will be recognized by those skilled in the art, the
amount or percentage of the active agent present in the composition
and dosage forms will vary. Thus, for example, the amount of active
agent is based, in part, upon the actual need of the patient and
can be determined by the attending clinician. In all cases,
however, the amount of the active agent present in the composition
and dosage forms is an amount such that the active agent is
significantly solubilized in the appropriately selected solubilizer
or solubilizers so that the aforementioned advantages of the
present invention are achieved.
[0085] Preferably, the compositions are formulated so as to contain
a sufficient amount, i.e., dose, of fenofibrate within a dosage
unit, e.g., a capsule. It is preferred that the amount of
fenofibrate will be present in the composition so as to provide
each dosage form with a unit dosage of from about 40 to about 250
mg, and preferably about 67 to about 200 mg of fenofibrate. It is
particularly preferred that the entire amount of fenofibrate is
solubilized in the composition. However, it is sometimes necessary
to add additional fenofibrate in non-solubilized form when the
fenofibrate solubility capacity of a given composition is exceeded.
Therefore, it is also an important feature of the present invention
that the fenofibrate present in the composition is significantly
solubilized. Typically, at least about 50% of the fenofibrate is
solubilized in the composition and preferably at least about 75% of
the fenofibrate is solubilized in the composition of the dosage
form. The dosage form contains fenofibrate solubilized in the
composition in an amount of at least about 40 mg, preferably in an
amount of at least about 67 mg, and more preferably in an amount of
at least about 100 mg.
[0086] The amount of solubilizer that can be included in the dosage
forms of the present invention is not particularly limited. When
the dosage forms are ultimately administered to a patient, however,
the amount of any given solubilizer is limited to a bioacceptable
amount. Bioacceptable amounts of solubilizers and other components
are readily determined by one of skill in the art by using routine
experimentation or searching the literature. In some circumstances,
it may be advantageous to include amounts of solubilizers far in
excess of bioacceptable amounts, for example, to maximize the
concentration of the fenofibrate, with excess solubilizer removed
prior to providing the composition to a patient. Excess solubilizer
may be removed using conventional techniques such as distillation,
spray drying, lyophilization or evaporation. Generally, the amount
of solubilizer in the composition will be from about 5 wt. % to
about 95 wt. %, preferably between about 20 wt. % to about 70 wt.
%.
[0087] The amount of additional components in the compositions can
be determined by one of ordinary skill in the art, according to the
desired property or properties to be imparted to the composition.
For example, the amount of a suspending agent may be determined by
adding gradual amounts of the agent until the desired homogeneity
of undissolved drug particles in the composition is achieved. For a
colorant, the amount of the colorant may determined by adding small
amounts of the colorant until the desired color of the composition
is achieved. For a surfactant, the amount of a surfactant may
determined by adding gradual amounts of the surfactant until the
desired wetting effect or dispersibility of the composition is
achieved. The amount of surfactant, when present, in the
composition will generally be up to about 80 wt. %, preferably
between about 10 wt. % to about 50 wt. %.
[0088] The pharmaceutical compositions of the present invention are
prepared by conventional methods well known to those skilled in the
art. The composition can be prepared by mixing the active agent,
the solubilizer, and optional additive according to methods well
known in the art. Excess solvent or solubilizer, added to
facilitate solubilization of the active agent and/or mixing of the
formulation components, can be removed before administration of the
pharmaceutical dosage form. The compositions can be further
processed according to conventional processes known to those
skilled in the art, such as lyophilization, encapsulation,
compression, melting, extrusion, balling, drying, chilling,
molding, spraying, spray congealing, coating, comminution, mixing,
homogenization, sonication, cryopelletization, spheronization and
granulation to produce the desired dosage form.
[0089] For dosage forms substantially free of water, i.e., when the
composition is provided in a pre-concentrated form for
administration or for later dispersion in an aqueous system, the
composition is prepared by simple mixing of the components to form
a pre-concentrate. The compositions comprising solubilized
fenofibrate can be further formulated into desirable dosage forms
utilizing skills well known in the art. For example, compositions
in liquid or semi-solid form can be filled into soft gelatin
capsules using appropriate filling machines. Alternatively, the
composition can also be sprayed, granulated or coated onto a
substrate to become a powder, granule or bead that can be further
encapsulated or tableted if the compositions solidify at room
temperature with or without the addition of appropriate solidifying
or binding agents. This approach allows for the creation of a
"fused mixture," a "solid solution" or a "eutectic mixture."
[0090] As previously indicated, the compositions may include
additional amounts of fenofibrate over the amount that is
solubilized in the composition. In such a case, fenofibrate can be
partially suspended in the composition in any desired crystalline
or amorphous form. Such partially solubilized and partially
suspended fenofibrate compositions can be prepared by adding solids
of fenofibrate of desired form and particle size. For example,
micronized crystalline fenofibrate having an average particle size
of less than 30 microns, nanosized crystalline fenofibrate having
an average particle size of less than 1 micron or meshed amorphous
fenofibrate may be added to the composition. Such micronized or
nanosized fenofibrate particles can be obtained by precipitation or
size reduction techniques well-known in the art. In addition,
partially suspended fenofibrate compositions may be obtained from a
supersaturated fenofibrate solution or by co-precipitation with an
additive from a fenofibrate solution.
[0091] IV. Dosage Forms:
[0092] In a preferred embodiment, the pharmaceutical composition is
present in a single dosage form. The dosage form(s) are not limited
with respect to size, shape or general configuration, and may
comprise, for example, a capsule, a tablet or a caplet, or a
plurality of granules, beads, powders or pellets that may or may
not be encapsulated. In addition, the dosage form may be a drink or
beverage solution or a spray solution that is administered orally.
Thus, for example, the drink or beverage solution may be formed by
adding a therapeutically effective amount of the composition in,
for example, a powder or liquid form, to a suitable beverage, e.g.,
water or juice.
[0093] A preferred dosage form is a capsule containing a
composition as described herein. The capsule material may be either
hard or soft and is generally made of a suitable compound such as
gelatin, starch or a cellulosic material. As is known in the art,
use of soft gelatin capsules places a number of limitations on the
compositions that can be encapsulated. See, for example, Ebert
(1978), "Soft Elastic Gelatin Capsules: A Unique Dosage Form,"
Pharmaceutical Technology 1(5). Two-piece hard gelatin capsules are
preferably sealed, such as with gelatin bands or the like. See, for
example, Remington: The Science and Practice of Pharmacy,
Nineteenth Edition. (1995) cited supra, which describes materials
and methods for preparing encapsulated pharmaceuticals. In this
embodiment, the encapsulated composition may be liquid or
semi-solid (e.g., a gel).
[0094] V. Utility and Administration:
[0095] In accordance with the present invention, the pharmaceutical
compositions and dosage forms can be administered to treat
patients. For example, the fenofibrate-containing compositions and
dosage forms described herein can be administered to patients who
would benefit from fenofibrate therapy. Patients suffering from any
condition, disease or disorder which can be effectively treated
with fenofibrate can benefit from the administration of a
therapeutically effective amount of the fenofibrate-containing
compositions described herein. In particular, however, the
fenofibrate-containing compositions are effective in treating lipid
disorders.
[0096] Dosage regimens and daily dosages for fenofibrate can vary,
as a number of factors are involved, including the particular
condition or severity of the lipid disorder, the presence of renal
and/or hepatic dysfunction and the age and general condition of the
patient. It is necessary that the dose administered be sufficient
to provide the desired pharmacological activity. Typical dosages
for fenofibrate are on the order of about 40 to about 250 mg/day,
generally in the range of about 67 to about 200 mg/day. The
compositions and dosage forms are useful in treating lipid
disorders.
[0097] The composition may be administered in the form of a capsule
wherein a patient swallows the entire capsule. Alternatively, the
composition may be contained in capsule which is then opened and
mixed with an appropriate amount of aqueous fluid such as water or
juice to form a drink or beverage for administration of the
composition. As will be appreciated, the composition need not be
contained in a capsule and may be housed in any suitable container,
e.g., packets, ampules, etc. Once prepared, the drink or beverage
is imbibed in its entirety thus effecting administration of the
composition. Preparation of the composition-containing drink or
beverage may be effected by the patient or by another, e.g., a
caregiver. As will be appreciated by those skilled in the art,
additional modes of administration are available.
[0098] It is to be understood that while the invention has been
described in conjunction with the preferred specific embodiments
thereof, that the description above as well as the examples which
follow are intended to illustrate and not limit the scope of the
invention. Other aspects, advantages and modifications within the
scope of the invention will be apparent to those skilled in the art
to which the invention pertains.
[0099] All patents, patent applications, and publications mentioned
herein, both supra and infra, are hereby incorporated by
reference.
EXPERIMENTAL
[0100] The practice of the present invention will employ, unless
otherwise indicated, conventional techniques of pharmaceutical
formulation, medicinal chemistry, and the like, which are within
the skill of the art. Such techniques are explained fully in the
literature. Preparation of various types of pharmaceutical
formulations are described, for example, in Remington: The Science
and Practice of Pharmacy, Nineteenth Edition. (1995) cited supra
and Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery
Systems, 6.sup.th Ed. (Media, Pa.: Williams & Wilkins,
1995).
[0101] In the following examples, efforts have been made to ensure
accuracy with respect to numbers used (e.g., amounts, temperature,
etc.) but some experimental error and deviation should be accounted
for. Unless indicated otherwise, temperature is in degrees C. and
pressure is at or near atmospheric. All components were obtained
commercially unless otherwise indicated. "Tween.RTM." and
"Arlacel.RTM." components are available from ICI Americas,
Wilmington, Del. "Cremophor.RTM." components are available from
BASF Corp., Mount Olive, N.J. "Imwitor.RTM." and "Miglyol.RTM."
components are available from Huls AG, Heme, Germany.
"Lauroglycol.RTM.," "Labrafil.RTM.," "Labrasol.RTM.,"
"Transcutol.RTM.," "Maisine.RTM." and "Capryol.RTM." components are
available from Gattefoss SA, Saint Priest, France. "Eastman.RTM."
components are available from Eastman Chemical Products, Inc.,
Kingsport, Tenn. "Captex.RTM.," and "Capmul.RTM." components are
available from Karlshamns USA, Inc., Columbus, Ohio. "Incrocas" and
"Crovol" components are available from Croda, Inc., Parsippany,
N.J.
[0102] In examples 1-7, the solubility of fenofibrate in various
solubilizers was determined using conventional techniques such as
incrementally adding fenofibrate until the solubilizer could no
longer solubilize additional fenofibrate.
Example 1
[0103]
1 Solubility of Fenofibrate in Propylene Glycol and Propylene
Glycol Esters Solubilizer Solubility (mg/g) Propylene Glycol
.about.5 Propylene Carbonate 134-150 Propylene glycol monocaprylate
(Capryol .RTM. 90) 150-160 Propylene glycol laurate (Lauroglycol
.RTM. FCC) 100-108 Propylene glycol dicaprylate/caprate (Miglyol
.RTM. 840) 136-150
Example 2
[0104]
2 Solubility of Fenofibrate in Glycerol, Glycerol Acetate, and
Acetylated Glycerol Esters Solubilizer Solubility (mg/g) Glycerol
<2 Triacetin 100-120 Distilled acetylated monoglyceride (Eastman
.RTM. 9-45) 136-150
Example 3
[0105]
3 Solubility of Fenofibrate in Glycerol and Glycerol Fatty Acid
Esters Solubility Solubilizer (mg/g) Glycerol <2 Glycerol
monooleate (Arlacel .RTM. 186) 45-50 Glycerol mono-, dicaprylate
(Imwitor .RTM. 988) 80-100 Glycerol mono-, dicaprylate/caprate
(Capmul .RTM. MCM) 67-80 Gycerol tricaprylate/caprate (Miglyol
.RTM. 812) 80-100 Glycerol tricaprylate/caprate/linoleate (Miglyol
.RTM. 818) 80-100 Olive Oil 40-50 Corn Oil 50-60 Safflower Oil
50-60
Example 4
[0106]
4 Solubility of Fenofibrate in Polyethylene Glycols and
Polyethylene Glycol Fatty Acid Esters Including Transesterification
Products of Polyethylene Glycol with Triglyceride/Vegetable Oil
Solubilizer Solubility (mg/g) Polyethylene glycol 200 25-33 PEG-8
monooleate 100-110 PEG-8 dioleate 100-110 PEG-8 dilaurate 127-140
PEG-6 corn oil (Labrafil .RTM. M2125 CS) 75-80 PEG-6 apricot kernel
oil (Labrafil .RTM. M1944 CS) 70-80 PEG-8 caprylic/capric
glycerides (Labrasol .RTM.) 100-110
Example 5
[0107]
5 Solubility of Fenofibrate in Esters of Organic Acid and Alcohol
Solubilizer Solubility (mg/g) Triethyl Citrate 140-150 Ethyl Oleate
100-108
Example 6
[0108]
6 Solubility of Fenofibrate in Vitamin E and Vitamin E Derivative
Solubilizer Solubility (mg/g) dl-alpha-tocopherol 175-200
d-alpha-tocopheryl acetate 90-100
Example 7
[0109]
7 Solubility of Fenofibrate in Nitrogen-Containing Solubilizers
Solubilizer Solubility (mg/g) Dimethylacetamide 900-1000
Dimethylformamide 830-900 N-methyl 2-pyrrolidone 750-800 N-ethyl
2-pyrrolidone 830-900
Examples 8-34
Compositions Comprising Fenofibrate
[0110] Compositions comprising fenofibrate in the examples were
prepared by weighing out the components in the described amount,
placing the components into an appropriate container, mixing the
components in an appropriate manner and, if necessary, heating to
facilitate the solubilization of fenofibrate in the compositions.
The compositions can be prepared by adding the components in any
order. For example, fenofibrate can be added to an individual
component or into mixtures of two or more components. The
composition can be prepared at room temperature or gently heated to
40-60.degree. C. The composition can also be prepared by melting
fenofibrate at a temperature above the melting point, i.e.,
79-82.degree. C., followed by mixing it with other components.
Traditional mixing techniques can be used including, for example,
mechanical agitation, stirring and sonication of the
components.
Example 8
[0111]
8 Component Amount (mg) Fenofibrate 67 Triacetin 700
Example 9
[0112]
9 Component Amount (mg) Fenofibrate 67 Capryol .RTM. 90 400
Incrocas 35 400
Example 10
[0113]
10 Component Amount (mg) Fenofibrate 100 Incrocas 35 500 Transcutol
.RTM. 500
Example 11
[0114]
11 Component Amount (mg) Fenofibrate 200 Incrocas 35 400 Capryol
.RTM. 90 400 Transcutol .RTM. 400
Example 12
[0115]
12 Amount (mg) Fenofibrate 67 Tween .RTM. 80 200 Eastman .RTM. 9-45
300 Triethyl Citrate 150
Example 13
[0116]
13 Component Amount (mg) Fenofibrate 100 Tween .RTM. 80 300 Eastman
.RTM. 9-45 500 Triethyl Citrate 200
Example 14
[0117]
14 Component Amount (mg) Fenofibrate 67 Incrocas 35 500 Eastman
.RTM. 9-45 400 Triethyl Citrate 100
Example 15
[0118]
15 Component Amount (mg) Fenofibrate 200 Labrasol .RTM. 400
Glycofurol 400
Example 16
[0119]
16 Component Amount (mg) Fenofibrate 100 Incrocas 35 300 Capryol
.RTM. 90 300 Miglyol .RTM. 840 300
Example 17
[0120]
17 Component Amount (mg) Fenofibrate 200 Olive Oil 600 Triethyl
Citrate 400
Example 18
[0121]
18 Component Amount (mg) Fenofibrate 67 Labrafil .RTM. M1944 CS 400
Safflower Oil 380
Example 19
[0122]
19 Component Amount (mg) Fenofibrate 67 Labrafil .RTM. M2125 CS 400
Corn Oil 380 Ethanol 120
Example 20
[0123]
20 Component Amount (mg) Fenofibrate 67 Cremophor .RTM. RH40 440
Maisine .RTM. I-35 400 dl-alpha-tocopherol 60 Ethanol 100
Example 21
[0124]
21 Component Amount (mg) Fenofibrate 100 PEG-8 dilaurate 500 PEG
400 400
Example 22
[0125]
22 Component Amount (mg) Fenofibrate 67 Tween .RTM. 80 300
Isopropyl Myristate 500 Ethanol 100
Example 23
[0126]
23 Amount (mg) Fenofibrate 100 Tween .RTM. 80 240 Ethyl Oleate 400
Ethanol 80
Example 24
[0127]
24 Component Amount (mg) Fenofibrate 200 dl-alpha-tocopherol
1000
Example 25
[0128]
25 Component Amount (mg) Fenofibrate 40 dl-alpha-tocopherol 600
Vitamin E-TPGS 200
Example 26
[0129]
26 Component Amount (mg) Fenofibrate 67 dl-alpha-tocopherol 600
Vitamin E-TPGS 300 Triethyl Citrate 100
Example 27
[0130]
27 Component Amount (mg) Fenofibrate 67 dl-alpha-tocopherol 400
Vitamin E-TPGS 200 Tween .RTM. 80 200 Triethyl Citrate 200
Example 28
[0131]
28 Component Amount (mg) Fenofibrate 67 dl-alpha-tocopherol 400
Labrafil .RTM. M1944 CS 400
Example 29
[0132]
29 Component Amount (mg) Fenofibrate 67 dl-alpha-tocopherol 500
Crovol M40 300 PEG 600 200
Example 30
[0133]
30 Component Amount (mg) Fenofibrate 67 dl-alpha-tocopherol 200
Crovol M40 200 Incrocas 35 400
Example 31
[0134]
31 Component Amount (mg) Fenofibrate 100 dl-alpha-tocopherol 260
Soybean Oil 80 Imwitor .RTM. 988 100 Crovol M40 100 Incrocas 35
460
Example 32
[0135]
32 Component Amount (mg) Fenofibrate 67 dl-alpha-tocopherol 400
Captex .RTM. 300 60 Capmul .RTM. MCM 100 Labrafil .RTM. M2125 CS
100 Cremophor .RTM. RH40 340
Example 33
[0136]
33 Component Amount (mg) Fenofibrate 67 d-alpha-tocopheryl acetate
500 Triacetin 150
Example 34
[0137]
34 Component Amount (mg) Fenofibrate 67 d-alpha-tocopheryl acetate
500 Labrasol .RTM. 200 Labrafil .RTM. M1944 CS 100
* * * * *