U.S. patent application number 11/998362 was filed with the patent office on 2009-01-01 for nanoparticulate formulations and methods for the making and use therof.
This patent application is currently assigned to Marinus Pharmaceuticals. Invention is credited to Kenneth Shaw, Mingbao Zhang.
Application Number | 20090004262 11/998362 |
Document ID | / |
Family ID | 39468517 |
Filed Date | 2009-01-01 |
United States Patent
Application |
20090004262 |
Kind Code |
A1 |
Shaw; Kenneth ; et
al. |
January 1, 2009 |
Nanoparticulate formulations and methods for the making and use
therof
Abstract
The present invention is directed to size-stabilized drug
nanoparticulate compositions and methods of preparation
thereof.
Inventors: |
Shaw; Kenneth; (Weston,
CT) ; Zhang; Mingbao; (Stamford, CT) |
Correspondence
Address: |
Davidson, Davidson & Kappel, LLC
485 7th Avenue, 14th Floor
New York
NY
10018
US
|
Assignee: |
Marinus Pharmaceuticals
Branford
CT
|
Family ID: |
39468517 |
Appl. No.: |
11/998362 |
Filed: |
November 28, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60861616 |
Nov 28, 2006 |
|
|
|
Current U.S.
Class: |
424/456 ;
424/451; 424/464; 424/489; 424/499; 424/501 |
Current CPC
Class: |
B82Y 5/00 20130101; A61K
9/0078 20130101; A61K 9/145 20130101; A61K 9/0073 20130101; A61K
9/5078 20130101; A61P 17/04 20180101; A61K 9/007 20130101; A61K
9/1652 20130101; A61K 9/2886 20130101; C07J 71/00 20130101; A61K
31/58 20130101; A61P 27/02 20180101; A61P 11/00 20180101; Y10S
977/773 20130101; A61K 47/14 20130101; A61K 9/0075 20130101; A61K
47/6949 20170801; Y10S 977/906 20130101; A61K 9/1623 20130101; A61K
9/008 20130101 |
Class at
Publication: |
424/456 ;
424/489; 424/499; 424/501; 424/464; 424/451 |
International
Class: |
A61K 9/48 20060101
A61K009/48; A61K 9/14 20060101 A61K009/14; A61K 9/20 20060101
A61K009/20 |
Claims
1. Drug complexed particles having a volume weighted median
diameter (D50) from about 50 nm to about 500 nm, each of the
particles comprising in association (i) a drug capable of forming a
cyclodextrin inclusion complex and having an aqueous solubility of
less than 1 mg/ml in a pH of about 7.4, (ii) a surface stabilizer,
and (iii) a complexing agent capable of forming a cyclodextrin
inclusion complex when the particles are cured for at least about 3
days.
2. The drug complexed particles of claim 1, wherein the complexing
agent is included in an amount effective to cause an initial
increase in the size of the particles, wherein the volume weighted
median diameter (D50) of the particles before the initial growth is
from about 100 to about 400 nm and the D50 at the end of the curing
time is 20% to 300% larger than the D50 measured before the curing
period.
3. The drug complexed particles of claim 1, wherein the surface
stabilizer is at least one non-ionic material selected from the
group consisting of binders, fillers, surfactants/wetting agents;
and/or at least one ionic surface stabilizer.
4. The drug complexed particles of claim 2, wherein the complexing
agent is selected from the group consisting of phenol, parabens,
ascorbic acid, methyl anthranilate, salicylic acid, acetosalicyclic
acid, tocopherol, organic acids, carboxylic acids, aromatic acids,
aromatic esters, acid salts of amino acids, benzaldehyde,
cinnimaldehyde, imidazole, menthol, thiophenol, m-aminobenzoic
acid, anthranilic acid, picolinic acids and alkyl esters thereof,
toluidides, sodium benzoate, para-aminobenzoic acid and esters,
sorbic and benzoic acids,
2,6-di-t-butyl-alpha-dimethylamino-p-cresol, t-butylhydroquinone,
di-t-amylhydroquinone, di-t-butylhydroquinone, butylhydroxytoluene
(BHT), butylhydroxyanisole (BHA), pyrocatechol, pyrogallol, esters,
isomeric compounds thereof, pharmaceutically acceptable salts
thereof, and mixtures of any of the foregoing.
5. The drug complexed particles of claim 4, wherein the complexing
agent is selected from the group consisting of methylparaben,
propylparaben, potassium methylparaben, sodium methylparaben,
methyl anthranilate, benzoic acid, sodium benzoate, and any
combinations or mixtures thereof.
6. The drug complexed particles of claim 4, which comprise from
about 0.1% to about 8%, w/w of the complexing agent.
7. The drug complexed particles of claim 5, wherein the surface
stabilizer is selected from the group consisting of cellulosics,
polyvinylpyrrolidones, polyethylene glycols, pluronics and any
combinations or mixtures thereof.
8. The drug complexed particles of claim 5, wherein the surface
stabilizer is selected from the group consisting of
hydroxypropylmethylcellulose, polyvinyl alcohol, docusate sodium,
sodium lauryl sulfate, polyvinylpyrrolidone, Plasdone, and mixtures
thereof.
9. The drug complexed particles of claim 2, wherein the volume
weighted diameter (D50) of the complexed particles does not change
by more than 10% after a time in consecutive measurements separated
by about 72 hours.
10. The drug complexed particles of claim 2, wherein the complexed
particles increase in effective particle size from about 0% to
about 200% upon dispersion in simulated gastric or intestinal fluid
as compared to dispersion in water under the same conditions.
11. The drug complexed particles of claim 2, wherein the D50 after
the endpoint is reached is less than about 500 nm.
12. A pharmaceutical composition, comprising the drug complexed
particles of claim 1 together with at least one pharmaceutically
acceptable excipient.
13. The pharmaceutical composition of claim 12, which is in a form
of a solid dosage form.
14. The pharmaceutical composition of claim 12, which is in a form
of a liquid suspension.
15. A method of treatment, comprising administering an effective
dose of the pharmaceutical composition of claim 13 to a human or
animal in need thereof.
16. A method of treatment, comprising administering an effective
dose of the pharmaceutical composition of claim 14 to a human or
animal in need thereof.
17. Size-stabilized drug complexed particles comprising a drug
capable of forming a cyclodextrin inclusion complex and having an
aqueous solubility of less than 1 mg/ml in a pH of about 7.4 in
association with effective amounts of a surface stabilizer and a
complexing agent capable of forming a cyclodextrin inclusion
complex, the size-stabilized drug complexed particles having a
volume weighted median diameter (D50) from about 50 nm to about 500
nm; the drug complexed particles exhibiting an increase in volume
weighted median diameter (D50) of from 0% to not more than about
200% when the formulation is dispersed in simulated gastric fluid
(SGF) or simulated intestinal fluid (SIF) at a concentration of 0.5
to 1 mg drug/mL and placed in a heated bath at 36.degree. to
38.degree. C. for 1 hour using a Type I or II dissolution apparatus
and a stirring rate of 75 RPM, as compared to the D50 of the drug
particles when the formulation is dispersed in distilled water
under the same conditions.
18. The size-stabilized drug complexed particles of claim 16,
wherein the surface stabilizer is at least one non-ionic material
selected from the group consisting of binders, fillers,
surfactants/wetting agents; and/or at least one ionic surface
stabilizer; and the complexing agent is selected from the group
consisting of phenol, parabens, ascorbic acid, methyl anthranilate,
salicylic acid, acetosalicyclic acid, tocopherol, organic acids,
carboxylic acids, aromatic acids, aromatic esters, acid salts of
amino acids, benzaldehyde, cinnimaldehyde, imidazole, menthol,
thiophenol, m-aminobenzoic acid, anthranilic acid, picolinic acids
and alkyl esters thereof, toluidides, sodium benzoate,
para-aminobenzoic acid and esters, phosphoric acids, sorbic and
benzoic acids, 2,6-di-t-butyl-alpha-dimethylamino-p-cresol,
t-butylhydroquinone, di-t-amylhydroquinone, di-t-butylhydroquinone,
butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), pyrocatechol,
pyrogallol, esters, isomeric compounds thereof, pharmaceutically
acceptable salts thereof, and mixtures of any of the foregoing.
19. A pharmaceutical composition, comprising the drug complexed
particles of claim 17 together with at least one pharmaceutically
acceptable excipient.
20. The pharmaceutical composition of claim 19, which is in a form
of a solid dosage form.
21. The pharmaceutical composition of claim 19, which is in a form
of a liquid suspension.
22. The size stabilized drug complexed particles of claim 17,
wherein the complexing agent is selected from the group consisting
of methylparaben, propylparaben, potassium methylparaben, sodium
methylparaben, methyl anthranilate, benzoic acid, sodium benzoate,
and any combinations or mixtures thereof.
23. The size-stabilized drug complexed particles of claim 15,
wherein the complexing agent is methyl anthranilate.
24. A method of treatment, comprising administering an effective
dose of the pharmaceutical composition of claim 20 to a human or
animal in need thereof.
25. A method of treatment, comprising administering an effective
dose of the pharmaceutical composition of claim 21 to a human or
animal in need thereof.
26. The size-stabilized drug complexed particles of claim 17, which
comprise from about 0.1% to about 8%, w/w of the complexing
agent.
27. The pharmaceutical composition of claim 20, which is an oral
solid dosage form providing an immediate, delayed, sustained, or
pulsatile release of the drug when orally administered to a human
or animal.
28. The pharmaceutical composition of claim 27, wherein the oral
solid dosage form is a tablet or a capsule.
29. The pharmaceutical composition of claim 19, wherein the drug
complexed particles are spray-layered along with effective amounts
of a water soluble spacer and an ionic dispersion modulator onto a
plurality of inert beads.
30. The pharmaceutical composition of claim 29, wherein the ionic
dispersion modulator is in an amount effective to provide a
satisfactory redispersibility of the beads with acceptable particle
size and stability.
31. The composition of claim 29, wherein the ionic dispersion
modulator is an organic or inorganic salt selected from the group
consisting of a magnesium salt, a calcium salt, a lithium salt, a
potassium salt, a sodium salt, a citrate salt, a succinate salt, a
fumarate salt, malate salt, maleate salt, a tartrate salt, a
glutarate salt, a lactate salt and mixtures thereof.
32. A method for preparing stabilized drug particles, comprising:
a) reducing the size of drug particles capable of forming a
cyclodextrin inclusion complex and having an aqueous solubility of
less than 1 mg/ml in a pH of about 7.4 into a size range of about
50 nm to about 200 nm; b) adding an effective amount of a surface
stabilizer to the drug particles before, during or after reducing
the size of the drug particles to form particles comprising the
drug and the surface stabilizer; and c) further stabilizing the
particles of step b) by adding an effective amount of a complexing
agent capable of forming a cyclodextrin inclusion complex to
provide particles that attain a stabilized size such that the
volume weighted median diameter (D50) of the particles is from
about 50 nm to about 500 nm.
33. The method of claim 32, wherein the complexing agent can be
added to the stabilized drug particles of step b) to provide
particles that attain a stabilized size such that the volume
weighted median diameter (D50) of the particles is from about 50 nm
to about 500 nm.
34. The method of claim 33, further comprising spraying layering
inert beads with a suspension of the stabilized drug particles
together with a water soluble spacer and an ionic dispersion
modulator in an amount effective to reduce the amount of water
soluble spacer needed to redisperse the spray-layered beads.
35. The method of claim 34, wherein the water soluble spacer
comprises from about 0 to about 60% and the ionic modulator
comprises from about 0 to about 40% of the spray-layered particles,
by weight stabilized drug particles.
36. The method of claim 35, wherein the ionic dispersion modulator
is selected from the group consisting of an organic salt, an
inorganic salt, and mixtures thereof.
37. The method of claim 36, wherein the inorganic salts is selected
from the group consisting of a magnesium salt, a calcium salt, a
lithium salt, a potassium salt, a sodium salt and mixtures thereof;
and the organic salt is selected from the group consisting of a
citrate salt, a succinate salt, a fumarate salt, a malate salt,
maleate salt, a tartrate salt, a glutarate salt, a lactate salt and
mixtures thereof.
38. A method of treatment, comprising administering the composition
of claim 33 to a human or animal in need thereof.
39. A solid pharmaceutical composition, comprising a plurality of
inert beads spray layered with a coating comprising (a) drug
complexed particles having a volume weighted median diameter (D50)
from about 50 nm to about 500 nm, each of the particles comprising
in association (i) a drug capable of forming a cyclodextrin
inclusion complex and having an aqueous solubility of less than 1
mg/ml in a pH of about 7.4, (ii) a surface stabilizer, (iii) a
complexing agent capable of forming a cyclodextrin inclusion
complex; together with effective amounts of (b) a water soluble
spacer and (c) an ionic dispersion modulator.
40. The pharmaceutical composition, of claim 39, further comprising
one or more pharmaceutically acceptable excipients.
41. The pharmaceutical composition, of claim 40, which is a liquid
suspension of said coated inert beads.
42. The pharmaceutical composition, of claim 40, wherein a
therapeutically effective dose of the coated inert beads are
incorporated into a hard gelatin capsule.
43. The pharmaceutical composition, of claim 42, wherein the coated
inert beads are further over-coated with a coating which imparts a
sustained or delayed release of the drug from the formulation when
the formulation is exposed to simulated gastrointestinal fluid.
44. The pharmaceutical composition, of claim 42, wherein a portion
of the coated inert beads incorporated into the hard gelatin
capsule are in immediate release form and a portion of the inert
beads incorporated into the hard gelatin capsule are in modified
release form selected from the group consisting of sustained
release, delayed release and a mixture of the foregoing, to provide
a pulsatile release of drug from the formulation when the
formulation is exposed to simulated gastrointestinal fluid.
45. An orally ingestible tablet, comprising a compressed mixture of
(a) drug complexed particles having a volume weighted median
diameter (D50) from about 50 nm to about 500 nm, each of the
particles comprising in association (i) a drug capable of forming a
cyclodextrin inclusion complex and having an aqueous solubility of
less than 1 mg/ml in a pH of about 7.4, (ii) a surface stabilizer,
(iii) a complexing agent capable of forming a cyclodextrin
inclusion complex; together with effective amounts of (b) a water
soluble spacer and (c) an ionic dispersion modulator; an inert
diluent; and a tableting lubricant.
45. The orally ingestible tablet of claim 45, further comprising
one or more excipients which impart a sustained or delayed or
pulsatile release of the drug from the formulation when the
formulation is exposed to simulated gastrointestinal fluid.
47. A size-stabilized nanoparticulate liquid composition comprising
a drug capable of forming a cyclodextrin inclusion complex and
having an aqueous solubility of less than 1 mg/ml in a pH of about
7.4 in association with effective amounts of a surface stabilizer
and a complexing agent capable of forming a cyclodextrin inclusion
complex, wherein the volume weighted median diameter (D50) of the
size-stabilized particles is from about 50 nm to about 500 nm after
curing.
48. The nanoparticulate liquid composition of claim 47, wherein the
composition further contains at least one additional
pharmaceutically acceptable excipient selected from the group
consisting of a hydrophilic polymer, a wetting agent, an ionic
dispersion modulator, a water soluble spacer, and any combinations
or mixture thereof.
49. The nanoparticulate liquid composition of claim 47, wherein the
liquid composition is converted to a solid nanoparticulate
composition by removal of solvent.
Description
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 60/861,616, filed on Nov. 28, 2006, the
disclosure of which is hereby incorporated by reference in its
entirety.
FIELD OF THE INVENTION
[0002] Described herein are nanoparticulate formulations of drugs
having an aqueous solubility of less than 1 mg/ml in a pH of about
7.4 which provide enhanced stability, physical and chemical
properties and can provide enhanced pharmacokinetic properties to
achieve an optimal balance between pharmacodynamic and side effect
profiles in mammals, and dosage forms containing the same, as well
as methods of making nanoparticulate drug formulations and their
use in the treatment of various disorders.
BACKGROUND OF THE INVENTION
[0003] It has been very difficult to formulate therapeutically
effective dosage forms specific for drugs having an aqueous
solubility of less than 1 mg/ml in a pH of about 7.4, across a
broad range of therapeutic agents (e.g. medroxyprogesterone
acetate, carbamazepine, phenyloin, nifedipine and ganaxolone).
Generally, conventional formulations of drugs having an aqueous
solubility less than 1 mg/ml in a pH of about 7.4 demonstrate
variable and low bioavailability and have also shown particularly
large exposure differences when the drug is administered in the fed
and fasted state. Based upon this difficulty, there exists a need
in the art for improved drug formulations and dosage forms for
drugs having an aqueous solubility less than 1 mg/ml in a pH of
about 7.4. Herein are described liquid and solid dosage drug
formulations which address this need and which provide improved
pharmacokinetic properties which maintain efficacy while reducing
side effects and enhancing subject compliance.
[0004] Various methods to improve the solubility and
bioavailability of drugs have been used by those skilled in the
art. One such method involves the comminuting in size of the drug
particles. Small particles have more surface area and therefore
dissolve into a fixed amount of media faster. This results in
higher oral bioavailability for water insoluble compounds
especially those which have restricted areas of absorption in the
GI tract, have high first pass clearance (liver metabolism) and
have a high dose requirement.
[0005] One way to provide for a small "nano" particle drug
formulation is to form a nanoparticle liquid formulation, e.g.,
nanosuspension. When dealing with nanosuspensions, the less water
soluble and more lipophilic the drug, the more difficult it is to
obtain a stable small particle "nanosuspension" in polar solvents
like water. Particle growth (Otswald Ripening) and aggregation must
be minimized in nanoparticulate compositions if the benefit of
small particle formulations is to be realized.
[0006] Preparation of nanosuspensions is known in the art. Most
current commercial technologies involve the use a water based
system to generate small particles (e.g., wet ball milling,
precipitation, high pressure homogenization). Many marketed small
particle formulations today are prepared utilizing wet ball milling
techniques. For example, one common technique entails grinding drug
in a milling chamber with grinding media (beads) to produce small
particles. For productivity, those skilled in the art appreciate
that one wants to mill for as short a period of time needed to make
a stable composition and also as concentrated in drug as possible.
Recirculation of a tank of drug suspension through a ball mill is
the most common technique. As the milling is a high energy process,
to avoid contamination from abraded materials (milling chamber and
grinding balls), the shortest milling time possible with the lowest
energy is the most preferred process. As oral nanoparticulate
formulations are formed generally to increase dissolution rates in
the gastrointestinal tract, maintaining a constant particle size
until the compound is absorbed is the key parameter to monitor.
[0007] The preparation of small particle pharmaceutical
compositions (effective particle size (D50) of less than 500 nm)
have been described since 1988 (H. Steffen B T Gattefosse No. 81,
1988 pp. 45-53; U.S. Pat. No. 4,540,602 (Motoyama, et al.); and
U.S. Pat. No. 5,145,684 (Liversidge, et al.)). These submicron
(nanoparticulate) compositions all describe using non-crosslinked
excipients associated with the surface of the small particle to
stabilize the composition from significant particle size growth
and/or agglomeration. Generally, surface stabilizers fall into two
categories: non-ionic (also called steric stabilizers or modifiers)
and ionic stabilizers. The most common non-ionic stabilizers are
excipients which are contained in classes known as binders,
fillers, surfactants and wetting agents. Limited examples of
non-ionic surface stabilizers are hydroxypropylmethyl cellulose,
polyvinylpyrrolidone, Plasdone, polyvinyl alcohol, Pluronics,
Tweens and Polyethyleneglycols (PEGs). A subset of surface
stabilizers commonly used is ionic in nature. These ionic surface
stabilizers tend to fall into the class of excipients which are
typically used as surfactants and wetting agents. Ionic stabilizers
used in the prior art are typically organic molecules bearing an
ionic bond such that the molecule is essentially fully charged in
the formulation. The two most described ionic surface stabilizers
are the long chain sulfonic acid salts sodium lauryl sulfate and
dioctyl sodium sulfosuccinate (DOSS). Broad ranges for all surface
stabilizers have been claimed in U.S. Pat. No. 5,145,684 (the '684
patent) ranging from 0.1% to 90% by weight of the composition.
Typically, one adds 20%-150% (wt % of drug) of a nonionic surface
stabilizer and 0.2%-5% of an ionic surface stabilizer (wt % of
drug) to achieve maximal particle size stabilization from these
surface stabilizers. Since 1988, many papers and patents have
published relating to nanoparticulate compositions and various ways
to optimize the method of manufacture, use and stability of such
compositions.
[0008] In preparing drug nanoparticles via a wet ball milling
process as described in the '684 patent, milling suspensions with
drug concentrations of 5-30% are typically milled with a hard
grinding media in a ball mill to obtain particles with a D50 in the
100-500 nm size range. The literature teaches that particle size
reduction using milling is conducted at a sufficient speed and time
to obtain a desired particle size. The surface stabilizers are
present or added to keep the particle size constant over a variety
of stability indicating measurements as compared to the particle
size (D50) obtained at the end of milling. One of the major issues
in wet ball milling is potential residual metals in the composition
due to extended milling or energy needed to obtain the desired
particle size (Jia, L. Current Nanoscience, 1, pp 237-243
(2005)).
[0009] Enhancing stability has been the focus of much research.
Stability is a broad reference and in the pharmaceutical industry
is generally recognized as testing needed to determine storage
stability (the stability of the formulation under storage over
time), purity stability (the purity profile of the formulation over
storage conditions), release or dispersion stability (the stability
of release or disintegration characteristics for the formulation in
water and physiological media). The physiological media for
dispersion stability is dependent on the route of administration
(simulated gastric and/or intestinal fluid for oral products,
saliva for buccal and sub-lingual products, etc). In general any
parameter important to the performance or tolerability of a
formulation must be monitored for stability.
SUMMARY OF THE INVENTION
[0010] Described herein are compositions, pharmaceutical
compositions, methods for treating, methods for formulating,
methods for producing, methods for manufacturing, treatment
strategies, pharmacokinetic strategies using nanoparticulate
formulations of drugs having an aqueous solubility of less than 1
mg/ml in a pH of about 7.4. The drugs that would benefit from this
approach are limited to those that can form a cyclodextrin
complex.
[0011] The inventors have prepared stable submicron drug particles
with particularly advantageous pharmaceutical properties. Stable
drug particles described herein comprise a complex of drug and a
complexing agent. Additional factors that affect stability and
particle size are described herein.
[0012] In certain embodiments, the present invention is directed to
drug complexed particles having a volume weighted median diameter
(D50) from about 50 nm to about 500 nm, each of the particles
comprising in association (i) a drug capable of forming a
cyclodextrin inclusion complex and having an aqueous solubility of
less than 1 mg/ml in a pH of about 7.4, (ii) a surface stabilizer,
and (iii) a complexing agent capable of forming a cyclodextrin
inclusion complex when the particles are cured for at least about 3
days. In certain embodiment, the complexing agent may be included
in an amount effective to cause an initial increase in the size of
the particles, wherein the volume weighted median diameter (D50) of
the particles before the initial growth is from about 100 to about
400 nm and the D50 at the end of the curing time is 20% to 300%
larger than the D50 measured before the curing period. For example,
in certain embodiments, the complexing agent is included in an
amount from about 0.1% to about 8%, w/w of the size-stabilized drug
particles
[0013] In certain embodiments, the volume weighted diameter (D50)
of the complexed particles does not change by more than 10% after a
time in consecutive measurements separated by about 72 hours.
[0014] In certain embodiments, the complexed particles increase in
effective particle size from about 0% to about 200% upon dispersion
in simulated gastric or intestinal fluid as compared to dispersion
in water under the same conditions.
[0015] In yet another embodiment, the present invention provides
for a pharmaceutical composition comprising the drug complexed
particles described above together with at least one
pharmaceutically acceptable excipient. In certain embodiments, the
pharmaceutical composition may be in the form of a solid dosage
form. In other embodiments, the pharmaceutical composition may be
in the form of a liquid dosage form, e.g., suspension. When
incorporated into a pharmaceutical composition comprising
pharmaceutically acceptable excipients, the amount of drug
complexed particles may range from about 1% to about 99%, based on
the weight of the entire composition and the amount of
pharmaceutically acceptable excipient may range from about 1 to
about 99% based on the weight of the total composition.
[0016] In another embodiment, the present invention is directed to
size-stabilized drug complexed particles comprising a drug capable
of forming a cyclodextrin inclusion complex and having an aqueous
solubility of less than 1 mg/ml in a pH of about 7.4 in association
with effective amounts of a surface stabilizer and a complexing
agent capable of forming a cyclodextrin inclusion complex, the
size-stabilized drug complexed particles having a volume weighted
median diameter (D50) from about 50 nm to about 500 nm; the drug
complexed particles exhibiting an increase in volume weighted
median diameter (D50) of from 0% to not more than about 200% when
the formulation is dispersed in simulated gastric fluid (SGF) or
simulated intestinal fluid (SIF) at a concentration of 0.5 to 1 mg
drug/mL and placed in a heated bath at 36.degree. to 38.degree. C.
for 1 hour using a Type I or II dissolution apparatus and a
stirring rate of 75 RPM, as compared to the D50 of the drug
particles when the formulation is dispersed in distilled water
under the same conditions.
[0017] In certain other embodiments, the present invention is
directed to a solid pharmaceutical formulation, comprising a
plurality of inert beads spray layered with a coating comprising
(a) drug complexed particles having a volume weighted median
diameter (D50) from about 50 nm to about 500 nm, each of the
particles comprising in association (i) a drug capable of forming a
cyclodextrin inclusion complex and having an aqueous solubility of
less than 1 mg/ml in a pH of about 7.4, (ii) a surface stabilizer,
(iii) a complexing agent capable of forming a cyclodextrin
inclusion complex; together with effective amounts of (b) a water
soluble spacer and (c) an ionic dispersion modulator.
[0018] In another embodiment, the present invention is directed to
an orally ingestible tablet, comprising a compressed mixture of (a)
drug complexed particles having a volume weighted median diameter
(D50) from about 50 nm to about 500 nm, each of the particles
comprising in association (i) a drug capable of forming a
cyclodextrin inclusion complex and having an aqueous solubility of
less than 1 mg/ml in a pH of about 7.4, (ii) a surface stabilizer,
(iii) a complexing agent capable of forming a cyclodextrin
inclusion complex; together with effective amounts of (b) a water
soluble spacer and (c) an ionic dispersion modulator; an inert
diluent; and a tableting lubricant.
[0019] In yet another embodiment, the present invention is directed
to a size-stabilized nanoparticulate liquid composition comprising
a drug capable of forming a cyclodextrin inclusion complex and
having an aqueous solubility of less than 1 mg/ml in a pH of about
7.4 in association with effective amounts of a surface stabilizer
and a complexing agent capable of forming a cyclodextrin inclusion
complex, wherein the volume weighted median diameter (D50) of the
size-stabilized particles is from about 50 nm to about 500 nm after
curing. The nanoparticulate liquid compositions, may further
contain at least one additional pharmaceutically acceptable
excipient selected from the group consisting of a hydrophilic
polymer, a wetting agent, an ionic dispersion modulator, a water
soluble spacer, and any combinations or mixture thereof.
[0020] In certain embodiments, the nanoparticulate liquid
composition is converted to a solid nanoparticulate composition by
removal of solvent (e.g., via spray drying, spray granulation,
spray layering onto inert cores).
[0021] In yet another embodiment, the present invention is directed
to a method for preparing stabilized drug particles, comprising: a)
reducing the size of drug particles capable of forming a
cyclodextrin inclusion complex and having an aqueous solubility of
less than 1 mg/ml in a pH of about 7.4 into a size range of about
50 nm to about 200 nm; b) adding an effective amount of a surface
stabilizer to the drug particles before, during or after reducing
the size of the drug particles to form particles comprising the
drug and the surface stabilizer; and c) further stabilizing the
particles of step b) by adding an effective amount of a complexing
agent capable of forming a cyclodextrin inclusion complex to
provide particles that attain a stabilized size such that the
volume weighted median diameter (D50) of the particles is from
about 50 nm to about 500 nm.
[0022] In certain embodiments, the size stabilized particles are
prepared by contacting drug particles with a complexing agent such
that the size of the particles exhibits an increase in volume
weighted median diameter of from about 20% to about 300% and an
endpoint is reached such that the particles are size-stabilized.
The endpoint can be, e.g., from about 1 to about 20 days.
[0023] In another embodiment, the present invention is directed to
a suspension of size-stabilized drug complexed particles comprising
a drug capable of forming a cyclodextrin inclusion complex and
having an aqueous solubility of less than 1 mg/ml in a pH of about
7.4 in association with effective amounts of a surface stabilizer
and a complexing agent capable of forming a cyclodextrin inclusion
complex, the size-stabilized drug complexed particles having a
volume weighted median diameter (D50) from about 50 nm to about 500
nm; the drug complexed particles exhibiting an increase in volume
weighted median diameter (D50) of from 0% to not more than about
200% when the formulation is dispersed in simulated gastric fluid
(SGF) or simulated intestinal fluid (SIF) at a concentration of 0.5
to 1 mg drug/mL and placed in a vial and heated in a bath at
36.degree. to 38.degree. C. for 1-3 hours as compared to the D50 of
the drug particles in suspension before dispersion into SGF or
SIF.
[0024] In certain embodiments, the size-stabilized drug particles
comprise from about 30 to about 95% drug, from about 3 to about 70%
surface stabilizer, based on the weight of the size-stabilized drug
particles, and from about 0.1% to about 8% complexing agent, based
on the weight of the size-stabilized drug particles.
[0025] In certain embodiments where the complexed size stabilized
drug particles are spray-layered or spray-dried, the particles
further comprise from about 0 to about 40% ionic dispersion
modulator and from about 0% to about 60% water soluble spacer,
based on the weight of the size-stabilized drug particles. In
certain embodiments, the amount of ionic dispersion modulator may
range from about 0.1% to 40%. The % weights are not meant to be
limiting.
[0026] The present invention is further directed to methods of
preparing the compositions disclosed herein, including but not
limited to, drug particles, liquid formulations, and solid dosage
forms (e.g., immediate release, sustained release, delayed release
and pulsatile release).
[0027] The present invention is also directed to methods of
treating subjects comprising administering to a subject any of the
compositions disclosed herein, including, but not limited to, drug
particles, liquid formulations, and oral solid dosage forms (e.g.,
immediate release, sustained release, delayed release and pulsatile
release).
[0028] In certain embodiments, the invention is directed to a solid
composition comprising particles comprising a complexed drug; and
an effective amount of an ionic dispersion modulator to reduce
agglomeration and particle size growth of the particles (e.g. upon
storage, dispersion in physiological fluids and water), wherein the
volume weighted median diameter (D50) of the particles is from
about 100 nm to about 500 nm.
[0029] In certain embodiments, the invention is directed to a solid
composition comprising particles comprising a complexed
nanoparticulate drug; and an ionic dispersion modulator in an
amount of from about 1% to about 50%, w/w, based on the weight of
the size stabilized particles, wherein the volume weighted median
diameter (D50) of the particles (dispersed in water and/or
physiological fluids) is from about 100 nm to about 500 nm.
[0030] In certain embodiments, the excipient comprises a water
soluble spacer. The water soluble spacer can be a saccharide or an
ammonium salt, a polyethylene glycol or urea that is a solid at
temperatures of 50.degree. C. or more. The saccharide can be
selected from the group consisting of fructose, sucrose, glucose,
lactose, mannitol and mixtures thereof. The polyethylene glycol can
be selected from PEG 3350, PEG 4000 or PEG 6000.
[0031] In other aspects, the invention is directed to
pharmaceutical particles comprising drug or a pharmaceutically
acceptable salt thereof, the complexed particles being stable
(suitable curing time) such that the volume weighted median
diameter (D50) of the particles does not increase by more than
about 50% after 28 days storage at room temperature, the volume
weighted median diameter (D50) of the particles prior to storage
being from about 50 nm to about 500 nm; the particles milled for a
sufficient time to achieve the stability. In other aspects, the
volume weighted median diameter (D50) of the particles does not
change by more than about 25% after 28 days storage at room
temperature (25.degree. C.) conditions, does not change by more
than about 15% after 28 days storage at room temperature, does not
change by more than about 10% after 28 days storage at room
temperature (25.degree. C.) and or does not change by more than
about 10% after 4 months storage at 25.degree. C./60% relative
humidity and 40.degree. C./75% relative humidity.
[0032] In another embodiment, the present invention is directed to
a formulation of solid size-stabilized drug complexed particles
comprising a drug capable of forming a cyclodextrin inclusion
complex and having an aqueous solubility of less than 1 mg/ml in a
pH of about 7.4 comprising (a) drug complexed particles having a
volume weighted median diameter (D50) from about 50 nm to about 500
nm, each of the particles comprising in association (i) a drug
capable of forming a cyclodextrin inclusion complex and having an
aqueous solubility of less than 1 mg/ml in a pH of about 7.4, (ii)
a surface stabilizer, (iii) a complexing agent capable of forming a
cyclodextrin inclusion complex, the drug complexed particles
exhibiting an increase in volume weighted median diameter (D50) of
from 0% to not more than about 200% when the formulation is
dispersed in simulated gastric fluid (SGF) or simulated intestinal
fluid (SIF) at a concentration of 0.5 to 1 mg drug/mL and placed in
a heated bath at 36.degree. to 38.degree. C. for 1-3 hours using a
Type I or II dissolution apparatus and a stirring rate of 75 RPM,
as compared to the D50 of the drug particles when the formulation
is dispersed in distilled water under the same conditions.
[0033] In certain embodiments, the invention is directed to a solid
composition (e.g., a powder, immediate release dosage form, or
controlled release dosage form) comprising size-stabilized drug
particles and at least one pharmaceutically acceptable excipient,
the size-stabilized drug particles exhibiting an increase in volume
weighted median diameter (D50) of from 0% to not more than about
200%, not more than about 150%, not more than about 100% or not
more than about 50%, when the formulation is dispersed in simulated
gastric fluid (SGF) or simulated intestinal fluid (SIF) at a
concentration of 0.5 to 1 mg drug/mL (in any suitable volume, e.g.,
15 mL to 1000 mL) and placed in a heated bath at 360 to 38.degree.
C. without stirring for 1 hour, as compared to the D50 of the drug
particles when the formulation is dispersed in distilled water
under the same conditions, wherein the volume weighted median
diameter (D50) of the drug particles dispersed in distilled water
is from about 50 nm to about 1000 nm, from about 100 nm to about
500 nm, or from about 100 nm to about 350 nm. The volume weighted
median diameter (D50) of the coated beads prior to dispersion can
be, e.g., from about 0.1 mm to about 5.0 mm. The solid formulation
can be, for example, a powder, a tablet, a capsule, etc.
[0034] In certain embodiments, the present invention is directed to
liquid pharmaceutical compositions containing size stabilized drug
particles comprising a drug complex exhibiting a D50 after
dispersion in SGF or SIF at 36 to 38.degree. C. for 1-3 hours of
not greater than about 500 nm, and in certain embodiments having a
ratio to D50 after such dispersion in SGF or SIF to the D50 prior
to dispersion of less than about 3:1.
[0035] Particle size measurement is generally described and well
known to those skilled in the art. The volume weighted median
diameter or D50 is a commonly accepted measure of particle size.
Sometimes one finds loose aggregates forming upon storage or under
physiological fluid testing. Loose aggregates can generally be
broken up via sonication. The formation of loose aggregates could
impact the pharmacokinetic performance (variability, systemic
levels and bioavailability) of a nanoparticulate formulation. The
impact of loose aggregation in a formulation or physiological fluid
must be ascertained on a compound by compound basis as the
performance of a formulation is dependent on a multitude of
variables (dose required, site of absorption, solubility,
crystalline properties and degree of aggregation) of the drug as
well as whether the formulation is a suspension, immediate release
or coated solid formulation protected from gastric fluids. In cases
of nanoparticulate formulations of water insoluble drugs it is
obvious that any formulation that results in less aggregation
(loose or otherwise) or particle growth as measured by an increase
in D50 values over time or when exposed to the physiological media
that the drug will be subjected prior or during absorption is most
preferred (more stable). One could theorize, however, that a
nanoparticulate formulation which is formed for a water soluble
compound that is being protected from storage degradation might
actually benefit from aggregates (longer absorption time due to
larger effective particle size). Significant tight aggregation
(unreversible) and particle size growth are obviously undesirable
as this would effectively loose the advantageous increased kinetic
dissolution of the drug.
[0036] Hydroxypropylmethyl cellulose, e.g., HPMC-15 and sodium
lauryl sulfate, have also been described as surface stabilizers of
drug nanoparticles in water (H. Steffen B T Gattefosse No. 81, 1988
pp. 45-53).
[0037] Preservatives are also sometimes added to nanosuspensions to
protect the formulation from contamination. For example, Megace ES
Suspension.RTM. (Parr) is preserved with benzoic acid (as sodium
benzoate buffered to pH 4.0 with citric acid and sodium
citrate).
[0038] In our U.S. patent application Ser. No. 11/606,222 entitled
"Solid Ganaxolone Formulations and Methods for the Making and Use
Thereof" and U.S. patent application Ser. No. 11/605,700 entitled
"Liquid Ganaxolone Formulations and Methods for the Making and Use
Thereof", both of which were filed on Nov. 28, 2006 and both of
which are hereby incorporated by reference, we disclosed ganaxolone
formulations which provide enhanced stability, physical and
chemical properties and can provide enhanced pharmacokinetic
properties to achieve an optimal balance between pharmacodynamic
and side effect profiles in mammals, and dosage forms containing
the same, as well as methods of making ganaxolone formulations and
their use in the treatment of epilepsy-related and other central
nervous system disorders. For example, this enhanced stability was
achieved via the preparation of particles comprising ganaxolone and
a complexing agent, wherein the volume weighted median diameter
(D50) of the particles is from about 50 nm to about 500 nm. The
complexing agent was disclosed as, for example, a paraben, benzoic
acid and mixtures thereof.
CERTAIN DEFINITIONS
[0039] As used herein, the terms "comprising," "including",
"containing" and "such as" are used in their open, non-limiting
sense.
[0040] The term "about" is used synonymously with the term
"approximately." As one of ordinary skill in the art would
understand, the exact boundary of "about" will depend on the
component of the composition. Illustratively, the use of the term
"about" indicates that values slightly outside the cited values,
i.e., plus or minus 0.1% to 10%, which are also effective and safe.
Thus compositions slightly outside the cited ranges are also
encompassed by the scope of the present claims.
[0041] For purposes of the invention, the term "drug" means any
therapeutically active agent capable of forming a cyclodextrin
inclusion complex in aqueous based solutions/suspensions. In
certain embodiments, such drugs (not as a cyclodextrin inclusion
complex) have an aqueous solubility of less than 1 mg/ml at a pH of
about 7.4.
[0042] "Bioavailability" refers to the degree to which a drug
becomes available at the site(s) of action after administration. By
way of illustration, the bioavailability of a drug formulation
refers to the percentage of the weight of drug dosed that is
delivered into the general circulation of the animal or human being
studied. The total exposure (AUC.sub.(0-.infin.)) of a drug when
administered intravenously is usually defined as 100% bioavailable
(F %). "Oral bioavailability" refers to the extent to which drug is
absorbed into the general circulation when the pharmaceutical
composition is taken orally as compared to intravenous injection.
The degree and timing in which an active agent becomes available to
the target site(s) after administration is determined by many
factors, including the dosage form and various properties, e.g.,
solubility and dissolution rate of the drug.
[0043] A "blood serum concentration" or "blood plasma
concentration" or "serum or plasma concentration or level",
typically measured in mg, .mu.g, or ng of a drug per ml, dl, or l
of serum or plasma absorbed into the bloodstream after
administration. As used herein, measurable plasma concentrations
are typically measured in ng/ml or .mu.g/ml. It is understood that
the plasma concentration of a drug may vary significantly between
subjects, due to variability with respect to metabolism and/or
possible interactions with other therapeutic agents. In accordance
with one aspect of the present invention, the blood plasma
concentration of drug may vary from subject to subject. Likewise,
values such as measured concentration of the active agent in the
plasma at the point of maximum concentration (C.sub.max) or time to
reach maximum plasma concentration (T.sub.max), or total area under
the plasma concentration time curve (AUC.sub.(0-.infin.)) may vary
from subject to subject.
[0044] "AUC.sub.(0-.tau.) or "exposure or bioavailability" is the
area under the curve of a graph of the concentration of the active
agent (typically plasma concentration) vs. time (.tau.), measured
from time 0 to .tau.. AUC.sub.(0-.tau.) is also used to define the
exposure to the drug over a defined period of time. Due to
variability, the amount necessary to constitute "a therapeutically
effective amount" of drug may vary from subject to subject.
[0045] "Carrier materials" include any commonly used excipients in
pharmaceutics and should be selected on the basis of compatibility
with drug and the release profile properties of the desired dosage
form.
[0046] The term "curing" means treating the drug (either before,
during or after particle size reduction) with a complexing agent
under suitable conditions to obtain a size stabilized drug product.
In certain embodiments, a measurement of stability can be via the
comparison of the particle size (e.g., D50) of the uncomplexed drug
versus the complexed drug.
[0047] The term "curing time" means a sufficient time until an
endpoint is reached such that the properties of the (complexed)
drug are stabilized. In certain embodiments, the curing time can be
measured as the time until a size stabilized particle size is
reached under a specified test condition. For example, a suitable
curing time may be such a time wherein the D50 of the (complexed)
drug particles do not change or substantially change after time in
consecutive measurements separated by approximately 72 hours, e.g.,
by more than the accuracy of the measuring instrument.+-.5%. in 72
hours after the curing period. Preferred curing times are 1-20
days, 2-15 days or 3-10 days. In other embodiments, a suitable
curing time may be such a time wherein the D50 of the (complexed)
drug particles do not change or substantially change after time in
consecutive measurements over 3 hours at 37.degree. C. in simulated
gastric and/or simulated intestinal fluid.
[0048] The term "complexed" or "complexed nanoparticulate drug"
indicates an association of molecules and/or a particle including
drug, a complexing agent and other components which results in
better particle size stability of drug particles or some other
desirable effect. In some cases, complexing agents initially
increase particle size (D50) before imparting stability or other
beneficial attributes to the formulation. In certain embodiments,
complexed drug or complexed nanoparticulate drug made by adding
complexing agents requires a curing time.
[0049] "Complexing agents" are small molecular weight molecules
which can form a cyclodextrin inclusion complex and after suitable
curing time impart additional stability to the drug. Complexing
agents include small compounds under MW 550. Complexing agents
include but are not limited to the group consisting of phenol,
parabens, ascorbic acid, methyl anthranilate, salicylic acid,
acetosalicyclic acid, tocopherol, organic acids, carboxylic acids,
aromatic acids, aromatic esters, acid salts of amino acids,
benzaldehyde, cinnimaldehyde, imidazole, menthol, thiophenol,
m-aminobenzoic acid, anthranilic acid, picolinic acids and alkyl
esters thereof, toluidides, sodium benzoate, methylparaben, sodium
methylparaben, para-aminobenzoic acid and esters, sorbic and
benzoic acids, 2,6-di-t-butyl-alpha-dimethylamino-p-cresol,
t-butylhydroquinone, di-t-amylhydroquinone, di-t-butylhydroquinone,
butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), pyrocatechol,
pyrogallol, esters, isomeric compounds thereof, pharmaceutically
acceptable salts thereof, and mixtures of any of the foregoing.
[0050] "Controlled release" or "modified release", consistent with
its use herein, means a dosage form for which the drug release
characteristics versus time and/or conditions at the site of
dissolution are chosen to accomplish therapeutic or convenience
objectives not offered by conventional immediate release dosage
forms. Controlled release dosage forms include sustained release,
prolonged release, pulsatile release and delayed release forms.
Controlled release dosage forms can provide therapeutically
effective levels of drug for an extended period of time and
therefore provide a longer therapeutic period relative to immediate
release forms. Addition of a complexing agent can also impart
additional suspension stability during freeze/thaw cycles and
boiling if sterilization is needed.
[0051] "Delayed release", consistent with its use herein, means a
dosage form that releases a portion or all drug at any time other
than immediately after administration and/or at any other location
in the gastrointestinal tract more distal to that which would have
been accomplished by an immediate release dosage form.
[0052] The term "disintegrate" is the dispersion of the dosage form
when contacted with gastrointestinal fluid. "Disintegration agents
or disintegrants" facilitate the breakup or disintegration of a
formulation. Examples of disintegration agents include a starch,
e.g., a natural starch such as corn starch or potato starch, a
pregelatinized starch such as National 1551 or Amijel.RTM., or
sodium starch glycolate such as Promogel.RTM. or Explotab.RTM., a
cellulose such as a wood product, microcrystalline cellulose, e.g.,
Avicel.RTM., Avicel.RTM. PH101, Avicel.RTM. PH102, Avicel.RTM.
PH105, Elcema.RTM. P100, Emcocel.RTM., Vivacel.RTM., Ming Tia.RTM.,
and Solka-Floc.RTM., methylcellulose, croscarmellose, or a
cross-linked cellulose, such as cross-linked sodium
carboxymethylcellulose (Ac-Di-Sol.RTM.), cross-linked
carboxymethylcellulose, or cross-linked croscarmellose, a
cross-linked starch such as sodium starch glycolate, a cross-linked
polymer such as crosspovidone, a cross-linked polyvinylpyrrolidone,
alginate such as alginic acid or a salt of alginic acid such as
sodium alginate, a clay such as Veegum.RTM. HV (magnesium aluminum
silicate), a gum such as agar, guar, locust bean, Karaya, pectin,
or tragacanth, sodium starch glycolate (Explotab.RTM.), bentonite,
a natural sponge, a surfactant, a resin such as a cation-exchange
resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in
combination starch, and the like.
[0053] "Drug absorption" or "absorption" typically refers to the
process of movement of drug from site of administration of a drug
across a barrier into a blood vessel or the site of action, e.g., a
drug moving from the gastrointestinal tract into the portal vein or
lymphatic system.
[0054] "Effective particle size" and "particle size" is
interchangeably used with "D50". By "D50", it is meant that 50% of
the particles are below and 50% of the particles are above a
defined measurement. D50 can be used to describe different
parameters (volume, length, number, area . . . etc). "Effective
particle size" or D50 as used herein indicates the volume-weighted
median diameter as measured by a laser/light scattering method or
equivalent, wherein 50% of the particles, by volume, have a smaller
diameter, while 50% by volume have a larger diameter. The volume
weighted D50 also relates to the percentage of weight of the
particle under a certain size. For example a D50 of 500 nm means
that 50% of the particulate mass is less than 500 nm in diameter
and 50% of the particulate mass is greater than 500 nm in diameter.
The effective particle size is measured by conventional particle
size measuring techniques well known to those skilled in the art.
Such techniques include, for example, sedimentation field flow
fractionation, photon correlation spectroscopy, light scattering
(e.g., with a Microtrac UPA 150), laser diffraction and disc
centrifugation. For the purposes of the compositions, formulations
and methods described herein, effective particle size is the
volume-weighted median diameter as determined using laser/light
scattering instruments and methods, e.g. a Horiba LA-910, or Horiba
LA-950. Similarly, "D90" is the volume-weighted diameter, wherein
90% of the particles, by volume, have a smaller diameter, while 10%
by volume have a larger diameter and "D10" is the volume-weighted
diameter, wherein 10% of the particles, by volume, have a smaller
diameter, while 90% by volume have a larger diameter. It is
sometimes useful to express the D50 value after sonication for 1
minute or less using about 40 watts of sonicating power at room
temperature (25.degree. C.).
[0055] An "enteric coating" is a substance that remains
substantially intact in the stomach but dissolves and releases the
drug in the small intestine and/or colon. Generally, the enteric
coating comprises a polymeric material that prevents release in the
low pH environment of the stomach but that ionizes or solubilizes
at a higher pH, typically a pH of 5 to 7, but at least above 3.0,
more or above 5, or even more specifically at a pH of about 5.5 to
about 7, and thus dissolves sufficiently in the small intestine
and/or colon to release the active agent therein. In some
embodiments, the enteric coatings release greater than 50% of the
drug that is coated in the small intestine. In other embodiments,
the enteric coating provides the release of a substantial portion
(greater than 40%) of the coated drug in the mid-small intestine,
e.g., the jejunum. Additionally, enteric coatings may comprise a
semi-permeable membrane which releases drug slowly in a non
pH-dependent manner.
[0056] The term "grinding media" refers to the material used in
milling to physically reduce the particle size of a composition.
For milling operations, preferred grinding media are spherical
balls of yttrium stabilized zirconium oxide, glass or a plastic
resin.
[0057] "Gastrointestinal fluid" is the fluid of the
gastrointestinal tract of a subject or the saliva of a subject or
the equivalent thereof. An "equivalent" of stomach or gastric
secretion" is an in vitro fluid having similar content and/or pH as
stomach secretions such as simulated gastric fluid (SGF) prepared
using USP guidance of about 0.1N HCl solution in water containing
about 0.03M NaCl at a pH of around 1.2. In addition, an
"equivalent" of intestinal secretion" is an in vitro fluid having
similar content and/or pH as intestinal secretions such as
simulated intestinal fluid (SIF) prepared using USP guidance is an
aqueous phosphate buffer system at pH of 6.7-6.9.
[0058] "Immediate Release" means a dosage form that releases at
least 80% of drug within 2 hours of administration, more
specifically, within 1 hour of addition to a commonly accepted
simulated gastric fluid. Typically an immediate release composition
is tested in dissolution apparatus (Type I or II most common) in an
amount considered to be therapeutic in patients and a volume of SGF
of 500-1000 mL.
[0059] "Ionic Dispersion Modulator" is defined as a salt (not a
sulfonic acid), which when added to a complexed small particle
composition will reduce the amount of certain ingredient(s) needed
to stabilize solid dosage forms or blends when dispersed in water,
SGF and SIF.
[0060] "Milling chamber void volume" is the open volume in a
milling chamber available to the milling slurry after grinding
media has been added. Milling chamber void volume is related to the
amount of grinding media (volume %) and the volume of open space
when the spherical beads are stacked on one another (grinding media
void volume). For 0.2-0.4 mm spherical milling grinding media, a
range of approx. 36-42% of the volume occupied by the grinding
beads is the grinding media void volume. Milling chamber void
volume (mL)=Total milling chamber volume (mL)-volume of grinding
media (mL)+grinding media void volume (mL).
[0061] "Milling residence time" is the time that a particle is
present in the milling chamber over the total time of milling to
obtain desired particles. Milling Residence Time (MRT) is defined
as: MRT (minutes)=Milling chamber void volume (ml).times.total
milling time (minutes)/Milling Slurry Vol. (ml)
[0062] The term "milling slurry" refers to a suspension containing
the drug for particle size reduction and other ingredients to
facilitate the milling process. The composition of the milling
slurry is usually not the final formulation composition.
[0063] The term "milling media" refers to the components of the
milling slurry minus the active pharmaceutical ingredient(s).
[0064] The term "milled slurry" refers the milling slurry after it
had been reduced to a small particle suspension by milling. The
most preferred milling slurries for a liquid dispersion are those
that meet particle size and compositions that can be diluted with
water and appropriate ingredients to obtain the final formulation.
For a solid dosage form, preferred milled slurries are those that
can be utilized with minimal manipulation to yield the final solid
dosage form.
[0065] "Pharmacodynamics" refers to the factors which determine the
biologic response observed relative to the concentration of drug at
a site of action.
[0066] "Pharmacokinetics" refers to the factors which determine the
attainment and maintenance of the appropriate concentration of drug
at a site of action.
[0067] "Preservatives" are compounds which inhibit microbial growth
and are typically added to dispersions to prevent microbes from
growing.
[0068] A "pulsatile release" dosage form is a dosage form capable
of providing more than one peak blood plasma concentration
following a single administration. A "pulsatile release"
formulation can contain a combination of immediate release,
sustained release, and/or delayed release formulations in the same
dosage form.
[0069] "Pharmacokinetic parameters" are parameters which describe
the in vivo characteristics of the drug over time, including, for
example plasma concentration of the drug. Pharmacokinetic
parameters include C.sub.max, T.sub.max, and AUC.sub.0-.tau. (each
discussed above).
[0070] "Solubilizers" include compounds such as triacetin,
triethylcitrate, ethyl oleate, ethyl caprylate, sodium lauryl
sulfate, sodium doccusate, vitamin E TPGS, dimethylacetamide,
N-methylpyrrolidone, N-hydroxyethylpyrrolidone,
polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl
cyclodextrins, ethanol, n-butanol, isopropyl alcohol, cholesterol,
bile salts, polyethylene glycol 200 to 600, glycofurol, transcutol,
propylene glycol, and dimethyl isosorbide, miglyol, glycerin,
glycerol, and the like.
[0071] "Spray Drying" is a process by which a solvent is removed
from a composition yielding a dried form of the ingredients in that
composition. Drying is effected by spraying the composition through
a nozzle into a heated environment containing a vacuum or a flow of
air or inert gas. Spray drying can produce amorphous or crystalline
powders of drugs or granulations, both which can be converted into
a solid dosage form by those skilled in the art.
[0072] "Spray Layering" is a procedure where a solution or
suspension containing ingredients are sprayed through a nozzle into
a fluidized bed containing particles which are coated with a film
containing the composition of the solution or suspension as the
solvent is removed by the flow of a heated gas. Spray layering
typically involves coating an inert core usually comprised of a
sugar and starch or cellulosics or combinations thereof. Such cores
are typically 20 to 35 mesh in size. Spray Layering is used
extensively for applying coatings (finish or enteric) to solid
dosage formulations as well as spherical beads containing a drug
for use in a capsule or tablet formulation.
[0073] "Size-stabilized" means the D50 does not substantially
change (greater than 50%) after an initial time is defined (e.g.,
after an appropriate curing time) and up to 4 months storage at
room temperature (25.degree. C.). For example, the size stabilized
drug particles described herein in an aqueous dosage form will not
show an increase in effective particle size of greater than 50%
over a four month storage period, and preferably no increase in
effective particle size of greater than 50% over a two year storage
period. Similarly, the size-stabilized drug particles described
herein in a liquid or solid form will show an increase in effective
particle size of about 0% to about 200% upon dispersion in
simulated gastric or intestinal fluid as compared to dispersion in
water under the same conditions. In some embodiments, the
formulations described herein does not produce any significant
amount of unidentified drug degradation impurities up to 4 months
storage at room temperature (25.degree. C.) at individual levels of
about greater than 0.1% by weight as compared to the impurity
levels at the initial time designation.
[0074] "Stabilizers" include agents which maintain a desirable
attribute of the formulation over a time interval including but not
limited to mechanical, chemical and temperature stressing that can
be tested in a laboratory setting. Such attributes include stable
particle size or homogeneity resulting in concentrations consistent
with the labeled potency and maintaining purity. Some but not all
of the attributes are listed above.
[0075] "Steady state," as used herein, is when the amount of drug
administered is equal to the amount of drug eliminated within one
dosing interval resulting in a plateau or constant plasma drug
exposure.
[0076] "Subject" as used herein is any mammal. Subjects include
individuals in need of drug treatment (patients) and individuals
not in need of drug treatment (e.g. normal healthy volunteers.
Humans are preferred subjects and patients.
[0077] "Delayed Release", consistent with its use herein, means a
dosage form that allows at least a one dose reduction in dosing
frequency per day as compared to the drug in conventional form,
such as a suspension or an immediate release solid dosage form.
[0078] A "therapeutically effective amount" or "effective amount"
is that amount of a pharmaceutical agent to achieve a
pharmacological effect. The term "therapeutically effective amount"
includes, for example, a prophylactically effective amount. An
"effective amount" of drug is an amount needed to achieve a desired
pharmacologic effect or therapeutic improvement without undue
adverse side effects. The effective amount of a drug will be
selected by those skilled in the art depending on the particular
patient and the disease. It is understood that "an effective
amount" or "a therapeutically effective amount" can vary from
subject to subject, due to variation in metabolism of drug, age,
weight, general condition of the subject, the condition being
treated, the severity of the condition being treated, and the
judgment of the prescribing physician.
[0079] "Treat" or "treatment" refers to any treatment of a disorder
or disease, such as preventing the disorder or disease from
occurring in a subject which may be predisposed to the disorder or
disease, but has not yet been diagnosed as having the disorder or
disease; inhibiting the disorder or disease, e.g., arresting the
development of the disorder or disease, relieving the disorder or
disease, causing regression of the disorder or disease, relieving a
condition caused by the disease or disorder, or reducing the
symptoms of the disease or disorder.
BRIEF DESCRIPTION OF THE DRAWINGS
[0080] FIG. 1 is a graph showing the curing curve of sonicated and
unsonicated complexed ganaxolone particles at room temperature
(25.degree. C.). FIG. 1a shows the curing curve of ganaxolone
particles complexed with sodium benzoate at pH 4.0. FIG. 1b shows
the curing curve of ganaxolone particles complexed with
parabens.
[0081] FIG. 2 is a graph showing the D50 vs. Time of paraben
complexed and sodium benzoate complexed (at pH 4.0) ganaxolone
particles at room temperature (25.degree. C.).
[0082] FIG. 3 is a graph showing stability plots (D50 vs. Time) of
uncomplexed ganaxolone particles with varying milled residence
times.
[0083] FIG. 4 is a graph showing measured D50 values for
uncomplexed ganaxolone particles as a function of milling residence
time for a typical milling run using a Dyno-Mill KDL equipped with
four 64 Mm polyurethane agitator discs.
[0084] FIG. 5 is a graph showing particle size distribution (after
1 minute low power sonication) of re-suspended solid dosage forms
containing sodium chloride (with and without methylparaben as the
complexing agent).
DETAILED DESCRIPTION OF THE INVENTION
[0085] Reference will now be made in detail to embodiments of the
compositions, formulations, and methods disclosed herein. Examples
of the embodiments are illustrated in the following Examples
section.
[0086] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of skill in the art to which the inventions described herein
belong. All patents and publications referred to herein are
incorporated by reference.
[0087] Many drugs are poorly soluble in water and other
pharmaceutically acceptable solvents. As a result of the low
aqueous solubility of the drugs of the present invention, there
exists a need in the art for drug formulations, which provide
increased bioavailability and therapeutic efficacy of the drugs
described herein. However, it is known that increasing the maximal
systemic levels (Cmax) of an active agent likewise results in the
possibility of increased side effects.
[0088] The drug formulations described herein can be administered
to a subject by conventional administration routes. Drug oral solid
dosage forms and oral aqueous suspensions are included herein.
Immediate, modified, controlled, and pulsatile release drug dosages
forms are provided herein.
[0089] It is now well-known that drugs which complex with
cyclodextrin have the required shape and size to fit at least
partially into the cavity of the hydrated cyclodextrin molecule;
see, for example, Brauns and Muller European Patent No. 0149197 B1.
and Challa et. al.; "Cyclodextrins in Drug Delivery: An Updated
Review". AAPS Pharm Sci Tech. 2005; 06(02): E329-E357. Such drugs
that can form a cyclodextrin inclusion complex are considered to be
within the scope of the invention.
[0090] The drug formulations described herein can comprise drug
particles having a D50 of less than about 500 nm. The starting drug
composition can be predominantly crystalline, predominantly
amorphous, or a mixture thereof. These drug particles can be made
by using any method known in the art for achieving particle sizes
of less than 500 nm including, for example, milling,
homogenization, supercritical fluid fracture or precipitation
techniques. Exemplary methods are described in U.S. Pat. Nos.
4,540,602 and 5,145,684, each of which is specifically incorporated
by reference.
[0091] Methods of making compositions comprising nanoparticles are
also described in U.S. Pat. Nos. 5,518,187; 5,718,388; 5,862,999;
5,665,331; 5,662,883; 5,560,932; 5,543,133; 5,534,270; 5,510,118;
5,470,583 and U.S. Pub. Appl. 2004/0067251, each of which is
specifically incorporated by reference.
Milling to Obtain Drug Dispersions Comprising Submicron
Particles
[0092] In certain embodiments, the drug is milled in order to
obtain submicron particles. The milling process can be a dry
process, e.g., a dry roller milling process, or a wet process,
i.e., wet-grinding. In some embodiments, this invention is
practiced in accordance with the wet-grinding process described in
U.S. Pat. Nos. 4,540,602, 5,145,684, 6,976,647 and EPO 498,482, the
disclosures of which are hereby incorporated by reference. Thus,
the wet grinding process can be practiced in conjunction with a
liquid dispersion medium and dispersing or wetting agents such as
described in these publications. Useful liquid dispersion media
include water, safflower oil, aqueous salt solutions, ethanol,
n-butanol, hexane, glycol and the like. The dispersing, and/or
wetting agents (alternatively referred to herein and in the prior
art as "surface stabilizers") can be selected from known organic
and inorganic pharmaceutical excipients such as described in U.S.
Pat. Nos. 4,540,602 and 5,145,684, and can be present in an amount
of 2.0-70%, preferably 3-50%, and more preferably 5-25% by weight
based on the total weight of the drug in the formulation.
[0093] The grinding media for the particle size reduction step can
be selected from rigid media preferably spherical or particulate in
shape, e.g., beads. However, grinding media in the form of other
non-spherical shapes are expected to be useful in the practice of
this invention.
[0094] The grinding media preferably can have a mean particle size
up to about 500 microns. In other embodiments of the invention, the
grinding media particles have a mean particle size preferably less
than about 500 microns, less than about 100 microns, less than
about 75 microns, less than about 50 microns, less than about 25
microns, less than about 5 microns, less than about 3 mm, less than
about 2 mm, less than about 1 mm, less than about 0.25 mm, or less
than about 0.05 mm. For fine grinding, the grinding media particles
preferably are from about 0.05 to about 0.6 mm, more preferably,
about 0.1 to about 0.4 mm in size. Smaller size grinding media will
result in smaller size drug particles as compared to the same
conditions using larger sized grinding media.
[0095] In selecting material, grinding media with higher density,
e.g., glass (2.6 g/cm.sup.3), zirconium silicate (3.7 g/cm.sup.3),
and zirconium oxide (5.4 g/cm.sup.3) and 95% zirconium oxide
stabilized with yttrium, are generally preferred for more efficient
milling. Zirconium oxide, such as 95% Zirconium oxide stabilized
with magnesia, zirconium silicate, and glass grinding media provide
particles having levels of contamination which are believed to be
acceptable for the preparation of therapeutic or diagnostic
compositions. However, other media, such as stainless steel,
titania, agate, glass and alumina, are believed to be useful. In
addition, polymeric media having a density typically from about 1
to about 2 g/cm.sup.3 are also expected to be useful.
[0096] If polymeric grinding media is utilized, then the grinding
media can comprise particles consisting essentially of the
polymeric resin. Alternatively, the grinding media can comprise
particles comprising a core having a coating of the polymeric resin
adhered thereon. The polymeric resin preferably has a density from
0.8 to 3.0 g/cm.sup.3. Higher density resins are preferred inasmuch
as it is believed that these provide more efficient particle size
reduction.
[0097] In general, polymeric resins suitable for use herein are
chemically and physically inert, substantially free of metals,
solvent and monomers, and of sufficient hardness and friability to
enable them to avoid being chipped or crushed during grinding.
Suitable polymeric resins include but are not limited to
crosslinked polystyrenes, such as polystyrene crosslinked with
divinylbenzene, styrene copolymers, polycarbonates, polyacetals,
such as Delrin.TM., vinyl chloride polymers and copolymers,
polyurethanes, polyamides, poly(tetrafluoroethylenes), e.g.,
Teflon.TM., and other fluoropolymers, high density polyethylenes,
polypropylenes, cellulose ethers and esters such as cellulose
acetate, polyhydroxymethacrylate, polyhydroxyethyl acrylate,
silicone containing polymers such as polysiloxanes, and the like.
The polymeric polymer can be biodegradable. Exemplary biodegradable
polymers include poly(lactides), poly(glycolide) copolymers of
lactides and glycolide, polyanhydrides, poly(hydroxyethyl
methacylate), poly(imino carbonates),
poly(N-acylhydroxyproline)esters, poly(N-palmitoyl hydroxyproline)
esters, ethylene-vinyl acetate copolymers, poly(orthoesters),
poly(caprolactones), and poly(phosphazenes). In the case of
biodegradable polymers, contamination from the media itself
advantageously can metabolize in vivo into biologically acceptable
products which can be eliminated from the body.
[0098] The core material preferably can be selected from materials
known to be useful as grinding media when fabricated as spheres or
particles. Suitable core materials include but are not limited to
zirconium oxides (such as 95% zirconium oxide stabilized with
magnesia or yttrium), zirconium silicate, glass, stainless steel,
titania, alumina, ferrite, and the like. Preferred core materials
have a density greater than about 2.5 g/cm.sup.3. The selection of
high density core materials is believed to facilitate efficient
particle size reduction.
[0099] Useful thicknesses of the polymeric coating on the core are
believed to range from about 1 to about 500 microns, although other
thicknesses outside this range may be useful in some applications.
The thickness of the polymer coating preferably is less than the
diameter of the core.
[0100] The cores can be coated with the polymeric resin by
techniques known in the art. Suitable techniques include spray
coating, fluidized bed coating, and melt coating. Adhesion
promoting or tie layers can optionally be provided to improve the
adhesion between the core material and the resin coating. The
adhesion of the polymer coating to the core material can be
enhanced by treating the core material to adhesion promoting
procedures, such as roughening of the core surface, corona
discharge treatment, and the like.
[0101] Grinding can take place in any suitable grinding mill.
Suitable mills include an airjet mill, a roller mill, a ball mill,
an attritor mill, a vibratory mill, a planetary mill, a sand mill
and a bead mill. A high energy media mill is preferred when small
particles are desired. The mill can contain a rotating shaft.
[0102] The preferred proportions of the grinding media, drug, the
optional liquid dispersion medium, and dispersing, wetting or other
particle stabilizing agents present in the grinding vessel can vary
within wide limits and depend on, for example, the size and density
of the grinding media, the type of mill selected, the time of
milling, etc. The process can be carried out in a continuous, batch
or semi-batch mode. In high energy media mills, it can be desirable
to fill 80-95% of the volume of the grinding chamber with grinding
media. On the other hand, in roller mills, it frequently is
desirable to leave the grinding vessel up to half filled with air,
the remaining volume comprising the grinding media and the liquid
dispersion media, if present. This permits a cascading effect
within the vessel on the rollers which permits efficient grinding.
However, when foaming is a problem during wet grinding, the vessel
can be completely filled with the liquid dispersion medium or an
anti-foaming agent may be added to the liquid dispersion.
[0103] The attrition time can vary widely and depends primarily
upon the particular drug substance or imaging agent, mechanical
means and residence conditions selected, the initial and desired
final particle size and so forth. For roller mills, processing
times from several days to weeks may be required. On the other
hand, milling residence times of less than about 2 hours are
generally required using high energy media mills.
[0104] After attrition is completed, the grinding media is
separated from the milled drug particulate product (in either a dry
or liquid dispersion form) using conventional separation
techniques, such as by filtration, sieving through a mesh screen,
and the like.
[0105] In one aspect of the invention, the grinding media comprises
beads having a size ranging from 0.05-4 mm, preferably 0.1-0.4 mm.
For example, high energy milling of drug with yttrium stabilized
zirconium oxide 0.4 mm beads for a milling residence time of 25
minutes to 1.5 hours in recirculation mode at 1200 to 3000 RPM. In
another example, high energy milling of drug with 0.1 mm zirconium
oxide balls for a milling residence time of 2 hours in batch mode.
Additionally, the milling temperature should not exceed 50.degree.
C. as the viscosity of the suspension may change dramatically.
Elevated temperatures also may result in precipitation of certain
polymers in the milling slurry and will increase wear on the mill
seals. If supplies of milled suspension exceeds the void milling
chamber volume then this process will require recycling the
material to a cooled holding tank and re-milling of the material
until the desired particle (D50) size and appropriate properties
are achieved in continuous mode and the mill is also jacketed with
cooling. In another aspect, the mill can be jacketed to help
control internal temperatures in both continuous or batch mode. In
our practice, this weight percentage is based on total weight of
the milling slurry. The milling concentration is from about 10% to
about 30% drug by weight vs. the milling slurry weight. The milling
media is defined as the weight of the slurry that is milled minus
the weight of the drug in that slurry. In one embodiment, the
concentration is 25% drug by weight vs. the milling media (weight).
In one embodiment, the milling media contains at least one wetting
and/or dispersing agent (alternatively referred to herein and in
the prior art as "surface stabilizers") to coat the initial drug
suspension so a uniform feed rate may be applied in continuous
milling mode. In another embodiment, batch milling mode is utilized
with a milling media containing at least one agent to adjust
viscosity and/or provide a wetting effect so that the drug is well
dispersed amongst the grinding media.
Microprecipitation to Obtain Drug Dispersions Comprising
Nanoparticles
[0106] Drug particles can also be prepared by homogeneous
nucleation and precipitation in the presence of a wetting agent or
dispersing agent as described in U.S. Pat. No. 5,560,932 and U.S.
Pat. No. 5,665,331, which are specifically incorporated by
reference. Such drug particles are storage stable and do not show
an appreciable increase in effective particle size over time. This
is a method of preparing stable dispersions of drug in the presence
of one or more dispersing or wetting agents (alternatively referred
to herein and in the prior art as "surface stabilizers") and one or
more colloid stability enhancing surface active agents. Such a
method comprises, for example: (1) dispersing drug in a suitable
liquid media; (2) adding the mixture from step (1) to a mixture
comprising at least on dispersing agent or wetting agent such that
at the appropriate temperature, the drug is dissolved; and (3)
precipitating the formulation from step (2) using an appropriate
anti-solvent (e.g., water). The method can be followed by removal
of any formed salt, if present, by dialysis or filtration and
concentration of the dispersion by conventional means. In one
embodiment, the drug particles are present in an essentially pure
form and dispersed in a suitable liquid dispersion media. A
preferred liquid dispersion medium is water. However, other liquid
media can be used including, for example, aqueous salt solutions,
oils (e.g., safflower, olive or cremephor), and solvents such as
ethanol, t-butanol, hexane, and glycol. The pH of the aqueous
dispersion media can be adjusted by techniques known in the art. In
this embodiment, the drug particles comprise a discrete phase
having been admixed with a dispersing agent or wetting agent.
Useful dispersing agents or wetting agents are experimentally
determined, but effectively minimize the difference in
lipophilicity of drug and the dispersion media by inducing a
non-covalent ordered complex between the media, the wetting agent,
and drug.
Homogenization to Obtain Drug Dispersions Comprising
Nanoparticles
[0107] In yet another embodiment, the drug particles described
herein are produced by high pressure homogenization (see generally
U.S. Pat. No. 5,510,118). Such a method comprises dispersing drug
particles in a liquid dispersion medium, followed by subjecting the
dispersion to repeated homogenization to reduce the particle size
of the drug to the desired effective average particle size. The
drug particles can be reduced in size in the presence of at least
one or more dispersing agents or wetting agents. Alternatively, the
drug particles can be contacted with one or more dispersing agents
or wetting agents either before or after attrition. Other
compounds, such as a diluent, can be added to the drug/dispersing
agent composition before, during, or after the size reduction
process. In one embodiment, unprocessed drug can then be added to a
liquid medium in which it is essentially insoluble to form a
premix. The concentration of the drug in the liquid medium can vary
from about 0.1-60% w/w, and preferably is from 5-30% (w/w). It is
preferred, but not essential, that the dispersing agents or wetting
agents be present in the premix. The concentration of the
dispersing agents or wetting agents can vary from about 0.1 to 90%,
and preferably is 1-75%, more preferably 20-60%, by weight based on
the total combined weight of the drug and dispersing agents or
wetting agents. The apparent viscosity of the premix suspension is
preferably less than about 1000 centipoise. The premix then can be
transferred to the microfluidizer and circulated continuously first
at low pressures, then at maximum capacity having a fluid pressure
of from about 3,000 to 30,000 psi until the desired particle size
reduction is achieved. The particles must be reduced in size at a
temperature which does not significantly degrade the drug substance
or cause significant particle size growth through solubilization.
Next, one of two methods can be used to collect the slurry and
re-pass it in a microfluidizer. The "discreet pass" method collects
every pass through the microfluidizer until all of the slurry has
been passed through before re-introducing it again to the
microfluidizer. This guarantees that every substance or particle
has "seen" the interaction chamber the same amount of times. The
second method re-circulates the slurry by collecting it in a
receiving tank and allowing the entire mixture to randomly mix and
pass through the interaction chamber.
[0108] If some dispersing agents and/or wetting agents, are not
present in the premix, they can be added to the dispersion after
attrition in an amount as described for the premix above.
Thereafter, the dispersion can be mixed, e.g., shaken or
stirred.
[0109] The relative amount of drug and dispersing agents and/or
wetting agents (alternatively referred to herein and in the prior
art as "surface stabilizers") can vary widely. The dispersing
agents and/or wetting agents preferably are present in an amount of
about 0.1-10 mg per square meter surface area of drug. The
dispersing agents or wetting agents can be present in an amount of
0.1-90%, preferably 5-50% by weight based on the total weight of
the dry drug particles during the particle size reduction.
[0110] The resulting drug dispersion is storage stable and consists
of the liquid dispersion medium and the above-described particles.
The dispersion of drug particles can be spray coated onto sugar
spheres or beads or onto a pharmaceutical excipient in a fluid-bed
spray coater by techniques well known in the art.
[0111] The drug particles generated by any of the methods described
herein can be utilized in solid or aqueous liquid dosage
formulations, such as controlled release formulations, pulsatile
dosage forms, multiparticulate dosage forms, solid dose fast melt
formulations, lyophilized formulations, tablets, capsules, aqueous
dispersions, or aerosol formulations.
The Use of Surface Stabilizers
[0112] In certain preferred embodiments, the drug particles are
prepared with the use of one or more materials known in the art as
surface stabilizers or modulators (previously or alternatively
referred to herein or in the art as wetting and/or dispersing
agents) which are, e.g., adsorbed on the surface of the drug
compound. The surface stabilizer(s) can be contacted with the drug
compound either before, during or after size reduction of the
compound. Generally, surface stabilizers fall into two categories:
non-ionic (also called steric stabilizers or modifiers) and ionic
stabilizers. The most common non-ionic stabilizers are excipients
which are contained in classes known as binders, fillers,
surfactants and wetting agents. Limited examples of non-ionic
surface stabilizers are hydroxypropylmethylcellulose,
polyvinylpyrrolidone, Plasdone, polyvinyl alcohol, Pluronics,
Tweens and polyethylene glycols (PEGs). A subset of surface
stabilizers commonly used is ionic in nature. These ionic surface
stabilizers tend to fall into the class of excipients which are
typically used as surfactants and wetting agents. Ionic stabilizers
used in the prior art are typically organic molecules bearing an
ionic bond such that the molecule is charged in the formulation.
The two most described ionic surface stabilizers are the long chain
sulfonic acid salts sodium lauryl sulfate and dioctyl sodium
sulfosuccinate (DOSS). Broad ranges for all surface stabilizers
have been claimed in U.S. Pat. No. 5,145,684 (the '684 patent)
ranging from 0.1% to 90% by weight of the composition. Typically,
one adds 20%-150% (wt % of drug) of a nonionic surface stabilizer
and 0.2%-5% of an ionic surface stabilizer (wt % of drug) to
achieve maximal particle size stabilization from these surface
stabilizers.
[0113] Conversion of a nanoparticulate composition containing
surface stabilizers is most commonly described via a spray drying,
spray granulation or spray layering process. These procedures are
well known in those skilled in the art. It is also common to add
additional excipients prior to removal of solvent in the
nanoparticulate suspension to aid in the dispersion of the solid
composition in medium in which the solid composition will be
exposed (e.g. gastrointestinal fluids) to further prevent
agglomeration and/or particle size growth of the small drug
particles. An example of such an additional excipient is a water
soluble spacer (also referred to as a redispersing agent) which has
been described is sucrose (U.S. Patent Application Publication No.
2004/0214746, the disclosure of which is hereby incorporated by
reference). Other examples of water soluble spacers include sugars,
polyethylene glycols, urea and quarternary ammonium salts.
Obtaining Size Stabilized Particles: Complexing Agents as Particle
Growth Stabilizers
[0114] A concern with the preparation of any small particle
suspension is the stability of the size-reduced (e.g., milled)
particles. After size reduction, the particles after a period of
time (e.g., four weeks) may tend to grow and/or agglomerate and
result in increased particle size as compared to the particles size
immediately after size reduction. When creating small particle
formulations (D50 not greater than about 500 nm) most compositions
never stabilize and continue to grow until large particles (1-30
microns) are realized. The rate at which these particles grow
depends on the composition and the residence time of e.g., milling.
The art around producing small particle compositions of organic
molecules has focused on various methods and compositions to
suppress particle growth or aggregation.
[0115] In contrast, one aspect of the invention is directed to the
use of complexing agent(s) which stabilize the size of the
particles. The addition of such complexing agent(s) initially
provide a rapid particle size growth over a curing period, and then
results in size-stabilized particles which have more desirable
attributes than the uncomplexed particles. Generally, the resultant
size-stabilized particles have a D50 value of not greater than
about 500 nm (the meaning of size-stabilized is defined herein at
paragraph [0073]). When combined with particles comprising drugs
useful in the present invention (preferably with effective amounts
of a surface stabilizer(s), such complexing agents provide added
stability and superior physical properties such as storage
stability, freeze/thaw stability, heat stability and stability in
the physiological medium (e.g., simulated gastrointestinal fluids)
that the formulation will be exposed to. This enhanced stability
allows the small particle compositions to be exposed to a variety
of conditions as mentioned in the previous sentence and/or to be
redispersed while maintaining a D50 not greater than about 500 nm.
Complexing agents also can minimize the milling time needed to
manufacture a stable nanoparticulate formulation and increase the
concentration of drug content in various formulations.
[0116] The types of complexing agents were not previously
identified in the art as providing such benefits and are small
molecular weight molecules (MW less than 550) which can form a
cyclodextrin inclusion complex and after suitable curing time
impart additional stability to the drug. Complexing agents include
but are not limited to aryl or heteroaryl (N, O, S) aromatic acids
and esters and salts thereof. Complexing agents can be substances
containing a phenol moiety, an aromatic ester moiety or an aromatic
acid moiety.
[0117] Examples of complexing agents include but are not limited to
phenol, parabens (e.g., methylparaben, propylparaben, potassium
methylparaben, sodium methylparaben), BHT, sorbic acid, ascorbic
acid, methyl anthranilate, salicylic acid, acetosalicyclic acid,
tocopherol, organic acids, carboxylic acids, aromatic acids,
aromatic esters, acid salts of amino acids, benzaldehyde,
cinnimaldehyde, imidazole, menthol, thiophenol, m-aminobenzoic
acid, anthranilic acid, picolinic acids and alkyl esters thereof,
toluidides, sodium benzoate, benzoic acid, para-aminobenzoic acid
and esters, sorbic and benzoic acids,
2,6-di-t-butyl-alpha-dimethylamino-p-cresol, t-butylhydroquinone,
di-t-amylhydroquinone, di-t-butylhydroquinone, butylhydroxytoluene
(BHT), butylhydroxyanisole (BHA), pyrocatechol, pyrogallol,
propyl/gallate, nordihydroguaiaretic acid, esters, and isomeric
compounds thereof, pharmaceutically acceptable salts thereof,
mixtures of any of the foregoing, and the like.
[0118] As demonstrated in the appended Examples, this growth in
particle size is especially observed, e.g., initially after adding
methylparaben with or without propylparaben or benzoic acid/sodium
benzoate. A non-preservative complexing agent providing similar
results in the appended Examples is methyl anthranilate.
[0119] The final storage stable particle size of a nanoparticulate
suspension as measured by volume-weighted-median (D50) is dependent
upon the concentration of the complexing agents and/or milling
residence time. When the concentration of complexing agents was
kept constant, the post-milling growth of particles correlates
closely with residence time. Therefore, certain aspects of the
present invention are directed to the unexpected observation that
the residence time that the active agent particles (e.g., drug
particles) are subjected to during the milling process, has an
impact on the variability of the subsequent growth in particles
size after milling. The milling residence time is defined by the
following equation:
Milling Residence Time=(milling chamber void volume/milling slurry
volume).times.milling time (Equation 1).
[0120] Within Equation 1 the void chamber volume is the void space
in the mill chamber that can be occupied by the milling slurry. It
is calculated by estimating the bead void space in the beads (for
0.4 mm yttrium-stabilized zirconium oxide beads, the bead void
space is approximately 36-40% of the beads volume) and void chamber
volume is the volume of the milling chamber-the volume of the
beads+the bead void space (all in the same volume units). When
milling under re-circulating conditions (passing multiple times
through a mill by creating a loop between a milling slurry in a
vessel and the mill, the disclosed residence times are obtained
using flow rates varying from 1/4 of the estimated void
volume/minute to 3 times (3.times.) the estimated void chamber
volume/minute. Ideally flow rates of 0.5.times. void chamber volume
per minute to 1.5.times. void volume per minute are used.
[0121] As demonstrated in the Examples section, it has been
observed that after obtaining a desired particle size, continued
milling which does not significantly reduce the particle size any
further, does produce more growth stable particles as compared to
the shorter milling residence time when measuring storage stability
of the formulation. One factor that may contribute to the growth of
the particle size is the association of a complexing agent with a
drug particle. It is also possible that this complex can further
associate with other particle excipients, e.g., a viscosity
enhancing agent or wetting agent (alternatively referred to herein
and in the prior art as "surface stabilizers"). These complexes
which are initially reversible under sonication, increase over the
curing time to become larger, size-stabilized particles. (See FIG.
1). The curing time is the time needed for the complex to become a
size-stabilized particle. The effect of the milling residence time
may affect the variability of size growth due to that prolonged
milling produces more particles with smoother surfaces that have
less area for contact and are less prone to aggregation. To
minimize cost and contamination of the formulation by abrasion of
grinding media and the portions of the mill in contact with the
milling slurry, a preferred embodiment is shorter and lower energy
milling by which a size stabilized nanoparticulate composition can
be formed by adding a complexing agent. Additional preferred
embodiments include nanoparticulate compositions in which addition
of a complexing agent allows for more concentrated drug
compositions.
[0122] Thus, certain embodiments of the present invention provide
pharmaceutical particles comprising complexed drug thereof which
exhibit a stable growth profile over time, i.e., the particles
provide a D50 ratio of 1.5:1 or less as compared to D50 after 4
months storage (25.degree. C.) with the D50 after a suitable curing
period. The novel nature of adding a small molecule complexing
agent is seen in some embodiments where one can reproducibly
increase the particle size by about 20% to 300% within 1-4 weeks
curing. After this curing period the particle size is stable for
many months.
[0123] In certain embodiments, the invention is directed to a
composition comprising particles comprising a drug (preferably with
a surface modifier(s) and an effective amount of a complexing agent
(added during or within 24-48 hours after particle size reduction)
to stabilize the particle growth after an initial particle growth
and endpoint is reached (curing time), wherein the volume weighted
median diameter (D50) of the particles before the initial growth is
from about 50 to about 200 nm and the D50 at the end of the curing
time is 20% to 300% larger than the D50 measured before the curing
period.
[0124] In further embodiments, the particles have a ratio of D50
values four months storage (25.degree. C.) after curing to of about
1.25:1 or less; or about 1.15:1 or less.
[0125] In order for the milled drug particles of the present
invention to provide a growth stable profile with drug particles in
the 100-500 nm range (D50), the particles have a preferred milling
residence time of at least 25 minutes if a complexing agent is
added. However, these times are not meant to be limiting. The
residence time necessary for obtaining a growth stable formulation
can be ascertained by one of skill in the art, given the guidance
provided by the present disclosure.
[0126] The resultant particles of the milling process disclosed
herein can have a D50 of less than 500 nm, less than 400 nm, less
than 300 nm, less than 200 nm or less than 100 nm. The resultant
particles can also have a D90 of less than 1 micron, less than 500
nm, less than 400 nm, less than 300 nm, less than 200 nm.
[0127] The end product of the milling processes to obtain growth
stable particles can comprise the active agent particles suspended
in water (i.e., a suspension).
[0128] Addition of a complexing agent during or preferably
post-milling was found to improve the physical stability (storage
and dispersed in simulated gastrointestinal fluids) of drug
particles formulations (e.g. liquid suspension and solid
formulations). The improvement in physical stability is believed to
be the result of the formation of complex's of drug particles and
the complexing agent which causes an increase in drug particle
size. Without being bound by theory, it is hypothesized that the
increase in drug particle size in complexing agent containing
formulations is achieved through a particle complex forming
process. For example, the complexing agent(s) can act as an
aggregating for drug particles to form drug-aggregates associated
with the complexing agent and possibly other ingredients in the
suspension. These aggregates are relatively weak during the early
stages (first 2-3 days) of the complex formation, e.g. in the case
of adding methylparaben or methylparaben and propylparaben or
parabens and benzoic acid/sodium benzoate to ganaxolone. This is
evident as sonication of the formulation in this stage can reduce
the particle size of the complex, apparently due to the loose
nature of the newly-formed complexes. Over a period of time, these
loose aggregates become permanent (irreversible) larger particles.
Generally, after no change in particle size growth is observed over
48 hours the curing process is complete. When methyl anthranilate
is used as a complexing agent with certain nanoparticulate
phenyloin compositions, the curing time is 5-7 days.
[0129] The initial target size for the drug particles considered
desirable by the inventors was in the range of about 100-200 nm.
When milling one gets a non-linear curve. Initially a large
decrease in particle size is obtained per unit milling time which
then decreases so that very little particle size change with
additional milling occurs. Longer milling times are generally
associated with an increase in residual materials (from the milling
chamber lining and balls) in the suspension. On the other hand, the
longer a drug is milled, it has been generally found (e.g., with
ganaxolone), the more stable it is to particle size growth over
time.
[0130] The inventors have found that when adding a preservative to
a suspension of drug particles (necessary to preserve the
suspension), e.g., ganaxolone in size range of 100-200 nm
manufactured using a surface stabilizer(s), it was noticed that the
drug particles exhibited a rapid rise in particle size that kept on
growing. For example, under high energy ball milling, if one grinds
Ganaxolone to 120-170 nm and then adds 0.1% methylparaben and 0.02%
propylparaben (very normal preserving levels), a rise in particle
size to 300 nm was noted, independent of when the milling process
was stopped (i.e., 120 nm sized drug particles grew to 300 nm; and
particles milled for less time and having a particles size of 170
nm grew to 300 nm) over a 10 day period or so. In view of this drug
particle size growth, the inventors added other preservatives to
milled suspensions not containing parabens. Benzalkonium salts were
not good (flocculation of particles). Addition of sodium
benzoate/benzoic acid showed a slower particle size growth than
parabens but also more than doubled over a few weeks. It was
thereafter noted that in the case where parabens were added to the
ganaxolone drug particle suspension, the particle size of the drug
particles stabilized (stopped growing) after a certain period in
time and after following for a few months no further changes were
noted. Despite this fact, it was noted that the methyl and propyl
paraben drug particle suspensions failed when tested for microbial
effectiveness. This was not predicted by the inventors as the
levels used were within 50% of their solubility limit. Thus, the
parabens were not acting as a preservative in the formulation. In
fact, a suitable amount of benzoic acid (added as sodium benzoate)
was added to the 300 nm drug particle suspension in order to pass
preservative testing. It is hypothesized by the inventors that the
parabens were tightly bound to the surface and therefore not able
to be an effective preservative. This hypothesis is provided for
possible explanatory purposes only, and is not meant to be limiting
in any way with respect to the appended claims.
[0131] Further studies demonstrated that the addition of
methylparaben (and to a lesser degree, propylparaben) gave
ganaxolone suspensions more stability than without it. It was
thereafter found that adding a non-preservative (methyl
anthranilate) caused a rapid rise in particle size which was then
stable. This was the first non-preservative that was identified as
a "complexing" agent. As one follows the ganaxolone particle size
curing period, it was seen that measuring particles size with and
without 60 seconds of sonication showed that initially a loose
association formed (could be reversed partially by sonication) but
after the curing period the particle size of the complexed
compositions was size stable to storage and dispersion in simulated
gastrointestinal fluids. Further evidence to show that
methylparaben was acting in a unique manner in the suspension was
seen by filtration. Taking a ganaxolone suspension (170 nm)
containing standard surface stabilizers but not methylparaben
(uncomplexed) could be filtered through a 450 nm filter and 95% of
the particles passed through the filter. After a paraben curing
period significant back pressure was seen in filtration and only a
few percent of the particles filtered through the 450 nm filter
even though at least 60% or more should have. Similar poor
filtration was even seen with 1 and 10 um filters. This result
indicated that the ionic/non-ionic stabilizers with ganaxolone and
parabens form a complicated complex that has a large effective
particle size via filtration (even though laser scattering only
shows 300 nm particles present).
[0132] The manufacture of size-stabilized drug particles can also
be accomplished using a wide range of drugs (as defined herein) and
complexing agents other than the parabens. For example,
nanoparticles of phenyloin (5,5-diphenylhydantoin) have been
complexed with methyl anthranilate to provide initial rapid
particle size growth followed by similarly size-stabilized
particles.
[0133] A common property of all complexing agents and drugs which
are capable of forming a complexed, size-stabilized particulate
composition is the ability of these complexing agents and drugs to
form a cyclodextrin inclusion complex. It is now understood that a
complexing agent, as the term is used in the present application,
may be defined as a low molecular weight organic molecule
(MW<550) capable of forming a cyclodextrin inclusion
complex.
[0134] Different complexing agents affect the drug (e.g.,
ganaxolone) complex formations differently. For example,
methylparaben drug complexes typically take 5 to 7 days to cure
while sodium benzoate and/or benzoic acid-drug aggregates take much
longer (up to 3 weeks) to cure, as illustrated in FIG. 2. FIG. 2
shows the particle size growth plots for both methylparaben and
propylparaben and sodium benzoate (adjusted to pH 4.0) with drug
100 to 200 nm particles. Both formulations contain 5% drug, 5%
HPMC, 1% PVA, 0.1 to 0.2% SLS. The parabens formulation contained
0.1% methylparaben, 0.02% propylparaben and 0.1% simethicone while
the sodium benzoate formulation contained 0.17% sodium benzoate,
0.13% citric acid and 0.01% sodium citrate (pH 4.0). It has
recently been found that the addition of methyl anthranilate can
form a complex which does not change after sonication after 1 day.
In the case of methyl anthranilate, approximately 0.05% was added
to a non-complexed drug particle suspension at 180 nm and a D50 of
390 nm was seen 72 hours later. Addition of 0.4% methyl
anthranilate increased one ganaxolone composition from 220 nm to
480 nm over 3 days which was not reversed by sonication. The 0.4%
complexed methyl anthranilate-ganaxolone complex showed no
aggregation in SIF or SGF while the uncomplexed ganaxolone
composition aggregated significantly. Percentages for liquid
formulations are given as wt %/w (weight %/total formulation
weight).
[0135] The cured drug-particles appear to have much better physical
stability than drug particles that do not contain the complexing
agent. Once the drug particle complexes are formed, no further
substantial increase in drug particle size is observed. Drug
particles of ganaxolone that were milled for less than 2 hours
milling residence time and do not contain complexing agents
continue to increase gradually in size over a number of months
(FIG. 3.).
[0136] Complexing agent concentrations also affect the complex
curing process. Higher concentrations lead to larger particles and
faster curing. For example, two identical drug particle
formulations (D50 of 140 nm) with 0.1% and 0.2% methylparaben had
D50 values of 190 and 300 nm respectively after the same curing
period.
[0137] Parabens are esters of para-hydroxybenzoic acid. Parabens
which can be utilized in the present invention include
methylparaben, ethylparaben, propylparaben, and butylparaben. Other
parabens which can be utilized in the present invention include
isobutylparaben, isopropylparaben, benzylparaben. Pharmaceutically
acceptable salts, e.g., sodium and potassium salts, can also be
utilized in the present invention. Especially preferred parabens
for use in the present invention include methylparaben and
propylparaben and their sodium salts. If the sodium salts of
parabens are utilized an equimolar amount of an organic acid, e.g.,
citric acid should be added.
[0138] Typically, milled drug particle suspensions are converted
into a solid dosage form. Governmental drug regulatory agencies
such as the FDA, requires justification of all ingredients and
their levels in a formulation. Therefore, it is quite uncommon for
a preservative to be included in a solid dosage form. With respect
to nano-sized dosage forms, commercialized solid dosage forms
prepared from a nanosuspension (e.g., TriCor.RTM.), Emmend.RTM.)
and Rapamune.RTM.)) do not contain any preservatives. As shown in
the examples, complexing agents impart significant stability
qualities into solid dosage forms.
[0139] The complexing agent can be present in any suitable amount,
e.g., from about 0.001% to about 5%, from about 0.01% to about
2.5%, from about 0.015% to about 1%, from about 0.1% to about 0.5%
or from about 0.02% to about 0.1%, based on the weight of the
milled slurry.
[0140] Certain embodiments of the invention are directed to
minimizing aggregation and/or particle size growth due to the
association of the drug particles and the complexing agent when
dispersed in simulated gastrointestinal fluids. These embodiments
are directed to pharmaceutical particles comprising drug thereof
associated with a complexing agent, the particles exhibiting a
ratio of D50 after dispersion in SGF or SIF at 36-38.degree. C. for
1-3 hours to D50 prior to dispersion in SGF or SIF of less than
about 3:1; less than about 2.7:1, less than about 2.5:1, less than
about 2:1, or less than about 1.5:1. In certain embodiments, the
invention is directed to pharmaceutical particles comprising drug
thereof stabilized with a complexing agent, the complexed particles
exhibiting a ratio of D50 after dispersion in SGF or SIF for 1-3
hours to D50 prior to dispersion of from about 1.5:1 to about 3:1;
from about 1.8:1 to about 2.7:1 or about 2:1 to about 1.5:1.
[0141] Certain embodiments of the invention are directed to the
"cured" complexes which exhibit size-stabilized particles. These
embodiments are directed to pharmaceutical particles comprising
drug thereof complexed with a complexing agent, the particles cured
for a sufficient time until an endpoint is reached such that the
D50 does not change by more than about 5% as measured over 3 days
after curing. In other embodiments, the particles are cured for a
sufficient time until an endpoint is reached such that the D50 does
not change by more than about 12%, more than about 10%, more than
about 8% or more than 5% over 1 month after the curing period.
[0142] In further embodiments, the particles are cured for a
sufficient time until an endpoint is reached such that the D50 does
not change by more than about 5% (over the instrument's variability
at the measure particle size) after 20 days after curing, 40 days
after curing, 60 days after curing, or 80 days after curing storage
conditions of 5.degree. C. to 25.degree. C. Cured drug particulate
complexes are more desirable as these compositions will provide a
more uniform result due to a decreased change in particle size over
time, better thermal stability and less aggregation in the
gastrointestinal tract.
[0143] The endpoint needed to reach size stabilized particles can
be ascertained by one skilled in the art. For example, the endpoint
can be reached in about 5 days to about 25 days; in about 5 days to
about 7 days, in about 7 days to about 14 days, in about 14 days to
about 21 days, or about 10 days to about 15 days.
[0144] In certain embodiments, the particles have a D50 prior to
storage of less than 350 nm, less than 250 nm or less than 150 nm.
In other embodiments, the particles have a D50 prior to storage of
from about 50 nm to about 350 nm, from about 75 nm to about 250 nm
or from about 100 nm to about 150 nm.
[0145] The benefits of having a complexed nanosuspension include
but are not limited to the following: (1) very stable particle size
once cured (e.g., no significant change in particle size after
about 2 years); (2) the non-complexed drug suspensions of similar
composition are generally less stable in simulated gastric and
intestinal fluids, e.g., when incubated at 37.degree. C. for 3
hours; (3) the complexed drug suspensions can be boiled and frozen
without a significant change in particle size, whereas
non-complexed drug suspensions have been found to double in size
(e.g., changing in particle size from 140 nm to 330 nm); (4) the
milling time can be decreased via the use of a complexing agent to
get a storage stable particle size as opposed to obtaining a
storage stable particle size by increasing milling time (also less
contamination). Milling time is also called residence time and is
the time a particle is in the mill when being recirculated through
the mill into a large tank. With complexing agents, milling
residence time to obtain a storage stable drug particle suspension
may be, e.g., from about 30 to about 35 minutes versus about 1.5 to
2 hours (which translates to a 3-4 time increase in
productivity).
[0146] Complexed drug suspensions comprising drug (e.g.,
Ganaxolone), HPMC, SLS, methylparaben, propylparaben, and PVA were
found to provide desirable pharmacokinetic results in animal
studies versus uncomplexed Ganaxolone formulations with D50 values
1/3 that of the complexed material. Surprisingly, the total
exposure (AUC) was slightly higher with the complexed and higher
D50 composition. Previous prior art claims that smaller particle
size result in increased bioavailability which is not the case with
complexed ganaxolone formulations. The smaller uncomplexed
formulation gave higher Cmax values as one would expect with
increased dissolution but not higher bioavailability. Higher Cmax
levels without an increase in bioavailability is an undesirable
attribute for some compounds as higher side effects will be seen
without any additional benefit.
[0147] Formulations containing drug complexes as described above
may provide a more desirable pharmacokinetic performance (e.g.,
improved bioavailability, reduction in variability, etc.).
[0148] Milling with Simethicone as an Anti-Foaming Agent
[0149] Foaming during the nanosizing of pharmaceutical products can
present formulation issues and can have negative consequences for
particle size reduction. For example, high levels of foam or air
bubbles in the mill can cause a drastic increase in viscosity
rendering the milling process inoperable. Even a very low level of
air presence can dramatically reduce milling efficiency causing the
desired particle size unachievable. This may be due to the
resultant air in the mill cushioning the milling balls and limiting
grinding efficiency. The air also can form a microemulsion with the
milled ingredients which presents many issues with respect to the
delivery of an accurate dose and palatability. Addition of a small
amount of simethicone is a very effective anti-foaming agent which
minimizes milling variability or special handling techniques to
avoid the introduction of air into the milling process.
Drugs
[0150] Suitable drugs which can form a cyclodextrin inclusion
complex for use in the present invention include, but are not
limited to, antineoplastics (anticancer/antitumor agents),
sedatives, antiinflammatory steroids (glucocorticoids such as
actometasone, betamethasone, beclomethasone, fluocinonide,
flunisolide, dexamethasone, cortisone, hydrocortisone,
methylprednisolone, mometasone, prednisolone, prednisone,
fluticasone, budesonide, and triamcinolone), tranquilizers,
anticonvulsants, antivirals, antihistaminics (fexofenadine),
vitamins/nutritional factors, emetics (apomorphine), anticoagulants
(dicumarol or coumadin), cardiotonics (including the cardiac
glycosides such as digoxin or digitoxin), diuretics, carbonic
anhydrase inhibitors, non-steroidal analgesic and/or
anti-inflammatory agents (NSAID's), androgens
(17-methyltestosterone and testosterone), estrogens, anabolic
agents (fluoxymesterone and methanstenolone), vasodilators,
anxiolytics (e.g, benzodiazepines) antidepressants (sertraline or
sulpiride), antipsychotics (ziprasidone, fluspirilene, pimozide and
penfluridole), hypnotics (etomidate) and/or steroidal
hypnotics/anesthetics (alfaxalone), antifungals, progestins,
antiprotozoals, anthelmintics, anesthetics (lidocaine),
vasoconstrictors, hypoglycemic (acetohexamide),
antibacterials/antibiotics, and anti-infectives, platelet
inhibitors, muscle relaxants, antiemetics (dimenhydrinate),
radiodiagnostics, antispasmodics, angiotensin converting enzyme
inhibitors, antiarrythmics, carbonic anhydrase inhibitors,
gastrointestinal agents such as loperamide and cisapride (including
H.sub.2-antagonists and other anti-ulcer agents), antihypertensives
especially including those useful as anti-glaucoma agents,
serotonin antagonists, narcotic antagonists, narcotic agonists,
mixed narcotic agonists-antagonists, pharmacologically active
proteins such as peptide hormones, prostaglandins (alprostadil,
prostacyclin or epoprostenol), dopaminergic agents (L-DOPA),
mineral corticoids (desoxycorticosterone), neurosteroids (except
for ganaxolone), enzymes, antibodies and other biologically
produced substances, anti-Parkinsonism/dopamineric agents and drugs
for treating Alzheimer's disease (THA).
[0151] Suitable neurosteroids may include, but are not limited to,
beta-hydroxy-delta 5-compounds, such as pregnenolone (PREG) and
dehydroepiandrosterone (DHEA), their sulfates, and reduced
metabolites such as the tetrahydroderivative of progesterone 3
alpha-hydroxy-5 alpha-pregnane-20-one (3 alpha,5 alpha-THPROG).
[0152] While ganaxolone can indeed form a cyclodextrin inclusion
complex, that drug has been described previously in our U.S. patent
application Ser. Nos. 11/606,222 and 11/605,700, both filed on Nov.
28, 2006, the disclosures of which are hereby incorporated by
reference in their entirety. However, ganaxolone is therefore
excluded from the claims of the present application.
[0153] Suitable antineoplastics for use in the present invention
include, but are not limited to chlorambucil, lomustine, melphalan,
methotrexate, hexamethylmelamine, teniposide, etoposide, semustine
(methyl CCNU), fazarabine (Ara-AC), mercaptopurine, tubulazole,
carmofur, carmustine, amsacrine, doxorubicin, bruceantin,
diaziquone, dideminin B, echinomycin and PCNU.
[0154] Suitable antiinflammatory steroids (glucocorticoids) for use
in the present invention include, but are not limited to
actometasone, betamethasone, beclomethasone, fluocinonide,
flunisolide, fludrocortisone, dexamethasone, cortisone,
hydrocortisone, methylprednisolone, mometasone, prednisolone,
prednisone, fluticasone, budesonide, triamcinolone and any
pharmaceutically acceptable salts thereof. For example, in certain
embodiments the glucocorticosteroid is triamcinolone acetonide.
[0155] Suitable estrogens for use in the present invention include,
but are not limited to, 17.beta.-estradiol,
17.alpha.-ethynylestradiol (ethinylestradiol), ethynylestradiol
3-methyl ether, estrone, mestranol and estriol. In certain
embodiments, the estrogen is a synthetic estrogens such as
diethylstilbestrol, benzestrol, dienestrol, hexestrol and the
like.
[0156] Suitable progestins for use in the present invention
include, but are not limited to, dimethisterone, norethindrone,
norethindrone acetate, norgestrel, norethynodrel, ethisterone,
medroxyprogesterone acetate and progesterone.
[0157] Suitable immunosuppressive agents for use in the present
invention include, but are not limited to, cyclosporine (also known
as cyclosporin A).
[0158] Suitable anticonvulsants for use in the present invention
include, but are not limited to, phenyloin (5,5-diphenylhydantoin)
and carbamazepine.
[0159] Suitable barbiturates for use in the present invention
include, but are not limited to, pentobarbital, phenobarbital and
secobarbital, which are variously useful as hypnotics,
anticonvulsants and sedatives as well.
[0160] Suitable antivirals for use in the present invention
include, but are not limited to, acyclovir, trifluridine,
zidovudine, vidarabine and virazole (also known as ribavirin).
[0161] Suitable vitamins/nutritional for use in the present
invention include, but are not limited to, factors such as retinol
(vitamin A), vitamin A-acetate, cholecalciferol, retinal, retinoic
acid (also known as tretinoin or Retin-A.TM.), isotretinoin,
etretinate, acitretin and .beta.-carotene, collectively referred to
herein as retinoids, as well as other fat-soluble vitamins such as
the E, D and K vitamins.
[0162] Beta-blockers suitable for use in the present invention
include, but are not limited to, timolol, atenolol, propranolol,
nadolol, carteolol, carvedilol, celiprolol, esmolol, labetalol,
metoprolol, penbutolol, pindolol and sotalol.
[0163] Diuretics suitable for use in the present invention include,
but are not limited to, chlorthalidone, furosemide, spironolactone,
and other sulfonamide-type and/or aldosterone antagonist-type
diuretics.
[0164] Angiotensin converting enzyme inhibitors (ACE inhibitors)
suitable for use in the present invention, include but are not
limited to, enalaprilic acid (the diacid, sometimes called
`enalaprilate`), the ethyl ester of enalaprilic acid (sometimes
called enalapril), captopril, lisinopril and SCH-33861.
[0165] Suitable non-steroidal analgesics and/or anti-inflammatory
agents for use in the present invention include, but are not
limited to, aspirin, ibuprofen, indomethacin, piroxicam, sulindac
and flurbiprofen.
[0166] Antibacterials/antibiotics, anti-infectives and/or
antifungal/antiprotozoal agents suitable for use in the present
invention include, but are not limited to, ampicillin, penicillin
G; tetracycline, chlortetracycline, oxytetracycline,
demeclocycline, methacycline, doxycycline, minocycline,
erythromycin, josamycin, rosamycin, tylosin, troleandomycin and
spiramycin, benzalkonium chloride, cetylpyridinium chloride,
chlorhexidine, econazole, clotrimazole, oxiconazole, bifonazole,
metronidazole (metronidazole benzoate), fenticonazole, miconazole,
sulconazole, tioconazole, isoconazole, butoconazole, ketoconazole,
doconazole, parconazole, orconazole, valconazole and lombazole,
terconazole, itraconazole, omidazole, camidazole, ipronidazole,
tinidazole and nimorazole, and flubendazole.
[0167] Suitable vasodilators include, but are not limited, to
coronary vasodilators such as nitroglycerin, flunarizine,
lidoflazine and mioflazine.
[0168] Carbonic anhydrase inhibitors suitable for use in the
present invention include, but are not limited to, acetazolamide,
chlorzolamide, ethoxzolamine, methazolamide, L-671,152 and
MK-927.
[0169] H.sub.2-antagonists suitable for use in the present
invention include, but are not limited to, famotidine, burimamide,
metiamide, cimetidine and oxmetidine.
[0170] Antihistaminics suitable for use in the present invention
include, but are not limited to, astemizole, levocabastine,
flunarizine, oxatomide and cinnarizine.
[0171] Anthelmintic agents suitable for use in the present
invention include, but are not limited to, thiabendazole,
oxibendazole, cambendazole, fenbendazole, flubendazole, albendazole
and oxfendazole.
[0172] Serotonin antagonists suitable for use in the present
invention include, but are not limited to, ketanserin, ritanserin,
altanserin, and mianserin.
[0173] Benzodiazepines suitable for use in the present invention,
include but are not limited to, chlordiazepoxide, diazepam,
medazepam, oxazepam, lorazepam, flunitrazepam, estazolam,
flurazepam, loprazolam, lormetazepam, nitrazepam, quazepam,
temazepam and triazolam.
[0174] In certain embodiments, the drug formulations comprise a
non-amorphous form of drug comprising drug particles having an
effective particle size by weight of less than about 500 nm. In
other embodiments, the drug particles have an effective particle
size by weight of less than about 400 nm, an effective particle
size by weight of less than about 300 nm, an effective particle
size by weight of less than about 200 nm, or an effective particle
size by weight of less than about 100 nm when measured by the above
techniques. In yet another embodiment, the drug particles have a
particle size distribution wherein the drug particles have an
effective particle size by weight of less than about 400 nm and
wherein the standard deviation of the particle size distribution is
less than about 100 nm.
[0175] In other embodiments, the drug particles by weight have a
particle size 500 nm, i.e., less than about 500 nm, less than about
400 nm, less than about 300 nm, less than about 200 nm, or less
than about 100 nm with less than at least 20%, at least about 15%
or at least about 10% of the total particles having a particle size
greater than 1 micron.
[0176] In one embodiment, the drug particles have a particle size
of around 300 nm with a distribution wherein 90% of the particles
by weight have an effective particle size by weight between about
100 nm and 800 nm. In another embodiment, the drug particles have a
particle size or around 100 nm and a distribution wherein 90% of
the particles by weight have an effective particle size by weight
between about 50 nm and 250 nm.
[0177] In other embodiments, the drug compositions described herein
comprise size stabilized drug particles having a particle size by
weight of less than 500 nm formulated with drug particles having a
particle size by weight of greater than 500 nm. In such
embodiments, the formulations have a particle size distribution
wherein about 10% to about 100% of the drug particles by weight are
between about 100 nm and about 300 nm, about 0% to about 90% of the
drug particles by weight are between about 300 nm and about 600 nm,
and about 0% to about 30% of the drug particles by weight are
greater than about 600 nm. In one embodiment, the formulation has a
particle size distribution wherein about 20% of the drug particles
by weight are between about 100 nm and about 300 nm, about 40% of
the drug particles by weight are between about 300 nm and about 600
nm, and about 30% of the drug particles by weight are greater than
about 600 nm. In still another embodiment, the formulation has a
particle size distribution wherein about 30% of the drug particles
by weight are between about 100 nm and about 300 nm, about 40% of
the drug particles by weight are between about 300 nm and about 600
nm, and about 30% of the drug particles by weight are greater than
about 600 nm. In yet another embodiment, the formulation has a
particle size distribution wherein about 50% of the drug particles
by weight are between about 100 nm and about 300 nm, about 40% of
the drug particles by weight are between about 300 nm and about 800
nm, and about 10% of the drug particles by weight are greater than
about 800 nm.
[0178] The drug particles generated by the methods described herein
can be utilized in solid or aqueous liquid dosage formulations,
such as controlled release formulations, solid dose fast melt
formulations, lyophilized formulations, tablets, capsules, aqueous
dispersions, or aerosol formulations.
Dosage Forms
[0179] The drug compositions described herein can be formulated for
administration to a subject via any conventional means including,
but not limited to, oral, parenteral (e.g., intravenous,
subcutaneous, or intramuscular), buccal, intranasal or transdermal
administration routes.
[0180] Moreover, the pharmaceutical drug compositions described
herein can be formulated into any suitable dosage form, including
but not limited to, aqueous oral dispersions, aqueous oral
suspensions, solid dosage forms including oral solid dosage forms,
aerosols, controlled release formulations, fast melt formulations,
effervescent formulations, self-emulsifying dispersions, solid
solutions, liposomal dispersions, lyophilized formulations,
tablets, capsules, pills, powders, delayed release formulations,
immediate release formulations, modified release formulations,
extended release formulations, pulsatile release formulations,
multiparticulate formulations, and mixed immediate release and
controlled release formulations. In some embodiments, drug
formulations provide a therapeutically effective amount of drug
over an interval of about 30 minutes to about 8 hours after
administration, enabling, for example, once-a-day, twice-a-day
(b.i.d.), or three times a day (t.i.d.) administration if desired.
In one embodiment, the drug particles are formulated into a
controlled release or pulsatile solid dosage form for b.i.d.
administration. In other embodiments, the drug particles are
dispersed in an aqueous dispersion for b.i.d. administration.
Generally speaking, one will desire to administer an amount of drug
needed to elicit a therapeutic effect in the minimal number of
dosings per unit time.
[0181] In certain embodiments of the invention, the stabilized drug
particle suspensions are converting to a solid form. There are
generally four ways to accomplish this: spray drying; spray
layering onto a core (fluidized bed); spray granulation (fluidized
bed); or adding more excipients and performing a spheronization
extrusion.
[0182] The inventors have found that several issues may arise when
removing water from the stabilized drug particle suspension in
order to prepare a solid dosage form. For example, there can be
particle aggregation in the solid state or particle aggregation
(increase in particle size) may occur when the solidified drug
particles are re-dispersed into a biological medium.
Spray-Layering
[0183] In a spray layering manufacture, the cores (e.g., inert
beads) are sprayed with droplets of the drug particle suspension,
e.g., in a Wurster column. The entire particle should preferably be
coated evenly. Then, the water in the suspension has to evaporate
before the beads circulated through the Wurster column again. It
has been found that uncomplexed drug particles can be spray layered
but are generally not stable in SGF and SIF. The complexed (cured
particles with a complexing agent) are generally more stable;
nevertheless, additional agents are typically added to make spray
layering (coating) work give optimal results.
[0184] In general, it is considered by those skilled in the art
that it is preferable to make the slurry to be sprayed as
concentrated in drug particles as possible. Spray drying
manufacture allows the drug concentration to approach 80% or
higher. In spray layering manufacture, however, it has been typical
to add a lot of sucrose into the drug particle dispersion, which is
believed to act as a water soluble spacer separating the drug
particles from agglomeration during spraying and re-dispersion. The
inventors have found that spray layered ganaxolone drug-complex
beads prepared by spray layering without sucrose had good water
redispersion, but aggregated more substantially in SGF and SIF. The
inventors then determined that adding a small amount of a salt such
as sodium chloride dramatically reduced the amount of sucrose
needed to help redisperse solid nanoparticulate composition with
good particle size and stability. For example, a 1.5 weight % (as
compared to drug) addition of NaCl reduced the amount of sucrose
(water soluble spacer 20-fold (from 100% weight of drug to 5%
weight of drug) to achieve minimal aggregation when dispersed in
SGF. This dramatic effect has been able to provide a greater
concentration of drug, thereby allowing more drug to be delivered
in one capsule unit. As the stability effects are seen primarily in
SGF and SIF, the salt is referred to as an "ionic dispersion
modulator" as it seems to have its best effects when redispersing
into an ionic medium.
[0185] In certain embodiments, the excipient comprises an ionic
dispersion modulator. The ionic dispersion modulator can be a salt
such as an organic or inorganic salt. In certain preferred
embodiments, the ionic dispersion modulator is an inorganic salt.
Suitable inorganic salts include, but are not limited to a
magnesium salt, a calcium salt, a lithium salt, a potassium salt, a
sodium salt and mixtures thereof. In certain preferred embodiments,
the inorganic salt is sodium chloride. In other preferred
embodiments, the salt is an organic salt. Suitable organic salts
include, but are not limited to a citrate salt, a succinate salt, a
fumarate salt, a malate salt, maleate salt, a tartrate salt, a
glutarate salt, a lactate salt and mixtures thereof. In yet other
embodiments, the ionic dispersion modulator includes one or more of
both an inorganic and organic salt.
[0186] The amount of ionic dispersion modulator included in a
spray-layering process should be an amount effective to provide a
satisfactory redispersibility of the beads with acceptable particle
size and stability, without causing the mixture to become a
semi-solid. Such an amount typically may comprise from about 0.2%
to about 5% as compared to weight of drug in the formulation.
Oral Solid Dosage Forms
[0187] In some embodiments, the solid dosage forms of the present
invention may be in the form of a tablet (including a suspension
tablet, a fast-melt tablet, a bite-disintegration tablet, a
rapid-disintegration tablet, an effervescent tablet, or a caplet),
a pill, a powder (including a sterile packaged powder, a
dispensable powder, or an effervescent powder), a capsule
(including both soft or hard capsules, e.g., capsules made from
animal-derived gelatin or plant-derived HPMC, or "sprinkle
capsules"), solid dispersion, solid solution, bioerodible dosage
form, controlled release formulations, pulsatile release dosage
forms, multiparticulate dosage forms, pellets, granules, or an
aerosol. In other embodiments, the pharmaceutical formulation is in
the form of a powder. In still other embodiments, the
pharmaceutical formulation is in the form of a tablet, including
but not limited to, a fast-melt tablet. Additionally,
pharmaceutical formulations of the present invention may be
administered as a single capsule or in multiple capsule dosage
form. In some embodiments, the pharmaceutical formulation is
administered in two, or three, or four, capsules or tablets.
[0188] In some embodiments, solid dosage forms, e.g., tablets,
effervescent tablets, and capsules, are prepared by mixing drug
particles with one or more pharmaceutical excipients to form a bulk
blend composition. When referring to these bulk blend compositions
as homogeneous, it is meant that the drug particles are dispersed
evenly throughout the composition so that the composition may be
readily subdivided into equally effective unit dosage forms, such
as tablets, pills, and capsules. The individual unit dosages may
also comprise film coatings, which disintegrate upon oral ingestion
or upon contact with diluents. These drug formulations can be
manufactured by conventional pharmaceutical techniques.
[0189] In certain aspects, the solid formulation is in the form of
a tablet or capsule containing the size stabilized complexed drug
particles and at least one surface stabilizer, the size stable drug
particles exhibiting an increase in volume weighted median diameter
(D50) of from 0% to not more than about 200%, not more than about
150%, not more than about 100%, or not more than about 50%, when
the tablets or capsules are dispersed in SGF or SIF (in any
suitable volume, e.g., 15 mL to 1000 mL) at a concentration of 0.5
to 1 mg drug/mL at 36.degree. to 38.degree. C. using a Type I or II
dissolution apparatus and a stirring rate of 75 RPM for 1 hour, as
compared to the D50 of the drug particles when the tablets or
capsules are dispersed in distilled water under the same
conditions, wherein the volume weighted median diameter (D50) of
the drug particles when the tablets or capsules are dispersed in
distilled water is from about 50 nm to about 1000 nm, from about
100 nm to about 500 nm, or from about 100 nm to about 350 nm.
[0190] In other aspects, the invention is directed to a solid
formulation (e.g., a powder, immediate release dosage form, or
controlled release dosage form) comprising size stabilized drug
particles and at least one pharmaceutically acceptable excipient,
the size stabilized drug particles exhibiting a volume weighted
median diameter (D50) of less than about 500 nm when the
formulation is dispersed in simulated gastric fluid (SGF) for one
hour followed by simulated intestinal fluid (SIF) for three
additional hours, at a concentration of 0.5 to 1 mg drug/mL (in any
suitable volume, e.g., 15 mL to 1000 mL) at a temperature of
36.degree. to 38.degree. C.
[0191] In still other aspects, the solid formulation is a tablet or
capsule containing the stabilized drug particles and at least one
excipient, the stable drug particles exhibiting a volume weighted
median diameter (D50) of less than about 500 nm when the tablets or
capsules are dispersed in simulated gastric fluid (SGF) for one
hour followed by simulated intestinal fluid (SIF) for three
additional hours, at a concentration of 0.5 to 1 mg drug/mL (in any
suitable volume, e.g., 15 mL to 1000 mL) at a temperature of
36.degree. to 38.degree. C. using a Type I or II dissolution
apparatus and a stirring rate of 75 RPM.
Preparation of Solid Dosage Forms
[0192] Conventional pharmaceutical techniques for preparation of
solid dosage forms include, e.g., one or a combination of methods:
(1) dry mixing, (2) direct compression, (3) milling, (4) dry or
non-aqueous granulation, (5) wet granulation, or (6) fusion. See,
e.g., Lachman et al., The Theory and Practice of Industrial
Pharmacy (1986). Other methods include, e.g., spray drying, pan
coating, melt granulation, granulation, fluidized bed spray drying
or coating (e.g., wurster coating), tangential coating, top
spraying, tableting, extruding and the like.
Formulation Components
[0193] The pharmaceutical solid dosage forms described herein can
comprise the drug compositions described herein and one or more
pharmaceutically acceptable additives such as a compatible carrier,
binder, complexing agent, ionic dispersion modulator, filling
agent, suspending agent, flavoring agent, sweetening agent,
disintegrating agent, dispersing agent, surfactant, lubricant,
colorant, diluent, solubilizer, moistening agent, plasticizer,
stabilizer, penetration enhancer, wetting agent, anti-foaming
agent, antioxidant, preservative, or one or more combination
thereof. In still other aspects, using standard coating procedures,
such as those described in Remington's Pharmaceutical Sciences,
20th Edition (2000), a film coating is provided around the drug
formulation. In one embodiment, some or all of the drug particles
are coated. In another embodiment, some or all of the drug
particles are microencapsulated. In yet another embodiment, some or
all of the drug is amorphous material coated and/or
microencapsulated with inert excipients. In still another
embodiment, the drug particles not microencapsulated and are
uncoated.
[0194] Suitable carriers for use in the solid dosage forms
described herein include, but are not limited to, acacia, gelatin,
colloidal silicon dioxide, calcium glycerophosphate, calcium
lactate, maltodextrin, glycerin, magnesium silicate, sodium
caseinate, soy lecithin, sodium chloride, tricalcium phosphate,
dipotassium phosphate, sodium stearoyl lactylate, carrageenan,
monoglyceride, diglyceride, pregelatinized starch,
hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate
stearate, sugars such as sucrose, microcrystalline cellulose,
lactose, mannitol, polyvinylpyrrolidone (PVP), cholesterol,
cholesterol esters, sodium caseinate, soy lecithin, taurocholic
acid, phosphotidylcholine, cellulose and cellulose conjugates,
sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride,
pregelatinized starch, and the like. See, e.g., Remington: The
Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack
Publishing Company, 1995); Hoover, John E., Remington's
Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;
Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,
Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage
Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams
& Wilkins 1999).
[0195] Suitable filling agents for use in the solid dosage forms
described herein include, but are not limited to, lactose, calcium
carbonate, calcium phosphate, dibasic calcium phosphate, calcium
sulfate, microcrystalline cellulose (e.g., Avicel.RTM., Avicel.RTM.
PH101, Avicel.RTM.PH102, Avicel.RTM. PH1105, etc.), cellulose
powder, dextrose, dextrates, dextran, starches, pregelatinized
starch, hydroxypropylmethylcellulose (HPMC),
hydroxypropylmethylcellulose phthalate,
hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose,
xylitol, lactitol, mannitol, sorbitol, sodium chloride,
polyethylene glycol, and the like.
[0196] "Diluents" increase bulk of the composition to facilitate
compression or create sufficient bulk for homogenous blend for
capsule filling. Such compounds include e.g., lactose, starch,
mannitol, sorbitol, dextrose, microcrystalline cellulose such as
Avicel.RTM.; dibasic calcium phosphate, dicalcium phosphate
dihydrate; tricalcium phosphate, calcium phosphate; anhydrous
lactose, spray-dried lactose; pregelatinized starch, compressible
sugar, such as Di-Pac.RTM. (Amstar); mannitol,
hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate
stearate, sucrose-based diluents, confectioner's sugar; monobasic
calcium sulfate monohydrate, calcium sulfate dihydrate; calcium
lactate trihydrate, dextrates; hydrolyzed cereal solids, amylose;
powdered cellulose, calcium carbonate; glycine, kaolin; mannitol,
sodium chloride; inositol, bentonite, polysaccharides (including
dextrates and maltodextrin), polyols (including mannitol, xylitol,
and sorbitol), cyclodextrins, and the like. Non water-soluble
diluents are compounds typically used in the formulation of
pharmaceuticals, such as calcium phosphate, calcium sulfate,
starches, modified starches and microcrystalline cellulose, and
microcellulose (e.g., having a density of about 0.45 g/cm.sup.3,
e.g. Avicel, powdered cellulose), and talc. Combinations of one or
more diluents can also be used.
[0197] "Plasticizers" are compounds used to soften the
microencapsulation material, film coatings or pharmaceutical blends
for compression to make them less brittle. Suitable plasticizers
include, e.g., polyethylene glycols such as PEG 300, PEG 400, PEG
600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene
glycol, oleic acid, triethyl cellulose and triacetin. In some
embodiments, plasticizers can also function as dispersing agents or
wetting agents.
[0198] "Surfactants or Wetting agents" also referred to as surface
stabilizers include compounds such as sodium lauryl sulfate, sodium
doccusate, triacetin, vitamin E TPGS, dioctylsulfosuccinate,
gelatin, casein, lecithin (phosphatides), dextran, gum acacia,
cholesterol, tragacanth, stearic acid, benzalkonium chloride,
calcium stearate, glycerol monostearate, cetostearyl alcohol,
cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene
alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000),
polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan
fatty acid esters (e.g., the commercially available Tweens.RTM.
such as e.g., Tween.RTM. 20, 60 and 80 (ICI Speciality Chemicals));
polyethylene glycols (e.g., Carbowaxs 3550.RTM. and 934.RTM. (Union
Carbide)), polyoxyethylene stearates, colloidal silicon dioxide,
phosphates, carboxymethylcellulose calcium, carboxymethylcellulose
sodium, methylcellulose, hydroxyethylcellulose, hydroxypropyl
methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone,
hydroxypropylmethylcellulose phthalate, noncrystalline cellulose,
magnesium aluminium silicate, triethanolamine, polyvinyl alcohol
(PVA), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene
oxide and formaldehyde (also known as tyloxapol, superione, and
triton), poloxamers (e.g., Pluronics F68.RTM. and F108.RTM., which
are block copolymers of ethylene oxide and propylene oxide);
poloxamines (e.g., Tetronic 908.RTM., also known as Poloxamine
9085.RTM., which is a tetrafunctional block copolymer derived from
sequential addition of propylene oxide and ethylene oxide to
ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.));
Tetronic 1508.RTM. (T-1508, a poloxamine) (BASF Wyandotte
Corporation), Tritons X-200.RTM., which is an alkyl aryl polyether
sulfonate (Rohm and Haas); Crodestas F-110.RTM., which is a mixture
of sucrose stearate and sucrose distearate (Croda Inc.);
p-isononylphenoxypoly-(glycidol), also known as Olin-IOG.RTM. or
Surfactant 10-G.RTM. (Olin Chemicals, Stamford, Conn.); Crodestas
SL-40.RTM. (Croda, Inc.); and SA90HCO, which is
C.sub.18H.sub.37CH.sub.2C(O)N(CH.sub.3)--CH.sub.2(CH.sub.2OH).sub.4(CH.su-
b.2OH).sub.2 (Eastman Kodak Co.); decanoyl-N-methylglucamide;
n-decyl .beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside;
n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside;
n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl
.beta.-D-thioglucopyranoside; PEG-phospholipid, PEG-cholesterol,
PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme,
random copolymers of vinyl pyrrolidone and vinyl acetate. The above
surfactants are commercially available or can be prepared by
techniques known in the art. Many are described in detail in the
Handbook of Pharmaceutical Excipients, published jointly by the
American Pharmaceutical Association and The Pharmaceutical Society
of Great Britain (The Pharmaceutical Press, 2000), specifically
incorporated by reference. Wetting agents include surfactants.
[0199] "Antifoaming agents" reduce foaming during processing which
can result in coagulation of aqueous dispersions, bubbles in the
finished form, or generally impair processing. Exemplary
anti-foaming agents include silicon emulsions or sorbitan
sesquoleate.
[0200] "Antioxidants" include, e.g., butylated hydroxytoluene
(BHT), butylhydroxyanisole (BHA), ascorbic acid, sodium ascorbate,
and tocopherol. Combinations of one or more antioxidants can also
be used.
[0201] Because the drugs utilized in certain embodiments of the
present invention have low solubility, they exhibit a strong
correlation between the rate of dissolution and bioavailability.
Thus, it is important to optimize the rate of dissolution in
biological matrices in order to enhance in vivo drug absorption. In
order to release the drug from a solid dosage form matrix as
efficiently as possible, disintegrants are often used in the
formulation, especially when the dosage forms are compressed with
binder. Disintegrants help rupturing the dosage form matrix by
swelling or capillary action when moisture is absorbed into the
dosage form. In some embodiments of the invention, the solid dosage
drug formulation has greater than about 1 w % of a disintegrant. In
various embodiments of the present invention, the solid dose drug
formulations have between about 1 w % to about 11 w % or between
about 2 wt % to about 8 wt % disintegrant. In yet other
embodiments, the drug formulations have greater than about 2 wt %
disintegrant. In some embodiments, combinations of disintegrants
provide superior dispersion characteristics compared to single
disintegrant at a similar total weight percentage.
[0202] Suitable disintegrants for use in the solid dosage forms
described herein include, but are not limited to, natural starch
such as corn starch or potato starch, a pregelatinized starch such
as National 1551 or Amijel.RTM., or a sodium starch glycolate such
as Promogel.RTM. or Explotab.RTM., a cellulose such as a wood
product, microcrystalline cellulose, e.g., Avicel.RTM., Avicel.RTM.
PH101, Avicel.RTM. PH102, Avicel.RTM. PH105, Elcema.RTM. P100,
Emcocel.RTM., Vivacel.RTM., Ming Tia.RTM., and Solka-Floc.RTM.,
methylcellulose, croscarmellose, or a cross-linked cellulose, such
as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol.RTM.),
cross-linked carboxymethylcellulose, or cross-linked
croscarmellose, a cross-linked starch such as sodium starch
glycolate, a cross-linked polymer such as crosspovidone, a
cross-linked polyvinylpyrrolidone, alginate such as alginic acid or
a salt of alginic acid such as sodium alginate, a clay such as
Veegum.RTM. HV (magnesium aluminum silicate), a gum such as agar,
guar, locust bean, Karaya, pectin, or tragacanth, sodium starch
glycolate, bentonite, a natural sponge, a surfactant, a resin such
as a cation-exchange resin, citrus pulp, sodium lauryl sulfate,
sodium lauryl sulfate in combination starch, and the like.
[0203] In one embodiment, Ac-Di-Sol is the disintegrant. The amount
of Ac-Di-Sol used in direct compression tableting may vary with
typical usage levels between 1 and 3 percent. When added to
granulations, generally the same percent is used as with a direct
compression formulation. It is often added to both the wet and
dried granulations and blends. The amount of Ac-Di-Sol used in
capsule formulations generally ranges from 3-6 percent. Reduced
interparticle contact within a capsule facilitates the need for
elevated levels of disintegrant. Capsules filled on automatic
dosater types of equipment, as opposed to semi-automatic or
hand-filled machines, are more dense and have a harder structure
due to the greater compressional forces needed to form the plug and
successfully transfer it into the gelatin or HPMC shell. Greater
plug hardness results in greater effectiveness of Ac-Di-Sol.
[0204] Binders impart cohesiveness to solid oral dosage form
formulations: for powder filled capsule formulation, they aid in
plug formation that can be filled into soft or hard shell capsules
and in tablet formulation, binders ensure that the tablet remains
intact after compression and help assure blend uniformity prior to
a compression or fill step. Materials suitable for use as binders
in the solid dosage forms described herein include, but are not
limited to, carboxymethylcellulose, methylcellulose (e.g.,
Methocel.RTM.), hydroxypropylmethylcellulose (e.g. Hypromellose USP
Pharmacoat-603), hydroxypropylmethylcellulose acetate stearate
(Aqoate HS-LF and HS), hydroxyethylcellulose,
hydroxypropylcellulose (e.g., Klucel.RTM.), ethylcellulose (e.g.,
Ethocel.RTM.), and microcrystalline cellulose (e.g., Avicel.RTM.),
microcrystalline dextrose, amylose, magnesium aluminum silicate,
polysaccharide acids, bentonites, gelatin,
polyvinylpyrrolidone/vinyl acetate copolymer, crosspovidone,
povidone, starch, pregelatinized starch, tragacanth, dextrin, a
sugar, such as sucrose (e.g., Dipac.RTM.), glucose, dextrose,
molasses, mannitol, sorbitol, xylitol (e.g., Xylitab.RTM.),
lactose, a natural or synthetic gum such as acacia, tragacanth,
ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone
(e.g., Povidone.RTM. CL, Kollidon.RTM. CL, Polyplasdone.RTM. XL-10,
and Povidone.RTM. K-12), larch arabogalactan, Veegum.RTM.,
polyethylene glycol, waxes, sodium alginate, and the like.
[0205] In general, binder levels of 20-70% are used in
powder-filled gelatin capsule formulations. Binder usage level in
tablet formulations is a function of whether direct compression,
wet granulation, roller compaction, or usage of other excipients
such as fillers which itself can act as moderate binder are used.
Formulators skilled in art can determine the binder level for the
formulations, but binder usage level of up to 70% in tablet
formulations is common.
[0206] Suitable lubricants or glidants for use in the solid dosage
forms described herein include, but are not limited to, stearic
acid, calcium hydroxide, talc, corn starch, sodium stearyl
fumarate, alkali-metal and alkaline earth metal salts, such as
aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates,
magnesium stearate, zinc stearate, waxes, Stearowet.RTM., boric
acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a
polyethylene glycol or a methoxypolyethylene glycol such as
Carbowax.TM., PEG 4000, PEG 5000, PEG 6000, propylene glycol,
sodium oleate, glyceryl behenate, glyceryl palmitostearate,
glyceryl benzoate, magnesium or sodium lauryl sulfate, mineral oil,
hydrogenated vegetable oil such as hydrogenated soybean oil
(Sterotex.RTM.), higher fatty acids and their alkali-metal and
alkaline earth metal salts, such as aluminum, calcium, magnesium,
zinc, stearic acid, sodium stearates, glycerol, talc,
Stearowet.RTM., colloidal silica such as Syloid.TM.,
Cab-O-Sil.RTM., a starch such as corn starch, silicone oil, a
surfactant, and the like.
[0207] Suitable suspending agents for use in the solid dosage forms
described here include, but are not limited to,
polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12,
polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or
polyvinylpyrrolidone K30, polyethylene glycol, e.g., the
polyethylene glycol can have a molecular weight of about 300 to
about 6000, or about 3350 to about 4000, or about 7000 to about
18000, vinyl pyrrolidone/vinyl acetate copolymer (S630), sodium
alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar
gum, xanthans, including xanthan gum, sugars, cellulosics, such as,
e.g., sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, hydroxyethylcellulose,
polysorbate-80, polyethoxylated sorbitan monolaurate,
polyethoxylated sorbitan monolaurate, povidone and the like.
[0208] Suitable antioxidants for use in the solid dosage forms
described herein include, for example, e.g., butylated
hydroxytoluene (BHT), butylhydroxyanisole (BHA), sodium ascorbate,
Vitamin E TPGS, ascorbic acid, sorbic acid and tocopherol.
[0209] "Erosion facilitators" include materials that control the
erosion of a particular material in gastrointestinal fluid. Erosion
facilitators are generally known to those of ordinary skill in the
art. Exemplary erosion facilitators include, e.g., hydrophilic
polymers, electrolytes, proteins, peptides, and amino acids.
Combinations of one or more erosion facilitator with one or more
diffusion facilitator can also be used in the present
invention.
[0210] It should be appreciated that there is considerable overlap
between additives used in the solid dosage forms described herein.
Thus, the above-listed additives should be taken as merely
exemplary, and not limiting, of the types of additives that can be
included in solid dosage forms of the present invention. The
amounts of such additives can be readily determined by one skilled
in the art, according to the particular properties desired.
[0211] In embodiments directed to solid dosage forms utilizing
substrates, the substrates can be, e.g., inert beads, or can be
selected from the group consisting of lactose, calcium carbonate,
calcium phosphate, dibasic calcium phosphate, calcium sulfate,
microcrystalline cellulose, cellulose powder, dextrose, dextrates,
dextran, starches, pregelatinized starch, sucrose, xylitol,
lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol
and mixtures thereof.
[0212] In embodiments directed to sustained or delayed dosage
forms, the dosage form can be a granulation comprising the drug
particles and the controlled release material, (e.g., hydrophobic
polymer or pH dependent material), the granulation compressed into
a tablet or filled into a capsule.
[0213] In other embodiments directed to sustained or delayed
release dosage forms, the dosage form can be a plurality of
pharmaceutically acceptable beads coated with the drug particles
and overcoated with the controlled release material, (e.g.,
hydrophobic polymer or pH dependent material), the overcoated beads
compressed into a tablet or filled into a capsule.
[0214] In other embodiments, one or more layers of the
pharmaceutical formulation are plasticized. Illustratively, a
plasticizer is generally a high boiling point solid or liquid.
Suitable plasticizers can be added from about 0.01% to about 50% by
weight (w/w) of the coating composition. Plasticizers include, but
are not limited to, diethyl phthalate, citrate esters, polyethylene
glycol, glycerol, acetylated glycerides, triacetin, polypropylene
glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate,
stearic acid, stearol, stearate, and castor oil.
Compressed Tablets
[0215] Compressed tablets are solid dosage forms prepared by
compacting the bulk blend drug formulations described above. In
various embodiments, compressed tablets which are designed to
dissolve in the mouth will comprise one or more flavoring agents.
In other embodiments, the compressed tablets will comprise a film
surrounding the final compressed tablet. In some embodiments, the
film coating can provide a delayed release of the drug formulation.
In other embodiments, the film coating aids in patient compliance
(e.g., Opadry.RTM. coatings or sugar coating). Film coatings
comprising Opadry.RTM. typically range from about 1% to about 3% of
the tablet weight. Film coatings for delayed release usually
comprise 2-6% of a tablet weight or 7-15% of a spray-layered bead
weight. In other embodiments, the compressed tablets comprise one
or more excipients.
Capsule Formulations
[0216] A capsule may be prepared, e.g., by placing the bulk blend
drug formulation, described above, inside of a capsule. In some
embodiments, the drug formulations (non-aqueous suspensions and
solutions) are placed in a soft gelatin capsule. In other
embodiments, the drug formulations are placed in standard gelatin
capsules or non-gelatin capsules such as capsules comprising HPMC.
In other embodiments, the drug formulations are placed in a
sprinkle capsule, wherein the capsule may be swallowed whole or the
capsule may be opened and the contents sprinkled on food prior to
eating. In some embodiments of the present invention, the
therapeutic dose is split into multiple (e.g., two, three, or four)
capsules. In some embodiments, the entire dose of the drug
formulation is delivered in a capsule form. For example, the
capsule may comprise e.g., from 0.01 mg to about 5 grams or any
dose known to one skilled in the art, such as between about 100 mg
to about 600 mg of drug. In some embodiments, the capsule may
comprise between about 100 to about 500 mg of drug. In other
embodiments, capsule may comprise about 300 mg to about 400 mg of
drug.
[0217] Another useful capsule has a shell comprising the material
of the rate-limiting membrane, including any of the coating
materials previously discussed, and filled with drug particles. A
particular advantage of this configuration is that the capsule may
be prepared independently of the drug particles, thus process
conditions that would adversely affect the drug can be used to
prepare the capsule. A preferred embodiment is a capsule having a
shell made of a porous or a pH-sensitive polymer made by a thermal
forming process. An especially preferred embodiment is a capsule
shell in the form of an asymmetric membrane; i.e., a membrane that
has a thin skin on one surface and most of whose thickness is
constituted of a highly permeable porous material. A preferred
process for preparation of asymmetric membrane capsules comprises a
solvent exchange phase inversion, wherein a solution of polymer,
coated on a capsule-shaped mold, is induced to phase-separate by
exchanging the solvent with a miscible non-solvent. Examples of
asymmetric membranes are disclosed in the European Patent
Specification 0 357 369 B1.
[0218] Yet another useful capsule, a "swelling plug device", can be
used. Drug particles can be incorporated into a non-dissolving
capsule-half of the device, which is sealed at one end by a
hydrogel plug. This hydrogel plug swells in an aqueous environment,
and, after swelling for a predetermined time, exits the capsule
thus opening a port through which the drug can leave the capsule
and be delivered to the aqueous environment. Preferred
hydrogel-plugged capsules are those which exhibit substantially no
release of drug from the dosage form until the dosage form has
exited the stomach and has resided in the small intestine for about
15 minutes or greater, preferably about 30 minutes or greater, thus
assuring that minimal drug is released in the stomach.
Hydrogel-plugged capsules of this type have been described in
patent application WO90/19168, which is incorporated herein by
reference. A drug swelling plug device may be prepared by loading
drug into a non-dissolving half-capsule shell which may be formed
from a wide variety of materials, including but not limited to
polyethylene, polypropylene, poly(methylmethacrylate),
polyvinylchloride, polystyrene, polyurethanes,
polytetrafluoroethylene, nylons, polyformaldehydes, polyesters,
cellulose acetate, and nitrocellulose. The open end of the capsule
shell is then "plugged" with a cylindrical plug formed from a
hydrogel-forming material, including but not limited to, a homo- or
co-poly(alkylene oxide) cross linked by reaction with isocyanate or
unsaturated cyclic ether groups, as described in PCT Application WO
90/09168. The composition and length of the hydrogel "plug" is
selected to minimize release of drug to the stomach, to decrease
the incidence and/or severity of gastrointestinal side effects. The
plugged capsule-half is finally sealed with a water-soluble, e.g.,
gelatin, capsule-half placed over the hydrogel-plugged end of the
drug-containing non-dissolving capsule-half. In an embodiment of
the "swelling plug device", the sealed device is coated with a
pH-sensitive enteric polymer or polymer mixture, for example
cellulose acetate phthalate or copolymers of methacrylic acid and
methylmethacrylate. The weight of the enteric polymer coat will
generally be from 2 to 20 wt %, preferably from 4 to 15 wt % of the
weight of the uncoated sealed capsule. When this preferred
"enteric-coated swelling plug device" is ingested orally, the
enteric coat prevents release drug in the stomach. The enteric coat
dissolves quickly, e.g., within about 15 minutes, in the duodenum,
triggering swelling of the hydrogel plug, exiting of the hydrogel
plug, and release of the incorporated drug into the
gastrointestinal tract at a time greater than about 15 minutes
after, and preferably greater than about 30 minutes after, the
dosage form has passed from the stomach into the duodenum.
Prototype unfilled "swelling plug devices" may be obtained from
Scherer DDS Limited, Clydebank, Scotland, under the designation
Pulsincap.TM..
[0219] In another embodiment, a drug complex formulation comprising
a dried drug complex granulation can be filled in a capsule. Drug
complex particle suspension comprising 10 to 30 wt % drug, 1 to 10
wt % hydroxypropylmethyl cellulose (Pharmacoat 603), 0.05 to 0.5 wt
% sodium lauryl sulfate, 0.015 to 0.2 wt % paraben such as
methylparaben, 0.001 to 0.05 wt % simethicone emulsion (30% in
water) 0.5 to 5% sucrose and 0.1 to 2% NaCl in water is pumped into
a spray granulator using standard parameters known by those skilled
in the art. Each wt % of the drug complex particle suspension is
based on the total weight of the suspension. The water is
evaporated under vacuum at a temperature of 70.degree. C. to
90.degree. C. The resulting drug complex granulation comprises
about 50-80 wt % of drug based on the total weight of the solid.
Additional excipients such as magnesium stearate, Mannitol and a
disintegrant can be added for flow and re-dispersion properties.
The dispersed solid (in SGF or SIF) generally have a median
particle size (D50) of about 50 nm to about 1000 nm, more
specifically, about 100 nm to about 500 nm. In one embodiment, the
capsule is a swelling plug device. In another embodiment, the
swelling plug device is further coated with cellulose acetate
phthalate or copolymers of methacrylic acid and
methylmethacrylate.
[0220] In yet another embodiment, spray layered drug particles or
spray layered drug complex particles are filled in a capsule. An
exemplary process for manufacturing the spray layered drug or drug
complex particles is the fluidized bed spraying process. Drug
suspensions or drug complex suspensions described above are sprayed
onto sugar or microcrystalline cellulose (MCC) beads (20-35 mesh)
with Wurster column insert at an inlet temperature of 50 to
60.degree. C. and air temp of 30 to 50.degree. C. A 15 to 20 wt %
total solids content suspension containing 45 to 80 wt % drug, 10
to 25 wt % hydroxypropylmethyl cellulose, 0.25 to 2 wt % of SLS, 10
to 18 wt % of sucrose, 0.01 to 0.3 wt % simethicone emulsion (30%
emulsion) and 0.3 to 10% NaCl, based on the total weight of the
solid content of the suspension, are sprayed (bottom spray) onto
the beads through 1.2 mm nozzles at 10 mL/min and 1.5 bar of
pressure until a layering of 400 to 700% wt % is achieved as
compared to initial beads weight. The resulting spray layered drug
particles or drug complex particles comprise about 30 to 70 wt % of
drug based on the total weight of the particles. In one embodiment
the capsule is a size 0 soft gelatin capsule In one embodiment, the
capsule is a swelling plug device. In another embodiment, the
swelling plug device is further coated with cellulose acetate
phthalate or copolymers of methacrylic acid and
methylmethacrylate.
[0221] In some embodiments the capsule includes at least 250 mg (or
at least 300 mg or at least 400 mg) drug and has a total weight of
less than 800 mg (or less that 700 mg). The capsule may contain a
plurality of drug-containing beads, for example spray layered
beads. In some embodiments the beads are 12-25% drug by weight. In
some embodiments some or all of the drug containing beads are
coated with a coating comprising 6 to 15% (or 8 to 12%) of the
total bead weight. Optimization work typically involves lower
loading levels and the beads constitute 30 to 60% of the finished
bead weight. Instead of or in addition to drug containing beads the
capsule may contain a granulated drug composition, wherein the
granulated composition comprises drug, or drug, and an ionic
dispersion modulator. In some embodiments the compositions
additionally comprise a complexing agent and an inorganic or
organic salt. For example the granulated composition in some
embodiments is comprised of 0.3 to 20% (or 1 to 10% or 1 to 5%) by
weight inorganic or organic salt. These granulations also typically
contain 5% to 30% of a binding agent, 2% to 25% of a water soluble
spacing agent and a wetting agent (0.5% to 2%) of the total
composition.
[0222] The capsule may be pulsatile release drug oral dosage form,
comprising: (a) a first dosage unit comprising a first drug dose
that is released substantially immediately following oral
administration of the dosage form to a patient; (b) a second dosage
unit comprising a second drug dose that is released approximately 3
to 7 hours following administration of the dosage form to a
patient. For pulsatile release capsules containing beads that can
be coated with a coating comprising 6 to 15% (or 8 to 12%) of the
total bead weight. In some embodiments the coating is a coating
that is insoluble at pH 1 to 2 and soluble at pH greater than
5.5.
[0223] In certain embodiments the pulsatile release capsule
comprises by weight 30 to 50% of the first drug dose and 50 to 70%
of the second drug dose. This pulsatile release capsule may contain
a plurality of beads in which some beads are immediate release
beads and other beads are formulated, for example with the use of a
coating, for modified release, typically 3 to 10 hours after
administration. In other embodiments the pulsatile release capsule
contains a plurality of beads formulated for modified release and
drug powder, for example spray granulated drug, for immediate
release.
[0224] The particles disclosed above can be prepared according to
any of the methods disclosed herein or by the methods described in
U.S. Pat. Nos. 6,375,986; 6,428,814; 6,432,381; 6,592,903;
6,908,626; or 6,969,529; the disclosures of which are hereby
incorporated by reference.
[0225] In certain embodiments, the invention is directed to a
pharmaceutical composition comprising particles comprising (i) drug
thereof, (ii) a polymer selected from the group consisting of
polyvinylpyrrolidone, polysaccharides, copolymers of vinyl acetate
and vinyl pyrrolidone, polyvinyl alcohol, copolymers of vinyl
acetate and vinyl alcohol, carboxyalkylcelluloses, cellulosic
polymers and mixtures thereof, and (iii) a material selected from
the group consisting of sodium lauryl sulfate and dioctyl sodium
sulfosuccinate (DOSS) and (iv) an ionic dispersion modulator and
(v) a water soluble spacer, wherein the D50 of the particles by
weight have an effective particle size of less than about 500 nm
(or any effective particle size, range, or any other characteristic
as disclosed herein), wherein the composition comprises (a) an
immediate release component comprising a first portion of the
particles and providing an immediate release of the drug or
pharmaceutically acceptable salt thereof; and (b) a controlled
release component comprising a second portion of the particles and
providing a controlled release of the drug or pharmaceutically
acceptable salt thereof.
Formulations Containing Coated Drug Particles
[0226] In some embodiments, the spray layered drug particles or
spray layered drug complex particles present in drug formulations,
such as the capsule formulation described above, is coated. Drug
particles can be with a modified release coating, such as an
enteric coating using cellulose acetate phthalate or copolymers of
methacrylic acid and methylmethacrylate. In one embodiment, the
enteric coating may be present in an amount of about 0.5 to 15 wt
%, more specifically, about 8 to 12 wt %, based on the weight of
the spray layered particles. In one embodiment, the spray layered
drug particles or spray layered drug complex particles coated with
the enteric coatings can be filled in a modified release capsule in
which both enteric coated and immediate release drug beads are
filled into a soft gelatin capsule. Additional suitable excipients
may also be filled with the coated particles in the capsule.
[0227] In another embodiment, mixtures of spray layered drug
particles or spray layered drug complex particles coated with the
enteric coatings and those without the enteric coatings at
appropriate ratios may be encapsulated in a suitable immediate
release capsule. The uncoated particles release drug immediately
upon administration while the coated particles do not release drug
until these particles reach intestine. By controlling the ratios of
the coated and uncoated particles, desirable pulsatile release
profiles may be obtained. In some embodiments, the ratios between
the uncoated and the coated particles are 20/80, or 30/70, or
40/60, or 50/50, w/w to obtain desirable release.
Tablet Spray Layered or Spray Dried Dosage Forms
[0228] In some embodiments, the spray dried drug complex particles
or spray layered drug complex particles described above can be
compressed into tablets with commonly used pharmaceutical
excipients. Any appropriate apparatus for forming the coating can
be used to make the enteric coated tablets, e.g., fluidized bed
coating using a wurster column, powder layering in coating pans or
rotary coaters; dry coating by double compression technique; tablet
coating by film coating technique, and the like. See, e.g., U.S.
Pat. No. 5,322,655; Remington's Pharmaceutical Sciences Handbook:
Chapter 90 "Coating of Pharmaceutical Dosage Forms", 1990.
[0229] In various embodiments, the spray dried drug complex
particles or spray layered drug complex particles described above
and one or more excipients are dry blended and compressed into a
mass, such as a tablet, having a hardness sufficient to provide a
pharmaceutical composition that substantially disintegrates within
less than about 30 minutes, less than about 35 minutes, less than
about 40 minutes, less than about 45 minutes, less than about 50
minutes, less than about 55 minutes, or less than about 60 minutes,
after oral administration, thereby releasing the drug formulation
into the gastrointestinal fluid.
[0230] In other embodiments, the spray dried drug complex particles
or spray layered drug complex particles with enteric coatings
described above and one or more excipients are dry blended and
compressed into a mass, such as a tablet. In one embodiment, the
enteric coated particles in the tablet substantially avoids release
of drug, for example less than 15 wt %, in the stomach but releases
substantially all drug (enterically coated), for example, greater
than 80 wt %, in the intestine.
[0231] In yet other embodiments, a pulsatile release drug
formulation comprises a first dosage unit comprising a formulation
made from drug containing granules made from a spray drying or
spray granulated procedure or a formulation made from drug complex
containing granules made from a spray drying or spray granulated
procedure without enteric coatings and a second dosage unit
comprising spray dried drug complex particles or spray layered drug
complex particles with enteric coatings. In one embodiment, the
first dosage unit and the second dosage unit are wet or dry blended
and compressed into a mass to make a pulsatile release tablet. In
one embodiment, the weight ratio between the uncoated particles and
the coated particles is about -1:4 to 4:1.
[0232] In another embodiment, binding, lubricating and
disintegrating agents are blended (wet or dry) to the spray dried
drug complex or drug complex spray layered beads to make a
compressible blend. The first and the second dosage units are
compressed separately and then compressed together to form a
bilayer tablet.
[0233] In yet another embodiment, the first dosage unit is in the
form of an overcoat and completely covers the second dosage
unit.
Microencapsulated Formulations
[0234] In one aspect of the present invention, dosage forms may
include microencapsulated drug formulations. In some embodiments,
one or more other compatible materials are present in the
microencapsulation material. Exemplary materials include, but are
not limited to, complexing agents, ionic dispersion modulators, pH
modifiers, erosion facilitators, anti-foaming agents, antioxidants,
flavoring agents, and carrier materials such as binders, suspending
agents, disintegration agents, filling agents, surfactants,
solubilizers, stabilizers, lubricants, wetting agents, and
diluents.
[0235] Materials useful for the microencapsulation described herein
include materials compatible with drug which sufficiently isolate
drug from other non-compatible excipients. Materials compatible
with drug of the present invention are those that delay the release
of the drug in vivo.
[0236] Exemplary microencapsulation materials useful for delaying
the release of the formulations comprising drug include, but are
not limited to, hydroxypropyl cellulose ethers (HPC) such as
Klucel.RTM. or Nisso HPC, low-substituted hydroxypropyl cellulose
ethers (L-HPC), hydroxypropyl methyl cellulose ethers (HPMC) such
as Seppifilm-LC, Pharmacoat.RTM., Metolose SR, Methocel.RTM.-E,
Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843,
methylcellulose polymers such as Methocel.RTM.-A,
hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,
HF-MS) and Metolose.RTM., Ethylcelluloses (EC) and mixtures thereof
such as E461, Ethocel.RTM., Aqualon.RTM.-EC, Surelease.RTM.,
Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethylcelluloses
such as Natrosol.RTM., carboxymethylcelluloses and salts of
carboxymethylcelluloses (CMC) such as Aqualon.RTM.-CMC, polyvinyl
alcohol and polyethylene glycol co-polymers such as Kollicoat
IR.RTM., monoglycerides (Myverol), triglycerides (KLX),
polyethylene glycols, modified food starch, acrylic polymers and
mixtures of acrylic polymers with cellulose ethers such as
Eudragit.RTM. EPO, Eudragit.RTM. L30D-55, Eudragit.RTM. FS 30D
Eudragit.RTM. L100-55, Eudragit.RTM. L100, Eudragit.RTM. S100,
Eudragit.RTM. RD100, Eudragit.RTM. E100, Eudragit.RTM. L12.5,
Eudragit.RTM. S12.5, Eudragit.RTM. NE30D, and Eudragit.RTM. NE 40D,
cellulose acetate phthalate, sepifilms such as mixtures of HPMC and
stearic acid, cyclodextrins, parabens, sodium chloride, and
mixtures of these materials.
[0237] In still other embodiments, plasticizers such as
polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 1450,
PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid,
and triacetin are incorporated into the microencapsulation
material. In other embodiments, the microencapsulating material
useful for delaying the release of the pharmaceutical compositions
is from the USP or the National Formulary (NF). In yet other
embodiments, the microencapsulation material is Klucel. In still
other embodiments, the microencapsulation material is methocel.
[0238] Microencapsulated drug may be formulated by methods known by
one of ordinary skill in the art. Such known methods include, e.g.,
spray drying processes, spinning disk-solvent processes, hot melt
processes, spray chilling methods, spray granulation via fluidized
bed, electrostatic deposition, centrifugal extrusion, rotational
suspension separation, polymerization at liquid-gas or solid-gas
interface, pressure extrusion, or spraying solvent extraction bath.
In addition to these, several chemical techniques, e.g., complex
coacervation, solvent evaporation, polymer-polymer incompatibility,
interfacial polymerization in liquid media, in situ polymerization,
in-liquid drying, and desolvation in liquid media could also be
used. Furthermore, other methods such as roller compaction,
extrusion/spheronization, coacervation, or nanoparticle coating may
also be used.
[0239] The spinning disk method allows for: 1) an increased
production rate due to higher feed rates and use of higher solids
loading in feed solution, 2) the production of more spherical
particles, 3) the production of a more even coating, and 4) limited
clogging of the spray nozzle during the process.
[0240] Spray granulation via a fluid bed is often more readily
available for scale-up. In various embodiments, the material used
in the spray-granulation encapsulation process is emulsified or
dispersed into the core material in a concentrated form, e.g.,
10-60% solids. The microencapsulation material is, in one
embodiment, emulsified until about 1 to 3 .mu.m droplets are
obtained. Once a dispersion of drug and encapsulation material is
obtained, the emulsion is fed as droplets into the heated chamber
of the spray granulator. In some embodiments, the droplets are
sprayed into the chamber or spun off a rotating disk. The
microspheres are then dried in the heated chamber and fall to the
bottom of the chamber where they are harvested.
[0241] Roller compaction, which involves dry granulation of single
powder or a blended mixture of powders by the use of pressure to
form dense compacts (the compacts are subsequently milled to a
desired particle size), provides another alternative. It is a
simple process that is readily available for use, and does not
involve the use of solvents for granulation. Thus, roller
compaction eliminates the exposure of sensitive active
pharmaceutical ingredients to moisture and drying. Roller
compaction can also provide some enhanced stability and
taste-masking characteristics to active pharmaceutical by diluting
and isolating such components in a granulated matrix of compatible
ingredients. Roller compaction also imparts increased density and
flow to the powder.
[0242] Extrusion/spheronization is another method that involves wet
massing of active pharmaceutical ingredients, followed by the
extrusion of the wet mass through a perforated plate to produce
short cylindrical rods. These rods are subsequently placed into a
rapidly rotating spheronizer to shape the cylindrical rods into
uniform spheres. The spheres are subsequently dried using a fluid
bed drier and then coated with a functional coating using a fluid
bed equipped with a Wurster insert and spray nozzle.
[0243] Coacervation involves microencapsulation of materials such
as active pharmaceutical ingredients and involves a three part
process of particle or droplet formation, coacerate wall formation,
and capsule isolation. This method can produce very small particle
size microcapsules (10-70 microns).
[0244] In one embodiment, the drug particles are microencapsulated
prior to being formulated into one of the above forms. In still
another embodiment, some or most of the drug particles are coated
prior to being further formulated by using standard coating
procedures, such as those described in Remington's Pharmaceutical
Sciences, 20th Edition (2000).
Coated or Plasticized Formulations
[0245] In other embodiments, the solid dosage drug formulations are
plasticized (coated) with one or more layers. Illustratively, a
plasticizer is generally a high boiling point solid or liquid.
Suitable plasticizers can be added from about 0.01% to about 50% by
weight (w/w) of the coating composition. Plasticizers include, but
are not limited to, diethyl phthalate, citrate esters, polyethylene
glycol, glycerol, acetylated glycerides, triacetin, polypropylene
glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate,
stearic acid, stearol, stearate, and castor oil.
[0246] In other embodiments a powder comprising the drug
formulations described herein may be formulated to comprise one or
more pharmaceutical excipients and flavors. Such a powder may be
prepared, for example, by mixing the drug formulation and optional
pharmaceutical excipients to form a bulk blend composition.
Additional embodiments also comprise a suspending agent and/or a
wetting agent. This bulk blend is uniformly subdivided into unit
dosage packaging or multi-dosage packaging units. The term
"uniform" means the homogeneity of the bulk blend is substantially
maintained during the packaging process. In some embodiments, at
least about 75% to about 85% of the drug has an effective particle
size by weight of less than 500 nm to about 100 nm. In other
embodiments, the drug comprises at least 90% drug particles having
an effective particle size by weight of less than 500 nm to about
100 nm.
Effervescent Powders
[0247] In still other embodiments, effervescent powders are also
prepared in accordance with the present invention. Effervescent
salts have been used to disperse medicines in water for oral
administration. Effervescent salts are granules or coarse powders
containing a medicinal agent in a dry mixture, usually composed of
sodium bicarbonate, citric acid and/or tartaric acid. When salts of
the present invention are added to water, the acids and the base
react to liberate carbon dioxide gas, thereby causing
"effervescence." Examples of effervescent salts include, e.g:
sodium bicarbonate or a mixture of sodium bicarbonate and sodium
carbonate, citric acid and/or tartaric acid. Any acid-base
combination that results in the liberation of carbon dioxide can be
used in place of the combination of sodium bicarbonate and citric
and tartaric acids, as long as the ingredients were suitable for
pharmaceutical use and result in a pH of about 6.0 or higher.
[0248] The method of preparation of the effervescent granules of
the present invention employs three basic processes: wet
granulation, dry granulation and fusion. The fusion method is used
for the preparation of most commercial effervescent powders. It
should be noted that, although these methods are intended for the
preparation of granules, the formulations of effervescent salts of
the present invention could also be prepared as tablets, according
to known technology for tablet preparation.
Wet and Dry Granulation
[0249] Wet granulation is one of the oldest methods of granule
preparation. The individual steps in the wet granulation process of
tablet preparation include milling and sieving of the ingredients,
dry powder mixing, wet massing, granulation, drying and final
grinding. In various embodiments, the drug composition is added to
the other excipients of the pharmaceutical formulation after they
have been wet granulated.
[0250] Dry granulation involves compressing a powder mixture into a
rough tablet or "slug" on a heavy-duty rotary tablet press. The
slugs are then broken up into granular particles by a grinding
operation, usually by passage through an oscillation granulator.
The individual steps include mixing of the powders, compressing
(slugging) and grinding (slug reduction or granulation). No wet
binder or moisture is involved in any of the steps. In some
embodiments, the drug formulation is dry granulated with other
excipients in the pharmaceutical formulation. In other embodiments,
the drug formulation is added to other excipients of the
pharmaceutical formulation after they have been dry granulated.
Solid Dispersions
[0251] In other embodiments, the drug formulations described herein
are solid dispersions. Methods of producing such solid dispersions
are known in the art and include, but are not limited to, for
example, U.S. Pat. Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485,
5,723,269, and U.S. Pub. Appl 2004/0013734, each of which is
specifically incorporated by reference. In some embodiments, the
solid dispersions of the invention comprise both amorphous and
non-amorphous drug and can have enhanced bioavailability as
compared to conventional drug formulations. In still other
embodiments, the drug formulations described herein are solid
solutions. Solid solutions incorporate a substance together with
the active agent and other excipients such that heating the mixture
results in dissolution of the drug and the resulting composition is
then cooled to provide a solid blend which can be further
formulated or directly added to a capsule or compressed into a
tablet. Methods of producing such solid solutions are known in the
art and include, but are not limited to, for example, U.S. Pat.
Nos. 4,151,273, 5,281,420, and 6,083,518, each of which is
specifically incorporated by reference.
Modified Release Forms, Including Controlled Release and Delayed
Release
[0252] The pharmaceutical solid oral dosage forms comprising the
drug formulations described herein can be immediate release, or can
be further formulated to provide a modified or controlled release
of drug.
[0253] In certain embodiments, the controlled release component
provides a release selected from the group consisting of sustained
release or delayed release.
[0254] In certain embodiments, the controlled release component
comprises a coating comprising a hydrophobic material, coated on
the second portion of particles.
[0255] In certain embodiments, the controlled release component
comprises a matrix comprising the second portion of particles
dispersed in a hydrophobic material.
[0256] In certain embodiments, the immediate release component and
the controlled release component are independently selected from
the group consisting of a tablet, a pill, multiparticulates, a
powder, a capsule, a solid dispersion, a solid solution, a pellet,
or a granule.
[0257] In certain embodiments, the hydrophobic material is selected
from the group consisting of an acrylic polymer, a cellulosic
polymer, shellac, zein, fatty alcohols, hydrogenated fats, fatty
acid esters, fatty acid glycerides, hydrocarbons, waxes, stearic
acid, stearyl alcohol, and mixtures thereof.
[0258] In certain embodiments, the hydrophobic material is an
enteric polymer.
[0259] In certain embodiments, the enteric polymer is selected from
the group consisting of shellac, acrylic polymers, cellulose
derivatives, polyvinyl acetate phthalate and mixtures thereof.
[0260] In certain embodiments, the delayed release component
provides a dose of the drug or pharmaceutically acceptable salt
thereof delayed by from about 2 hours to about 12 hours after
administration.
[0261] In certain embodiments, the delayed release component
provides a dose of the drug or pharmaceutically acceptable salt
thereof delayed by from about 2 hours to about 8 hours after
administration.
[0262] In certain embodiments, the delayed component provides a
dose of the drug or pharmaceutically acceptable salt thereof
delayed by from about 3 hours to about 7 hours after
administration.
[0263] In certain embodiments, the controlled release component
provides a sustained release of the drug or pharmaceutically
acceptable salt thereof for about 2 hours to about 6 hours after
administration.
[0264] In certain embodiments, the controlled release component
provides a sustained release of the drug or pharmaceutically
acceptable salt thereof for about 3 hours to about 10 hours after
administration.
[0265] In certain embodiments, the coating further comprises a
plasticizer, a colorant, a detackifier, a surfactant, an
anti-foaming agent, a lubricant or a mixture thereof.
[0266] In certain embodiments, the immediate release component and
the controlled release component independently comprise one or more
pharmaceutically acceptable additives from the group consisting of
carriers, binders, filling agents, suspending agents, flavoring
agents, sweetening agents, disintegrating agents, dispersing
agents, surfactants, lubricants, colorants, diluents, solubilizers,
moistening agents, plasticizers, stabilizers, penetration
enhancers, wetting agents, anti-foaming agents, antioxidants,
preservatives, or one or more combinations thereof.
[0267] The pharmaceutical dosage forms disclosed herein having an
immediate release component and a controlled release component in
this section (XIII) can provide any pharmacokinetic profile as
disclosed herein.
[0268] In some embodiments, the solid dosage forms described herein
can be formulated as a delay release dosage form such as enteric
coated delayed release oral dosage forms, i.e., as an oral dosage
form of a pharmaceutical composition as described herein which
utilizes an enteric coating to affect release in the small
intestine of the gastrointestinal tract. The enteric coated dosage
form may be a compressed or molded or extruded tablet/mold (coated
or uncoated) containing granules, powder, pellets, beads or
particles of the active ingredient and/or other composition
components, which are themselves coated or uncoated. The enteric
coated oral dosage form may also be a capsule (coated or uncoated)
containing pellets, beads or granules of the solid carrier or the
composition, which are themselves coated or uncoated. Enteric
coatings may also be used to prepare other controlled release
dosage forms including extended release and pulsatile release
dosage forms.
[0269] An "enterically coated" formulation of drug is intended to
mean that some or most of the drug has been enterically coated to
ensure that at least some of the drug is released after entering
the small intestine, rather than the acidic environment of the
stomach. In some embodiments, about 40% to about 60% of the coated
drug particles are released in the middle region of the small
intestine to minimize interaction with bile acids and minimize food
effects. In some embodiments, the enterically coated formulations
provide the release of greater than 80% of drug in the small
intestine.
[0270] The enteric coating material should be non-toxic and is
predominantly soluble in the intestinal fluid, but substantially
insoluble in the gastric fluids. Examples include polyvinyl acetate
phthalate (PVAP), commercially available under trade names of
Opadry.RTM. Enteric or Acryl-eze MP from Colorcon.RTM.,
hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose
acetate phthalate (CAP), methacrylic acid copolymer,
hydroxypropylmethylcellulose succinate, cellulose acetate
succinate, cellulose acetate hexahydrophthalate,
hydroxypropylmethylcellulose hexahydrophthalate,
hydroxypropylmethylcellulose phthalate (HPMCP), cellulose
propionate phthalate, cellulose acetate maleate, cellulose acetate
trimellitate, cellulose acetate butyrate, cellulose acetate
propionate, methacrylic acid/methacrylate polymer, methacrylic
acid-methyl methacrylate copolymer, ethyl
methacrylate-methylmethacrylate-chlorotrimethylammonium ethyl
methacrylate copolymer, and the like, and combinations comprising
one or more of the foregoing enteric polymers. Other examples
include natural resins, such as shellac, SANDARAC, copal
collophorium, and combinations comprising one or more of the
foregoing polymers. Yet other examples of enteric polymers include
synthetic resin bearing carboxyl groups. The methacrylic acid:
acrylic acid ethyl ester copolymers are commercially available
under the trade names of "Eudragit.RTM. L", such as Eudragit.RTM. L
30-D55 from Degussa.
[0271] Enteric coatings should be applied to a sufficient thickness
such that the entire coating does not appreciably dissolve in the
gastrointestinal fluids at pH below about 5 after 1 hour, but does
dissolve at pH about 5 and above. It is expected that any anionic
polymer exhibiting a pH-dependent solubility profile can be used as
an enteric coating in the practice of the present invention to
achieve delivery to the lower gastrointestinal tract. In some
embodiments the polymers for use in the present invention are
anionic carboxylic polymers. In other embodiments, the polymers and
compatible mixtures thereof, and some of their properties, include,
but are not limited to: Shellac--also called purified shellac, a
refined product obtained from the resinous secretion of an insect.
This coating dissolves in media of pH>7; Acrylic polymers: The
performance of acrylic polymers (primarily their solubility in
biological fluids) can vary based on the degree and type of
substitution. Examples of suitable acrylic polymers include
methacrylic acid copolymers and ammonia methacrylate copolymers.
The Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) are
available as solubilized in organic solvent, aqueous dispersion, or
dry powders. The Eudragit series RL, NE, and RS are insoluble in
the gastrointestinal tract but are permeable and are used primarily
for colonic targeting. The Eudragit series E dissolve in the
stomach. The Eudragit series L, L-30D and S are insoluble in
stomach and dissolve in the intestine; Opadry Enteric are also
insoluble in stomach and dissolve in the intestine; Cellulose
Derivatives--Examples of suitable cellulose derivatives are: ethyl
cellulose; reaction mixtures of partial acetate esters of cellulose
with phthalic anhydride. The performance can vary based on the
degree and type of substitution. Cellulose acetate phthalate (CAP)
dissolves in pH>6. Aquateric (FMC) is an aqueous based system
and is a spray dried CAP psuedolatex with particles<1 .mu.m.
Other components in Aquateric can include pluronics, Tweens, and
acetylated monoglycerides. Other suitable cellulose derivatives
include: cellulose acetate trimellitate (Eastman); methylcellulose
(Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate
(HPMCP); hydroxypropylmethyl cellulose succinate (HPMCS); and
hydroxypropylmethylcellulose acetate succinate (e.g., AQOAT (Shin
Etsu)). The performance can vary based on the degree and type of
substitution. For example, HPMCP such as, HP-50, HP-55, HP-55S,
HP-55F grades are suitable. The performance can vary based on the
degree and type of substitution. For example, suitable grades of
hydroxypropylmethylcellulose acetate succinate include, but are not
limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which
dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH.
These polymers are offered as granules, or as fine powders for
aqueous dispersions; PolyVinyl Acetate Phthalate (PVAP). PVAP
dissolves in pH>5 and it is much less permeable to water vapor
and gastric fluids.
[0272] In some embodiments, the coating can, and usually does,
contain a plasticizer and possibly other coating excipients such as
colorants, talc, and/or magnesium stearate, which are well known in
the art. Suitable plasticizers include triethyl citrate (Citroflex
2), triacetin (glyceryl triacetate), acetyl triethyl citrate
(Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl
phthalate, tributyl citrate, acetylated monoglycerides, glycerol,
fatty acid esters, propylene glycol, and dibutyl phthalate. In
particular, anionic carboxylic acrylic polymers usually will
contain 10-25% by weight of a plasticizer, especially dibutyl
phthalate, polyethylene glycol, triethyl citrate and triacetin.
Conventional coating techniques such as spray or pan coating are
employed to apply coatings. The coating thickness must be
sufficient to ensure that the oral dosage form remains intact until
the desired site of topical delivery in the intestinal tract is
reached.
[0273] In other embodiments, the drug formulations described herein
are delivered using a pulsatile dosage form. In such a pulsatile
release drug oral dosage form, a first dose of the drug is released
followed by a second dose of the drug released approximately 3 to 7
hours following administration of the dosage form. For example,
such pulsatile dosage forms may comprise: (a) a first dosage unit
comprising a first dose of drug that is released substantially
immediately following oral administration of the dosage form to a
patient; (b) a second dosage unit comprising a second dose of drug
that is released approximately 3 to 7 hours following
administration of the dosage form to a patient. Pulsatile dosage
forms comprising the drug formulations described herein may be
administered using a variety of formulations known in the art. For
example, such formulations include, but are not limited to, those
described in U.S. Pat. Nos. 5,011,692, 5,017,381, 5,229,135, and
5,840,329, each of which is specifically incorporated by reference.
Other dosage forms suitable for use with the drug formulations are
described in, for example, U.S. Pat. Nos. 4,871,549, 5,260,068,
5,260,069, 5,508,040, 5,567,441 and 5,837,284, all of which are
specifically incorporated by reference. In one embodiment, the
controlled release dosage form is pulsatile release solid oral
dosage form comprising at least two groups of particles, each
containing the drug formulation described herein. The first group
of particles provides a substantially immediate dose of drug upon
ingestion by a subject. The first group of particles can be either
uncoated or comprise a coating and/or sealant. The second group of
particles comprises coated particles, which comprise from about 2%
to about 75%, preferably from about 2.5% to about 70%, and more
preferably from about 40% to about 70%, by weight of the total dose
of the drug in said formulation, in admixture with one or more
binders. The coating comprises a pharmaceutically acceptable
ingredient in an amount sufficient to provide a delay of from about
2 hours to about 7 hours following ingestion before release of the
second dose. Suitable coatings include one or more differentially
degradable coatings such as, by way of example only, pH sensitive
coatings (enteric coatings) such as acrylic resins (e.g.,
Eudragit.RTM. EPO, Eudragit.RTM. L30D-55, Eudragit.RTM. FS 30D
Eudragit.RTM. L100-55, Eudragit.RTM. L100, Eudragit.RTM. S100,
Eudragit.RTM. RD100, Eudragit.RTM. E100, Eudragit.RTM. L12.5,
Eudragit.RTM. S12.5, and Eudragit.RTM. NE30D, Eudragit.RTM. NE
40D.RTM.) either alone or blended with cellulose derivatives, e.g.,
ethylcellulose, or non-enteric coatings having variable thickness
to provide differential release of the drug formulation.
[0274] Many other types of controlled release systems known to
those of ordinary skill in the art and are suitable for use with
the drug formulations described herein. Examples of such delivery
systems include, e.g., polymer-based systems, such as polylactic
and polyglycolic acid, polyanhydrides and polycaprolactone; porous
matrices, nonpolymer-based systems that are lipids, including
sterols, such as cholesterol, cholesterol esters and fatty acids,
or neutral fats, such as mono-, di- and triglycerides; hydrogel
release systems; silastic systems; peptide-based systems; wax
coatings, bioerodible dosage forms, compressed tablets using
conventional binders and the like. See, e.g., Liberman et al.,
Pharmaceutical Dosage Forms, 2.sup.nd Ed., Vol. 1, pp. 209-214
(1990); Singh et al., Encyclopedia of Pharmaceutical Technology,
2.sup.nd Ed., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725,
4,624,848, 4,968,509, 5,461,140, 5,456,923, 5,516,527, 5,622,721,
5,686,105, 5,700,410, 5,977,175, 6,465,014 and 6,932,983, each of
which is specifically incorporated by reference.
[0275] In another embodiment, a modified release dosage formulation
may comprise a combination of: (a) a compressed tablet core
comprising complexed drug particles, a surface stabilizer, an ionic
dispersion modifier, a water soluble spacer, a pharmaceutically
acceptable water swellable polymer, and an osmotic agent; and (b)
an outer coating layer which completely covers the tablet core and
comprises a pH sensitive coating. An optional sealing coat may be
applied to the compressed tablet core and an optional coating layer
comprising an enteric coating agent may be applied under the outer
coating layer as an inner coating or as an overcoat over the outer
coating layer. The tablet core may be compressed using a smooth
faced tablet die. In one embodiment, the active agent is drug.
[0276] The osmotic agent in this dosage form is any non-toxic
pharmaceutically acceptable water soluble compound which will
dissolve sufficiently in water and increase the osmotic pressure
inside the tablet core. Suitable osmotic agents include simple
sugars and salts such as sodium chloride, potassium chloride,
magnesium sulfate, magnesium sulfate, magnesium chloride, sodium
sulfate, lithium sulfate, urea, inositol, sucrose, lactose,
glucose, sorbitol, fructose, mannitol, dextrose, magnesium
succinate, potassium acid phosphate and the like. The preferred
osmotic agent for the tablet core is a simple sugar such as
anhydrous lactose in the range of 0-50% by weight, based on the
weight of the compressed, uncoated tablet.
[0277] The water swellable polymer may be any pharmaceutically
acceptable polymer which swells and expands in the presence of
water to slowly release drug. These polymers include polyethylene
oxide, methylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose and the like. In a preferred
embodiment, the water swellable polymer will be polyethylene oxide
(obtained from Union Carbide Corporation under the trade name
Polyox WSR Coagulant or Polyox WSR N 80). These materials form a
viscous gel in water or other solvent system at a sufficient
concentration to control the release of the drug. This will
generally require a concentration of the pharmaceutically
acceptable, water swellable polymer of about 0-50% by weight of the
compressed, uncoated tablet.
[0278] The outer coating comprises a pH sensitive coating which
functions as an enteric polymer in that it does not begin to
dissolve until pH conditions in excess of the pH of the stomach
region are encountered. The pH sensitive coating is the same type
of material that is described above. The pH sensitive coating may
be present in an amount of about 0.5-15 wt %, more specifically,
about 8-12 wt %, based on the weight of the coated tablet core.
[0279] Certain controlled release formulation may release less than
about 20 wt % of drug in the formulation within the first three
hours after administration and more than about 60 percent of drug
between 3 and 10 hours. Other controlled release drug formulation
may release less than about 50 percent within the first three hours
after administration and about 50 percent of drug between 3 and 10
hours.
[0280] Colorants, detackifiers, surfactants, antifoaming agents,
lubricants (e.g., carnuba wax or PEG) may be added to the coatings
besides plasticizers to solubilize or disperse the coating
material, and to improve coating performance and the coated
product.
[0281] A particularly suitable methacrylic copolymer is Eudragit
L.RTM., particularly L-30D.RTM. and Eudragit 100-55.RTM.,
manufactured by Rohm Pharma, Germany. In Eudragit L-30D.RTM., the
ratio of free carboxyl groups to ester groups is approximately 1:1.
Further, the copolymer is known to be insoluble in gastrointestinal
fluids having pH below 5.5, generally 1.5-5.5, i.e., the pH
generally present in the fluid of the upper gastrointestinal tract,
but readily soluble or partially soluble at pH above 5.5, i.e., the
pH values present in the small intestine.
[0282] In some embodiments, materials include shellac, acrylic
polymers, cellulosic derivatives, polyvinyl acetate phthalate, and
mixtures thereof. In other embodiments, materials include
Eudragit.RTM. series E, L, RL, RS, NE, L, L300, S, 100-55,
cellulose acetate phthalate, Aquateric, cellulose acetate
trimellitate, ethyl cellulose, hydroxypropylmethylcellulose
phthalate, hydroxypropylmethylcellulose acetate succinate,
polyvinyl acetate phthalate, and Cotteric.
[0283] In other aspects, the invention is directed to an oral solid
dosage form comprising (i) a controlled release component
comprising a first portion of particles comprising drug; and a
controlled release material, and (ii) an immediate release
component comprising a second portion of particles comprising drug,
the first and second portion of drug particles having a volume
weighted median diameter (D50) of from about 50 nm to about 1000
nm, from about 100 nm to about 450 nm, or from about 100 nm to
about 350 nm. The ratio of drug in controlled release to immediate
release can be, e.g., from about 4:1 to about 1:4, from about 3:2
to about 2:3, or about 1:1. The controlled release component can be
in any form, including but not limited to (i) a plurality of
pharmaceutically acceptable beads coated with the first portion of
drug particles and overcoated with the controlled release material
(optionally a film coat comprising a material such as
hydroxypropylmethylcellulose or polyvinyl alcohol can be included
on the beads prior to coating with the drug particles), (ii) a
plurality of matrices comprising the first portion of drug
particles dispersed in the controlled release material, (iii) a
tablet comprising the first portion of drug particles dispersed in
the controlled release material, or (iv) a granulation comprising
the first portion of drug particles and the controlled release
material. The immediate release component can be in any form,
including but not limited to (i) plurality of pharmaceutically
acceptable beads coated with the second portion of drug particles,
(ii) a plurality of matrices comprising the second portion of drug
particles dispersed in an excipient, (iii) a tablet comprising the
second portion of drug particles dispersed in excipient, or (v) a
granulation comprising the second portion of drug particles and
excipient. Alternatively, the immediate release component can be
included in the dosage form in powder form.
[0284] In certain embodiments, the controlled release component and
the immediate release component are contained in a capsule.
[0285] In other embodiments, the controlled release component is a
tablet and the immediate release component is coated onto the
tablet.
[0286] In further embodiments, the controlled release component and
the immediate release component are in a bi-layer tablet.
[0287] In still other embodiments, the controlled release component
comprises a plurality of pharmaceutically acceptable beads coated
with the first portion of drug particles and overcoated with the
controlled release material and the immediate release component
comprises a plurality of pharmaceutically acceptable beads coated
with the second portion of drug particles, the controlled release
component and immediate release component contained in a
capsule.
[0288] In another aspect, the controlled release component
comprises a plurality of pharmaceutically acceptable beads coated
with the first portion of drug particles and overcoated with the
controlled release material and the immediate release component
comprises a tablet comprising the second portion of drug particles
dispersed in an excipient, the controlled release component and
immediate release component contained in a capsule.
[0289] In still another embodiments, controlled release component
comprises a plurality of pharmaceutically acceptable beads coated
with the first portion of drug particles and overcoated with the
controlled release material and the immediate release component
comprises a granulation comprising the second portion of drug
particles and an excipient, the controlled release component and
immediate release component contained in a capsule.
[0290] In another embodiment, the controlled release component
comprises a plurality of pharmaceutically acceptable beads coated
with the first portion of drug particles and overcoated with the
controlled release material, and the immediate release component
comprises a granulation comprising the second portion of drug
particles and an excipient, the controlled release component
dispersed in the immediate release component in the form of a
compressed tablet.
[0291] In further embodiments, the controlled release component
comprises a compressed tablet and the immediate release component
is compression coated over the controlled release tablet.
[0292] In embodiments directed to drug coated beads, controlled
release material can be coated onto the drug layered bead in an
amount, e.g., from about 3% to about 25%, or from about 10% to
about 20%, based on the total weight of the component.
[0293] In certain embodiments, the dosage forms of the present
invention provide pulsatile release of two or more doses of drug.
The dosage form can provide an immediate release dose after
administration and at least one additional dose at a time after
administration selected from the group consisting of 3-8 hours,
6-10 hours, 10-14 hours, 14-18 hours, 16-20 hours and 22-24
hours.
[0294] In certain embodiments, the invention is directed to an oral
solid dosage form comprising drug particles and a controlled
release material, the drug particles having a volume weighted
median diameter (D50) of from about 50 nm to about 1000 nm, the
dosage form providing a controlled release of the drug to provide a
therapeutic effect for about 8 to about 24 hours after
administration.
[0295] In other embodiments, the invention is directed to an oral
solid dosage form comprising particles comprising drug; and a pH
dependent polymer, the drug particles having a volume weighted
median diameter (D50) from about 50 nm to about 1000 nm, the dosage
form providing a delayed release of the drug for a time period from
about 2 to about 12 hours after administration.
[0296] The dosage forms can be prepared according to any of the
methods disclosed herein or by the methods described in U.S. Pat.
Nos. 5,209,746; 5,213,808; 5,221,278; 5,260,068; 5,260,069;
5,308,348; 5,312,390; 5,318,588; 5,340,590; 5,391,381; 5,456,679;
5,472,708; 5,508,040; 5,840,329; 5,980,508; 6,214,379; 6,228,398;
6,248,363; 6,514,518; 6,569,463; 6,607,751; 6,627,223; 6,730,325;
6,793,936; 6,902,742 and 6,923,988, the disclosures of which are
hereby incorporated by reference.
Liquid Formulations
[0297] In some embodiments, pharmaceutical drug formulations are
provided comprising the drug particles described herein and at
least one dispersing agent or suspending agent for oral
administration to a subject. The drug formulation may be a powder
and/or granules for suspension, and upon admixture with water, a
substantially uniform suspension is obtained. As described herein,
the aqueous dispersion can comprise amorphous and non-amorphous
drug particles of consisting of multiple effective particle sizes
such that drug particles having a smaller effective particle size
are absorbed more quickly and drug particles having a larger
effective particle size are absorbed more slowly. In certain
embodiments the aqueous dispersion or suspension is an immediate
release formulation. In another embodiment, an aqueous dispersion
comprising amorphous drug particles is formulated such that about
50% of the drug particles are absorbed within about 3 hours after
administration and about 90% of the drug particles are absorbed
within about 10 hours after administration. In other embodiments,
addition of a complexing agent to the aqueous dispersion results in
a larger span of drug containing particles to extend the drug
absorption phase such that 50-80% of the particles are absorbed in
the first 3 hours and about 90% are absorbed by about 10 hours.
[0298] A suspension is "substantially uniform" when it is mostly
homogenous, that is, when the suspension is composed of
approximately the same concentration of drug at any point
throughout the suspension. Preferred embodiments are those that
provide concentrations essentially the same (within 15%) when
measured at various points in a drug aqueous oral formulation after
shaking. Especially preferred are aqueous suspensions and
dispersions, which maintain homogeneity (up to 15% variation) when
measured 2 hours after shaking. The homogeneity should be
determined by a sampling method consistent with regard to
determining homogeneity of the entire composition. In one
embodiment, an aqueous suspension can be re-suspended into a
homogenous suspension by physical agitation lasting less than 1
minute. In another embodiment, an aqueous suspension can be
re-suspended into a homogenous suspension by physical agitation
lasting less than 45 seconds. In yet another embodiment, an aqueous
suspension can be re-suspended into a homogenous suspension by
physical agitation lasting less than 30 seconds. In still another
embodiment, no agitation is necessary to maintain a homogeneous
aqueous dispersion.
[0299] In some embodiments, the drug powders for aqueous dispersion
described herein comprise size stabilized drug particles having an
effective particle size by weight of less than 500 nm formulated
with drug particles having an effective particle size by weight of
greater than 500 nm. In certain embodiments, the formulations have
a particle size distribution wherein about 10% to about 100% of the
drug particles by weight are between about 75 nm and about 500 nm,
about 0% to about 90% of the drug particles by weight are between
about 150 nm and about 400 nm, and about 0% to about 30% of the
drug particles by weight are greater than about 600 nm. The drug
particles described herein can be amorphous, semi-amorphous,
crystalline, semi-crystalline, or mixture thereof.
[0300] In one embodiment, the aqueous suspensions or dispersions
described herein comprise drug particles or drug complex at a
concentration of about 20 mg/ml to about 150 mg/ml of suspension.
In another embodiment, the aqueous oral dispersions described
herein comprise drug particles or drug complex particles at a
concentration of about 25 mg/ml to about 75 mg/ml of solution. In
yet another embodiment, the aqueous oral dispersions described
herein comprise drug particles or drug complex at a concentration
of about 50 mg/ml of suspension. The aqueous dispersions described
herein are especially beneficial for the administration of drug to
infants (less than 2 years old), children under 10 years of age and
any patient group that is unable to swallow or ingest solid oral
dosage forms.
[0301] Liquid drug formulation dosage forms for oral administration
can be aqueous suspensions selected from the group including, but
not limited to, pharmaceutically acceptable aqueous oral
dispersions, emulsions, solutions, and syrups. See, e.g., Singh et
al., Encyclopedia of Pharmaceutical Technology, 2.sup.nd Ed., pp.
754-757 (2002). In addition to drug particles, the liquid dosage
forms may comprise additives, such as: (a) disintegrating agents;
(b) dispersing agents; (c) wetting agents; (d) at least one
preservative, (e) viscosity enhancing agents, (f) at least one
sweetening agent, (g) at least one flavoring agent, and (h) a
complexing agent. In some embodiments, the aqueous dispersions can
further comprise a crystalline inhibitor.
[0302] Examples of disintegrating agents for use in the aqueous
suspensions and dispersions include, but are not limited to, a
starch, e.g., a natural starch such as corn starch or potato
starch, a pregelatinized starch such as National 1551 or
Amijel.RTM., or sodium starch glycolate such as Promogel.RTM. or
Explotab.RTM.; a cellulose such as a wood product, microcrystalline
cellulose, e.g., Avicel.RTM., Avicel.RTM. PH101, Avicel.RTM. PH102,
Avicel.RTM. PH105, Elcema.RTM. P100, Emcocel.RTM., Vivacel.RTM.,
Ming Tia.RTM., and Solka-Floc.RTM., methylcellulose,
croscarmellose, or a cross-linked cellulose, such as cross-linked
sodium carboxymethylcellulose (Ac-Di-Sol.RTM.), cross-linked
carboxymethylcellulose, or cross-linked croscarmellose; a
cross-linked starch such as sodium starch glycolate; a cross-linked
polymer such as crosspovidone; a cross-linked polyvinylpyrrolidone;
alginate such as alginic acid or a salt of alginic acid such as
sodium alginate; a clay such as Veegum.RTM. HV (magnesium aluminum
silicate); a gum such as agar, guar, locust bean, Karaya, pectin,
or tragacanth; sodium starch glycolate; bentonite; a natural
sponge; a surfactant; a resin such as a cation-exchange resin;
citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate in
combination starch; and the like.
[0303] Dispersing/suspending agents and/or viscosity modulating
agents include materials that control the diffusion and homogeneity
of a drug through liquid media or a granulation method or blend
method. In some embodiments, these agents also facilitate the
effectiveness of a coating or eroding matrix. Viscosity enhancing
agents are agents which are typically added to a particulate
dispersion to increase the viscosity and prevent or slow settling
of the particles. Viscosity enhancing agents in solid dosage forms
are used on occasion to form a gel matrix as water permeates the
solid dosage form and can delay the release of the pharmaceutically
active ingredient(s). In some embodiments, the dispersing agents
suitable for the aqueous suspensions and dispersions described
herein are known in the art and include, for example, hydrophilic
polymers, electrolytes, Tween.RTM. 60 or 80, PEG,
polyvinylpyrrolidone (PVP; commercially known as Plasdone.RTM.),
and the carbohydrate-based dispersing agents such as, for example,
hydroxypropylcellulose and hydroxypropylcellulose ethers (e.g.,
HPC, HPC-SL, and HPC-L), hydroxypropylmethylcellulose and
hydroxypropylmethylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC
K15M, and HPMC K100M), carboxymethylcellulose sodium,
methylcellulose, hydroxyethylcellulose,
hydroxypropylmethylcellulose phthalate,
hydroxypropylmethylcellulose acetate stearate, noncrystalline
cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl
alcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer
(Plasdone.RTM., e.g., S-630), 4-(1,1,3,3-tetramethylbutyl)-phenol
polymer with ethylene oxide and formaldehyde (also known as
tyloxapol), poloxamers (e.g., Pluronics F68.RTM., F88.RTM., and
F108.RTM., which are block copolymers of ethylene oxide and
propylene oxide); and poloxamines (e.g., Tetronic 908.RTM., also
known as Poloxamine 908.RTM., which is a tetrafunctional block
copolymer derived from sequential addition of propylene oxide and
ethylene oxide to ethylenediamine (BASF Corporation, Parsippany,
N.J.)). In other embodiments, the dispersing agent is selected from
a group comprising one of the following agents: hydrophilic
polymers; electrolytes; Tween.RTM. 60 or 80; PEG;
polyvinylpyrrolidone (PVP); hydroxypropylcellulose and
hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L);
hydroxypropyl methylcellulose and hydroxypropyl methylcellulose
ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and
Pharmacoat.RTM. 603 (Shin-Etsu)); carboxymethylcellulose sodium;
methylcellulose; hydroxyethylcellulose;
hydroxypropylmethyl-cellulose phthalate;
hydroxypropylmethyl-cellulose acetate stearate; non-crystalline
cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl
alcohol (PVA); 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with
ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics
F68.RTM., F88.RTM., and F108.RTM., which are block copolymers of
ethylene oxide and propylene oxide); or poloxamines (e.g., Tetronic
908.RTM., also known as Poloxamine 908.RTM.).
[0304] Wetting agents (including surfactants) suitable for the
aqueous suspensions and dispersions described herein are known in
the art and include, but are not limited to, acetyl alcohol,
glycerol monostearate, polyoxyethylene sorbitan fatty acid esters
(e.g., the commercially available Tweens.RTM. such as e.g., Tween
20.RTM. and Tween 80.RTM. (ICI Specialty Chemicals)), and
polyethylene glycols (e.g., Carbowaxs 3350.RTM. and 1450.RTM., and
Carpool 934.RTM. (Union Carbide)), oleic acid, glyceryl
monostearate, sorbitan monooleate, sorbitan monolaurate,
triethanolamine oleate, polyoxyethylene sorbitan monooleate,
polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl
sulfate, sodium docusate, triacetin, vitamin E TPGS, sodium
taurocholate, simethicone, phosphotidylcholine and the like.
[0305] Typically amounts of preservatives needed to pass
anti-microbial effectiveness testing as described by USP and EU
methodology are used to test appropriate preservative levels.
Suitable preservatives for the aqueous suspensions or dispersions
described herein include, for example, potassium sorbate, parabens
(e.g., methylparaben and propylparaben) and their salts, benzoic
acid and its salts, other esters of parahydroxybenzoic acid such as
butylparaben, alcohols such as ethyl alcohol or benzyl alcohol,
phenolic compounds such as phenol, or quaternary compounds such as
benzalkonium chloride. Preservatives, as used herein, are
incorporated into the dosage form at a concentration sufficient to
inhibit microbial growth. In one embodiment, the aqueous liquid
dispersion can comprise methylparaben and propylparaben in a
concentration ranging from about 0.01% to about 0.3% methylparaben
by weight to the weight of the aqueous dispersion and 0.005% to
0.03% propylparaben by weight to the total aqueous dispersion
weight. In yet another embodiment, the aqueous liquid dispersion
can comprise methylparaben 0.05 to about 0.1 weight % and
propylparaben from 0.01-0.02 weight % of the aqueous dispersion. In
yet another embodiment, the aqueous liquid dispersion can comprise
sodium benzoate 0.05 to about 0.1 weight % of the aqueous
dispersion and pH adjusted from 3.5 to 5.0.
[0306] Suspensions or dispersions described herein include, but are
not limited to, methyl cellulose, xanthan gum,
carboxymethylcellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, Plasdone.RTM. S-630, carbomer,
polyvinyl alcohol, alginates, acacia, chitosans and combinations
thereof. The concentration of the viscosity enhancing agent will
depend upon the agent selected and the viscosity desired.
[0307] Examples of natural and artificial sweetening agents
suitable for the aqueous suspensions or dispersions described
herein include, for example, acacia syrup, acesulfame K, alitame,
anise, apple, aspartame, banana, Bavarian cream, berry, black
currant, butterscotch, calcium citrate, camphor, caramel, cherry,
cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus
punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool
citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol,
fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza
(licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime,
lemon cream, monoammonium glyrrhizinate (MagnaSweet.RTM.), maltol,
mannitol, maple, marshmallow, menthol, mint cream, mixed berry,
neohesperidine DC, neotame, orange, pear, peach, peppermint,
peppermint cream, Prosweet.RTM. Powder, raspberry, root beer, rum,
saccharin, safrole, sorbitol, spearmint, spearmint cream,
strawberry, strawberry cream, stevia, sucralose, sucrose, sodium
saccharin, saccharin, aspartame, acesulfame potassium, mannitol,
talin, sucralose, sorbitol, Swiss cream, tagatose, tangerine,
thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry,
wintergreen, xylitol, or any combination of these flavoring
ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange,
cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime,
lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and
mixtures thereof. In one embodiment, the aqueous liquid dispersion
can comprise a sweetening agent or flavoring agent in a
concentration ranging from about 0.0001% to about 10.0% the weight
of the aqueous dispersion. In another embodiment, the aqueous
liquid dispersion can comprise a sweetening agent or flavoring
agent in a concentration ranging from about 0.0005% to about 5.0 wt
% of the aqueous dispersion. In yet another embodiment, the aqueous
liquid dispersion can comprise a sweetening agent or flavoring
agent in a concentration ranging from about 0.0001% to 0.1 wt %,
from about 0.001% to about 0.01 weight %, or from 0.0005% to 0.004%
of the aqueous dispersion.
[0308] In addition to the additives listed above, the liquid drug
formulations can also comprise inert diluents commonly used in the
art, such as water or other solvents, solubilizing agents, and
emulsifiers.
[0309] In certain embodiments, the invention is directed to an oral
liquid dosage form comprising from about 2.5% to about 5% size
stabilized drug complex particles, from about 2% to about 5%
hydroxypropylmethyl cellulose, about 0.5% to about 1.5% polyvinyl
alcohol, from about 0.1% to about 0.3% sodium lauryl sulfate, from
about 0.005% to about 0.02% simethicone, from about 0.01% to about
0.03% sucralose, from about 0.05% to about 0.1% methylparaben, from
about 0.01% to about 0.02% propylparaben, from about 0.05 to about
0.1% sodium benzoate, from about 0.05% to about 0.15% citric acid,
from about 0.005 to about 0.1% sodium citrate and from about 0.002%
to about 0.004% flavoring, the liquid having a pH of about 3.8 to
about 4.2, wherein all percentages are weight percent to the total
liquid formulation weight.
[0310] In certain embodiments, the invention is directed to an oral
liquid dosage form comprising size stabilized complexed drug
particles and at least one pharmaceutically acceptable excipient,
the particles suspended in a pharmaceutically acceptable liquid
vehicle, wherein the volume weighted median diameter (D50) after a
suitable curing time does not change by more than about 15% after
10 days storage at room temperature, by more than about 12% after
10 days storage at room temperature, by more than about 10% after
10 days storage at room temperature, by more than about 8% after 10
days storage at room temperature, by more than about 15% after 20
days of storage at room temperature, by more than about 15% after
40 days of storage at room temperature, by more than about 15%
after 60 days of storage at room temperature, or by more than about
15% after 80 days of storage at room temperature. In certain
aspects, the volume weighted median diameter (D50) of the size
stabilized drug complex particles prior to storage is from about
100 nm to about 500 nm, or from about 100 nm to about 350 nm.
[0311] In certain embodiments, the invention is directed to an oral
liquid dosage form wherein the volume weighted median diameter
(D50) of the size stabilized drug complex particles do not change
by more than about 15% when placed in a glass vial and heated in a
100.degree. C. oil bath for 20 minutes, does not change by more
than about 15% when placed in a glass vial and heated in a
100.degree. C. oil bath for 4 hours, does not change by more than
about 10% when placed in a glass vial and heated in a 100.degree.
C. oil bath for 20 minutes, does not change by more than about 5%
when placed in a glass vial and heated in a 100.degree. C. oil bath
for 20 minutes, or does not change when placed in a glass vial and
heated in a 100.degree. C. oil bath for 20 minutes (within the
accuracy of the particle size measurement procedure).
[0312] In still further embodiments, the invention is directed to
an oral liquid dosage form the volume weighted median diameter
(D50) of the size stabilized drug complex particles does not change
by more than about 25% when placed in a HDPE container and frozen
and thawed three or more times with the time frozen for each cycle
being at least 12 hours. The frozen temperature can be any suitable
freezing temperature, e.g., from about -80.degree. C. to about
-20.degree. C.
[0313] In certain embodiments, the oral liquid dosage form is
prepared by contacting drug particles with a complexing agent,
wherein the size of the particles exhibits an increase in volume
weighted median diameter (D50) of from about 20% to about 300% and
reaching an endpoint such that the particles are size
stabilized.
[0314] In certain solid formulations, the size stabilized drug
complex particles are dispersed in a liquid to form a suspension
and the suspension is spray coated onto the plurality of
substrates, or spray granulated with the plurality of substrates.
In further embodiments the drug particles are dispersed in a liquid
to form a suspension and the suspension is spray dried to form a
powder which is then granulated and added to a capsule or
granulated and compressed into a tablet. The suspension can be,
e.g., about 5% to about 35%, or about 15% to about 25% total
solids. The drug concentration in the solids can be, e.g., from
about 20% to about 80%.
[0315] In embodiments directed to liquid dosage forms, the liquid
dosage form can include at least one excipient selected from
hydroxypropylmethylcellulose, sodium lauryl sulfate, methyl
anthranilate, sodium benzoate, citric acid, sodium citrate,
simethicone, sucralose and flavoring. For example, the liquid
dosage form can comprise about 5% drug, about 5%
hydroxypropylmethylcellulose (2910), about 0.1% sodium lauryl
sulfate, about 0.4% methylanthranilate about 0.1% sodium benzoate,
about 0.12% citric acid, about 0.06% sodium citrate, about 0.01%
simethicone, and 0.02% sucralose. These ingredients and % amounts
are not meant to be limiting.
Emulsions
[0316] In some embodiments, the pharmaceutical drug formulations
described herein can be self-emulsifying drug delivery systems
(SEDDS). Emulsions are dispersions of one immiscible phase in
another, usually in the form of droplets. Generally, emulsions are
created by vigorous mechanical dispersion. SEDDS, as opposed to
emulsions or microemulsions, spontaneously form emulsions when
added to an excess of water without any external mechanical
dispersion or agitation. An advantage of SEDDS is that only gentle
mixing is required to distribute the droplets throughout the
solution. Additionally, water or the aqueous phase can be added
just prior to administration, which ensures stability of an
unstable or hydrophobic active ingredient. Thus, the SEDDS provides
an effective delivery system for oral and parenteral delivery of
hydrophobic active ingredients. SEDDS may provide improvements in
the bioavailability of hydrophobic active ingredients. Methods of
producing self-emulsifying dosage forms are known in the art
include, but are not limited to, for example, U.S. Pat. Nos.
5,858,401, 6,667,048, and 6,960,563, each of which is specifically
incorporated by reference.
[0317] Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol,
ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butyleneglycol, dimethylformamide, sodium
lauryl sulfate, sodium doccusate, cholesterol, cholesterol esters,
taurocholic acid, phosphotidylcholine, oils, such as cottonseed
oil, groundnut oil, corn germ oil, olive oil, castor oil, and
sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols, fatty acid esters of sorbitan, or mixtures of these
substances, and the like.
Intranasal Formulations
[0318] Intranasal formulations are known in the art and are
described in, for example, U.S. Pat. Nos. 4,476,116, 5,116,817 and
6,391,452, each of which is specifically incorporated by reference.
Drug formulations prepared according to these and other techniques
well-known in the art are prepared as solutions in saline,
employing benzyl alcohol or other suitable preservatives,
fluorocarbons, and/or other solubilizing or dispersing agents known
in the art. See, for example, Ansel, H. C. et al., Pharmaceutical
Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995).
Preferably these compositions and formulations are prepared with
suitable nontoxic pharmaceutically acceptable ingredients. These
ingredients are known to those skilled in the preparation of nasal
dosage forms and some of these can be found in REMINGTON: THE
SCIENCE AND PRACTICE OF PHARMACY, 21st edition, 2005, a standard
reference in the field. The choice of suitable carriers is highly
dependent upon the exact nature of the nasal dosage form desired,
e.g., solutions, suspensions, ointments, or gels. Nasal dosage
forms generally contain large amounts of water in addition to the
active ingredient. Minor amounts of other ingredients such as pH
adjusters, emulsifiers or dispersing agents, preservatives,
surfactants, gelling agents, complexing agents or buffering and
other stabilizing and solubilizing agents may also be present.
Preferably, the nasal dosage form should be isotonic with nasal
secretions.
Buccal Formulations
[0319] Buccal formulations comprising the drug formulations
described herein may be administered using a variety of
formulations known in the art. For example, such formulations
include, but are not limited to, U.S. Pat. Nos. 4,229,447,
4,596,795, 4,755,386, and 5,739,136, each of which is specifically
incorporated by reference. In addition, the buccal dosage forms
described herein can further comprise a bioerodible (hydrolyzable)
polymeric carrier that may also serves to adhere the dosage form to
the buccal mucosa. The buccal dosage form is fabricated so as to
erode gradually over a predetermined time period, wherein drug
delivery is provided essentially throughout. Buccal drug delivery,
as will be appreciated by those skilled in the art, avoids the
disadvantages encountered with oral drug administration, e.g., slow
drug absorption, degradation of the active agent by fluids present
in the gastrointestinal tract and/or first-pass inactivation in the
liver. With regard to the bioerodible (hydrolysable) polymeric
carrier, it will be appreciated that virtually any such carrier can
be used, so long as the desired drug release profile is not
comprised, and the carrier is compatible with drug and any other
components that may be present in the buccal dosage unit.
Generally, the polymeric carrier comprises hydrophilic
(water-soluble and water-swellable) polymers that adhere to the wet
surface of the buccal mucosa. Examples of polymeric carriers useful
herein include acrylic acid polymers e.g., those known as
"carbomers" (Carbopol.RTM., which may be obtained from B.F.
Goodrich, is one such polymer). Other components may also be
incorporated into the buccal dosage forms described herein include,
but are not limited to, disintegrants, diluents, binders,
lubricants, flavoring, colorants, preservatives, and the like.
Transdermal Formulations
[0320] Transdermal formulations described herein may be
administered using a variety of devices which have been described
in the art. For example, such devices include, but are not limited
to, U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683,
3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073,
3,996,934, 4,031,894, 4,060,084, 4,069,307, 4,077,407, 4,201,211,
4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280,
5,869,090, 6,923,983, 6,929,801 and 6,946,144, each of which is
specifically incorporated by reference in its entirety. In some
embodiments, the transdermal delivery device used with the drug
formulations described herein can comprise a power source, radio
frequency, or a brief electrical current to micro-electrodes in the
skin creating "channels" or "pores" in the stratum corneum to
facilitate the delivery of the drug formulation, such methods are
known in the art and are described in, for example U.S. Pat. Nos.
6,611,706, 6,708,060, and 6,711,435, each of which is specifically
incorporated by reference in its entirety. In other embodiments,
the transdermal delivery device can comprise a means for porating
the stratum corneum, e.g., micro-lancing, application of sonic
energy, or hydraulic puncturing, to facilitate the delivery of the
drug formulation, such methods are known in the art and are
described in, for example, U.S. Pat. Nos. 6,142,939 and 6,527,716,
each of which is specifically incorporated by reference in its
entirety. The pores described by the methods herein are typically
about 20-50 microns in depth and do not extend into areas of
innervation or vascularization.
[0321] The transdermal dosage forms described herein may
incorporate certain pharmaceutically acceptable excipients which
are conventional in the art. In general, the transdermal
formulations described herein comprise at least three components:
(1) a drug complex formulation; (2) a penetration enhancer; and (3)
an aqueous adjuvant. In addition, transdermal formulations can
include additional components such as, but not limited to, gelling
agents, creams and ointment bases, and the like. In some
embodiments, the transdermal formulation can further comprise a
woven or non-woven backing material to enhance drug absorption and
prevent the removal of the transdermal formulation from the skin.
In other embodiments, the transdermal formulations described herein
can maintain a saturated or supersaturated state to promote
diffusion into the skin.
Injectable Formulations
[0322] Size stabilized drug complex formulations suitable for
intramuscular, subcutaneous, or intravenous injection may comprise
physiologically acceptable sterile aqueous or non-aqueous
solutions, dispersions, suspensions or emulsions, and sterile
powders for reconstitution into sterile injectable solutions or
dispersions. Examples of suitable aqueous and non-aqueous carriers,
diluents, solvents, or vehicles including water, ethanol, polyols
(propylene glycol, polyethylene-glycol, glycerol, cremophor and the
like), suitable mixtures thereof, vegetable oils (such as olive
oil) and injectable organic esters such as ethyl oleate. Proper
fluidity can be maintained, for example, by the use of a coating
such as lecithin, by the maintenance of the required particle size
in the case of dispersions, and by the use of surfactants. Drug
formulations suitable for subcutaneous injection may also contain
additives such as preserving, wetting, emulsifying, and dispensing
agents. Prevention of the growth of microorganisms can be ensured
by various antibacterial and antifungal agents, such as parabens,
benzoic acid, benzyl alcohol, chlorobutanol, phenol, sorbic acid,
and the like. It may also be desirable to include isotonic agents,
such as sugars, sodium chloride, and the like. Prolonged drug
absorption of the injectable pharmaceutical form can be brought
about by the use of agents delaying absorption, such as aluminum
monostearate and gelatin. Drug suspension formulations designed for
extended release via subcutaneous or intramuscular injection can
avoid first pass metabolism and lower dosages of drug will be
necessary to maintain plasma levels in therapeutic range. In such
formulations, the particle size of the drug particles and the range
of the particle sizes of the drug particles can be used to control
the release of the drug by controlling the rate of dissolution in
fat or muscle.
Sterile Drug Formulations
[0323] Some of the drug formulations described herein can be
sterile filtered. This property obviates the need for heat
sterilization, which can harm or degrade drug, as well as result
effective particle size growth.
[0324] Sterile filtration can be difficult because of the required
small particle size of the composition. However, this method is
suitable and commonly used for dispersions comprising
nanoparticles. Filtration is an effective method for sterilizing
homogeneous solutions when the membrane filter pore size is less
than or equal to about 0.2 microns (200 nm) because a 0.2 micron
filter is sufficient to remove essentially all bacteria. Sterile
filtration is normally not used to sterilize conventional
suspensions of micron-sized drug because the drug particles are too
large to pass through the membrane pores.
[0325] Because some of the size stabilized drug-complex
formulations described herein can be sterilized via autoclaving,
and because the formulations can have a very small drug effective
average particle size, some sterilized drug formulations are
suitable for parenteral administration. Additionally, a sterile
drug formulation is particularly useful in treating
immunocompromised patients, infants or juvenile patients, patients
with head trauma and the elderly.
Combination Therapies
[0326] The compositions and methods described herein may also be
used in conjunction with other well known therapeutic reagents that
are selected for their particular usefulness against the condition
that is being treated. In general, the compositions described
herein and, in embodiments where combinational therapy is employed,
other agents do not have to be administered in the same
pharmaceutical composition, and may, because of different physical
and chemical characteristics, have to be administered by different
routes. The determination of the mode of administration and the
advisability of administration, where possible, in the same
pharmaceutical composition, is well within the knowledge of the
skilled clinician. The initial administration can be made according
to established protocols known in the art, and then, based upon the
observed effects, the dosage, modes of administration and times of
administration can be modified by the skilled clinician.
[0327] The particular choice of compounds used will depend upon the
diagnosis of the attending physicians and their judgment of the
condition of the patient and the appropriate treatment protocol.
The compounds may be administered concurrently (e.g.,
simultaneously, essentially simultaneously or within the same
treatment protocol) or sequentially, depending upon the nature of
the proliferative disease, the condition of the patient, and the
actual choice of compounds used. The determination of the order of
administration, and the number of repetitions of administration of
each therapeutic agent during a treatment protocol, is well within
the knowledge of the skilled physician after evaluation of the
disease being treated and the condition of the patient.
[0328] It is understood that the dosage regimen to treat, prevent,
or ameliorate the condition(s) for which relief is sought, can be
modified in accordance with a variety of factors. These factors
include the disorder from which the subject suffers, as well as the
age, weight, sex, diet, and medical condition of the subject. Thus,
the dosage regimen actually employed can vary widely and therefore
can deviate from the dosage regimens set forth herein.
[0329] The pharmaceutical agents which make up the combination
therapy disclosed herein may be a combined dosage form or in
separate dosage forms intended for substantially simultaneous
administration. The pharmaceutical agents that make up the
combination therapy may also be administered sequentially, with
either therapeutic compound being administered by a regimen calling
for two-step administration. The two-step administration regimen
may call for sequential administration of the active agents or
spaced-apart administration of the separate active agents. The time
period between the multiple administration steps may range from, a
few minutes to several hours, depending upon the properties of each
pharmaceutical agent, such as potency, solubility, bioavailability,
plasma half-life and kinetic profile of the pharmaceutical agent.
Circadian variation of the target molecule concentration may also
determine the optimal dose interval.
[0330] In some embodiments, the drug formulation is administered
with at least one other agent, e.g., an anti-convulsant agent, an
anti-anxiety agent or an anti-depression agent.
Controlled Exposure Profiles
[0331] In certain embodiments, about 40% of the drug is released
from the dosage form within about 3 hours and about 95% of the drug
is released from the dosage form within about 10 hours after
administration. In yet another embodiment, about 30% of the drug is
released from the dosage form within about 3 hours and about 90% of
the drug is released from the dosage form within about 10 hours
after administration. In yet another embodiment, about 80% of the
drug is released from the dosage form within about 2 hours and
about 90% of the drug is released from the dosage form within about
10 hours after administration.
Reduced Fed/Fasted Effects Associated with the Administration of
Drug
[0332] It is generally known in the art that if a positive
fed/fasted effect is seen with a pharmaceutical agent, it is
typically related to the dose of the active agent administered such
that a lower dose of an active agent will have a lower ratio of
AUC.sub.(fed)/AUC.sub.(fasted) and a higher dose of an active agent
will have a higher ratio of AUC.sub.(fed)/AUC.sub.(fasted). In
addition, it is known that dosage forms which substantially
eliminate the effects of food on the therapeutic window (levels for
efficacy vs. levels giving side effects) are safer than those
dosage forms which do not. Thus dosage forms that provide reduced
fed/fasted effects provide decreased risks and reduce the potential
for side effects, thereby increasing subject safety and compliance.
Fed/fasted conditions are in accordance with FDA guidelines for
testing drug exposure in the fed and fasted states.
[0333] Conventional formulations of drug display large fed/fasted
effects in a manner that is not limited to dose dependency. The
drug formulations described herein are less effected by the fed or
fasted state of the subject being administered the formulation. The
systemic exposure of the drug formulations described herein is less
sensitive to the type of meal ingested than conventional drug
formulations. This means that there is a reduced difference in the
AUC.sub.(0-.tau.) values of drug when the drug formulations are
administered in the fed versus the fasted state at therapeutically
effective doses. Thus, described herein are drug formulations that
can substantially reduce the effect of food on the pharmacokinetics
of drug. In one embodiment, the drug formulation is an aqueous
dispersion that when administered to a child under 12 yeas old or
adult not capable of swallowing a solid formulation, provides a
ratio of the AUC.sub.(0-.infin.) or AUC.sub.(0-.tau.) values of
drug, when administered in the fed versus the fasted state, of less
than about 4. In another embodiment, the drug formulation is a
solid oral dosage form that when administered to a human over
twelve years old provides a the ratio of the AUC.sub.(0-.tau.)
values of drug, when administered in the fed versus the fasted
state, of less than about 3. In still another embodiment, the drug
formulation is a solid oral dosage form that when administered to a
human over twelve years old provides a ratio of the
AUC.sub.(0-.tau.) values of drug, when administered in the fed
versus the fasted state, of less than about 2. In yet another
embodiment, the drug formulation is a solid oral dosage form that
when administered to a human over twelve years old provides a ratio
of the AUC.sub.(0-.tau.) values of drug, when administered in the
fed versus the fasted state, of less than about 1.5. In still
another embodiment, the drug formulation is a solid oral dosage
form that when administered to a human over twelve years old
provides a ratio of the AUC.sub.(0-.tau.) values of drug, when
administered in the fed versus the fasted state, ranging from about
3 to about 1.5. In another embodiment, the drug formulation is a
solid oral dosage form that when administered to a human over
twelve years old provides a ratio of the AUC.sub.(0-.tau.) values
of drug, when administered in the fed versus the fasted state, of
about 2.
Dose Amounts
[0334] The drug formulations described herein are administered and
dosed in accordance with good medical practice, taking into account
the clinical condition of the individual patient, the site and
method of administration, scheduling of administration, and other
factors known to medical practitioners. In human therapy, the
dosage forms described herein preferably deliver drug formulations
that maintain a therapeutically effective amount of drug at steady
state while reducing the side effects associated with an elevated
C.sub.max blood plasma level of drug.
[0335] In various other embodiments of the present invention, the
amount of drug administered to a subject via a solid dosage form is
the amount known in the art to achieve a therapeutically effective
concentration of drug in the bloodstream of a human or animal in
need thereof. For example, the amount of drug may range from about
0.01 micrograms to about 6 g. In other embodiments, the amount of
drug may range from about 0.1 mg to about 1000 mg. In other
embodiments, the amount of drug may range from about 1 mg to about
500 mg, from about 50 mg to about 800 mg or from about 300 mg to
about 700 mg. In one embodiment, a drug formulation is administered
in a solid dosage form at a concentration of about 250 mg to about
650 mg. In another embodiment, the drug formulation is administered
in a solid dosage form at concentration of about 300-400 mg. In
another aspect, the solid oral dosage form can be administered
twice a day (b.i.d). In yet another aspect, the solid oral dosage
form is a controlled release dosage form administered b.i.d.
providing a pulsatile release of drug such that the C.sub.max of
blood plasma drug is reduced to avoid adverse effects while
simultaneously reducing fed/fasted effects and maintaining total
exposure (AUC.sub.(0-.infin.)).
[0336] A therapeutically effective concentration of an oral aqueous
suspension or dispersion comprising a drug formulation described
herein, administered according to the methods described herein, is
typically in the range of about 20 mg/ml to about 150 mg/ml final
concentration. In one embodiment, a drug formulation is
administered as an aqueous oral suspension at a concentration of
about 25 mg/ml to about 100 mg/ml final concentration. In another
embodiment, a drug formulation is administered as an aqueous oral
suspension at a concentration of about 50 mg/ml final
concentration. The aqueous oral suspensions comprising a drug
formulation described herein can be administered both as a single
dose per day or given multiple times within a 24 hour period. In
one aspect, the aqueous oral suspension can be administered three
times a day (t.i.d). In another aspect, the aqueous oral suspension
can be administered twice a day (b.i.d.).
[0337] Contemplated compositions of the present invention provide a
therapeutically effective amount of drug over an interval of about
30 minutes to about 8 hours after administration, enabling, for
example, once-a-day, twice-a-day, three times a day, and etc.
administration if desired.
[0338] In further embodiments, greater than about 95%; or greater
than about 90%; or greater than about 80%; or greater than about
70% of the drug dosed by weight is absorbed into the bloodstream
within 8 hours after administration.
[0339] In other embodiments, the pharmaceutical formulations
provide a release profile for an immediate release dosage form of
the drug, whereby using methods described in Example 29, whereby
about 80% (or about 70% or about 90%) of the drug is released from
the dosage form within about 1 hours in SGF and for a delayed
release drug dosage form about 60% of the (or preferably 70% or
80%) is released from the composition within about 3 hours in
SIF.
Pharmacokinetic Analysis
[0340] Plasma concentrations of drug referenced herein are intended
to mean total drug concentrations including both free and bound
drug. Any formulation giving the desired pharmacokinetic profile is
suitable for administration according to the present methods.
Exemplary types of formulations giving such profiles are liquid
dispersions and solid dose forms of the drug formulation described
herein. Aqueous dispersions of drug are size stable at temperatures
from 4.degree. C. to 40.degree. C. for at least 4 months.
[0341] Certain drug compositions and formulations described herein
display enhanced pharmacokinetic (PK) and pharmacodynamic (PD)
profiles and/or minimized side effects as compared to conventional
drug formulations known in the art.
[0342] Certain formulations described herein reduce the risk of
drug side effects (e.g., ataxia, sedation and somnolence) relative
to conventional drug formulations. In certain embodiments improved
performance compared to conventional drug formulations can be seen
on acute doses. In other embodiments, maximal benefit of the drug
formulations described herein can be seen at steady state.
[0343] Any hypotheses provided herein are for possible explanatory
purposes only, and is not meant to be limiting in any way with
respect to the appended claims. All U.S. patent references
discussed in the specification are hereby incorporated by
reference.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0344] This invention is further illustrated by the following
examples that should not be construed as limiting. Those of skill
in the art of pharmaceutical formulation will readily appreciate
that certain modifications to the examples described herein may be
needed, particularly for changes in formulation batch size. Any
methods, materials, or excipients which are not particularly
described will be generally known and available to those skilled in
the drug design and assay and pharmacokinetic analysis.
[0345] The particle size data, for examples in which a ganaxolone
or phenyloin particle size is reported, were obtained using a
Horiba LA-910 Laser Light Scattering Particle Size analyzer (Horiba
Instruments, Irvine, Calif.) and reported as volume weighted median
(D50). Studies of ganaxolone or phenyloin particles in liquids,
beads, powders and immediate release dosage forms in SGF and SIF
are performed by dispersing an appropriate amount of the ganaxolone
or phenyloin formulation into 20 mL (unless otherwise specified) of
SGF or SIF in a vial to obtain a measuring concentration of
ganaxolone or phenyloin of about 0.5 mg/mL. For example, in one
embodiment, 200 mg of a ganaxolone suspension formulation
containing 5 wt % of ganaxolone and appropriate levels of HPMC,
PVA, SLS, and complexing agents was dispersed into 20 mL of SGF or
SIF in a vial for measurement. The vial is immersed in an oil bath
kept at 36 to 38.degree. C. for 3 h. The sample is assessed
visually for signs of flocculation and particle size is measured on
a Horiba LA-910 to obtain D50 values.
[0346] Compositions/formulations are expressed weight percent (%
wt) of the total composition for liquid suspensions and as weight
percent (% wt) to the drug (API) for solid compositions unless
specified otherwise.
Abbreviations
[0347] The following abbreviations are used in the examples below.
Other abbreviations used in the examples will be understood by
those of skill in the art of pharmaceutical formulations.
GNX Ganaxolone
HDPE High Density Polyethylene
HPMC Hydroxypropylmethylcellulose-2910
[0348] PVA Polyvinyl alcohol (USP)
SLS Sodium Lauryl Sulfate
[0349] DOSS Sodium docusate SGF Simulated gastric fluid USP without
enzyme SIF Simulated intestinal fluid USP without enzyme
WT Weight
[0350] rt room temperature D50 Volume weighted median particle
size
MCC Microcrystalline Cellulose
API Active Pharmaceutical Ingredient
[0351] DI water: Deionized water
Example 1
Preparation of USP Simulated Gastric and Intestinal Fluid
Simulated Intestinal Fluid (SIF)
[0352] Monobasic potassium phosphate (6.8 g) and sodium hydroxide
(0.616 g) are added into 250 ml of distilled water in a 1000 ml
volumetric flask and swirled until dissolved. 700 ml distilled
water is added and the pH checked. The pH is adjusted to pH
6.8+/-0.1 by adding either 0.2N sodium hydroxide or 0.2N
hydrochloric acid and the volume is brought to 1000 ml.
Simulated Gastric Fluid (SGF)
[0353] Sodium chloride (2 g), 750 ml distilled water, and 7.0 ml of
concentrated hydrochloric acid are added into a 1000 ml volumetric
flask. The flask is swirled to mix and the volume brought to 1000
ml with distilled water. The pH should be approx. 1.2.
Example 2
Particle Size Measurement Method
[0354] The following methods and settings for particle size
measurement were used for all D50 values for ganaxolone and
phenyloin.
Particle Size Method Using Horiba Laser Scattering Particle Size
Distribution Analyzer LA-910
[0355] Particle size measurement using Horiba laser scattering
particle size distribution analyzer is generally well known for
those skilled in the art. It is important that the parameters be
kept constant when measuring different samples if they are used for
comparison purposes. For ganaxolone and phenyloin nanoparticulate
compositions, instrument settings and sample preparation method are
described below:
Instrument Settings and Parameters:
[0356] Measure Conditions: Circulation=4; ultrasonic time=1;
agitation=1; sampling times: red laser=10, blue lamp=2; preferred %
transmittance: blue lamp=75-80%; blank: red laser=10, blue lamp=2.
For D50 values after sonication, the sonication power is set to low
and the sonication time is 1 minute.
[0357] Display Settings:
[0358] Form of distribution: standard (Gaussian)=10 iterations; RR
Index=1.15-010; distribution base: volume; size class=passing
(underclass).
Example 2A
Sample Preparation and Particle Size (D50) Determination
[0359] For concentrated nanoparticle drug suspensions, dilute the
nanoparticulate composition with deionized water to approximately 5
mg/mL API concentration. Shake well for 15-30 seconds. Add 120 mL
of deionized water to the chamber, turn agitation and recirculation
settings on. Transfer the nanoparticulate suspension via a pipette
to the sample chamber in sufficient quantity to reach the
transmittance range of 75-80% blue lamp. If a suspension or
stability indicating dispersion is at a concentration of
approximately 0.5 mg/ml do not further dilute if not necessary and
use directly for particle size measurement. Transfer the sample to
be measured via a pipette to up to the desired transmittance range
(75-80% blue lamp). Take a measurement and collect the D50 value.
This will be the unsonicated particles size. Sonicate for 1 min and
take a measurement again to collect D50 value. This will be the
particle size after 1 minute sonication. One can also use this
procedure obtain other particle size parameters such as D10 or D90
values.
Example 2B
General Particle Size Method for Solid Formulations Containing
Insoluble Excipients
[0360] Use the following method if measuring formulations where
insoluble excipients are added: Calculate the amount of insoluble
excipients that will be present in the measurement of the
composition and conduct the particle size experiment using these
insoluble excipients and the same conditions as will be used in the
measurement of D50 with the composition. Blank the instrument and
drain. Measure the particle size (D50) of the composition as
described above. This process subtracts any particle size
interference from the insoluble excipients. In the case where the
only insoluble excipient are MCC cores, pipette the dispersed
suspension (excluding MCC cores) to the Horiba chamber containing
120 ml distilled water. Measure the particle size as per method
2A.
Examples 3A-B
Dispersion Testing
Example 3A
Dispersion Testing for Aggregation of Liquid and Solid
Nanoparticulate Compositions
[0361] General method: The solid or liquid nanoparticulate
composition is placed in a 25 ml HDPE vial with HDPE cap and is
diluted with 15-20 ml of simulated gastric or intestinal fluid to
achieve a final API concentration of approx 0.5 mg/ml. The vial is
agitated manually for until completely dispersed (generally 15-30
seconds). The vial is then placed in a heated oil bath at
36-38.degree. C. unstirred unless specified otherwise until the
desired test time. The vial is removed from the bath and inspected
visually for signs of flocculation. After shaking the contents of
the vial for 15-30 seconds manually, the particle size is
determined (D50) using a Horiba-LA-910 particle analyzer as
described in Example 2. A comparison of D50 values (e.g. after and
before addition to SGF or SIF) is used to define the degree of
particle aggregation or growth. Initial D50 values before addition
to the dispersion media is used as the initial for liquid
compositions. Initial D50 value for a solid composition is the D50
of the liquid composition prior to removal of liquid (e.g. a spray
suspension of API prior to spray drying, spray granulation or spray
layering).
Example 3B
[0362] Dispersion of Tablets and Capsules (Immediate and Delayed
Release) of Nanoparticulate Compositions
[0363] Place the drug solid dosage form in a type I (e.g, beads and
capsules) or type II (e.g., tablets) dissolution apparatus with
basket at 36-38.degree. C. containing SGF at 0.5 to 1.0 mg/ml API
concentration for the immediate release component. Stir at 75 RPM
and sample at 1 hour for the particle size. Measure the particle
size as described as Example 2. For a controlled release dosage,
follow the preparation above but incubate in SGF for 2 hours,
replace the SGF with SIF (0.5 to 1 mg/mL API concentration) and
incubate for an additional 3 hours. Measure the particle size (D50)
as described in Example 2.
Example 4
Preparation of Complexed Ganaxolone Nanoparticulate Compositions in
the Presence of a Complexing Agent
[0364] The purpose of this example is to show that the complexing
agent can be present during milling to obtain complexed ganaxolone
nanoparticles.
[0365] Ganaxolone was wet milled in a 600 ml chamber using a
DYNO-Mill KDL equipped with four 64 mm polyurethane agitator discs.
The mill was operated at 3000 RPM or a tip speed of 10 m/sec. The
mill was loaded with 88 vol % of 0.4 mm yttrium stabilized
zirconium oxide beads. The milling slurry (1200 g) contained 25 wt
% ganaxolone (Marinus Pharmaceuticals Inc., Connecticut, USA), 5 wt
% hydroxypropyl methylcellulose (Pharmacoat 603), 0.0333 wt % 30%
simethicone emulsion, 0.3 wt % sodium lauryl sulfate and 0.2 wt %
methylparaben. This slurry was circulated through the mill via a
peristaltic pump and returned to a cooled reservoir where it was
re-circulated through the mill. The mill was operated in this
recirculation mode, keeping the slurry temperature at 35-40.degree.
C., for a total of 410 minutes (90 minutes residence time). The
product slurry was filtered through a 20 micron polypropylene
cartridge filter. The mill was flushed with 300 mL of the milling
media (milling slurry minus ganaxolone). The total weight of the
milled slurry was 1185 g. The concentration of ganaxolone was
determined to be 20.5% by HPLC. The particle size (D50) measured on
a Horiba LA 910 was 0.164 .mu.m unsonicated/0.153 .mu.m after 1
minute sonication. After 7 days at room temperature, the particle
size increased to 0.320 .mu.m (unsonicated)/0.309 .mu.m (after 1
minute sonication). This formulation was then used in different
studies as described in other examples. The D50 did not change by
more than 10% after this curing period for the duration of all
other studies conducted with this formulation.
Examples 5A-C
Preparation of Ganaxolone Nanoparticulate Suspension without a
Complexing Agent
Example 5A
Residence Time 75 Minutes
[0366] The purpose of this example is to demonstrate preparation of
an aqueous ganaxolone dispersion without a complexing agent.
[0367] Ganaxolone milling slurry (1200 g) having the same
composition as described in Example 4 without methylparaben was
milled as in Example 4 for 75 minutes of residence time. After
filtration through a 20 micron polypropylene cartridge filter and
the mill was flushed with 300 mL of milling media, milled
ganaxolone slurry (1271 g) was obtained. The concentration of
ganaxolone was 21.25% by HPLC. The particle size (D50) measured on
a Horiba LA 910 was 0.103 .mu.m (unsonicated)/0.102 .mu.m (after 1
min sonication). D50 increased slightly after storage under
refrigerated conditions. This formulation was used in other
examples.
Example 5B
Residence Time 24 Minutes
[0368] Powdered ganaxolone aqueous dispersion (1200 g) comprising a
mixture of 30 wt % ganaxolone and 5 wt % HPMC, 0.2 wt % sodium
lauryl sulfate and 100 ppm simethicone was milled in a DYNO Mill
KDL as described for Example 5A. After 24.0 minutes of residence
time, D50 was 163 nm.
Example 5C
Residence Time 50.8 Minutes
[0369] Powdered ganaxolone aqueous dispersion (1200 g) comprising a
mixture of 15 wt % ganaxolone and 3 wt % HPMC was milled in a DYNO
Mill KDL as described for Example 5A. During milling, 2 portions of
0.05% w/w sodium lauryl sulfate were added to keep the milling
slurry fluid. After 50.8 minutes of residence time, D50 was 116
nm.
Example 6
Preparation of Uncomplexed Ganaxolone Nanoparticulate Suspension
Containing HPMC, SLS and Simethicone
[0370] Powdered ganaxolone aqueous dispersion (1500 g) comprising a
mixture of 25 wt % ganaxolone, 5 wt % HPMC, 0.1 wt % sodium lauryl
sulfate and 0.028 wt % simethicone 30% emulsion (all based on total
weight of the dispersion in deionized water) was milled in a DYNO
Mill KDL as described in Example 5. After 43 minutes of residence
time, the D50 was 0.113 .mu.m (unsonicated)/0.112 (after 1 minute
sonication). The final ganaxolone concentration was 22.6% by HPLC.
This formulation was used in Example 12.
Example 7
Preparation of Uncomplexed Ganaxolone Nanoparticulate Suspension
Containing HPMC and Sodium Lauryl Sulfate and Stability
[0371] Powdered ganaxolone in deionized water (180 g) containing a
30 wt % ganaxolone (Marinus Pharmaceuticals Inc., Connecticut,
USA), 3 wt % HPMC, and 0.1% wt sodium lauryl sulfate (all based on
total weight of suspension) was milled in a DYNO Mill KDL (Willy A.
Bachofen A. G., Maschinenfabrik, Basel, Switzerland) with a 300 mL
glass batch chamber and utilizing 0.1 mm zirconium oxide beads (260
mL, 85% of the chamber volume). The milling was conducted for 120
min at a tip speed of 22.5 m/s. The particle size (D50) after
milling was 0.106 .mu.m unsonicated. The milled slurry (105 g) was
diluted with 150 g of deionized water containing 7 wt % HPMC and
0.1 wt % SLS to give a 15 wt % gnx suspension. A sample of this 15
wt % slurry was further diluted using 100 g of the slurry and 500 g
of deionized water containing 5% HPMC and 0.1% SLS to give a final
concentration of 2.5% ganaxolone in 5% HPMC, 0.1% SLS and water.
The particle size (D50) remained unchanged at room temperature
(25.degree. C.) after 4 months. This ganaxolone nanoparticle
suspension underwent flocculation upon incubation in SGF and SIF
(shown below) using the method as described in Example 3. This
material was used in one oral dog pharmacokinetics study (Example
27, formulation 27A) to show pharmacokinetics of an uncomplexed
ganaxolone suspension (D50 of 110 nm) which demonstrated good
storage stability but aggregation in simulated gastric and
intestinal fluids.
TABLE-US-00001 Initial SGF 90 min SIF 90 min D50 (.mu.m)
unsonicated/ 0.110 0.390/0.118 0.535/0.134 1 min sonication Visual
observation Flocculation Flocculation
Example 8
Preparation of Uncomplexed Phenytoin Nanoparticulate Suspension
Containing HPMC, SLS and Simethicone
[0372] The purpose of this study was to prepare a nanoparticulate
suspension of a structurally different water insoluble compound
capable of forming a cyclodextrin inclusion complex (Phenyloin,
5,5-diphenylhydantoin) to further exemplify the benefits of
stabilizing nanoparticulate compositions with a complexing
agent.
A milling slurry (164 g) containing by weight percent 20 wt %
Phenyloin 5% wt HPMC, 0.1 wt % SLS, 0.03 wt % simethicone 30%
emulsion and 74.87% deionized water was milled in the same manner
as described in Example 7 for 35 minutes using 0.3 mm zirconium
oxide balls (260 ml, 85% of chamber volume). The particle size
(D50) after milling was 0.150 .mu.m unsonicated/0.127 .mu.m after 1
min sonication.
Examples 9A-B
Preparing Phenytoin Nanoparticulate Compositions with and without a
Complexing Agent
[0373] The purpose of this example was to create complexed and
uncomplexed phenyloin nanoparticulate suspensions to further
exemplify the benefits of a complexing agent and an ionic
dispersion modulator in forming more stable solid nanoparticulate
compositions.
Example 9A
Uncomplexed Phenyloin Nanoparticulate Compositions
[0374] A milling slurry (1500 g) comprising a mixture of 20% wt
phenyloin, 5 wt % HPMC (Pharmacoat 603), 0.1 wt % SLS and 0.028 wt
% simethicone 30% emulsion was milled in a DYNO Mill KDL as
described in Example 6 for a residence time of 26 minutes (total
milling time of 145 minutes) to obtain 1419.6 g of milled
suspension after filtration. The D50 after milling was 0.141 .mu.m
unsonicated and 0.128 .mu.m after 1 minute sonication. The
uncomplexed composition after 5 days at room temperature had a D50
of 0.169 .mu.m unsonicated/0.144 .mu.m after 1 minute
sonication.
Example 9B
Complexed Phenytoin Nanoparticulate Compositions
[0375] To a portion of the milled phenyloin suspension (496.1 g) of
Example 9A was added methyl anthranilate (2 g, 0.4%) as a
complexing agent. The milled material with the complexing agent was
allowed to cure for 5 days. The D50 for the complexed material
after 5 days of curing time was 0.206 .mu.m unsonicated/177 .mu.m
after 1 minute sonication.
[0376] The complexed and uncomplexed suspensions were used to
create solid dose nanoparticulate phenyloin compositions described
in Examples 18 and 24.
Example 10
Stability Studies of Complexed and Uncomplexed Aqueous Phenyloin
Nanoparticulate Compositions in SGF and SIF
[0377] This example demonstrates that enhanced stability of a
phenyloin nanoparticulate suspension in USP simulated gastric and
intestinal fluids can be obtained by addition of a complexing
agent.
[0378] A sample of the uncomplexed phenyloin nanoparticle
suspension (17 g) prepared in Example 8 was added methyl
anthranilate (71.4 mg, 0.42%) and the suspension was allowed to
cure for 5 days at room temperature (25.degree. C.).
[0379] The initial D50 value for the uncomplexed suspensions at the
time of study were 0.162 .mu.m unsonicated/0.123 .mu.m after 1
minute sonication, whereas the initial D50 value for the complexed
suspensions were 0.169 .mu.m unsonicated/0.159 .mu.m after 1 min
sonication.
[0380] The uncomplexed and complexed suspensions were incubated
side by side in SGF and SIF using the method described in Example
3. The uncomplexed composition visibly flocculated and settled to
the bottom of the vials after 1 hour whereas the complexed
composition remained dispersed in both conditions for the 3 hour
period. Additionally, the complexed composition in both SGF and SIF
showed less particle size changes when examining both unsonicated
and sonicated D50 values to initial values as well as demonstrating
less loose aggregation (difference between D50 unsonicated and
sonicated for 1 minute). The results are shown in Table 1.
TABLE-US-00002 TABLE 1 D50 values for Complexed and Uncomplexed
Aqueous Phenytoin Nanoparticulate Compositions Before and After
Incubation in SGF and SIF Methyl D50 (.mu.m) anthranilate Initial
D50 (.mu.m) unsonicated/1 min (% wt/ unsonicated/1 min sonication
after 3 Incubation Entry Phenytoin) sonication hours incubation
Medium 1 2.1 0.169/0.159 0.302/0.219 SGF 2 2.1 0.169/0.159
0.316/0.211 SIF 3 0 0.162/0.123 0.868/0.322 SGF 4 0 0.162/0.123
1.18/0.298 SIF
Examples 11A-C
Comparative Stability Studies of Complexed and Uncomplexed
Ganaxolone Nanoparticle Suspensions
[0381] This example demonstrates the enhanced stability of
ganaxolone nanoparticulates complexed with methylparaben compared
with uncomplexed ganaxolone nanoparticulates after incubation in
SGF, SIF, heating to 100.degree. C. and conducting several
freeze/thaw cycles.
Example 11A
Stability in SGF and SIF at 36-38.degree. C.
[0382] The complexed ganaxolone nanosuspension of Example 4 and
uncomplexed ganaxolone nanosuspension of Example 5A after a curing
time (for complexed preparations) of at least 7 days of storage at
room temperature (20-25.degree. C.) were incubated side by side in
SGF and SIF using the method described in Example 3. The D50 of the
complexed formulation (Entry 1, Table 2) increased only slightly
(<23% unsonicated and 9% after 1 minute sonication) from its
initial values. In contrast, the D50 of the uncomplexed formulation
(Entry 2, Table 2) increased at least 560% unsonicated and 153%
after 1 minute sonication from its initial values. The 1.5-fold
increase in D50 after sonication indicates the formation of either
strong aggregation or particle growth. Similar trends were observed
after doubling the amount of HPMC and SLS versus ganaxolone
(Entries 3-4, table 2). Doubling the HPMC and SLS amounts versus
ganaxolone was achieved by diluting a 5 g sample from Examples 4
and 5 with 5 g of deionized water containing 5 wt % HPMC, 0.3 wt %
SLS and 0.033 wt % simethicone (30% emulsion).
TABLE-US-00003 TABLE 2 Comparative gastric and intestinal stability
studies of methylparaben complexed (initial D50: 0.320 .mu.m
unsonicated/0.309 .mu.m after 1 minute sonication) and uncomplexed
(initial D50: 0.136 .mu.m unsonicated/0.112 .mu.m 1 minute
sonication) ganaxolone nanoparticle suspensions D50 (.mu.m) HPMC
SLS Methylparaben No Sonication/1 Test Entry %(wt/GNX) %(wt/GNX)
%(wt/GNX) min sonication conditions.sup.1 1 24.4 1.46 0.98
0.382/0.324 A 0.394/0.326 B 2 23.5 1.41 0 0.897/0.290 A 7.36/0.283
B 3 47.1 2.82 0 0.828/0.258 A 0.933/0.267 B 4 48.8 2.93 0.98
0.350/0.314 A 0.353/0.313 B .sup.1Incubation conditions: A, SGF,
36-38.degree. C., 3 h; B. SIF, 36-38.degree. C., 3 h see Example 3
for method.
Example 11B
D50 Stability of Complexed and Uncomplexed Ganaxolone Liquid
Nanoparticulate Compositions After Heating at 100.degree. C.
[0383] The milled compositions of Example 4 (complexed) and Example
5A (uncomplexed) (approximately 2 g each) were placed in 25 mL
glass vials and sealed with a plastic cap. The vials were heated in
a 100.degree. C. oil bath. The D50 of the complexed formulation did
not change after heating for 4 h (both unsonicated and 1 minute
sonication) (Table 3). In contrast, D50 of the uncomplexed
suspension continued to grow over the 4 hour period and doubled in
size from initial values as shown in Table 3.
TABLE-US-00004 TABLE 3 Changes in D50 values for Complexed and
Uncomplexed Liquid Ganaxolone Nanoparticulate Compositions D50
(.mu.m) after 20 D50 (.mu.m) after Initial D50 (.mu.m) min at
100.degree. C. 4 h at 100.degree. C. Suspension unsonicated/after
unsonicated/after unsonicated/after Formulation 1 min sonication 1
min sonication 1 min sonication Methylparaben 0.320/0.298
0.326/0.311 0.320/0.310 complexed Uncomplexed 0.149/0.140
0.246/0.207 0.317/0.302
Example 11C
Stability of Complexed and Uncomplexed Ganaxolone Compositions
After Freeze/Thaw Cycles
[0384] Ganaxolone formulations of Example 4 (complexed) and Example
5A (uncomplexed) were tested for freeze thaw stability as
follows:
[0385] Ten grams of each formulation was placed into a 25 ml HDPE
scintillation vial with HDPE cap. These were placed into a 500 ml
glass beaker containing approx. 1 inch of Styrofoam packing (to
slow freezing process) and placed into an insulated carton
containing crushed dry ice. The vials were stored overnight and
then thawed at room temperature for 1 hour. This process was
repeated until 3 freeze/thaw cycles had been completed. The D50 was
measured and compared to control material stored at room
temperature in the same container closure system. The D50 of the
complexed formulation did not change after 3 freeze/thaw cycles
(Table 4). In contrast, D50 of the uncomplexed formulation
increased 450% (unsonicated) and 144% (1 minute sonication) after
the same treatment (Table 4).
TABLE-US-00005 TABLE 4 Particle size (D50) before and after
freezing/thaw cycles for complexed ganaxolone particles and
uncomplexed ganaxolone particles Initial D50 (.mu.m) D50 (.mu.m)
after 3 freeze/ unsonicated/after thaw cycles unsonicated/
Formulation 1 min sonication after 1 min sonication Methylparaben
0.320/0.298 0.319/0.310 complexed Uncomplexed 0.149/0.140
0.822/0.341
Example 12
Stability of Complexed Ganaxolone Aqueous Nanoparticulate
Suspensions in SGF and SIF
[0386] Aliquots of the uncomplexed ganaxolone suspension from
Example 6 were diluted with either diluent A or diluent B (diluent
composition listed in tabular form below) in 1:2 ratio (Example 6
Suspension/Diluent) to provide two 75 mg/ml ganaxolone nanoparticle
suspension; One with 0.1 wt % methylparaben and 0.02 wt %
propylparaben as complexing agents (Diluent A) and the other with
0.09 wt % sodium benzoate as the complexing agent with pH adjusted
to 4 by the sodium citrate buffer (Diluent B). Additionally both
formulations contained the following: 5 wt % HPMC, 1 wt % PVA, 0.1
wt % SLS. The two formulations were allowed to cure for at least
5-7 days (paraben complexed formulation) and 20 days (sodium
benzoate complexed formulation) to reach a stable particle size
(D50) of 0.314 .mu.m (unsonicated)/0.311 .mu.m (after 1 minute
sonication) for the paraben complexed formulation and 0.321 .mu.m
(unsonicated)/0.314 .mu.m (after 1 minute sonication) for the
sodium benzoate complexed formulation at a pH of 4.
TABLE-US-00006 Diluent A Diluent B Ingredients % wt % wt
Hypromellose (Pharmacoat 603) 5.00 5.00 Polyvinyl Alcohol 1.50 1.50
Sodium Lauryl Sulfate 0.10 0.10 Methylparaben 0.15 0.00
Propylparaben 0.03 0.00 sodium benzoate 0.00 0.14 citric acid
anhydrous 0.00 0.18 Sodium citrate 0.00 0.014 Deionized water 93.22
93.07 Total: 100.00 100.00
[0387] The complexed ganaxolone nanoparticulate suspensions as
described above were incubated in SGF and SIF at 36-38.degree. C.
for 3 h as in the method described in Example 3. The results are
listed in Table 5 which showed virtually no increase in particle
size (D50) after incubation in SGF and SIF.
TABLE-US-00007 TABLE 5 Test results in SGF and SIF for Complexed
and Uncomplexed Aqueous Nanoparticulate Ganaxolone Compositions D50
(.mu.m) after D50 (.mu.m) after Complexing incubation in SGF
incubation in SIF agent/amount Initial D50 (.mu.m), for 3 h, no for
3 h no (% wt of total unsonicated/after sonication/after
sonication/after Entry formulation) 1 min sonication 1 min
sonication 1 min sonication A Methylparaben/0.1% 0.314/0.311
0.326/0.313 0.344/0.330 Propylparaben/0.02% B Sodium 0.321/0.314
0.322/0.312 0.329/0.313 benzoate/0.09% Citric acid/0.12% Sodium
citrate/0.0093% .sup.a The composition of the test formulations
are: 7.5 wt % ganaxolone, 5 wt % HPMC, 1 wt % PVA, 0.1 wt % SLS in
addition to the amounts of complexing agents and pH adjusting
agents listed in Table 5.
Example 13
SGF Stability of Methyl Anthranilate Complexed Versus Uncomplexed
Ganaxolone Nanoparticulate Suspensions
[0388] To the uncomplexed ganaxolone nanoparticulate suspension
prepared as in Example 6 was added 0.1 wt % or 0.4 wt % methyl
anthranilate. All suspensions (with and without methyl anthranilate
as the complexing agent) were kept at room temperature to allow
sufficient curing time to obtain complexed particles. The complexed
suspensions were tested in SGF with the uncomplexed control as per
Example 3. The results are shown in Table 6 below. The complexed
formulation showed virtually no change from initial after
incubation in SGF. In contrast, the uncomplexed control showed
3-fold increase in D50 unsonicated and 1.6-fold after 1 min
sonication.
TABLE-US-00008 TABLE 6 D50 values for Complexed (methyl
anthranilate) and Uncomplexed Aqueous Ganaxolone Nanoparticulate
Compositions in SGF Initial D50 (.mu.m) D50 (.mu.m) in SGF
Formulation unsonicated/after unsonicated/after Type 1 min
sonication 1 min sonication Uncomplexed 0.215/0.188 0.656/0.312
Complexed with 0.1 wt % 0.311/0.306 0.363/0.306 Methyl Anthranilate
Complexed with 0.4 wt % 0.480/0.460 0.541/0.465 Methyl
Anthranilate
Example 14
Preparation of Pharmaceutically Useful Complexed Ganaxolone
Suspension Formulations (50 mg/mL) from Milled Uncomplexed
Ganaxolone Nanoparticulate Suspensions
[0389] This example illustrates the dilution to 50 mg/mL ganaxolone
nanoparticulate suspension formulations.
Method A (One-Step Dilution):
[0390] An uncomplexed ganaxolone nanoparticulate suspension of
known ganaxolone concentration prepared as described in Example 5A
is diluted with appropriate amount of diluent containing
appropriate levels of excipients and other necessary components
such as preservatives, complexing agents, flavoring, sweetener and
antifoaming agent to achieve 50 mg/mL drug concentration.
Method B (Two-Step Dilution):
[0391] An uncomplexed ganaxolone nanoparticulate suspension
prepared as described in Example 5A is first diluted to an
intermediate drug concentration (ca. 80 mg/mL) with appropriate
amount of diluent containing appropriate levels of surface
stabilizers excipients and all necessary components such as
preservatives, complexing agents, antifoaming agents, flavoring and
sweeteners. For example, for a milled uncomplexed ganaxolone
nanoparticulate suspension with an initial (milling slurry)
ganaxolone concentration of 25 wt % is diluted by mixing one part
of the milled suspension with two parts of the diluent to obtain an
intermediate concentration of complexed ganaxolone nanoparticulate
suspension of about 8 wt %. The precise ganaxolone concentration is
then determined by appropriate assay (e.g. HPLC). The final
dilution to 50 mg/mL ganaxolone is performed with an appropriate
amount of diluent containing the correct levels of all excipients
and other components.
Example 15
Preparation of Solid Nanoparticulate Particles Via Rotary
Evaporator Drying and Composition Optimization for Solid
Nanoparticulate Compositions
[0392] This method was applied for ganaxolone nanoparticulate
composition optimization. The method described below can be
generally applied to other water insoluble nanoparticulate
compositions.
General Method for Drying Aqueous Nanoparticulate Compositions to
Solids
[0393] A general method for drying small samples of complexed and
uncomplexed nanoparticulate compositions for solid dose
optimization studies is as follows: One gram of complexed or
uncomplexed nanoparticulate suspension was placed in a 25 ml glass
scintillation vial then fitted onto a Buchi rotary evaporator
R-124. The vial was rotated at 150-175 rpm and the water bath
temperature set at 70.degree.-90.degree. C. Full vacuum was applied
(2 to 4 mbar) over a 2 minute period and continued for 20 to 25
minutes until all visible signs of moisture were gone. This method
yields vials containing solids which are used for incubation
studies.
[0394] During optimization for a solid composition, additional
components were added to the nanoparticulate suspensions prior to
drying as follows: The components were weighed into the vial first
and 0.5 g of deionized water was added to dissolve or disperse the
component(s). To this solution/suspension was added 1.0 g of the
nanoparticulate suspension. The contents of the vial were swirled
manually for 15-30 seconds followed by evaporation of water as
described above.
Example 16
Stability of Complexed and Uncomplexed Solid Ganaxolone
Nanoparticulate Compositions in SGF and SIF
[0395] Complexed and uncomplexed aqueous ganaxolone milled
suspensions from Examples 4 and 5A respectively were used and
additional components were added and removal of water was conducted
as by the method described in Example 15.
[0396] D50 changes from the initial values with and without
sonication are listed in Table 7. Incubation in SGF and SIF were
conducted using the method described in Example 3. Complexed
Ganaxolone nanoparticles showed 2-4 fold increase in unsonicated
D50 values versus initial values. No change in sonicated D50 values
was observed. Uncomplexed ganaxolone nanoparticles showed a 27-fold
increase in unsonicated D50 values versus initial values and still
showed a 7-9-fold increase in sonicated D50 values versus initial
values. For the complexed formulation, addition of sucrose prior to
drying reduced aggregation and/or particle size growth (2-fold
increase in D50 unsonicated in SIF versus initial and no increase
in D50 values sonicated or unsonicated in SGF from initial). In
contrast, the uncomplexed formulation with sucrose added still
showed unsonicated D50 increasing >18-fold versus initial
values, and at least a doubling of the D50 from initial values with
sonication.
TABLE-US-00009 TABLE 7 Comparative Incubation Results in SGF and
SIF of Dried Ganaxolone Nanoparticulate Compositions: Methylparaben
Complexed (Initial D50: 0.310 .mu.m unsonicated/0.298 .mu.m after 1
minute sonication) versus Uncomplexed (Initial D50: 0.147 .mu.m
unsonicated/0.140 .mu.m after 1 minute sonication). D50 (.mu.m)
Sucrose % HPMC SLS % Methylparaben No sonication/1 dispersing Entry
(wt/GNX) (wt/GNX) (wt/GNX) % (wt/GNX) min sonication
conditions.sup.1 1 0 47.1 2.82 0 4.02/1.12 SGF, 3 h 4.13/1.24 SIF,
3 h 2 0 48.8 2.93 0.98 0.636/0.314 SGF, 3 h 1.28/0.322 SIF, 3 h 3
103.8 46.7 2.8 0.98 0.383/0.292 SGF, 3 h 0.588/0.304 SIF, 3 h 4
104.4 47.1 3.1 0 2.72/0.293 SGF, 3 h 5.46/0.301 SIF, 3 h .sup.1All
conditions run as in Example 3
Examples 17A-B
Effect of an Ionic Dispersion Modulator in Complexed and
Uncomplexed Ganaxolone Nanoparticulate Solid Compositions
[0397] This example shows the effect of various amounts of an ionic
dispersion modulator (e.g., sodium chloride) on stabilizing and
reducing the amount of sucrose needed to reduce changes in D50
values (from initial) when dispersed in SGF and SIF.
Example 17A
Preparation of Solid Ganaxolone Nanoparticulate Compositions
Containing an Ionic Dispersion Modulator by Rotary Evaporator
Drying
[0398] The following is an example of preparing solid complexed and
uncomplexed ganaxolone nanoparticulate compositions listed in Table
8 by the method of Example 15. Other compositions listed in Table 8
were prepared using the same procedure by adding the appropriate
amount of salt and sucrose unless otherwise specified in Table
8.
[0399] The following components were placed in a 25 ml glass
scintillation vial: 5.13 mg of sucrose crystals and 12.5 mg of 25
wt % sodium chloride solution. Deionized water (0.5 g) was then
added to dissolve the sucrose crystals and to achieve a homogeneous
solution.
[0400] The complexed ganaxolone suspension (1 g) of Example 4
containing 20.5 wt % ganaxolone, 5.0 wt % HPMC, 0.3 wt % sodium
lauryl sulfate, 0.2 wt % methylparaben 0.03 wt % simethicone (30%
emulsion in water) was then added to the vial and the mixture was
swirled to mix well. The contents in the vial were then dried per
Example 15. This produced the composition listed in Table 8, Entry
7.
TABLE-US-00010 TABLE 8 Compositions Demonstrating benefits of an
Ionic Dispersion modulator Nanoparticulate NaCl Deionized
Ganaxolone solution water Entry .sup.c Suspension (g) (25 wt %)
Sucrose (g) (g) 1 1.0 0.3 0 0.5 2 1.0 0.1 0 0.5 3 1.0 0.050 0 0.5 4
1.0 0.025 0 0.5 5 1.0 0.0125 0 0.5 6 1.0 0.0125 0.01025 0.5 7 1.0
0.0125 0.00513 0.5 8 1.0 0.0164 0 0.5 9 1.0 .sup. 0.050 .sup.a 0
0.5 10 1.0 0 0 0.5 .sup. 11 .sup.b 1.0 .sup. 0.050 .sup.a 0 0.5
.sup.a Salt was added as solid; .sup.b The nanoparticle slurry was
from Example 5A; .sup.c Complexed Ganaxolone suspension from
Example 4 was used in Entry Nos. 1-10.
Example 17B
Dispersion Results of Dried Complexed and Uncomplexed Ganaxolone
Nanoparticles in Both SGF and SIF
[0401] Table 9 shows the degree of aggregation of solid
nanoparticulate complexed and uncomplexed ganaxolone compositions
incubated in SGF and SIF. The Entry number in Table 9 corresponds
to the compositions given in Table 8.
[0402] Sodium chloride as an ionic dispersion modulator is very
effective in preventing aggregation in SGF and SIF when used with a
complexed nanoparticle formulation. Addition of an ionic dispersion
modulator also allows the complexed solid nanoparticulate
formulation to have a higher drug concentration by requiring less
of a water soluble spacer (e.g. sucrose) to achieve minimal
aggregation. This ability to create more stable and concentrated
solid formulation is needed in preparing commercially viable
compositions of drugs requiring a high dose.
[0403] Addition of an ionic dispersion modulator allows for more
concentrated drug compositions.
TABLE-US-00011 TABLE 9 Effect of an Ionic Dispersion Modulator on
the Dispersion of Dried Ganaxolone Compositions (With and Without a
Complexing Agent) in Simulated Gastric and Intestinal Fluid (SGF
and SIF) Simethicone Methyl- D50(.mu.m) HPMC SLS 30% emulsion
paraben NaCl Sucrose unsonicated/1 Dispersion Entry % wt/GNX %
wt/GNX % wt/GNX % wt/GNX % wt/GNX % wt/GNX min sonication
conditions.sup.1 10 24.4 1.46 0.15 0.98 0 0 13.2/0.332 A 0.286 B 9
24.4 1.46 0.15 0.98 24.4 0 0.344/0.319 A 11 23.5 1.41 0.14 0 23.5 0
22.7/8.9 A 5 24.4 1.46 0.15 0.98 1.5 0 3.17/0.337 A 4.45/0.353 C 6
24.4 1.46 0.15 0.98 1.5 5 0.364/0.316 A 0.396/0.322 C 0.490/0.331 D
0.561/0.329 E 7 24.4 1.46 0.15 0.98 1.5 2.5 0.395/0.323 A
0.370/0.312 C 0.416/0.326 D 0.533/0.331 E 8 24.4 1.46 0.15 0.98 2.0
0 0.548/0.334 A 0.506/0.326 C 4 24.4 1.46 0.15 0.98 3.0 0
0.355/0.319 A 0.367/0.315 C 0.485/0.329 D 0.609/0.334 E 3 24.4 1.46
0.15 0.98 6.1 0 0.338/0.314 A 0.429/0.337 C 2 24.4 1.46 0.15 0.98
12.2 0 0.353/0.317 A 0.367/0.318 C 9 24.4 1.46 0.15 0.98 24.4 0
0.440/0.322 D 0.459/0.324 E 1 24.4 1.46 0.15 0.98 36.6 0
0.346/0.315 A 0.372/0.317 C .sup.1Dispersion conditions: A, SGF, 5
min, rt; B, deionized water, 5 min, rt; C, SIF, 5 min, rt; D, SGF,
3 h, 36-38.degree. C., stirred; E, SIF, 3 h, 36-38.degree. C.,
stirred.
Example 18
Effect of an Ionic Dispersion Modulator (Sodium Chloride) on
Complexed and Uncomplexed Nanoparticulate Phenyloin Solid
Compositions
[0404] The complexed and uncomplexed phenyloin nanoparticulate
suspensions of Example 9, were diluted (1:1 by weight, 5 g of each)
with deionized water containing 6.25 wt % HPMC and 0.125 wt % SLS
to obtain phenyloin nanoparticulate suspensions containing 10 wt %
phenyloin, 5.625 wt % HPMC, 0.1125 wt % SLS for rotary evaporated
drying. The suspensions (0.5 g) containing appropriate amount of
urea and/or sodium chloride were dried on a Buchi rotary evaporator
using the method described in Example 15 to obtain dried phenyloin
nanoparticulate powders. The dried phenyloin nanoparticulate
powders were incubated in SGF per Example 3. The results are shown
in Table 10 below:
TABLE-US-00012 TABLE 10 Effect of an Ionic Dispersion Modulator
(NaCl) on the Dispersion of Rotary Evaporated Solid Complexed and
Uncomplexed Phenytoin Nanoparticulate Compositions in SGF. D50
(.mu.m) after incubation in SGF HPMC SLS Methyl Sucrose Urea NaCl
(36.degree.-38.degree. C., 70 minutes) % wt/ % wt/ anthranilate %
wt/ % wt/ % wt/ 1 min Entry API API % wt/API API API API
Unsonicated sonication 1.sup.a 56.25 1.125 2 0 0 0 5.87 0.299
2.sup.a 56.25 1.125 2 0 100 0 3.493 0.273 3.sup.a 56.25 1.125 2 0 0
5 8.914 0.353 4.sup.a 56.25 1.125 2 10 0 5 23.64 5.961 5.sup.a
56.25 1.125 2 0 8 5 0.405 0.249 0.283 0.206 (DI water) (DI water)
6.sup.a 56.25 1.125 2 0 8 0 3.894 0.287 0.290 0.216 (DI water) (DI
water) 7.sup.a 56.25 1.125 2 0 0 20 0.325 0.228 8.sup.b 56.25 1.125
0 0 8 5 16.642 1.926 .sup.aPrepared from methyl anthranilate (0.4
wt %) complexed phenytoin nanoparticulate suspension with initial
D50 (.mu.m) of 0.211(unsonicated)/0.187(after 1 min sonication);
.sup.bPrepared from uncomplexed phenytoin nanoparticulate
suspension with initial D50 (.mu.m) of 0.161(unsonicated)/0.141
(after 1 min sonication).
In the above example, urea was identified as a water soluble
spacer.
Examples 19-20
[0405] Examples 19-20 below demonstrate that certain complexed
ganaxolone spray dried and spray layered compositions containing an
ionic dispersion modulator have less aggregation in SGF and SIF
(unsonicated) by a factor of greater than 10-fold. Additionally the
examples below show less aggregation for certain complexed
phenyloin nanoparticulate formulations than for uncomplexed.
Example 19
Preparation of Complexed Ganaxolone Nanoparticulate Suspension for
Spray Layering and Spray Drying
[0406] Complexed ganaxolone nanoparticulate suspensions for spray
layering and spray drying were prepared by milling a slurry (7000
g) containing 28.3 wt % ganaxolone, 3 wt % HPMC, 0.15 wt % SLS and
0.033 wt % simethicone (as a 30% emulsion) as described in Example
6. After milling, a complexing agent (methylparaben sodium, 12.60
g), SLS (11.52 g), citric acid anhydrous (13.91 g) and deionized
water (3972.93 g) were added and stirred for 20 minutes. After
stirring, the suspension was packaged in a HDPE container and kept
at room temperature (25.degree. C.) to cure. After a curing time of
2 weeks, additional components (e.g. sucrose, PEG, salt) were added
and diluted with water to desired concentration for spray layering
or spray drying. D50 values were 0.336 .mu.m (unsonicated)/0.332
.mu.m (after 1 min sonication).
Examples 20A-C
Spray Layered Complexed and Uncomplexed Ganaxolone Nanoparticulate
Composition
[0407] The spray-layered complexed and uncomplexed ganaxolone
nanoparticulate compositions of Examples 20A-C were prepared using
the following method:
[0408] A Mini Glatt 8560 (Glatt Air Techniques, Ramsey, N.J.) was
configured for fluid bed coating using a 0.5 mm Schlick nozzle with
a Wurster column (3.5 cm.times.9.5 cm) set 10 mm above the bottom
of the chamber floor. The temperature of the bed was monitored with
an internal probe. A peristaltic pump was used to introduce the
spray solutions through the nozzle. The unit was first pre-heated
for one hour at 56.degree. C. The bed chamber was opened and 40 g
of MCC beads (Celphere, CP-305) was introduced and a pressure of
0.36 bar was used to fluidize the bed. To minimize electrostatic
charges, water was immediately sprayed (atomization pressure 0.26
bar). After 1-2 minutes of spraying, the feed line was switched to
a stirred vessel containing the ganaxolone spray slurry.
[0409] Examples 20A and 20B demonstrate optimization of SGF
dispersion testing results of a complexed ganaxolone spray layered
composition (immediate release) for dog pharmacokinetics described
below in Example 27. Example 20C describes spray layering of an
uncomplexed ganaxolone nanoparticulate composition.
[0410] The ingredients contained in the solid composition of each
of the compositions of Examples A-C are shown in Table 11A.
TABLE-US-00013 TABLE 11A Solid composition of spray layered
ganaxolone nanoparticulate compositions (complexed vs uncomplexed)
Solid Composition (% wt of total solid excluding MCC cores) Methyl
Spray PEG PEG Sodium paraben Citric Methyl Simethi- Form GNX HPMC
SLS 400 4000 Sucrose chloride sodium acid paraben cone 20A 69.54
20.05 2.37 3.92 0 0 3.13 0.46 0.50 0 0.02 20B 49.99 12.30 0.26 0
3.16 33.36 0.64 0 0 0.28 0.02 20C 68.16 16.04 0.96 0 14.81 0 0 0 0
0 0.03
[0411] The dispersion testing results for each of the compositions
of Examples 20A-C are shown in Table 11B.
TABLE-US-00014 TABLE 11B Dispersion Results in SGF or Water Initial
D50 Dispersion D50 (.mu.m) (.mu.m) Spray unsonicated/1
unsonicated/1 Testing Formulation min sonication min sonication
Conditions.sup.A 20A 0.339/0.332 6.67/0.369 SGF, 20B 0.356/0.346
0.395/0.370 SGF, 0.366/0.343 Deionized Water 20C 0.170/0.160
0.202/0.196 Deionized Water 5.57/0.392 SGF, .sup.AConditions were
36-38.degree. C. for 3 hours unless specified otherwise.
Example 20A
Complexed Ganaxolone Spray Formulation
[0412] A total of 38.1 g of the ganaxolone spray slurry was sprayed
over 39 minutes (average spray rate approximately 1 ml/min). The
bed temperature ranged from 45 to 49.degree. C. The spray layered
beads were dried for an additional 7 minutes after the spraying was
completed. Spray layered beads (47 g) were isolated. Theoretical
loading of layered solid: 19.7%.
Example 20B
Complexed Ganaxolone Spray Formulation
[0413] A total of 80 g of slurry was sprayed onto 40 g of MCC beads
(Celphere CP-305) over a period of 105 minutes to obtain 63 g of
spray layered beads (57.5% loading). The bed temperature was
maintained at 43-47.degree. C. and inlet air temperature was
54.degree. C.
Example 20C
Uncomplexed Ganaxolone Spray Formulation
[0414] This spray formulation was prepared by adding PEG 4000 (3 wt
% of total formulation) to the uncomplexed ganaxolone
nanoparticulate suspension of Example 5A. A total of 93 g of slurry
was sprayed onto 40 g of MCC beads (Celphere CP-305) over a period
of 110 minutes to obtain 58 g of spray layered beads (45% loading).
The bed temperature was maintained at 36-44.degree. C. and inlet
air temperature was 48.degree. C.
Examples 21A-B
Spray Dried Complexed and Uncomplexed Ganaxolone Nanoparticulate
Composition
Example 21A
Spray Dried Complexed Ganaxolone Nanoparticulate Compositions
[0415] To the complexed ganaxolone nanoparticle suspension of
Example 19 was added sucrose, and sodium chloride. The mixture was
diluted with deionized water to obtain the following composition
suitable for spray drying: 14.47 wt % Ganaxolone, 1.91 wt % HPMC,
0.96 wt % SLS, 2.15 wt % sucrose, 1.43 wt % NaCl, 0.04 wt %
methylparaben and 0.006 wt % simethicone 30% emulsion. This slurry
(478 g) was spray dried on a Buchi B-191 Mini Spray Drier to obtain
63.4 g of dry ganaxolone nanoparticle powder. The process
parameters were as the following: average spray rate: 5.3 g/min;
outlet temperature: 64-66.degree. C.; inlet temperature:
108-114.degree. C.; airflow: 85% aspiration. D50 values for the
ganaxolone nanoparticles were 0.329 .mu.m unsonicated/0.318 .mu.m
after 1 minute sonication upon re-dispersion in water. D50 values
in SGF were 0.317 .mu.m unsonicated/0.306 .mu.m 1 minute
sonication.
Example 21B
Spray Dried Uncomplexed Ganaxolone Nanoparticulate Composition
[0416] To an uncomplexed ganaxolone nanoparticle suspension milled
in a similar fashion as described in Example 6 was added PEG 3350
and diluted with deionized water to obtain the following
composition: 22.88 wt % Ganaxolone, 4.78 wt % HPMC, 0.19 wt % SLS,
4.31 wt % PEG 3350 and 0.032 wt % simethicone 30% emulsion. This
slurry was spray dried on a Buchi B-191 Mini Spray Drier in a
similar fashion as described in above Example 20A to obtain dry
ganaxolone nanoparticulate powder in 62% yield. D50 of the
ganaxolone nanoparticles was 0.249 .mu.m unsonicated/0.220 .mu.m
after 1 minute sonication upon re-dispersion in water. D50 in SGF
was 4.71 .mu.m unsonicated/2.54 .mu.m after 1 minute
sonication.
Example 22
Preparation of an Enteric Coated (Controlled Release) Complexed
Ganaxolone Formulation
[0417] The complexed spray layered beads prepared as described in
Example 20B is spray coated with an enteric coating formulation
having the following composition:
TABLE-US-00015 Component Amount (g) Eudragit L30 D-55 (Degussa) 96
Triethyl citrate 4 Talc 8 Water 95
[0418] The coating process is carried out as follows:
[0419] Charge 140 g of spray layered IR beads and 1 g talc to the
pre-heated mini Glatt, which has been configured with a 3.5
cm.times.9.5 cm Wurster column and a 0.5 mm Schlick nozzle as
described in Examples 20A-C. The thermostat on the Glatt is set to
40.degree. C. and the drying air pressure to 0.20 bar.
[0420] Eudragit enteric coating formulation is introduced to the
mini Glatt via a peristaltic pump that is positioned in close
proximity. The coating formulation is well stirred during the
coating. The Eudragit slurry is added at 2.5 ml/min with an
atomization pressure of 0.92 bar. The bed temperature is maintained
between 26 and 28.degree. C.
[0421] After completion of the coating process, the coated beads
are allowed to cool for 5 minutes. After cooling, one hundred and
thirty grams (130 g) of the Eudragit slurry is coated onto the
beads. This amounts to 18.4% of coating solids. The weight of the
coated beads isolated is 166 g.
Example 23
Preparation of Solid Complexed Ganaxolone Particles Via Spray
Granulation
[0422] A Mini Glatt (Glatt Air Techniques, Ramsey, N.J.) is
configured for top spray with a fluid bed. A 0.5 mm Schlick-type
nozzle is inserted above the fluid bed. Then, 50 g of lactose
monohydrate (Kerry) is added and fluidized with 0.27 bar pressure.
The apparatus is heated to 50.degree. C. for approximately 30 min
with bed fluidization pressure of 0.20-0.25 bar.
[0423] A ganaxolone slurry comprising 14 wt % ganaxolone, 3.5 wt %
HPMC, 8 wt % sucrose, 0.08 wt % methylparaben, 0.07 wt % sodium
benzoate, 0.14% citric acid, 0.9 wt % PEG 4000, 0.4 wt % sodium
chloride is introduced by a peristaltic pump through the
top-mounted nozzle.
[0424] The spray pressure ranges from 0.27 to 0.35 bar and the bed
temperature is held at 40-45.degree. C. while spraying at 1 to 2
ml/min. The fine powered lactose becomes granular during the
spraying. A total of 36 g of 21% solids is sprayed, for a solids
loading of 20%.
Examples 24A-D
A Spray Layered Complexed and Uncomplexed Phenyloin Nanoparticulate
Composition
[0425] A Mini Glatt 8560 was configured for spray layering as
described in Examples 20 A-C. The unit was pre-heated at 60.degree.
C. The bed chamber was opened and 75 g of MCC beads (Celphere,
CP-305) was introduced and a pressure of 0.30-0.32 bar was used to
fluidize the bed. To minimize electrostatic charges, water was
immediately sprayed (atomization pressure 1 bar). After 1-2 minutes
of spraying, the feed line was switched to a stirred vessel
containing the phenyloin spray slurry. The bed temperature was
maintained at 36-41.degree. C. during spraying. The spray layered
beads were incubated in SGF per Example 3 and the testing results
are shown in Table 12.
Example 24A
Uncomplexed Phenytoin Spray Composition
[0426] This formulation was prepared by adding sucrose (5.4 g),
sodium chloride (0.2 g), SLS (0.06 g) and deionized water to the
uncomplexed phenyloin nanoparticulate suspension of Example 9
(100.0 g). It was sprayed at 2.5 ml/min. After completion of the
spray layering, 96.8 g of spray layered beads were obtained. The
loading was 29%.
Example 24B
Complexed Phenyloin Spray Composition
[0427] This formulation was prepared and spray layered as described
for the above formulation 24A except using the complexed phenyloin
nanoparticulate of Example 9. After completion of spraying, 101.1 g
of spray layered beads was obtained. The loading was 34.8%.
Example 24C
Uncomplexed Phenytoin Spray Composition
[0428] This formulation was prepared by adding a solution of urea
(0.8 g), sodium chloride (0.5 g) in deionized water (2 g) to the
uncomplexed phenyloin nanoparticulate suspension of Example 9 (50.0
g). The resultant suspension was diluted with deionized water (50
g) containing 6.25 wt % HPMC, 0.125 wt % SLS and 0.08 wt %
simethicone 30% emulsion. This suspension was spray layered onto 75
g of the MCC beads (Celphere CP-305) as described for spray
formulation 24A. After completion, phenyloin spray layered beads
(87.2 g) was obtained. The loading of phenyloin on the beads was
16.2%.
Example 24D
Complexed Phenytoin Spray Composition
[0429] This formulation was prepared and spray layered onto 75 g of
MCC cores as described above for Formulation 24C except using the
complexed phenytion nanoparticulate suspension of Example 9. After
completion of the spray layering, 86.8 g of spray layered beads was
obtained. The loading was 15.7%.
TABLE-US-00016 TABLE 12 Dispersion SGF testing results of spray
layered uncomplexed and complexed phenytoin nanoparticulate
compositions.sup.1 D50 (.mu.m) after incubation in SGF per Example
3 unless Spray Solid Composition as % weight to Drug specified
otherwise Formu- Methyl 1 min lation HPMC SLS anthranilate Urea
Sucrose NaCl Unsonicated sonication 24A 25.0 0.8 0 0 27.0 1.0 23.34
5.51 24B 25.0 0.8 2 0 27.0 1.0 8.55 0.291 24C 56.25 1.125 0 8 0 5
9.13 0.289 3.74 0.223 (DI water) (DI water) 24D 56.25 1.125 2 8 0 5
0.320 0.267 0.304 0.205 (DI water) (DI water) .sup.1Initial D50
(.mu.m) values: 0.192 (unsonicated)/0.141 (after 1 min sonication)
for the uncomplexed and 0.209 (unsonicated)/0.177 (after 1 min
sonication) for the complexed phenytoin nanoparticulate
composition.
[0430] The purpose of the following examples is to describe
preparation and testing of various solid dosage forms comprising
drug nanoparticles.
Example 25
Pharmacokinetics of Nanoparticulate Formulations in Beagle Dogs
[0431] Purpose-bred Beagle dogs are obtained and housed in a
USDA-approved facility in accordance with AAALAC guidelines.
Expected dog weights are from 8 to 12.0 kg at the beginning of the
evaluation, and are weighed prior to each period of the study.
Animals are block randomized into groups of 3 per treatment. Each
study will test a complexed drug composition. Fasted animals are
fasted overnight with water prior to each study day. Designated fed
dogs are fed a can (about 400 g) of Alpo "Chunky Beef for Dogs,"
which has 55% of total calories from fat, approximately 45 minutes
prior to dosing. If the liquid suspension is to be administered
without dilution, the dose is given via oral gavage followed by a
7.5 to 10 ml/kg water flush. Standard laboratory chow and water are
offered ad libitum 4 h after dosing. To eliminate the variability
of drug absorption among the dogs, all studies should be conducted
in a randomized crossover design. Approximately 2 milliliters of
blood sample are withdrawn with a 21G needle and via direct
venipuncture sampling at predose, 15 min, 30 min, 1 h, 2 h, 4 h, 6
h, 8 h, 10 h, 24 h and 48 h. Blood is immediately transferred to a
potassium EDTA blood collection tube (VACUTAINER, Becton Dickinson,
Franklin Lakes, N.J., USA) and is stored on ice until the samples
are centrifuged at 2500-4000 rpm for 15 min. The plasma is
transferred to polypropylene tubes, and samples are stored at
-70.degree. C. until analyzed by a suitable method (e.g. liquid
chromatography/tandem weight spectrometry).
Example 26
Dog Pharmacokinetics with Complexed and Uncomplexed Aqueous
Ganaxolone Nanoparticulate Compositions
[0432] The uncomplexed ganaxolone formulation 26A from Example 7
(final composition of 2.5 wt % ganaxolone, 5 wt % HPMC, 0.1 wt %
SLS,) showed an approx. 3 and 2-fold increase in Cmax and AUC in
the Fed and fasted state respectively. The uncomplexed ganaxolone
formulation 26B prepared from a concentrated slurry as in Example 6
(final composition of 5 wt % ganaxolone, 5 wt % HPMC, 0.2 wt % SLS
and 1 wt % Polyvinyl alcohol (PVA) (all based on total weight of
formulation). Uncomplexed formulation 26B gave a decrease in Cmax
levels and AUC by about 50% as compared to uncomplexed formulation
26A. Administering the complexed ganaxolone formulation prepared
from a concentrated slurry as in Example 6 (final composition of 5
wt % ganaxolone, 5 wt % HPMC, 0.1 wt % SLS, 1 wt % PVA, 0.1 wt %
methylparaben, 0.02 wt % propyl paraben, 0.09 wt % sodium benzoate,
0.12 wt % citric acid and 0.0093 wt % sodium citrate) gave the most
desirable pharmacokinetic performance by achieving optimal
bioavailability and reduced variability and Cmax. Achieving a high
bioavailability (AUC) with a larger particle size (2-fold higher
due to complexing agent and curing) was surprising as
bioavailability is thought to increase as the particle size
decreases. In the case of Ganaxolone, complexed compositions of the
type in formulation 26C allow for greater overall exposure while
minimizing sedation due to high Cmax values.
TABLE-US-00017 TABLE 13 Comparative PK results in beagle dogs for
ganaxolone suspension formulations at comparable dose levels (5
mg/kg) PVA/ Complexing Formulation Particle Size Agent C.sub.max
AUC.sub.0-72 hr Reference (D50) (Methylparaben) (ng/mL) (ng*h/mL)
Food Intake Formulation 26A 110 nm None/None 448 .+-. 96 2422 .+-.
1059 Fasted Formulation 26A 110 nm None/None 1194 .+-. 104 4637
.+-. 2600 Fed Formulation 26B 140 nm Yes/None 268 .+-. 36 1643 .+-.
295 Fasted Formulation 26B 140 nm Yes/None 640 .+-. 92 3525 .+-.
1190 Fed Formulation 26C 320 nm Yes/Yes 243 .+-. 40 1855 .+-. 321
Fasted Formulation 26C 320 nm Yes/Yes 642 .+-. 40 5512 .+-. 681
Fed
Example 27
Pharmacokinetic Analysis of Solid Ganaxolone Nanoparticulate
Compositions in Beagle Dogs
[0433] The following example demonstrates that in cases where loose
aggregation can be totally reversed by sonication, a measurable
difference in pharmacokinetic performance can be seen. Although the
impact of loose aggregates on pharmacokinetic performance will be
dependent on specific compounds, this example illustrates with
immediate release complexed ganaxolone spray layered beads in
gelatin capsules that the most preferred embodiments are those that
demonstrate the smallest changes in D50 values measured unsonicated
versus after 1 min sonication.
[0434] The solid ganaxolone formulations from Example 20A and 20B
were placed into gelatin capsules to deliver a 5 mg/kg dose of
ganaxolone to beagle dogs in the fasted state. The fasted state was
chosen as this condition tends to show more pharmacokinetic
differences in nanoparticulate formulations of water insoluble
drugs. These formulations were chosen as they were part of the
solid dose optimization process and exhibited different degrees of
loose aggregation. As can be seen below in Table 14, a 3-fold
improvement in bioavailability (AUC) was seen with solid complexed
ganaxolone capsules versus capsules containing solid complexed
ganaxolone that demonstrated more loose aggregation in SGF.
TABLE-US-00018 TABLE 14 D50 (.mu.m) in SGF Formulation
Unsonicated/after C.sub.max AUC.sub.0-72 h Reference 1 min
sonication (SD)(ng/mL) (SD)(ng*h/mL) Formulation 20A 6.67/0.369 150
(94) 756 (332) Formulation 20B 0.395/0.370 135 (40) 2294 (1574) SD
= Standard Deviation
Example 28
Immediate Release Capsules with and without Complexing Agent
[0435] Suspensions (1200 grams) in water containing 25 wt %
ganaxolone, 5.0 wt % hydroxypropyl methylcellulose (Pharmacoat
603), 0.0333 wt % of 30% simethicone emulsion, and 0.2 wt % sodium
lauryl sulfate, either with 0.05 wt % methylparaben (capsule Ex. 1)
or with no methylparaben (capsule Ex. 2, 5.2 wt % of HPMC instead
of 5 wt %) are prepared. Each wt % is based on the total weight of
the suspension.
[0436] The ganaxolone particles are milled using conditions as
described in Example 4. For formulations with complexing agent
(Capsule Form 1), ganaxolone nanoparticles having a particle size
(D50) of about 120 nm as measured by Horiba LA 910 particle size
analyzer are obtained immediately after milling. This
volume-weighted-median particle size grows to about 220 nm after 7
days of curing at ambient temperature, indicating that ganaxolone
complex is formed. The D50 does not change after this curing period
for the duration of the study. For Capsule Form 2 (without
complexing agent), ganaxolone nanoparticles having the same
particle size (D50) (about 120 nm) are obtained immediately after
milling.
[0437] Sucrose (48.5 g) and NaCl (6.5 g) (together about 13 wt % of
solids) and water (800 ml) is added to each of the ganaxolone
suspensions for Capsule Form 1 and 2 and the resulting mixtures are
homogenized for 20 minutes for spray drying. The compositions of
the mixtures to be spray dried are given in Table 15.
TABLE-US-00019 TABLE 15 Composition of spray mixture prior to spray
layering Capsule Example 2 Capsule Example 1 Ganaxolone (No
Paraben) Ganaxolone Complex Wt % based on Weight, Wt %/total
Weight, total solid Component gram solid wt, % gram weight, %
Ganaxolone 300 71.7 300 71.4 HPMC 60 14.3 62.4 14.9 Simethicone
0.12 0.03 0.12 0.03 SLS 2.4 0.57 2.4 0.57 Methylparaben 0.60 0.14 0
0 Sucrose 48.5 11.6 48.5 11.5 Sodium 6.5 1.6 6.5 1.5 chloride Total
418.12 100 419.92 100
[0438] For each of Capsule Form 1 and 2, 100 grams of
microcrystalline cellulose (MCC) beads (e.g. Celphere, 30/35 mesh)
are added to a Glatt GPCG-3 fluidized bed with Wurster column
insert (4 inch), inlet temperature of about 55.degree. C. and air
temp of about 40.degree. C. (total air volume approx. 175 cubic
cm/hr). About 2000 grams of each spray mixture are sprayed (bottom
spray) through 1.2 mm nozzles at 11 ml/min and 1.5 bar of pressure
until a layering of about 400 wt % is achieved as compared to
initial beads weight. The theoretical compositions of the spray
layered complexed ganaxolone particles (Capsule Form 1) and
ganaxolone particles (Capsule Form 2) are shown in Table 16.
TABLE-US-00020 TABLE 16 Composition of spray layered beads Capsule
Form 2 Ganaxolone Capsule Form 1 (No Methyl Paraben) Ganaxolone
Complex Wt % based on Weight, Wt %/total Weight, total solid
Component gram solid wt, % gram weight, % Ganaxolone 300 57.9 300
57.7 HPMC 60 11.6 62.4 12.0 Simethicone 0.12 0.02 0.12 0.02 SLS 2.4
0.46 2.4 0.46 Methylparaben 0.60 0.12 0 0 Sucrose 48.5 9.4 48.5 9.3
NaCl 6.5 1.25 6.5 1.25 MCC beads 100 19.3 100 19.2 Total 518.12 100
519.92 100
[0439] The spray layered ganaxolone complexed particles (Capsule
Form 1) or ganaxolone particles (Capsule Form 2) are then filled
into gelatin capsules with a fill weight of 518-520 mg coated beads
to achieve a 300 mg dose.
Example 29
Delayed Release Capsules
[0440] Drug complexed particles (e.g., prepared as set forth for
the ganaxolone nanoparticles in the above examples) spray-layered
onto inert beads (500 g) are loaded directly into a rotary
granulator/coater (Freund CF-360 granulator) for enteric coating.
The rotating particle bed is sprayed with a coating solution
containing 50 wt % Eudragit.RTM. L 30-D55, 2.5 wt % talc, 1.5 wt %
dibutyl sebecate, 20 wt % ethanol, 23.5 wt % isopropyl alcohol, and
2.5 wt % water. A coating level of about 8 wt % is achieved. The
ganaxolone content in each coated bead is about 53.4 wt % based on
the total weight of the coated beads.
[0441] A suitable amount of the coated beads are hand-filled into
gelatin capsule shells, respectively, to form modified release
capsules. These particulates are substantially insoluble in the
stomach due to the enteric coating but substantially soluble in the
intestine.
Example 30
Coated Tablets
[0442] To spray-dried drug complexed particles (e.g., prepared as
set forth for the ganaxolone nanoparticles in Example 21, Prosolv
90, and Dipotassium Phosphate Powder are added sequentially into a
Bohle Bin Blender (BL07C, Warminster, Pa., USA) and blended for
10.+-.0.1 minutes at 11.+-.1 rpm. Additional Prosolv 90 and Sodium
Starch Glycolate are added and blended for 10.+-.0.1 minutes at
11.+-.1 rpm. The material is then milled and then passed through a
0.5 mm screen (35 Mesh).
TABLE-US-00021 Blend Component Weight % w/w Silicified
Microcrystalline Cellulose, NF 4.255 kg 37.0 (Prosolv 90) Sodium
Starch Glycolate, NF, EP 0.230 kg 2.00 Sodium Chloride 0.287 kg 2.5
Magnesium Stearate 0.0575 kg 0.5 Dipotassium Phosphate Powder, USP,
PE 0.230 kg 2.00 Spray dried drug nanoparticle powder 6.44 kg 56.0
Totals 11.5 kg 100.0
[0443] The drug blend is loaded into a tablet compressing machine,
such as a Fette 1200 B Tool Tablet Press (TP06) or equivalent, and
tablets are formed using oval upper and lower punches.
[0444] Optionally, an enteric coat is applied to the tablet cores
as follows: The enteric coating comprising Opadry.RTM. Enteric from
Colorcon.RTM. and the over coat comprising Opadry.RTM. clear
applied sequentially as aqueous coating suspensions using a coating
pan. The tablet cores are preheated to 46.degree. C. (Exhaust air
temperature). The pan speed is adjusted to provide adequate tablet
flow and the coating suspensions are sprayed onto the tablets at an
atomizing air pressure of 18-30 psi; an inlet air temperature of
60-70.degree. C. for over coat, and of 42-50.degree. C. for the
enteric coat; an exhaust air temperature of 40 to 50.degree. C. for
the over coat and 30 to 35.degree. C. for the enteric coat; a spray
rate of 15 to 50 ml/min.; and an inlet air flow of 175 to 300 CFM.
One of skill in the art will understand that the processing
parameters for coating are dependent in part upon the size of the
batch to be coated and can be adjusted accordingly. The enteric
coating should be applied so that a tablet core weight gain of 8-15
w %/tablet core weight is achieved. Cellulose acetate phthalate,
hydroxypropyl methylcellulose phthalate, polyvinyl acetate
phthalate, a methacrylic acid copolymer, hydroxypropyl
methylcellulose acetate succinate, shellac, cellulose acetate
trimellitate, or a combination comprising one or more of the
foregoing enteric polymers may be used in place of the Opadry
Enteric coating.
[0445] In the preceding specification, the invention has been
described with reference to specific exemplary embodiments and
examples thereof. It will, however, be evident that various
modifications and changes may be made thereto without departing
from the broader spirit and scope of the invention as set forth in
the claims that follow. The specification and drawings are
accordingly to be regarded in an illustrative manner rather than a
restrictive sense.
* * * * *