U.S. patent application number 11/356682 was filed with the patent office on 2006-06-29 for drug microparticles.
Invention is credited to Anna Drabkin, Moshe Flashner-Barak, Itzhak E. Lerner, Naomi Moldavski, Vered Rosenberger.
Application Number | 20060141050 11/356682 |
Document ID | / |
Family ID | 28675427 |
Filed Date | 2006-06-29 |
United States Patent
Application |
20060141050 |
Kind Code |
A1 |
Lerner; Itzhak E. ; et
al. |
June 29, 2006 |
Drug microparticles
Abstract
Provided are microparticles of active pharmaceutical
ingredients, drug delivery vehicles comprising same, and methods
for making them.
Inventors: |
Lerner; Itzhak E.; (Petach
Tikva, IL) ; Rosenberger; Vered; (Jerusalem, IL)
; Flashner-Barak; Moshe; (Petach Tikva, IL) ;
Drabkin; Anna; (Tzur Hadassah, IL) ; Moldavski;
Naomi; (Jerusalem, IL) |
Correspondence
Address: |
Kenyon & Kenyon LLP
One Broadway
New York
NY
10004
US
|
Family ID: |
28675427 |
Appl. No.: |
11/356682 |
Filed: |
February 17, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10400100 |
Mar 25, 2003 |
|
|
|
11356682 |
Feb 17, 2006 |
|
|
|
60367957 |
Mar 26, 2002 |
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Current U.S.
Class: |
424/489 ;
514/573; 977/906 |
Current CPC
Class: |
A61K 9/167 20130101;
A61K 9/1694 20130101; A61P 35/00 20180101; A61K 31/519 20130101;
B01J 13/02 20130101; A61K 9/1682 20130101; A61K 9/1676 20130101;
B01J 13/125 20130101 |
Class at
Publication: |
424/489 ;
977/906; 514/573 |
International
Class: |
A61K 31/557 20060101
A61K031/557; A61K 9/14 20060101 A61K009/14 |
Claims
1. A pharmaceutical composition comprising microparticles of
oxybutynin that are not mechanically micronized.
2. The pharmaceutical composition of claim 1 wherein the
microparticles of oxybutynin have mean dimensions of about 100 nm
to about 10 .mu.m.
3. The composition of claim 1 wherein at least about 75 weight-% of
the oxybutynin of a sample of the composition comprising 100 mg of
oxybutynin dissolves from the composition within about 180 minutes
when dissolution is measured at 37.degree. C. with an apparatus II
dissolution tester as described in the United States Pharmacopoeia
operating at about 50 RPM in a medium consisting essentially of 100
mL of 50 mM aqueous phosphate buffer, pH .about.6.8.
4. The pharmaceutical composition of claim 1 wherein at least about
60 weight-% of the oxybutynin of the sample of the composition
comprising 100 mg of oxybutynin dissolves from the composition
within about 90 minutes when dissolution is measured at 37.degree.
C. with an apparatus II dissolution tester as described in the
United States Pharmacopoeia operating at about 50 RPM in a medium
consisting essentially of 100 mL of 50 mM aqueous phosphate buffer,
pH .about.6.8.
5. The pharmaceutical composition of claim 1 wherein at least about
20 weight-% of the oxybutynin of the sample of the composition
comprising 100 mg of oxybutynin dissolves from the composition
within about 30 minutes when dissolution is measured at 37.degree.
C. with an apparatus II dissolution tester as described in the
United States Pharmacopoeia operating at about 50 RPM in a medium
consisting essentially of 100 mL of 50 mM aqueous phosphate buffer,
pH 6.8.
6. A pharmaceutical composition comprising microparticles of
oxybutynin that have not been micronized by a mechanical process
selected from high energy milling and high pressure homogenization,
from which pharmaceutical composition about 75 weight-% of the
oxybutynin of a sample of the composition comprising 100 mg of
oxybutynin dissolves from the composition within about 180 minutes
when dissolution is measured at 37.degree. C. with an apparatus II
dissolution tester as described in the United States Pharmacopoeia
operating at about 50 RPM in a medium consisting essentially of 100
mL of 50 mM aqueous phosphate buffer, pH .about.6.8.
7. The pharmaceutical composition of claim 6 wherein the
microparticles of oxybutynin have mean dimensions of about 100 nm
to about 10 .mu.m.
8. The pharmaceutical composition of claim 6 wherein about 60
weight-% of the oxybutynin of the sample of the composition
comprising 100 mg of oxybutynin dissolves from the composition
within about 90 minutes when dissolution is measured at 37.degree.
C. with an apparatus II dissolution tester as described in the
United States Pharmacopoeia operating at about 50 RPM in a medium
consisting essentially of 100 mL of 50 mM aqueous phosphate buffer,
pH .about.6.8.
9. The pharmaceutical composition of claim 6 wherein about 20
weight-% of the oxybutynin of the sample of the composition
comprising 100 mg of oxybutynin dissolves from the composition
within about 30 minutes when dissolution is measured at 37.degree.
C. with an apparatus II dissolution tester as described in the
United States Pharmacopoeia operating at about 50 RPM in a medium
consisting essentially of 100 mL of 50 mM aqueous phosphate buffer,
pH .about.6.8.
10. A pharmaceutical composition comprising microparticles of
oxybutynin obtained by sublimation of a sublimable carrier from a
solid solution of oxybutynin in the sublimable carrier.
11. The pharmaceutical composition of claim 10 wherein the
microparticles of oxybutynin have mean dimensions of about 100 nm
to about 10 .mu.m.
12. The composition of claim 10 from which pharmaceutical
composition the oxybutynin has a dissolution rate of: about 20
weight-% dissolved within about 30 minutes, or about 60 weight-%
dissolved within about 90 minutes, or about 75 weight-% dissolved
within about 180 minutes when dissolution is measured on a sample
of the composition comprising 100 mg of oxybutynin, at 37.degree.
C. with an apparatus II dissolution tester as described in the
United States Pharmacopoeia operating at about 50 RPM in a medium
consisting essentially of 100 mL of 50 mM aqueous phosphate buffer,
pH .about.6.8.
13. The pharmaceutical composition of claim 10 wherein at least
about 20 weight-% of the oxybutynin of a sample of the composition
comprising 100 mg of oxybutynin dissolves from the composition
within about 30 minutes when dissolution is measured at 37.degree.
C. with an apparatus II dissolution tester as described in the
United States Pharmacopoeia operating at about 50 RPM in a medium
consisting essentially of 100 mL of 50 mM aqueous phosphate buffer,
pH .about.6.8.
14. The pharmaceutical composition of claim 10 wherein at least
about 60 weight-% of the oxybutynin of a sample of the composition
comprising 100 mg of oxybutynin dissolves from the composition
within about 90 minutes when dissolution is measured at 37.degree.
C. with an apparatus II dissolution tester as described in the
United States Pharmacopoeia operating at about 50 RPM in a medium
consisting essentially of 100 mL of 50 mM aqueous phosphate buffer,
pH .about.6.8.
15. The pharmaceutical composition of claim 10 wherein at least
about 75 weight-% of the oxybutynin of a sample of the composition
comprising 100 mg of oxybutynin dissolves from the composition
within about 180 minutes when dissolution is measured at 37.degree.
C. with an apparatus II dissolution tester as described in the
United States Pharmacopoeia operating at about 50 RPM in a medium
consisting essentially of 100 mL of 50 mM aqueous phosphate buffer,
pH .about.6.8.
16. The pharmaceutical composition of claim 10 wherein the
sublimable carrier is selected from the group consisting of
menthol, thymol, camphor, t-butanol, trichloro-t-butanol,
imidazole, coumarin, acetic acid (glacial), dimethylsulfone, urea,
vanillin, camphene, salicylamide, and 2-aminopyridine.
17. The pharmaceutical composition of claim 16 wherein the
sublimable carrier is menthol.
18. The pharmaceutical composition of claim 10 wherein the
microparticles are deposited on at least one or a plurality of
pharmaceutical carrier particles.
19. The pharmaceutical composition of claim 10 wherein the
microparticles are deposited on one or more pharmaceutical carrier
particles consisting essentially of a non-hydrosoluble
material.
20. The pharmaceutical composition of claim 19 wherein the
non-hydrosoluble material is microcrystalline cellulose.
21. A pharmaceutical composition comprising pharmaceutical carrier
particles consisting essentially of a non-hydrosoluble material
and, deposited thereon, microparticles of oxybutynin that are
obtained by sublimation of a sublimable carrier from a solid
solution of oxybutynin in the sublimable carrier, wherein at least
about 75 weight-% of the oxybutynin of a sample of the composition
comprising 100 mg of oxybutynin dissolves from the pharmaceutical
composition within at most about 180 minutes when dissolution is
measured at 37.degree. C. with an apparatus II dissolution tester
as described in the United States Pharmacopoeia operating at about
50 RPM in a medium consisting essentially of 100 mL of 50 mM
aqueous phosphate buffer, pH .about.6.8.
22. The pharmaceutical composition of claim 21 wherein the
microparticles of oxybutynin have mean dimensions of about 100 nm
to about 10 .mu.m.
23. The pharmaceutical composition of claim 10 wherein the
microparticles are deposited on one or more pharmaceutical carrier
particles consisting essentially of a hydrosoluble material.
24. The pharmaceutical composition of claim 23 wherein the
hydrosoluble material is selected from the group consisting of
sugar particles and lactose particles.
25. A process for preparing an oxybutynin delivery vehicle
comprising the steps of: a) forming a solid solution of oxybutynin
and a sublimable carrier on the surface of a pharmaceutical carrier
particle; and b) subliming the sublimable carrier from the solid
solution to deposit microparticles of oxybutynin on the surface of
the pharmaceutical carrier particle to obtain the oxybutynin
delivery vehicle.
Description
RELATED APPLICATONS
[0001] The present application is a Continuation of U.S.
Non-Provisional application Ser. No. 10/400,100, filed on Mar. 25,
2003, and claims the benefit of the Mar. 26, 2002 filing date of
U.S. Provisional Patent Application No. 60/367,957.
FIELD OF THE INVENTION
[0002] The present invention relates to microparticles of drugs,
especially drugs that are poorly soluble in water, and to methods
for making them.
BACKGROUND OF THE INVENTION
[0003] Many important drugs have poor oral bioavailability because
they are poorly soluble in water. Many approaches have been
suggested to overcome this problem. Although some approaches have
been used, with limited commercial success, each approach has its
own drawbacks and limitations.
[0004] In one approach, a water-soluble prodrug of a poorly
water-soluble drug is made [1-4]. The prodrug approach is limited
to those molecules that have functionality amenable to facile
removal in the body to form the drug. Not all poorly water-soluble
drugs are so endowed. Furthermore, the prodrug would likely be
considered a new chemical entity and require separate approval from
regulatory agencies, adding considerable time and cost to bringing
the product to market.
[0005] The bioavailability of poorly water-soluble drugs has been
improved by decreasing the particle size of the drug to increase
the surface area. Milling [5-6], high pressure homogenization
[7-8], spray drying [9], lyophilization of solutions in
water-organic solvent mixtures [10], and lyophilization of
solutions inorganic solvents [11-12] have been tried. Size
reduction is, in principal, generally applicable for improving
bioavailability, but achieving size reduction by, for example, high
energy milling, requires special equipment and is not always
applicable. High pressure homogenization requires special equipment
and requires organic solvents that can remain in the comminuted
product. Spray drying also requires solvents and generally produces
particles that are too large.
[0006] Lyophilization is usually limited to materials that are
soluble in water in any event, although there have been some
efforts at using organic solvents.
[0007] The solubility of poorly soluble antibiotics has been
improved by complexation with polymers or cyclodextrins. Polymer
complexes have been formed with PVP in organic solvent [13a], or
with PVP in heated water [13]. Other drugs have been complexed with
cyclodextrins and polymers [14-15].
[0008] The bioavailability of poorly soluble drugs has been
improved by dispersing the drug in a soluble polymer, often with
addition of surfactants [16-24].
[0009] Some combinations of techniques have shown added
improvement. For example spraying and drying a dispersion of drug
and polymer or cyclodextrin on pellets in a fluidized bed dried
[25-26]. The combination of solid dispersion and lyophilization to
improve solubility has been demonstrated [27], and the use of solid
dispersions absorbed on a carrier having a large surface area has
also been demonstrated [28].
[0010] Clearly, there is a need for a simpler and generally
applicable means of making and delivering particles of drugs having
a size below 10 .mu.m and especially below 1 .mu.m.
[0011] Many of the above-described techniques require forming
particles by solvent removal which, in turn, entails concentration
of a solution. During solution concentration, solute molecules,
which in solution are statistically separated into individual
molecules and small clusters or aggregates, are drawn together to
form larger molecular aggregates. When the solute drug eventually
precipitates, relatively larger crystals are formed.
[0012] Lyophilization (freeze drying) has the advantage of allowing
the solvent to be removed whilst keeping the solute relatively
immobile, thereby suppressing enlargement of clusters or
aggregates. When the solvent is removed, the formed crystals are
smaller or the material is amorphous, reflecting the separation of
the molecules in the frozen solution state. Molecular separation
can be improved and aggregate formation still further suppressed by
lyophilizing a more dilute solution, although one pays a hefty
price in energy requirements for removing more solvent.
Lyophilization is usually a very slow, energy intensive process and
usually requires high vacuum equipment. Furthermore, there is a
tendency for the crystals formed to aggregate in the free state,
undoing the job that the freeze drying did. This tendency can
sometimes be overcome with additives, but these must be compatible
with the entire system.
[0013] Amorphous or nanoparticulate materials tend to show poor
bulk flow properties as powders, requiring formulation work to be
able to fill them into capsules. While these problems are not
insurmountable, they add further limitations in the usefulness of
the system. Many of the existing limitations are overcome by the
present invention.
SUMMARY OF THE INVENTION
[0014] The present invention relates to a drug delivery vehicle
including a pharmaceutical carrier particle, especially a
pharmaceutical carrier particle that is a sugar particle, a starch
particle, a lactose particle, or a particle of microcrystalline
cellulose, bearing microparticles of a drug, especially a drug
having poor solubility in water, wherein the microparticles of the
drug are deposited on the pharmaceutical carrier particle from a
solid solution of the drug in a sublimable carrier such as menthol,
thymol, camphor, t-butanol, trichloro-t-butanol, imidazole,
coumarin, acetic acid (glacial), dimethylsulfone, urea, vanillin,
camphene, salicylamide, and 2-aminopyridine. The drug delivery
vehicle of the present invention is useful for delivering a drug,
especially a drug that has poor solubility in water, to a mammal,
especially a human, in need of treatment with that drug.
[0015] In another aspect, the present invention relates to a method
of making a microparticle including the steps of forming a solid
solution of the drug in a sublimable carrier and removing the
sublimable carrier from the solid solution by, for example,
sublimation. Sublimation can be accomplished in a fluidized bed
apparatus.
[0016] In another aspect, the present invention relates to a method
of making a drug delivery vehicle including the steps of forming a
solid solution of the drug and a sublimable carrier on the surface
of a pharmaceutical carrier particle, especially a pharmaceutical
carrier particle that is a sugar particle, a starch particle, a
lactose particle, or a particle of microcrystalline cellulose, and
removing the sublimable carrier from the solid solution, for
example by sublimation, to deposit microparticles of the drug on
the pharmaceutical carrier particle. The solid solution can be
formed on the carrier particle by, for example, combining drug,
sublimable carrier, and a solvent (for example ethanol), applying
the combination to the carrier particle, and removing the solvent.
The solid solution can also be formed by applying a combination of
drug and molten sublimable carrier to the particle and allowing the
combination to cool to form the solid solution on the carrier
particle.
[0017] In yet another aspect, the present invention relates to
pharmaceutical compositions that include microparticles of the
present invention, which microparticles can be born by a drug
delivery vehicle of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The present invention provides microparticles of a
pharmacologically active substance, i.e. a drug, and a method for
making them. The invention also provides a drug delivery vehicle
for administering a pharmacologically active substance, and methods
for making it, wherein the delivery vehicle includes at least one
pharmaceutical carrier particle bearing microparticles of the drug,
which microparticles are made according to the present
invention.
[0019] Microparticles of the present invention are formed as
described hereinbelow and generally have mean dimensions on the
order of about 100 nm, up to about 10 .mu.m. Microparticles
according to the present invention can have a regular shape, e.g.
essentially spherical, or they can have an irregular shape. The
material of which microparticles are comprised can be crystalline
or it can be at least partly amorphous. Preferably the material is
at least partly amorphous.
[0020] As used herein in connection with a measured quantity, the
term about refers to the normal variation in that measured quantity
that would be expected by the skilled artisan making the
measurement and exercising a level of care commensurate with the
objective of the measurement and the precision of the measuring
equipment used.
[0021] Any pharmagologically active substance (drug) can be used in
the practice of the present invention. However, drugs having poor
water solubility (poorly water soluble drugs), and hence relatively
lower bioavailability, are preferred and the advantages of the
present invention are more fully realized with poorly water-soluble
drugs. For purposes of the present invention, a drug is considered
to be poorly water soluble if it has a solubility of less than
about 20 mg/per milliliter of water. Examples of drugs having poor
water solubility include fenofibrate, itraconazole, bromocriptine,
carbamazepine, diazepam, paclitaxel, etoposide, camptothecin,
danazole, progesterone, nitrofurantoin, estradiol, estrone,
oxfendazole, proquazone, ketoprofen, nifedipine, verapamil, and
glyburide, to mention just a few. The skilled artisan knows other
drugs having poor water solubility.
[0022] Pharmaceutical carrier particles useful for making the
delivery vehicle of the present invention are made of comestible
substances and are well known in the art. Examples of useful
pharmaceutical carrier particles include particles, that can be
non-pariel pellets, typically between about 0.1 mm. and about 2 mm.
in diameter, and made of, for example, starch, particles of
microcrystalline cellulose, lactose particles or, particularly,
sugar particles. Suitable sugar particles (pellets, e.g. non-pariel
103, Nu-core, Nu-pariel) are commercially available in sizes from
35 to 40 mesh to 18 to 14 mesh. Particles of microcrystalline
cellulose are preferred pharmaceutical carrier particles. The
skilled artisan knows other pellets or spheres useful as
pharmaceutical carrier particles.
[0023] The microparticles of the drug or pharmacologically active
substance of the present invention are obtained by removing a
sublimable carrier from a solid solution of the drug in the
sublimable carrier. The drug or pharamaceutically active substance
can be present with the sublimable carrier in the solid solution as
discrete molecules, or it can be present in aggregates of a few
hundred, a few thousand, or more molecules. The drug need only be
dispersed on a sufficiently small scale so that sufficiently small,
discrete microparticles are ultimately obtained. Preferably, the
drug or pharmagolocigally active substance in the solid solution is
dissolved in the sublimable carrier.
[0024] Sublimable carriers useful in the practice of the present
invention form solid solutions with the drug at an easily
accessible temperature and can be removed from the solid solution
without heating the solid solution to a temperature above the
melting point of the solid solution, for example by sublimation.
Sublimable carriers have a measurable vapor pressure below their
melting point. Preferred sublimable carriers have a vapor pressure
of at least about 10 Pascal, more preferably at least about 50
Pascal at about 10.degree. or more below their normal melting
points. Preferably, the sublimable carrier has a melting point
between about -10.degree. C. and about 200.degree. C., more
preferably between about 20.degree. C. and about 60.degree. C.,
most preferably between about 40.degree. C. and about 50.degree. C.
Preferably, the sublimable carrier is a substance that is
classified by the United States Food and Drug Administration as
generally recognized as safe (i.e., GRAS). Examples of suitable
sublimable carriers include menthol, thymol, camphor, t-butanol,
trichloro-t-butanol, imidazole, coumarin, acetic acid (glacial),
dimethylsulfone, urea, vanillin, camphene, salicylamide, and
2-aminopyridine. Menthol is a particularly preferred sublimable
carrier.
[0025] The solid solutions of the present invention can exist as a
true homogeneous crystalline phase of the interstitial or
substitutional type, composed of distinct chemical species
occupying the lattice points at random, or they can be a dispersion
of discrete molecules or aggregates of molecules in the sublimable
carrier.
[0026] The solid solutions can be made by combining a drug with
molten sublimable carrier, then cooling the combination to below
the melting point of the solid solution. The solid solutions can
also be formed by combining drug and sublimable carrier in an
organic solvent and evaporating the organic solvent to obtain a
solid solution of drug in sublimable carrier. Ethanol is an example
of a preferred organic solvent that can be used in the practice of
the present invention.
[0027] The solid solution can also include a compound or polymer
that forms a dispersion with the drug.
[0028] In a preferred embodiment, the solid solution is formed on
the surface of at least one pharmaceutical carrier particle and
preferably a plurality of pharmaceutical carrier particles. For
example, a molten combination of drug and carrier can be applied to
the surface of a pharmaceutical carrier particle where it is
allowed to cool to form the solid solution on the surface of the
pharmaceutical carrier particle. A solid solution can also be
formed at the surface of a pharmaceutical carrier particle by
applying a combination of solvent, drug, and sublimable carrier to
at least one, and preferably a plurality of, pharmaceutical carrier
particle(s) and evaporating the organic solvent to obtain the solid
solution on the surface of the pharmaceutical carrier particle.
[0029] Application to the pharmaceutical carrier particles can be
by any particle coating technique known in the art, for example
using fluidized bed equipment or a spray coater. When used, organic
solvent is removed after application by exposing the coated carrier
particles to vacuum or a stream of heated or non-heated air using
particle handling equipment well known in the art.
[0030] When no solvent is used, application is at a temperature
above the melting point of the sublimable carrier. When drug and
sublimable carrier are combined with solvent, application is at a
temperature such that drug and sublimable carrier remain in
solution in the solvent.
[0031] The microparticles of the present invention are formed by
removal of sublimable carrier from a solid solution, made as
described above, at a temperature below the melting point of the
solid solution. The solid solution must be kept at a temperature
below its melting point to preserve the solid solution during the
process of removing the sublimable carrier. The sublimable carrier
can be removed from the solid solution by, for example, treating
the solid solution, deposited on a pharmaceutical carrier particle
where applicable, in a stream of air, preferably heated air, in,
for example, a fluidized bed drier.
[0032] In those embodiments in which the solid solution is coated
on the surface of a pharmaceutical carrier particle, the sublimable
carrier can be removed by exposing the coated particles to heat,
vacuum, heat and vacuum, or to a stream of heated or non-heated
air, for example in a fluidized bed dryer. Exposing coated
pharmaceutical carrier particles to a stream of air (heated or not)
in a fluidized bed dryer is a preferred means of removing
sublimable carrier from solid solution coated on pharmaceutical
carrier particles in order to form the microparticles of the
present invention on the surface of the carrier particles.
[0033] Removal of sublimable carrier from the solid solution,
whether coated on a pharmaceutical carrier particle or not, results
in formation of the microparticles of the present invention.
[0034] In another embodiment of the present invention, the
microparticles of drug or the pharmaceutical carrier particles
bearing microparticles of a drug are formulated into pharmaceutical
compositions that can be made into dosage forms, in particular oral
solid dosage forms such as capsules and compressed tablets, as are
well known in the art.
[0035] Compressed tablets are formulated from pharmaceutical
compositions containing the microparticles of the pharmacologically
active substance or drug, or using pharmaceutical carrier particles
bearing such microparticles, and pharmacologically inert
(pharmaceutically acceptable) additives or excipients.
[0036] For making a tablet, it will typically be desirable to
include one or more benign pharmaceutical excipients in the
pharmaceutical composition. The pharmaceutical composition of the
present invention may contain one or more diluents added to make
the tablet larger and, hence, easier for the patient and caregiver
to handle. Common diluents are microcrystalline cellulose (e.g.
Avicel.RTM.), microfine cellulose, lactose, starch, pregelitinized
starch, calcium carbonate, calcium sulfate, sugar, dextrates,
dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic
calcium phosphate, kaolin, magnesium carbonate, magnesium oxide,
maltodextrin, mannitol, polymethacrylates (e.g. Eudragit.RTM.),
potassium chloride, powdered cellulose, sodium chloride, sorbitol
and talc.
[0037] Binders also may be included in tablet formulations to help
hold the tablet together after compression. Some typical binders
are acacia, alginic acid, carbomer (e.g. carbopol),
carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin,
guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose,
hydroxypropyl cellulose (e.g. Klucel.RTM.), hydroxypropyl methyl
cellulose (e.g. Methocel.RTM.), liquid glucose, magnesium aluminum
silicate, maltodextrin, methylcellulose, polymethacrylates,
povidone (e.g. Kollidon.RTM., Plasdone.RTM.), pregelatinized
starch, sodium alginate and starch.
[0038] The tablet may further include a disintegrant to accelerate
disintegration of the tablet in the patient's stomach.
Disintegrants include alginic acid, carboxymethyl cellulose
calcium, carboxymethylcellulose sodium, colloidal silicon dioxide,
croscarmellose sodium (e.g. Ac-Di-Sol.RTM., Primellose.RTM.),
crospovidone (e.g. Kollidon.RTM., Polyplasdone.RTM.), guar gum,
magnesium aluminum silicate, methyl cellulose, microcrystalline
cellulose, polacrilin potassium, powdered cellulose, pregelatinized
starch, sodium alginate, sodium starch glycolate (e.g.
Explotab.RTM.) and starch.
[0039] A pharmaceutical composition for making compressed tablets
may further include glidants, lubricants, flavorings, colorants and
other commonly used excipients.
[0040] Pharmaceutical carrier particles bearing microparticles of a
drug made in accordance with the present invention have excellent
bulk flow properties and can be used directly, alone or in
combination with carrier particles that do not carry a drug, to
make capsule dosage forms. If necessary, diluents such as lactose,
mannitol, calcium carbonate, and magnesium carbonate, to mention
just a few, can be formulated with the microparticle-bearing
pharmaceutical carrier particles when making capsules
[0041] Liquid oral pharmaceutical compositions of the present
invention comprise microparticles or microparticle-bearing
pharmaceutical carrier particles and a liquid carrier such as
water, vegetable oil, alcohol, polyethylene glycol, propylene
glycol or glycerin, most preferably water.
[0042] Liquid oral pharmaceutical compositions may contain
emulsifying agents to disperse uniformly throughout the composition
the active ingredient, drug delivery vehicle, or excipient having
low solubility in the liquid carrier. Emulsifying agents that may
be useful in liquid compositions of the present invention include,
for example, gelatin, egg yolk, casein, cholesterol, acacia,
tragacanth, chondrus, pectin, methyl cellulose, carbomer,
cetostearyl alcohol and cetyl alcohol.
[0043] Liquid oral pharmaceutical compositions of the present
invention may also contain a viscosity enhancing agent to improve
the mouth-feel of the product and/or coat the lining of the
gastrointestinal tract. Such agents include acacia, alginic acid
bentonite, carbomer, carboxymethylcellulose calcium or sodium,
cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar
gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl
methyl cellulose, maltodextrin, polyvinyl alcohol, povidone,
propylene carbonate, propylene glycol alginate, sodium alginate,
sodium starch glycolate, starch tragacanth and xanthan gum.
[0044] The liquid oral pharmaceutical composition also may contain
sweetening agents, such as sorbitol, saccharin, sodium saccharin,
sucrose, aspartame, fructose, mannitol and invert sugar;
preservatives and chelating agents such as alcohol, sodium
benzoate, butylated hydroxy toluene, butylated hydroxyanisole and
ethylenediamine tetraacetic acid; and buffers such as guconic acid,
lactic acid, citric acid or acetic acid, sodium gluconate, sodium
lactate, sodium citrate or sodium acetate.
[0045] The present invention is further illustarted with the
followin non-limiting examples.
EXAMPLE 1
Solubility of Selected Drugs in Menthol
[0046] The following general procedure was repeated with several
drugs with menthol carrier.
[0047] Menthol (10 grams) was melted on a stirring hot plate with
magnetic stirring, then heated to the desired temperature indicated
in Table 1. The desired drug was added in small increments (0.1
grams) and stirred to obtain a clear solution. The desired drug was
added in increments until no more drug dissolved in the menthol.
The weight of material added to the menthol melt that still gave a
clear solution was taken as the solubility of the active drug at
the indicated temperature. The results are given in Table 1.
TABLE-US-00001 TABLE 1 Solubility of selected active drug
substances in menthol Active drug temperature Solubility substance
(.degree. C.) (% w/w) Azithromycin 63 40.0 Cyclosporin 55 39.2
Diazepam 43 5.7 Fenofibrate 60 37.5 Itraconazole 61 1.0 Oxybutynin
60 9.1 Risperidone 70 8.3 Salicylic acid 43 16.0 Simvastatin 63
30.0
EXAMPLE 2
Improvement of the Dissolution of Fenofibrate by "Menthol
Micronization"
[0048] Menthol (50 grams) was heated in a jacketed reactor to
60.degree. C. After melting, the melt was stirred at 100 rpm.
Fenofibrate (25 grams) was added and the mixture stirred at 100 rpm
and 60.degree. C. until full dissolution was achieved.
Microcrystalline cellulose (Avicel ph 102, 55 grams) was added to
the melt and the mixture was stirred for 30 minutes. The heat
source was then removed and the mass allowed to cool to room
temperature with the stirring continued at 100 rpm for a further 30
minutes.
[0049] The obtained mass was milled through a 6.35 mm screen in a
Quadro Comil mill at 1300 rpm. The milled product was allowed to
cool to 25.degree. C. and milled again through 1.4 mm screen to
obtain a powder in which the fenofibrate is dissolved in menthol
and coated on the microcrystalline cellulose.
[0050] The powder was transferred to a fluid bed dryer (Aeromatic
model STREA1) where the menthol was removed by drying for three
hours at 30-32.degree. C. with the fan at 7-8 Nm.sup.3/hr. A
powder, 62 grams, was obtained. This powder was an essentially
"micronized" fenofibrate deposited on microcrystalline
cellulose.
[0051] A sample of this powder containing 100 mg of the fenofibrate
was tested for dissolution in a USP Apparatus II dissolution tester
in 900 ml 0.5% sodium lauryl sulfate (SLS) in water at 37.degree.
C. and 100 rpm. The fenofibrate in the dissolution medium was
determined by HPLC on an Hypersil.RTM. ODS column with UV detection
at 286 nm. The results are shown in Table 2. Fenofibrate
"micronized" by the menthol method gave 100% dissolution in two
hours. An equivalent simple combination of fenofibrate (control,
not deposited from menthol) with microcrystalline cellulose gave
40.2% dissolution in 3 hours, while a mechanically micronized
fenofibrate raw material mixed with microcrystalline cellulose gave
72.1% dissolution in 3 hours. TABLE-US-00002 TABLE 2 Dissolution of
menthol treated fenofibrate time (minutes) % dissolved 15 44.0 +/-
1.3 30 73.6 +/- 2.9 60 82.3 +/- 0.6 90 93.1 +/- 4.2 120 102.7 +/-
0.2 180 104.9 +/- 0.8
EXAMPLE 3
Improvement of the Dissolution of Oxybutynin chloride by "Menthol
Micronization"
[0052] Menthol (80 grams) was melted and oxybutynin chloride (8
grams) and microcrystalline cellulose (89.5 grams) were added and
treated as in Example 2 to give a powder of "micronized" oxybutynin
chloride on microcrystalline cellulose.
[0053] The dissolution of oxybutynin chloride from this powder (a
sample of powder containing 100 mg of the active drug) was tested
in a USP apparatus II dissolution tester in 100 ml of 50 mM
phosphate buffer pH=6.8 at 37.degree. C. and 50 rpm. The oxybutynin
content of the dissolution sample was measured by spectrophotometer
at 225 nm. The results are given in Table 3. The dissolution
reached 79.2% at three hours. An equivalent simple combination of
the oxybutynin chloride raw material with microcrystalline
cellulose that was not treated with the "menthol micronization"
method gave only 22.1% dissolution in three hours. TABLE-US-00003
TABLE 3 Dissolution of menthol treated oxybutynin time (minutes) %
dissolved 30 21.5 +/- 0.4 90 59.7 +/- 1.2 180 79.2 +/- 1.0
EXAMPLE 4
Improvement of the Dissolution of Risperidone by "Menthol
Micronization"
[0054] Menthol (50 grams) was melted and risperidone (4.5 grams)
and microcrystalline cellulose (62.5 grams) were added and treated
according to the procedure in Example 2. A sample of the resulting
powder (containing 50 mg of risperidone) was tested in a USP
apparatus II dissolution tester using 900 ml of water at 37.degree.
C. and 100 rpm. The concentration of risperidone in the dissolution
samples was measured using a spectrophotometer at 240 nm.
[0055] The results of the dissolution of the "menthol micronized"
powder and of the control simple combination of risperidone and
microcrystalline cellulose (not treated with menthol) are shown in
Table 4. The menthol deposited risperidone gave 100% dissolution in
30 minutes, whereas the control mixture gave 31.9% in thirty
minutes and 63.7% in three hours. TABLE-US-00004 TABLE 4
Dissolution of menthol treated risperidone vs. control time
(minutes) % dissolved test % dissolved control 15 69.3 +/- 0.5 17.5
+/- 2.6 30 99.9 +/- 1.0 31.9 +/- 3.5 60 102.3 +/- 0.8 41.7 +/- 5.6
90 102.8 +/- 1.2 48.2 +/- 8.3 120 53.2 +/- 11.1 180 63.7 +/-
8.3
EXAMPLE 5
Improvement of the Dissolution of Cyclosporin by "Menthol
Micronization"
[0056] Menthol (80 grams) was melted and cyclosporin (20 grams) and
microcrystalline cellulose (100 grams) were added and treated as in
Example 2. A sample of this powder (containing 10 mg of "menthol
micronized" cyclosporin) was tested for dissolution in 900 ml water
in a USP apparatus II dissolution unit at 37.degree. C. and 100
rpm. The cyclosporin content of the dissolution samples was
determined spectrophotometrically at 215 nm. The dissolution of the
menthol deposited material and of a control mixture of cyclosporin
and microcrystalline cellulose (not deposited from menthol) are
presented in Table 5. The cyclosporin dissolution from the powder
having cyclosporin deposited from menthol was about twice that of
the control (simple combination), and the maximum dissolution was
achieved in shorter time. TABLE-US-00005 TABLE 5 Dissolution of
menthol treated cyclosporin vs. control time (minutes) % dissolved
test % dissolved control 30 9.2 +/- 0.3 0.1 +/- 0.0 60 11.9 +/- 0.3
1.3 +/- 0.5 90 13.1 +/- 0.5 3.1 +/- 0.2 120 13.3 +/- 0.3 5.1 +/-
0.2 180 14.3 +/- 0.8 7.1 +/- 0.3
EXAMPLE 6 (COMPARATIVE)
Attempted Improvement in Itraconazole Dissolution by "Menthol
Micronization"
[0057] Menthol (92 grams) was melted as in Example 2. Itraconazole
(3.6 grams) was added and mixed well in the melt. A solution was
not formed because itraconazole has a solubility of only 1% in
menthol at 60.degree. C. (see Table 1). To the suspension of
itraconazole in menthol was added microcrystalline cellulose (90
grams) and the mixture treated as in Example 2. The dissolution of
the itraconazole was measured from a powder sample containing 100
mg of the drug in 900 ml of 0.1 N HCl in a USP apparatus II
dissolution tester at 37.degree. C. and 100 rpm. The dissolved
itraconazole was measured spectrophotometrically at 251 nm. The
results of the dissolution are shown in Table 6. The dissolution
was about 8% at 30 minutes and the same at three hours. A control
simple mixture of itraconazole and microcrystalline cellulose (not
deposited from menthol) gave essentially the same results (7.8% in
three hours). TABLE-US-00006 TABLE 6 Dissolution of menthol treated
itraconazole time (minutes) % dissolved 30 8.8 +/- 0.4 90 8.0 +/-
0.6 180 8.1 +/- 0.1
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