U.S. patent application number 09/792189 was filed with the patent office on 2002-06-06 for antifungal product, use and formulation thereof.
Invention is credited to Isbister, James D., Rudnic, Edward M., Treacy, Donald J. JR., Wassink, Sandra E..
Application Number | 20020068078 09/792189 |
Document ID | / |
Family ID | 27103964 |
Filed Date | 2002-06-06 |
United States Patent
Application |
20020068078 |
Kind Code |
A1 |
Rudnic, Edward M. ; et
al. |
June 6, 2002 |
Antifungal product, use and formulation thereof
Abstract
An antifungal product is comprised of at least three dosages
forms, each of which has a different release profile, with the
C.sub.max for the antifungal product being reached in less than
about twelve hours. In one embodiment, there is an immediate
release dosage form, as well as two or more delayed release dosage
forms, with each of the dosage forms having a different release
profile, wherein each reaches a C.sub.max at different times.
Inventors: |
Rudnic, Edward M.; (N.
Potomac, MD) ; Isbister, James D.; (Potomac, MD)
; Treacy, Donald J. JR.; (Arnold, MD) ; Wassink,
Sandra E.; (Frederick, MD) |
Correspondence
Address: |
Elliot M. Olstein, Esq.
c/o Carella, Byme, Bain, Gilfillan,
Cecchi, Stewart & Olstein
6 Becker Farm Road
Roseland
NJ
07068
US
|
Family ID: |
27103964 |
Appl. No.: |
09/792189 |
Filed: |
February 22, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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09792189 |
Feb 22, 2001 |
|
|
|
09687236 |
Oct 13, 2000 |
|
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Current U.S.
Class: |
424/408 |
Current CPC
Class: |
A61K 31/7048 20130101;
A61K 9/2081 20130101; A61K 9/5084 20130101; A61P 31/10
20180101 |
Class at
Publication: |
424/408 |
International
Class: |
A01N 025/34 |
Claims
What is claimed is:
1. An antifungal product comprising: a first antifungal dosage
form, a second antifungal dosage form, and a third antifungal
dosage form, each of said first, second and third antifungal dosage
forms comprising an antifungal and a pharmaceutically acceptable
carrier, said three dosage forms having different release profiles,
said antifungal product reaching a C.sub.max in less than about
twelve hours.
2. The product of claim 1 wherein the first dosage form is an
immediate release dosage form.
3. The product of claim 2 wherein the C.sub.max for the product is
reached no earlier than four hours after administration.
4. The product of claim 2 wherein the immediate release dosage form
contains at least 20% and no more than 50% of the total dosage of
antifungal.
5. The product of claim 4 wherein the product is an oral dosage
form.
6. The product of claim 5 wherein the antifungal released from the
second dosage in the form reaches a C.sub.max in the serum after
C.sub.max is reached in the serum for antifungal released from the
first dosage form.
7. The product of claim 6 wherein the antifungal released from the
third dosage form reaches a C.sub.max in the serum after the
antifungal released from the second dosage form reaches a C.sub.max
in the serum.
8. The antifungal product of claim 1 wherein said antifungal
product includes a total dosage of antifungal that is effective for
a twenty four hour period.
9. The product of claim 1 and further comprising a fourth
antifungal dosage form comprising an antifungal and a
pharmaceutically acceptable carrier, wherein antifungal released
from the fourth dosage form reaches a C.sub.max in the serum after
C.sub.max is achieved in the serum for antifungal released from
each of the first, second and third dosage forms.
10. A process for treating a fungal infection in a host comprising:
administering to a host the antifungal product of claim 1.
11. A process for treating a fungal infection in a host comprising:
administering to a host the antifungal product of claim 2.
12. A process for treating a fungal infection in a host comprising:
administering to a host the antifungal product of claim 3.
13. A process for treating a fungal infection in a host comprising:
administering to a host the antifungal product of claim 4.
14. A process for treating a fungal infection in a host comprising:
administering to a host the antifungal product of claim 5.
15. A process for treating a fungal infection in a host comprising:
administering to a host the antifungal product of claim 6.
16. A process for treating a fungal infection in a host comprising:
administering to a host the antifungal product of claim 7.
17. A process for treating a fungal infection in a host comprising:
administering to a host the antifungal product of claim 8.
18. A process for treating a fungal infection in a host comprising:
administering to a host the antifungal product of claim 9.
Description
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 09/687,236 filed Oct. 13, 2000.
[0002] This invention relates to an antifungal product, as well as
the use and formulation thereof.
[0003] A wide variety of antifungals have been used, and will be
used, in order to combat fungal infection. In general, such
antifungals can be administered by a repeated dosing of immediate
release dosage forms, which results in poor compliance or as a
controlled release formulation (slow release) at higher
administered doses. The present invention is directed to providing
for an improved antifungal product.
[0004] In accordance with one aspect of the present invention,
there is provided an antifungal pharmaceutical product which is
comprised of at least two, preferably at least three, antifungal
dosage forms. Such dosage forms are formulated so that each of the
dosage forms has a different release profile.
[0005] In a particularly preferred embodiment, there are at least
two, preferably at least three dosage forms, each of which has a
different release profile and the release profile of each of the
dosage forms is such that the dosage forms each start release of
the antifungal contained therein at different times after
administration of the antifungal product.
[0006] Thus, in accordance with an aspect of the present invention,
there is provided a single or unitary antifungal product that has
contained therein at least two, preferably at least three
antifungal dosage forms, each of which has a different release
profile, whereby the antifungal contained in each of such dosage
forms is released at different times.
[0007] In accordance with a further aspect of the invention, the
antifungal product may be comprised of at least four different
dosage forms, each of which starts to release the antifungal
contained therein at different times after administration of the
antifungal product.
[0008] The antifungal product generally does not include more than
five dosage forms with different release times.
[0009] In accordance with a preferred embodiment, the antifungal
product has an overall release profile such that when administered
the maximum serum concentration of the total antifungal released
from the product is reached in less than twelve hours, preferably
in less than eleven hours. In an embodiment, the maximum serum
concentration of the total antifungal released from the antifungal
product is achieved no earlier than four hours after
administration.
[0010] In accordance with one preferred embodiment of the
invention, there are at least three dosage forms. One of the at
least three dosage forms is an immediate release dosage form
whereby initiation of release of the antifungal therefrom is not
substantially delayed after administration of the antifungal
product. The second and third of the at least three dosage forms is
a delayed dosage form (which may be a pH sensitive or a non-pH
sensitive delayed dosage form, depending on the type of antifungal
product), whereby the antifungal released therefrom is delayed
until after initiation of release of the antifungal from the
immediate release dosage form. More particularly, the antifungal
release from the second of the at least two dosage forms achieves a
C.sub.max (maximum serum concentration in the serum) at a time
after the antifungal released from the first of the at least three
dosage forms achieves a C.sub.max in the serum, and the antifungal
released from the third dosage form achieves a C.sub.max in the
serum after the C.sub.max of antifungal released from the second
dosage form.
[0011] In one embodiment, the second of the at least two dosage
forms initiates release of the antifungal contained therein at
least one hour after the first dosage form, with the initiation of
the release therefrom generally occurring no more than six hours
after initiation of release of antifungal from the first dosage
form of the at least three dosage forms.
[0012] In general, the immediate release dosage form produces a
C.sub.max for the antifungal released therefrom within from about
0.5 to about 2 hours, with the second dosage form of the at least
three dosage forms producing a C.sub.max for the antifungal
released therefrom in no more than about four hours. In general,
the C.sub.max for such second dosage form is achieved no earlier
than two hours after administration of the antifungal product;
however, it is possible within the scope of the invention to
achieve C.sub.max in a shorter period of time.
[0013] As hereinabove indicated, the antifungal product may contain
at least three or at least four or more different dosage forms. For
example, if the antifungal product includes a third dosage form,
the antifungal released therefrom reaches a C.sub.max at a time
later than the C.sub.max is achieved for the antifungal released
from each of the first and second dosage forms. In a preferred
embodiment, release of antifungal from the third dosage form is
started after initiation of release of antifungal from both the
first dosage form and the second dosage form. In one embodiment,
C.sub.max for antifungal release from the third dosage form is
achieved within eight hours.
[0014] In another embodiment, the antifungal product contains at
least four dosage forms, with each of the at least four dosage
forms having different release profiles, whereby the antifungal
release from each of the at least four different dosage forms
achieves a C.sub.max at a different time.
[0015] As hereinabove indicated, in a preferred embodiment,
irrespective of whether the antifungal contains at least two or at
least three or at least four different dosage forms each with a
different release profile, C.sub.max for all the antifungal
released from the antifungal product is achieved in less than
twelve hours, and more generally is achieved in less than eleven
hours.
[0016] In a preferred embodiment, the antifungal product is a once
a day product, whereby after administration of the antifungal
product, no further product is administered during the day; i.e.,
the preferred regimen is that the product is administered only once
over a twenty-four hour period. Thus, in accordance with the
present invention, there is a single administration of an
antifungal product with the antifungal being released in a manner
such that overall antifungal release is effected with different
release profiles in a manner such that the overall C.sub.max for
the antifungal product is reached in less than twelve hours. The
term single administration means that the total antifungal
administered over a twenty-four hour period is administered at the
same time, which can be a single tablet or capsule or two or more
thereof, provided that they are administered at essentially the
same time.
[0017] Applicant has found that a single dosage antifungal product
comprised of at least three antifungal dosage forms each having a
different release profile is an improvement over a single dosage
antifungal product comprised of an antifungal dosage form having a
single release profile. Each of the dosage forms of antifungal in a
pharmaceutically acceptable carrier may have one or more
antifungals and each of the dosage forms may have the same
antifungal or different antifungals.
[0018] It is to be understood that when it is disclosed herein that
a dosage form initiates release after another dosage form, such
terminology means that the dosage form is designed and is intended
to produce such later initiated release. It is known in the art,
however, notwithstanding such design and intent, some "leakage" of
antifungal may occur. Such "leakage" is not "release" as used
herein.
[0019] If at least four dosage forms are used, the fourth of the at
least four dosage form may be a sustained release dosage form or a
delayed release dosage form. If the fourth dosage form is a
sustained release dosage form, even though C.sub.max of the fourth
dosage form of the at least four dosage forms is reached after the
C.sub.max of each of the other dosage forms is reached, antifungal
release from such fourth dosage form may be initiated prior to or
after release from the second or third dosage form.
[0020] The antifungal product of the present invention, as
hereinabove described, may be formulated for administration by a
variety of routes of administration. For example, the antifungal
product may be formulated in a way that is suitable for topical
administration; administration in the eye or the ear; rectal or
vaginal administration; as nose drops; by inhalation; as an
injectable; or for oral administration. In a preferred embodiment,
the antifungal product is formulated in a manner such that it is
suitable for oral administration.
[0021] For example, in formulating the antifungal product for
topical administration, such as by application to the skin, the at
least two different dosage forms, each of which contains an
antifungal, may be formulated for topical administration by
including such dosage forms in an oil-in-water emulsion, or a
water-in-oil emulsion. In such a formulation, the immediate release
dosage form is in the continuous phase, and the delayed release
dosage form is in a discontinuous phase. The formulation may also
be produced in a manner for delivery of three dosage forms as
hereinabove described. For example, there may be provided an
oil-in-water-in-oil emulsion, with oil being a continuous phase
that contains the immediate release component, water dispersed in
the oil containing a first delayed release dosage form, and oil
dispersed in the water containing a third delayed release dosage
form.
[0022] It is also within the scope of the invention to provide an
antifungal product in the form of a patch, which includes
antifungal dosage forms having different release profiles, as
hereinabove described.
[0023] In addition, the antifungal product may be formulated for
use in the eye or ear or nose, for example, as a liquid emulsion.
For example, the dosage form may be coated with a hydrophobic
polymer whereby a dosage form is in the oil phase of the emulsion,
and a dosage form may be coated with hydrophilic polymer, whereby a
dosage form is in the water phase of the emulsion.
[0024] Furthermore, the antifungal product with at least three
different dosage forms with different release profiles may be
formulated for rectal or vaginal administration, as known in the
art. This may take the form of a cream or emulsion, or other
dissolvable dosage form similar to those used for topical
administration.
[0025] As a further embodiment, the antifungal product may be
formulated for use in inhalation therapy by coating the particles
and micronizing the particles for inhalation.
[0026] In a preferred embodiment, the antifungal product is
formulated in a manner suitable for oral administration. Thus, for
example, for oral administration, each of the dosage forms may be
used as a pellet or a particle, with a pellet or particle then
being formed into a unitary pharmaceutical product, for example, in
a capsule, or embedded in a tablet, or suspended in a liquid for
oral administration.
[0027] Alternatively, in formulating an oral delivery system, each
of the dosage forms of the product may be formulated as a tablet,
with each of the tablets being put into a capsule to produce a
unitary antifungal product. Thus, for example, antifungal products
may include a first dosage form in the form of a tablet that is an
immediate release tablet, and may also include two or more
additional tablets, each of which provides for a delayed release of
the antifungal, as hereinabove described, whereby the C.sub.max of
the antifungal released from each of the tablets is reached at
different times, with the C.sub.max of the total antifungal
released from the antifungal product being achieved in less than
twelve hours.
[0028] The formulation of an antifungal product including at least
three dosage forms with different release profiles for different
routes of administration is deemed to be within the skill of the
art from the teachings herein. As known in the art, with respect to
delayed release, the time of release can be controlled by the
concentration of antifungals in the coating and/or the thickness of
the coating.
[0029] In formulating an antifungal product in accordance with the
invention, in one embodiment, the immediate release dosage form of
the product generally provides from about 20% to about 50% of the
total dosage of antifungal to be delivered by the product, with
such immediate release dosage forms generally providing at least
25% of the total dosage of the antifungal to be delivered by the
product. In many cases, the immediate release dosage form provides
from about 20% to about 30% of the total dosage of antifungal to be
delivered by the product; however, in some cases it may be
desirable to have the immediate release dosage form provide for
about 45% to about 50% of the total dosage of antifungal to be
delivered by the product.
[0030] The remaining dosage forms deliver the remainder of the
antifungal. If more than one delayed release dosage form is used,
in one embodiment, each of the delayed release dosage forms may
provide about equal amounts of antifungal; however, they may also
be formulated so as to provide different amounts.
[0031] In accordance with the present invention, each of the dosage
forms contains the same antifungal; however, each of the dosage
forms may contain more than one antifungal.
[0032] In one embodiment, where the composition contains one
immediate release component and two delayed release components, the
immediate release component provides from 20% to 35% (preferably
20% to 30%), by weight, of the total antifungal; where there is
three delayed release components, the immediate release component
provides from 15% to 30%, by weight, of the total antifungal; and
where there are four delayed release components, the immediate
release component provides from 10% to 25%, by weight, of the total
antifungal.
[0033] With respect to the delayed release components, where there
are two delayed release components, the first delayed release
component (the one released earlier in time) provides from 30% to
60%, by weight, of the total antifungal provided by the two delayed
release components with the second delayed release component
providing the remainder of the antifungal.
[0034] Where there are three delayed release components, the
earliest released component provides 20% to 35% by weight of the
total antifungal provided by the three delayed release components,
the next in time delayed release component provides from 20% to
40%, by weight, of the antifungal provided by the three delayed
release components and the last in time providing the remainder of
the antifungal provided by the three delayed release
components.
[0035] When there are four delayed release components, the earliest
delayed release component provides from 15% to 30%, by weight, the
next in time delayed release component provides from 15% to 30%,
the next in time delayed release component provides from 20% to
35%, by weight, and the last in time delayed release component
provides from 20% to 35%, by weight, in each case of the total
antifungal provided by the four delayed release components.
[0036] The Immediate Release Component
[0037] The immediate release portion of this system can be a
mixture of ingredients that breaks down quickly after
administration to release the antifungal. This can take the form of
either a discrete pellet or granule that is mixed in with, or
compressed with, the other three components.
[0038] The materials to be added to the antifungals for the
immediate release component can be, but are not limited to,
microcrystalline cellulose, corn starch, pregelatinized starch,
potato starch, rice starch, sodium carboxymethyl starch,
hydroxypropylcellulose, hydroxypropylmethylcellulose,
hydroxyethylcellulose, ethylcellulose, chitosan, hydroxychitosan,
hydroxymethylatedchitosan, cross-linked chitosan, cross-linked
hydroxymethyl chitosan, maltodextrin, mannitol, sorbitol, dextrose,
maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone
(PVP), acrylic acid derivatives (Carbopol, Eudragit, etc.),
polyethylene glycols, such a low molecular weight PEGs
(PEG2000-10000) and high molecular weight PEGs (Polyox) with
molecular weights above 20,000 daltons.
[0039] It may be useful to have these materials present in the
range of 1.0 to 60% (W/W).
[0040] In addition, it may be useful to have other ingredients in
this system to aid in the dissolution of the drug, or the breakdown
of the component after ingestion or administration. These
ingredients can be surfactants, such as sodium lauryl sulfate,
sodium monoglycerate, sorbitan monooleate, sorbitan monooleate,
polyoxyethylene sorbitan monooleate, glyceryl monostearate,
glyceryl monooleate, glyceryl monobutyrate, one of the non-ionic
surfactants such as the Pluronic line of surfactants, or any other
material with surface active properties, or any combination of the
above.
[0041] These materials may be present in the rate of 0.05-15%
(W/W).
[0042] The Non-pH Sensitive Delayed Release Component
[0043] The components in this composition are the same immediate
release unit, but with additional polymers integrated into the
composition, or as coatings over the pellet or granule.
[0044] Materials that can be used to obtain a delay in release
suitable for this component of the invention can be, but are not
limited to, polyethylene glycol (PEG) with molecular weight above
4,000 daltons (Carbowax, Polyox), waxes such as white wax or bees
wax, paraffin, acrylic acid derivatives (Eudragit), propylene
glycol, and ethylcellulose.
[0045] Typically these materials can be present in the range of
0.5-25% (W/W) of this component.
[0046] The pH Sensitive (Enteric) Release Component
[0047] The components in this composition are the same as the
immediate release component, but with additional polymers
integrated into the composition, or as coatings over the pellet or
granule.
[0048] The kind of materials useful for this purpose can be, but
are not limited to, cellulose acetate pthalate, Eudragit L, and
other pthalate salts of cellulose derivatives.
[0049] These materials can be present in concentrations from 4-20%
(W/W).
[0050] Sustained Release Component
[0051] The components in this composition are the same as the
immediate release component, but with additional polymers
integrated into the composition, or as coatings over the pellet or
granule.
[0052] The kind of materials useful for this purpose can be, but
are not limited to, ethylcellulose, hydroxypropylmethylcellulose,
hydroxypropylcellulose, hydroxyethylcellulose,
carboxymethylcellulose, methylcellulose, nitrocellulose, Eudragit
R, and Eudragit RL, Carbopol, or polyethylene glycols with
molecular weights in excess of 8,000 daltons.
[0053] These materials can be present in concentrations from 4-20%
(W/W).
[0054] As hereinabove indicated, the units comprising the
antifungal composition of the present invention can be in the form
of discrete pellets or particles contained in the capsule, or
particles embedded in a tablet or suspended in a liquid
suspension.
[0055] The antifungal composition of the present invention may be
administered, for example, by any of the following routes of
administration: sublingual, transmucosal, transdermal, parenteral,
etc., and preferably is administered orally. The composition
includes a therapeutically effective amount of the antifungal,
which amount will vary with the antifungal to be used, the disease
or infection to be treated, and the number of times that the
composition is to be delivered in a day. The composition is
administered to a host in an amount effective for treating a fungal
infection.
[0056] The following are representative examples of some
antifungals that can be employed in the composition of the
invention: amphotericin B, flucytosine, fluconazole, griseofulvin,
miconazole nitrate, terbinafine hydrochloride, ketoconazole,
itraconazole, undecylenic acid and chloroxylenol, ciclopirox,
clotrimazole, butenafine hydrochloride, nystatin, naftifine
hydrochloride, oxiconazole nitrate, selenium sulfide, econazole
nitrate, terconazole, butoconazole nitrate, carbol-fuchsin,
clioquinol, methylrosaniline chloride, sodium thiosulfate,
sulconazole nitrate, terbinafine hydrochloride, tioconazole,
tolnaftate, undecylenic acid and undecylenate salts (calcium
undecylenate, copper undecylenate, zinc undecylenate).
[0057] The invention will be further described with respect to the
following examples; however, the scope of the invention is not
limited thereby. All percentages in this specification, unless
otherwise specified, are by weight.
[0058] Immediate Release Component
[0059] Formulate the composition by mixing the ingredients in a
suitable pharmaceutical mixer or granulator such as a planetary
mixer, high-shear granulator, fluid bed granulator, or extruder, in
the presence of water or other solvent, or in a dry blend. If water
or other solvent was used, dry the blend in a suitable
pharmaceutical drier, such as a vacuum oven or forced-air oven. The
product may be sieved or granulated, and compressed using a
suitable tablet press, such as a rotary tablet press.
1 Example 1: Fluconazole 65% (W/W) Microcrystalline cellulose 20
Povidone 10 Croscar,ellose sodium 5 Example 2: Fluconazole 55%
(W/W) Microcrystalline cellulose 25 Povidone 10 Croscarmellose
sodium 10 Example 3: Fluconazole 65% (W/W) Microcrystalline
cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5
Example 4: Fluconazole 75% (W/W) Polyethylene glycol 4000 10
Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 5:
Fluconazole 75% (W/W) Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5 Example 6: Ketoconazole 65% (W/W)
Microcrystalline cellulose 20 Hydroxypropylcellulose 10
Croscarmellose sodium 5 Example 7: Ketoconazole 75% (W/W)
Microcrystalline cellulose 15 Hydroxypropylcellulose 5
Croscarmellose sodium 5 Example 8: Ketoconazole 75% (W/W)
Polyethylene glycol 4000 10 Polyethylene glycol 2000 10
Hydroxypropylcellulose 5 Example 9: Ketoconazole 75% (W/W)
Polyethylene glycol 8000 20 Polyvinylpyrrolidofle 5 Example 10:
Griseofulvin 65% (W/W) Microcrystalline cellulose 20
Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 11:
Griseofulvin 75% (W/W) Microcrystalline cellulose 15
Hydroxypropylcellulose 5 Croscarmellose sodium 5 Example 12:
Griseofulvin 75% (W/W) Polyethylene glycol 4000 10 Polytheylene
glycol 2000 10 Hydroxypropylcellulose 5 Example 13: Cirpofloxacin
75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5
Example 14: Terbinafine HCl 75% (W/W) Polyethylene glycol 4000 10
Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 15:
Terbinafme HCl 75% (W/W) Polyethylene Glycol 4000 20
Polyvinylpyrrolidone 5
[0060] Non pH Sensitive Delayed Release Component
[0061] Formulate the composition by mixing the ingredients in a
suitable pharmaceutical mixer or granulator such as a planetary
mixer, high-shear granulator, fluid bed granulator, or extruder, in
the presence of water or other solvent, or in a hot melt process.
If water or other solvent was used, dry the blend in a suitable
pharmaceutical drier, such as a vacuum oven or forced-air oven.
Allow the product to cool, the product may be sieved or granulated,
and compressed using a suitable tablet press, such as a rotary
tablet press.
2 Ingredient Conc. (% W/W) Example 16: Fluconazole 65% (W/W)
Microcrystalline cellulose 20 Polyox 10 Croscarmellose sodium 5
Example 17: Fluconazole 55% (W/W) Microcrystalline cellulose 25
Polyox 10 Glyceryl monooleate 10 Example 18: Fluconazole 65% (W/W)
Polyox 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example
19: Fluconazole 75% (W/W) Polyethylene glycol 4000 10 Polyethylene
glycol 2000 10 Eudragit RL 30D 5 Example 20: Fluconazole 75% (W/W)
Polyethylene glycol 8000 20 Ethylcellulose 5 Example 21:
Ketoconazole 70% (W/W) Polyox 20 Hydroxypropylcellulose 5
Croscarmellose sodium 5 Example 22: Ketoconazole 75% (W/W) Polyox
15 Hydroxypropylcellulose 5 Ethylcellulose 5 Example 23:
Ketoconazole 75% (W/W) Polyethylene glycol 4000 10 Polyethylene
glycol 2000 10 Eudragit RL 30D 5 Example 24: Ketoconazole 80% (W/W)
Polyethylene glycol 8000 10 Polyvinylpyrrolidone 5 Eudgragit R 30D
5 Example 25: Griseofulvin 65% (W/W) Polyethylene glycol 4000 20
Hydroxypropylcellulose 10 Eudragit RL 30D 5 Example 26:
Griseofulvin 75% (W/W) Microcrystalline cellulose 15
Hydroxypropylcellulose 5 Ethylcellulose 5 Example 27: Griseofulvin
80% (WIW) Polyethylene glycol 4000 10 Polyethylene glycol 2000 5
Eudgragit RL 30D 5 Example 28: Griseofulvin 75% (W/W) Polyethylene
glycol 8000 20 Ethylcellulose 5 Example 29: Terbinafine HCl 75%
(W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10
Eudragit RL 30D 5 Example 30: Terbinafine HCl 75% (W/W)
Polyethylene glycol 8000 20 Ethylcellulose 5
[0062] Enteric Release Component
[0063] Formulate the ingredients by mixing the ingredients in a
suitable pharmaceutical mixer or granulator such as a planetary
mixer, high-shear granulator, fluid bed granulator, or extruder, in
the presence of water or other solvent, or in a hot melt process.
If water or other solvent was used, dry the blend in a suitable
pharmaceutical drier, such as a vacuum oven or forced-air oven.
Allow the product to cool, the product may be sieved or granulated,
and compressed using a suitable tablet press, such as a rotary
tablet press.
3 Ingredient Conc. (% W/W) Example 31: Fluconazole 65% (W/W)
Microcrystalline cellulose 20 Cellulose Acetate Pthalate 15 Example
32: Fluconazole 55% (W/W) Microcrystalline cellulose 25 Cellulose
Acetate Pthalate 10 Hydroxypropylmethylcellulose 10 Example 33:
Fluconazole 65% (W/W) Polyox 20 Hydroxypropylcellulose pthalate 10
Eudragit L30D 5 Example 34: Fluconazole 75% (W/W) Polyethylene
glycol 2000 10 Eudragit L 30D 10 Eudragit RL 30D 5 Example 35:
Fluconazole 40% (W/W) Microcrystalline Cellulose 40 Cellulose
Acetate Pthalate 10 Example 36: Ketoconazole 70% (W/W)
Hydroxypropylcellulose pthalate 15 Croscarmellose sodium 10 Example
37: Ketoconazole 70% (W/W) Eudragit L 30D 15 Hydroxypropylcellulose
10 Ethylcellulose 5 Example 38: Ketoconazole 75% (W/W) Polyethylene
glycol 2000 10 Eudragit L 30D 15 Example 39: Ketoconazole 40% (W/W)
Lactose 50 Eudgragit L 30D 10 Example 40: Griseofulvin 65% (W/W)
Microcrystalline Cellulose 20 Eudragit L 30D 10 Example 41:
Griseofulvin 75% (W/W) Microcrystalline Cellulose 15
Hydroxypropylcellulose pthalate 10 Example 42: Griseofulvin 80%
(W/W) Lactose 10 Eudragit L 30D 10 Example 43: Griseofulvin 70%
(W/W) Polyethylene glycol 4000 20 Cellulose acetate pthalate 10
Example 44: Terbinafine HCl 60% (W/W) Polyethylene glycol 2000 10
Lactose 20 Eudragit L 30D 10 Example 45: Terbinafine HCl 70% (W/W)
Microcrystalline cellulose 20 Cellulose acetate pthalate 10
[0064] Sustained Release Component
[0065] Formulate the composition by mixing the ingredients in a
suitable pharmaceutical mixer or granulator such as a planetary
mixer, high-shear granulator, fluid bed granulator, or extruder, in
the presence of water or other solvent, or in a hot melt process.
If water or other solvent was used, dry the blend in a suitable
pharmaceutical drier, such as a vacuum oven or forced-air oven.
Allow the product to cool, the product may be sieved or granulated,
and compressed using a suitable tablet press, such as a rotary
tablet press.
4 Ingredient Conc. (% W/W) Example 46: Fluconazole 65% (W/W)
Ethylcellulose 20 Polyox 10 Hydroxypropylmethylcellulose 5 Example
47: Fluconazole 55% (W/W) Lactose 25 Polyox 10 Glyceryl monooleate
10 Example 48: Fluconazole 70% (W/W) Polyox 20
Hydroxypropylcellulose 10 Example 49: Ketoconazole 75% (W/W)
Lactose 15 Hydroxypropylcellulose 5 Ethylcellulose 5 Example 50:
Ketoconazole 75% (W/W) Polyethylene glycol 4000 10 Lactose 10
Eudragit RL 30D 5 Example 51: Ketoconazole 80% (W/W) Polyethylene
glycol 8000 10 Hydroxypropylmethylcellulose 5 Eudgragit RS 30D 5
Example 52: Griseofulvin 75% (W/W) Hydroxyethylcellulose 10
Polyethylene glycol 4000 10 Hydroxypropylcellulose 5 Example 53:
Griseofulvin 75% (W/W) Lactose 10 Povidone (PVP) 10 Polyethylene
glycol 2000 5 Example 54: Terbinafine HCl 75% (W/W) Polyethylene
glycol 4000 10 Povidone (PVP) 10 Hydroxypropylcellulose 5 Example
55: Terbinafine HCl 75% (W/W) Lactose 15 Polyethylene glycol 4000 5
Polyvinylpyrrolidone 5 Example 56: Ketoconazole 40% (W/W) Eudragit
S100 50 Triethyl Citrate 10 Example 57: Ketoconazole 50% (W/W)
Sureteric 50 Example 58: Ketoconazole 50% (W/W) Eudragit S100 45
Triethyl Citrate 5
[0066] Three Pulses
EXAMPLE 59
1. Antifungal Matrix Pellet Formulation and Preparation Procedure
(Immediate Release)
[0067] A. Pellet Formulation
[0068] The composition of the antifungal matrix pellets provided in
Table 1.
5TABLE 1 Composition of Antifungal Pellets Component Percentage (%)
Antifungal 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10 Purified
Water Total 100 *PVP K29/32 was added as a 20% w/w aqueous solution
during wet massing.
[0069] B. Preparation Procedure for Antifungal Matrix Pellets
[0070] 1.2.1 Blend Antifungal and Avicel.RTM. PH 101 using a Robot
Coupe high shear granulator.
[0071] 1.2.2 Add 20% Povidone K29/32 binder solution slowly into
the powder blend under continuous mixing.
[0072] 1.2.3 Extrude the wet mass using an LCI Bench Top
Granulator. The diameter of the screen of the Bench Top Granulator
was 1.0 mm.
[0073] 1.2.4 Spheronize the extrudate using a Model SPH20 Caleva
Spheronizer.
[0074] 1.2.5 Dry the spheronized pellets at 50.degree. C.
overnight.
[0075] 1.2.6 Pellets between 16 and 30 Mesh were collected for
further processing.
[0076] 1.3 Preparation of an Eudragit.RTM. L 30 D-55 Aqueous
Coating Dispersion
[0077] A. Dispersion Formulation
[0078] The composition of the aqueous Eudragit L30D-55 dispersion
applied to the Antifungal matrix pellets is provided below in Table
2.
6TABLE 2 Eudragit .RTM. L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%) Eudragit .RTM. L 30 D-55 55.0 Triethyl
Citrate 1.6 Talc 8.0 Purified Water 37.4 Solids Content 25.5
Polymer Content 15.9
[0079] B. Preparation Procedure for an Eudragit.RTM. L 30 D-55
Aqueous Dispersion
[0080] 1.3.1 Suspend triethyl citrate and talc in deionized
water.
[0081] 1.3.2 The TEC/talc suspension is then homogenized using a
PowerGen 700 high shear mixer.
[0082] 1.3.3 Add the TEC/talc suspension slowly to the
Eudragit.RTM. L 30 D-55 latex dispersion while stirring.
[0083] 1.3.4 Allow the coating dispersion to stir for one hour
prior to application onto the Antifungal matrix pellets.
[0084] 1.4 Preparation of an Eudragit.RTM. S 100 Aqueous Coating
Dispersion
[0085] A. Dispersion Formulation
[0086] The composition of the aqueous Eudragit.RTM. S 100
dispersion applied to the Antifungal matrix pellets is provided
below in Table 3.
7TABLE 3 Eudragit .RTM. S 100 Aqueous Coating Dispersion Component
Percentage (%) Part A Eudragit .RTM. S 100 12.0 1 N Animonium
Hydroxide 6.1 Triethyl Citrate 6.0 Purified Water 65.9 Part B Talc
2.0 Purified Water 8.0 Solid Content 20.0 Polymer Content 12.0
[0087] B. Preparation Procedure for an Eudragit.RTM. S 100 Aqueous
Dispersion
[0088] Part I:
[0089] (i) Dispense Eudragit.RTM. S 100 powder in deionized water
with stirring.
[0090] (ii) Add ammonium hydroxide solution drop-wise into the
dispersion with stirring.
[0091] (iii) Allow the partially neutralized dispersion to stir for
60 minutes.
[0092] (iv) Add triethyl citrate drop-wise into the dispersion with
stirring. Stir for about 2 hours prior to the addition of Part
B.
[0093] Part II:
[0094] (i) Disperse talc in the required amount of water
[0095] (ii) Homogenize the dispersion using a PowerGen 700D high
shear mixer.
[0096] (iii) Part B is then added slowly to the polymer dispersion
in Part A with a mild stirring.
[0097] 1.5 Coating Conditions for the Application of Aqueous
Coating Dispersions
[0098] The following coating parameters are used to coat matrix
pellets with each of the Eudragit.RTM. L 30 D-55 and Eudragit.RTM.
S 100 aqueous film coating.
8 Coating Equipment STREA 1 .TM. Table Top Laboratory Fluid Bed
Coater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet
Air Temperature 40 to 45.degree. C. Outlet Air Temperature 30 to
33.degree. C. Atomization Air Pressure 1.8 Bar Pump Rate 2 gram per
minute
[0099] (i) Coat matrix pellets with L30 D-55 dispersion such that
you apply 12% coat weight gain to the pellets.
[0100] (ii) Coat matrix pellets with S100 dispersion such that you
apply 20% coat weight gain to the pellets.
[0101] 1.6 Encapsulation of the Antifungal Pellets
[0102] Pellets are filled into size 00 hard gelatin capsules at a
ratio of 30%:30%:40%: Immediate-release matrix pellets uncoated,
L30 D-55 coated pellets and S100 coated pellets respectively. The
capsule is filled with the three different pellets to achieve the
desired dosage.
[0103] Three Pulses
EXAMPLE 60
Antifungal Pellet Formulation and Preparation Procedure
[0104] 60.1 Pellet Formulations for Subsequent Coating
[0105] The composition of the Antifungal trihydrate matrix pellets
provided in Table 4.
9TABLE 4 Composition of Antifungal Matrix Pellets Component
Percentage (%) Antifungal Trihydrate powder 92 Avicel PH 101 7.0
Hydroxypropyl methylcellulose, NF* 1.0 Total 100 *Hydroxypropyl
methylcellulose was added as a 2.9% w/w aqueous solution during wet
massing.
[0106] 60.2 Preparation Procedure for Antifungal Matrix Pellets
[0107] 60.2.1 Blend Antifungal and Avicel.RTM. PH 101 using a low
shear blender.
[0108] 60.2.2 Add the hydroxypropyl methylcellulose binder solution
slowly into the powder blend under continuous mixing.
[0109] 60.2.3 Extrude the wet mass using an LCI Bench Top
Granulator. The diameter of the screen of the Bench Top Granulator
is 0.8 mm.
[0110] 60.2.4 Spheronize the extrudate using a QJ-230 Spheronizer
using a small cross section plate.
[0111] 60.2.5 Dry the spheronized pellets at 60.degree. C. using a
fluid bed dryer until the exhaust temperature reaches 40.degree.
C.
[0112] 60.2.6 Pellets between 20 and 40 Mesh were collected for
further processing.
[0113] 60.3 Preparation of an Eudragit.RTM. L 30 D-55 Aqueous
Coating Dispersion
[0114] 60.3.1 Dispersion Formulation
[0115] The composition of the aqueous Eudragit L30D-55 dispersion
applied to the antifungal matrix pellets is provided below in Table
5.
10TABLE 5 Eudragit .RTM. L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%) Eudragit .RTM. L 30 D-55 41.6 Triethyl
Citrate 2.5 Talc 5.0 Purified Water 50.9 Solids Content 20.0
Polymer Content 12.5
[0116] 60.4 Preparation Procedure for an Eudragit.RTM. L 30 D-55
Aqueous Dispersion
[0117] 60.4.1 Suspend triethyl citrate and talc in deionized
water.
[0118] 60.4.2 The TEC/talc suspension is mixed using laboratory
mixer.
[0119] 60.4.3 Add the TEC/talc suspension from slowly to the
Eudragit.RTM. L 30 D-55 latex dispersion while stirring.
[0120] 60.4.4 Allow the coating dispersion to stir for one hour
prior to application onto the antifungal matrix pellets.
[0121] 60.5 Preparation of an Eudragit.RTM. S 100 Aqueous Coating
Dispersion
[0122] 60.5.1 Dispersion Formulation
[0123] The composition of the aqueous Eudragit.RTM. S 100
dispersion applied to the Antifungal matrix pellets is provided
below in Table 6.
11TABLE 6 Eudragit .RTM. S 100 Aqueous Coating Dispersion Component
Percentage (%) Part A Eudragit .RTM. S 100 10.0 1 N Ammonium
Hydroxide 5.1 Triethyl Citrate 5.0 Water 64.9 Part B Talc 5.0 Water
10.0 Solid Content 25.0 Polymer Content 10.0
[0124] 60.6 Preparation Procedure for an Eudragit.RTM. S 100
Aqueous Dispersion
[0125] Part A:
[0126] 60.6.1 Dispense Eudragit.RTM. S 100 powder in deionized
water with stirring.
[0127] 60.6.2 Add ammonium hydroxide solution drop-wise into the
dispersion with stirring.
[0128] 60.6.3 Allow the partially neutralized dispersion to stir
for 60 minutes.
[0129] 60.6.4 Add triethyl citrate drop-wise into the dispersion
with stirring and let stir overnight prior to the addition of Part
B.
[0130] Part B:
[0131] 60.6.5 Disperse talc in the required amount of water
[0132] 60.6.6 Stir the dispersion using an overhead laboratory
mixer.
[0133] 60.6.7 Part B is then added slowly to the polymer dispersion
in Part A with a mild stirring.
[0134] 60.7 Coating Conditions for the Application of Aqueous
Coating Dispersions
[0135] The following coating parameters are used for both the
Eudragit.RTM. L 30 D-55 and Eudragit.RTM. S 100 aqueous film
coating processes.
12 Coating Equipment STREA 1 .TM. Table Top Laboratory Fluid Bed
Coater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet
Air Temperature 40 to 45.degree. C. Outlet Air Temperature 30 to
33.degree. C. Atomization Air Pressure 1.8 Bar Pump Rate 2-6 gram
per minute
[0136] 60.7.1 Coat matrix pellets with L30 D-55 dispersion such
that you apply 20% coat weight gain to the pellets.
[0137] 60.7.2 Coat matrix pellets with S100 dispersion such that
you apply 37% coat weight gain to the pellets.
[0138] 60.8 Preparation of Antifungal Granulation (Immediate
Release Component) for Tabletting
13TABLE 7 Composition of Antifungal Granulation Component
Percentage (%) Antifungal Trihydrate powder 92 Avicel PH 101 7.0
Hydroxypropyl methylcellulose, NF* 1.0 Total 100 *Hydroxypropyl
methylcellulose was added as a 2.9% w/w aqueous solution during wet
massing.
[0139] 60.8.1 Blend Antifungal and Avicel.RTM. PH 101 using a low
shear blender.
[0140] 60.8.2 Add the hydroxypropyl methylcellulose binder solution
slowly into the powder blend under continuous mixing.
[0141] 60.8.3 Dry the granulation at 60.degree. C. using a fluid
bed dryer until the exhaust temperature reaches 40.degree. C.
[0142] 60.8.4 Granules between 20 and 40 Mesh are collected for
further processing.
[0143] 60.9 Tabletting of the Antifungal Pellets
14TABLE 8 Composition of Antifungal Tablets Component Percentage
(%) Antifungal granules 32.5 Avicel PH 200 5.0 Antifungal L30D-55
coated pellets 30 Antifungal S100 coated pellets 30 Colloidal
silicon dioxide 1.5 Magnesium stearate 1.0 Total 100
[0144] 60.9.1 Blend the Antifungal granules, Avicel PH-200,
Antifungal pellets and colloidal silicon dioxide for 15 minutes in
a tumble blender.
[0145] 60.9.2 Add the magnesium stearate to the blender, and blend
for 5 minutes.
[0146] 60.9.3 Compress the blend on a rotary tablet press.
[0147] 60.9.4 The fill weight should be adjusted to achieve the
desired dosage.
[0148] Four pulses
EXAMPLE 61
1 Antifungal Matrix Pellet Formulation and Preparation
Procedure
[0149] 61.1 Pellet Formulation
[0150] The composition of the Antifungal matrix pellets provided in
Table 9.
15TABLE 9 Composition of Antifungal Pellets Component Percentage
(%) Antifungal 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10
Purified Water Total 100 *PVP K29/32 was added as a 20% w/w aqueous
solution during wet massing.
[0151] 61.2 Preparation Procedure for Antifungal Matrix Pellets
[0152] 61.2.1 Blend Antifungal and Avicel.RTM. PH 101 using a Robot
Coupe high shear granulator.
[0153] 61.2.2 Add 20% Povidone K29/32 binder solution slowly into
the powder blend under continuous mixing.
[0154] 61.2.3 Extrude the wet mass using an LCI Bench Top
Granulator. The diameter of the screen of the Bench Top Granulator
was 1.0 mm.
[0155] 61.2.4 Spheronize the extrudate using a Model SPH20 Caleva
Spheronizer.
[0156] 61.2.5 Dry the spheronized pellets at 50.degree. C.
overnight.
[0157] 61.2.6 Pellets between 16 and 30 Mesh were collected for
further processing.
[0158] 61.3 Preparation of an Eudragit.RTM. L 30 D-55 Aqueous
Coating Dispersion
[0159] 61.3.1 Dispersion Formulation
[0160] The composition of the aqueous Eudragit L30D-55 dispersion
applied to the Antifungal matrix pellets is provided below in Table
10.
16TABLE 10 Eudragit .RTM. L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%) Eudragit .RTM. L 30 D-55 55.0 Triethyl
Citrate 1.6 Talc 8.0 Purified Water 37.4 Solids Content 25.5
Polymer Content 15.9
[0161] 61.4 Preparation Procedure for an Eudragit.RTM. L 30 D-55
Aqueous Dispersion
[0162] 61.4.1 Suspend triethyl citrate and talc in deionized
water.
[0163] 61.4.2 The TEC/talc suspension is then homogenized using a
PowerGen 700 high shear mixer.
[0164] 61.4.3 Add the TEC/talc suspension slowly to the
Eudragit.RTM. L 30 D-55 latex dispersion while stirring.
[0165] 61.4.4 Allow the coating dispersion to stir for one hour
prior to application onto the Antifungal matrix pellets.
[0166] 61.5 Preparation of an Eudragit.RTM. S 100 Aqueous Coating
Dispersion
[0167] 61.5.1 Dispersion Formulation
[0168] The composition of the aqueous Eudragit.RTM. S 100
dispersion applied to the Antifungal matrix pellets is provided
below in Table 11.
17TABLE 11 Eudragit .RTM. S 100 Aqueous Coating Dispersion
Component Percentage (%) Part A Eudragit .RTM. S 100 12.0 1 N
Ammonium Hydroxide 6.1 Triethyl Citrate 6.0 Purified Water 65.9
Part B Talc 2.0 Purified Water 8.0 Solid Content 20.0 Polymer
Content 12.0
[0169] 61.6 Preparation Procedure for an Eudragit.RTM. S 100
Aqueous Dispersion
[0170] Part A:
[0171] 61.6.1 Dispense Eudragit.RTM. S 100 powder in deionized
water with stirring.
[0172] 61.6.2 Add ammonium hydroxide solution drop-wise into the
dispersion with stirring.
[0173] 61.6.3 Allow the partially neutralized dispersion to stir
for 60 minutes.
[0174] 61.6.4 Add triethyl citrate drop-wise into the dispersion
with stirring. Stir for about 2 hours prior to the addition of Part
B.
[0175] Part B:
[0176] 61.6.5 Disperse talc in the required amount of water
[0177] 61.6.6 Homogenize the dispersion using a PowerGen 700D high
shear mixer.
[0178] 61.6.7 Part B is then added slowly to the polymer dispersion
in Part A with a mild stirring.
[0179] 61.7 Coating Conditions for the Application of Aqueous
Coating Dispersions
[0180] The following coating parameters are used for coating with
each of the Eudragit.RTM. L 30 D-55 and Eudragit.RTM. S 100 aqueous
film coatings.
18 Coating Equipment STREA 1 .TM. Table Top Laboratory Fluid Bed
Coater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet
Air Temperature 40 to 45.degree. C. Outlet Air Temperature 30 to
33.degree. C. Atomization Air Pressure 1.8 Bar Pump Rate 2 gram per
minute
[0181] 61.7.1 Coat matrix pellets with L30 D-55 dispersion such
that you apply 12% coat weight gain to the pellets.
[0182] 61.7.2 Coat matrix pellets with L30 D-55 dispersion such
that you apply 30% coat weight gain to the pellets.
[0183] 61.7.3 Coat matrix pellets with S100 dispersion such that
you apply 20% coat weight gain to the pellets.
[0184] 61.8 Encapsulation of the Antifungal Pellets
[0185] Pellets are filled into size 00 hard gelatin capsules at a
ratio of 20%:30%:20%:30% Immediate-release matrix pellets
(uncoated), L30 D-55 coated pellets 12% weight gain, L30D-55 coated
pellets 30% weight gain and S100 coated pellets respectively. The
capsule is filled with the four different pellets to achieve the
desired dosage.
[0186] The present invention is particularly advantageous in that
there is provided an antifungal product which provides an
improvement over twice a day administration of the antifungal and
an improvement over a once a day administration of the
antifungal.
[0187] Numerous modification and variations of the present
invention are possible in light of the above teachings and
therefore, within the scope of the appended claims the invention
may be practiced otherwise than as particularly described.
* * * * *