U.S. patent application number 17/185217 was filed with the patent office on 2022-01-20 for once daily formulations of tetracyclines.
The applicant listed for this patent is TCD Royalty Sub, LLC. Invention is credited to Rong-Kun Chang, Arash Raoufinia, Niraj Shah.
Application Number | 20220016041 17/185217 |
Document ID | / |
Family ID | 1000005872276 |
Filed Date | 2022-01-20 |
United States Patent
Application |
20220016041 |
Kind Code |
A1 |
Chang; Rong-Kun ; et
al. |
January 20, 2022 |
Once Daily Formulations Of Tetracyclines
Abstract
Disclosed are once-daily formulations containing tetracyclines,
especially doxycycline. Such formulations are useful, for instance,
for the treatment of collagenase destructive enzyme-dependent
diseases, such as periodontal disease and acne, and acute and
chronic inflammatory disease states, such as rosacea and
arthritis.
Inventors: |
Chang; Rong-Kun; (Rockville,
MD) ; Raoufinia; Arash; (Vienna, VA) ; Shah;
Niraj; (Finksburg, MD) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TCD Royalty Sub, LLC |
New York |
NY |
US |
|
|
Family ID: |
1000005872276 |
Appl. No.: |
17/185217 |
Filed: |
February 25, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16171940 |
Oct 26, 2018 |
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17185217 |
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14728266 |
Jun 2, 2015 |
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16171940 |
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14219231 |
Mar 19, 2014 |
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14728266 |
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13920538 |
Jun 18, 2013 |
8709478 |
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14219231 |
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12926933 |
Dec 17, 2010 |
8470364 |
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13920538 |
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12155676 |
Jun 6, 2008 |
8206740 |
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12926933 |
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10819620 |
Apr 7, 2004 |
7749532 |
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12155676 |
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60460963 |
Apr 7, 2003 |
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60547964 |
Feb 26, 2004 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2027 20130101;
A61K 9/4808 20130101; A61K 9/5084 20130101; A61K 9/167 20130101;
A61K 9/2054 20130101; A61K 9/5078 20130101; A61K 9/209 20130101;
A61K 31/65 20130101 |
International
Class: |
A61K 9/48 20060101
A61K009/48; A61K 9/20 20060101 A61K009/20; A61K 9/24 20060101
A61K009/24; A61K 9/50 20060101 A61K009/50; A61K 9/16 20060101
A61K009/16; A61K 31/65 20060101 A61K031/65 |
Claims
1. An oral pharmaceutical composition containing a tetracycline,
which at a once-daily dosage will give steady state blood levels of
the tetracycline of a minimum of about 0.1 .mu.g/ml and a maximum
of about 1.0 .mu.g/ml.
2. The composition of claim 1, which at a once-daily dosage will
give steady state blood levels of the tetracycline of between about
0.3 .mu.g/ml to about 0.8 .mu.g/ml.
3. The composition of claim 1, wherein the tetracycline is
doxycycline.
4-7. (canceled)
8. The composition of claim 1, which is a combination of a
component containing a tetracycline in an immediate release (IR)
formulation and a second component containing a tetracycline in a
delayed release (DR) formulation, wherein the ratio of IR to DR is
from about 99:1 to about 70:30.
9. The composition of claim 8, wherein the tetracycline is
doxycycline.
10. The composition of claim 9, wherein the ratio of immediate
release component to delayed release component is from about 80:20
to about 70:30.
11. The composition of claim 9, wherein the ratio of immediate
release component to delayed release component is 75:25.
12-17. (canceled)
18. An oral pharmaceutical dosage form containing between 25 and 50
mg. of a tetracycline.
19. The dosage form of claim 18, wherein the tetracycline is
doxycycline.
20. The dosage form of claim 19, which contains about 40 mg. of
doxycycline.
21. The dosage form of claim 18, which is in an immediate release
formulation.
22. The dosage form of claim 18, which is a granule, tablet,
pellet, powder, sachet, capsule, gel, dispersion or suspension.
23-24. (canceled)
25. The dosage form of claim 19, wherein a portion thereof is of a
delayed release formulation, and another portion is of an immediate
release formulation.
26. A method for treating a collagenase dependent disease or
condition, and/or acute or chronic inflammatory condition in a
mammal, comprising administering a daily dose of a tetracycline
composition according to claim 1 to the mammal, for at least a time
sufficient to ameliorate the disease or condition.
27. The method of claim 26, wherein the mammal is a human.
28. The method of claim 26, wherein the disease or condition is
selected from periodontal disease, rosacea, acne, dry eye,
rheumatoid arthritis, hyperparathyroidism, and diabetes.
29. The method of claim 28, wherein the disease is periodontal
disease.
30. (canceled)
31. The method of claim 28, wherein the condition is rosacea.
32. (canceled)
33. The method of claim 28, wherein the condition is dry eye.
34-48. (canceled)
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 16/171,940, filed on Oct. 26, 2018, which is a continuation of
U.S. application Ser. No. 14/728,266, filed on Jun. 2, 2015, now
abandoned, which is a continuation of U.S. application Ser. No.
14/219,231, filed on Mar. 19, 2014, now abandoned, which is a
continuation of U.S. application Ser. No. 13/920,538, filed on Jun.
18, 2013, now U.S. Pat. No. 8,709,478, which is a continuation of
U.S. application Ser. No. 12/926,933, filed on Dec. 17, 2010, now
U.S. Pat. No. 8,470,364, which is a continuation of U.S.
application Ser. No. 12/155,676, filed on Jun. 6, 2008, now U.S.
Pat. No. 8,206,740, which is a continuation of U.S. application
Ser. No. 10/819,620, filed on Apr. 7, 2004, now U.S. Pat. No.
7,749,532, which claims the benefit of U.S. Provisional Application
No. 60/460,963, filed on Apr. 7, 2003 and of U.S. Provisional
Application No. 60/547,964, filed on Feb. 26, 2004. The entire
teachings of the above applications are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention is concerned with once-daily
compositions of tetracyclines, which can be used for the treatment
of acute or chronic diseases, for instance those with inflammatory
components. More specifically, the present invention is directed to
a pharmaceutical composition of doxycycline for the treatment of
diseases or conditions in which collagen destructive enzymes or
molecules involved with such things as inflammation are
contributing factors, and which is a once daily formulation. The
compositions are especially useful for treating such common disease
states as periodontal disease, rosacea, dry eye, acne and
rheumatoid arthritis.
BACKGROUND OF THE INVENTION
[0003] Conventionally, doxycycline and related tetracyclines are
used as broad spectrum antibiotics to treat various bacterial
infections. Tetracyclines interfere with the protein synthesis of
Gram positive and Gram-negative bacteria by preventing the binding
of aminoacyl-tRNA to the ribosome. Their action is bacteriostatic
(preventing growth of bacteria) rather than killing (bactericidal).
The doses commonly used for doxycycline to achieve the antibiotic
effect are 100 mg and 50 mg.
[0004] Doxycycline, as well as other tetracyclines, also has other
therapeutic uses in addition to its antibiotic properties. For
example, doxycycline is known to inhibit the activity of collagen
destruction enzymes such as collagenase, gelatinase, and elastase.
Its collagenase inhibition activity has been used to treat
periodontal disease. For another example, doxycycline can inhibit
lipase produced by the bacterium P. acnes and thus reduces the
availability of free fatty acids that are involved in inflammation.
Doxycycline may also reduce inflammation by reducing cytokine
levels so that the integrity of the follicular wall is preserved.
Thus, doxycycline also has the potential in treating skin diseases,
such as acne.
[0005] Investigators have found that sub-antimicrobial doses of
tetracyclines are useful in the treatment of various ailments,
although the mechanisms responsible for the effects are not
entirely clear. For instance, U.S. Pat. No. 6,455,583 discloses
treating meibomian gland disease by oral administration of
non-antimicrobial amounts of a tetracycline to the patient. U.S.
Pat. No. 6,100,248 teaches a method of inhibiting cancer growth by
administering tetracyclines which have been chemically modified to
attenuate or delete their antibacterial activity. Methods to reduce
collagenolytic enzymes by administration of amounts of a
tetracycline that are generally lower than the normal amounts used
for antimicrobial therapy are disclosed in U.S. Pat. No. 4,666,897.
The patents cited in this paragraph are hereby incorporated herein
by reference.
[0006] In the market, there are two implantable products for
site-specific use in the treatment of periodontal disease. The
PerioChip.RTM. is a small, orange-brown chip, which is inserted
into periodontal pockets. Each PerioChip.RTM. contains 2.5 mg of
chlorhexidine gluconate in a biodegradable, resorbable matrix. It
is recommended that PerioChip.RTM. treatment be administered once
every three months in pockets that remain at 5 mm or deeper. A
second product, Atridox.RTM., is an injectable, resorbable gel,
which provides the subgingival controlled-release of 42.5 mg
doxycycline for approximately one week. Additionally, there is now
available a new oral medication called Periostat.RTM., which
delivers 20 mg doxycycline systemically as a collagenase inhibitor
used in patients with adult periodontal disease. Most people would
prefer to take a pill to the implant. However, Periostat.RTM.
requires twice daily dosing and raises concerns about patient
compliance. Thus, it would be highly beneficial to develop a
once-a-day formulation for doxycycline.
[0007] While doxycycline is generally effective for treating
infection, the use of doxycycline can lead to undesirable side
effects. For example, the long-term administration of the
antibiotic doxycycline can reduce or eliminate healthy biotic
flora, such as intestinal flora, and can lead to the production of
antibiotic resistance organisms or the overgrowth of yeast and
fungi. Because of the undesirable side effects from its antibiotic
properties, there is a need for a unique dose and an improved
formulation to deliver doxycycline such that the anti-collagen
destructive enzymes or other such beneficial effect of
tetracyclines, especially doxycycline, is attained, but
antibacterial effects are avoided.
SUMMARY OF THE INVENTION
[0008] The present invention is in its broadest sense directed to
pharmaceutical compositions of tetracyclines designed to provide an
extended release profile in vivo of levels of active ingredient
that at steady state are high enough to be effective to have a
beneficial effect in the treatment of a disease or condition, but
not as high as to exert an antibacterial effect. Such
pharmaceutical compositions are formulated into dosage forms that
can be taken once a day.
[0009] One object of the present invention is to provide a
pharmaceutical composition of doxycycline, which can be given once
a day yet meet the steady state blood levels required for the
treatment or prevention of diseases or conditions caused by
overproduction of collagenase, such as periodontal disease, or
other biochemicals associated with certain disease states which
could be regulated with doxycycline, such as conditions involving
inflammation, without the undesirable effects of long term
antibiotic activity.
[0010] One object of the present invention is to provide a
once-daily pharmaceutical composition containing doxycycline that
will give steady state blood levels of doxycycline of a minimum of
about 0.1 .mu.g/ml and a maximum of about 1.0 .mu.g/ml.
[0011] In one aspect of the invention is an immediate release
formulation of doxycycline containing less than 50 mg but more than
25 mg, preferably about 40 mg. doxycycline base.
[0012] In another aspect, the invention is directed to a
pharmaceutical composition of doxycycline that contains an
immediate release (IR) component of the drug and a delayed release
(DR) component of the drug, which are combined into one dosage unit
for once-daily dosing. The components can be present in various
ratios, although preferred are ratios of about 70:30 to about
80:20, and most preferred 75:25, IR:DR, with the total dosage of
doxycycline being less than about 50 mg. and preferably about 40
mg. The ratio refers to the dose breakdown between IR and DR, e.g.,
80:20 means 80% of 40 mg is from IR portion and 20% of 40 mg is
from DR portion.
[0013] Yet another object of the invention is to provide a method
for treating diseases or conditions in which collagenase is
produced in excessive amounts causing pathological destruction of
tissues, such as periodontal disease, rheumatoid arthritis,
hyperparathyroidism, diabetes and acne, by administering the
once-daily dosage of doxycycline. See, e.g., U.S. Pat. No.
4,666,897 of Golub.
[0014] Another object of the present invention is to provide a
method for systemic treatment of rosacea, a dermatological
condition of humans, by administering the once-daily dosage of
doxycycline according to the present invention.
[0015] Another object of the invention is to provide processes for
preparing the once-daily compositions of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 shows dissolution profiles for doxycycline
monohydrate immediate-release beads within the scope of the present
invention, which were determined by utilizing a computer algorithm
that is based on a compartmental absorption and transit model to
deconvolute in vivo release profiles from in vivo human plasma
data. The in silico model was first validated and tested using
human plasma data from immediate release dosage forms.
[0017] FIG. 2 shows in silico dissolution profiles for doxycycline
monohydrate delayed-release beads.
[0018] FIG. 3 shows in silico dissolution profiles for the
composite capsules with 75% of immediate-release beads and 25% of
delayed-release beads.
[0019] FIG. 4 shows predicted blood levels vs. time profiles at
steady state for various treatments (i.e., 40 mg once-a-day IR
formula, 40 mg once-a-day IR and DR combinations at 70:30 and 80:20
ratios, and twice-a-day 20 mg doxycycline treatment).
[0020] FIG. 5 represents the pharmacokinetic profiles of 75:25
IR:DR (40 mg.) formulation at day 1 and day 7 (steady state) in
humans.
[0021] FIG. 6 compares the pharmacokinetic curves of 75:25 IR:DR
(40 mg.) formulation with the Periostat.RTM. 20 mg. twice daily
dosage form.
DETAILED DESCRIPTION OF THE INVENTION
[0022] While the following description is directed primarily to
doxycycline, it is contemplated that the present invention is
applicable to other tetracyclines, particularly other tetracyclines
that have similar in vivo absorption profiles as doxycycline, more
specifically tetracyclines that have a similar region of absorption
in the gastrointestinal tract as doxycycline. Different kinds of
tetracyclines and the beneficial effects on various disease states
are disclosed in, for example, WO 02/083106 and U.S. Pat. No.
6,638,922, each of which are incorporated in their entireties
herein by reference.
[0023] The present invention can be accomplished by providing an
orally administered composition of, as an example, doxycycline
which is designed to provide certain steady state blood levels of
the drug, while in a formulation that requires that the mammal,
preferably human, to take only one dosage a day. The compositions
of the present invention are intended to be useful in lieu of
multiple daily dosing, such as twice-daily dosing, of compositions
that achieve the same effects. The preferred blood level of
doxycycline, or other tetracyclines of comparable physiological and
absorption properties, is between about 0.1 and about 1.0 .mu.g/ml
at the steady state. Preferably, the blood levels stay within the
preferred blood level, with daily dosing, for the entire course of
treatment. More preferably, the blood levels are between about 0.3
.mu.g/ml and about 0.8 .mu.g/ml.
[0024] The above blood serum levels allow for the desired
anti-collagenase and anti-inflammatory activity of doxycycline,
without being accompanied by undesirable antibiotic activity. It
was surprisingly found that these levels can be accomplished with a
single daily dose of an immediate release formulation containing
below 50 mg. but more than 25 mg., preferably about 40 mg.
doxycycline base.
[0025] "About" means within the pharmaceutically acceptable limits
found in the United States Pharmacopia (USP-NF 21), 2003 Annual
Edition, or available at www.usp.org, for amount of active
pharmaceutical ingredients. With respect to blood levels, "about"
means within FDA acceptable guidelines.
[0026] By "immediate release" formulation is meant a dosage form
that is intended to release substantially all of the active
ingredient on administration with no enhanced, delayed or extended
release effect. Such a composition of doxycycline can be in the
form of a liquid suspension or solution, or as a solid such as a
tablet, pellet (used interchangeably with bead or beadlet herein),
particle, capsule or gel. Preferred in the present invention are
tablets, or beadlets in a capsule.
[0027] As pharmaceutically active ingredients, any form of the
tetracycline compound can be used provided it will comply with the
required blood serum levels of the present invention. Doxycycline,
for instance, is commonly used in pharmaceutical formulations under
two chemical forms: the monohydrate form and the hyclate form. The
monohydrate is the base molecule hydrated with one molecule of
water and is used in the formulation of capsules and, in some
markets, powder oral suspensions (to be reconstituted with water).
The hyclate is a hydrochloric acid salt solvated with water and
ethanol and is typically used in the formulation of capsules or
tablets. The amount of doxycycline in the compositions of the
present invention refers to doxycycline base. Also, in the
compositions of the present invention there may be more than one
active ingredient. That is, the doxycycline can be combined with
another therapeutic or nutritional substance in the dosage
forms.
Immediate Release Dosage Forms
[0028] There are many ways known in the art to formulate such
immediate release dosage forms. For instance, an immediate release
tablet can be prepared by mixing doxycycline with a bulking agent
such as microcrystalline cellulose, for example, AVICEL.RTM. (FMC
Corp.) or EMCOCEL.RTM. (Mendell Inc.); dicalcium phosphate, for
example, EMCOMPRESS.RTM. (Mendell Inc.); calcium sulfate, for
example, COMPACTROL.RTM. (Mendell Inc.); and starches, for example,
STARCH 1500. Additionally, one can add a disintegrating agent, such
as microcrystalline cellulose, starches, crospovidone, for example,
POLYPLASDONE XL.RTM. (International Specialty Products); sodium
starch glycolate, for example, EXPLOTAB.RTM. (Mendell Inc.); and
croscarmellose sodium, for example, AC-DI-SOL.RTM. (FMC Corp.).
Antiadherants and glidants employed herein can include talc,
cornstarch, silicon dioxide, sodium lauryl sulfate, colloidal
silica dioxide, and metallic stearates.
[0029] Lubricants may be employed, such as magnesium stearate,
calcium stearate, sodium stearate, stearic acid, sodium stearyl
fumarate, sterotex, talc, waxes and the like. Binding agents may be
employed, such as polyvinyl pyrollidone, starch, methylcellulose,
hydroxypropyl methylcellulose, carboxymethyl cellulose, and the
like.
[0030] The present invention is preferably formulated into a tablet
prepared using methods known in the art, including a wet
granulation method and a direct compression method. The oral
tablets are prepared using any suitable process known to the art.
See, for example, Remington's Pharmaceutical Sciences, 18th
Edition, A. Gennaro, Ed., Mack Pub. Co. (Easton, Pa. 1990),
Chapters 88-91, the entirety of which is hereby incorporated by
reference. Typically, the active ingredient, doxycycline, is mixed
with pharmaceutically acceptable excipients (e.g., the binders,
lubricants, etc. listed above) and compressed into tablets.
Preferably, the dosage form is prepared by a wet granulation
technique or a direct compression method to form uniform
granulates. Alternatively, the active ingredient(s) can be mixed
with the granulate after the granulate is prepared. The moist
granulated mass is then dried and sized using a suitable screening
device to provide a powder, which can then be filled into capsules
or compressed into matrix tablets or caplets, as desired.
[0031] In a preferred embodiment, the tablets are prepared using
the direct compression method. The direct compression method offers
a number of potential advantages over a wet granulation method,
particularly with respect to the relative ease of manufacture. In
the direct compression method, at least one pharmaceutically active
agent and the excipients or other ingredients are sieved through a
stainless steel screen, such as a 40 mesh steel screen. The sieved
materials are then charged to a suitable blender and blended for 10
minutes with an intensifier bar for three minutes. The blend is
then compressed into tablets on a rotary press using appropriate
tooling.
[0032] As mentioned above, another preferred dosage form for the
immediate release composition is a capsule containing immediate
release beadlets or pellets. Methods for making such pellets are
set forth in the section below (i.e., the IR pellets). The pellets
are filled into capsules, for instance gelatin capsules, by
conventional techniques.
Combination IR/DR Dosage Forms
[0033] In another embodiment of the present invention is a
composition having a substantially immediate release dose of
doxycycline, followed by at least one additional dose at a
predetermined time, in a unit dosage. The first immediate release
dose of the composition can be in the form of powder, granule,
beadlet, or tablet; the second delayed-release portion can be
coated granular, coated beadlet, coated tablet, or uncoated matrix
tablet. The ratio between the immediate-release portion, or
component, and the delayed-release portion, or component, can be
used to adjust the in vitro drug release profile and in vivo blood
concentration profile. By providing such a drug release profile,
the compositions eliminate the need for a second dose for the day.
Additionally, the total dose of doxycycline is below 50 mg. to
avoid the undesirable side effects from its antibiotic properties,
but more than 25 mg. to achieve the anti-collagenase and/or
anti-inflammatory effect.
[0034] Several dosage form variations can be used to achieve a
product with these attributes. For example, an immediate-release
powder blend can be encapsulated with a delayed-release tablet or
delayed-release pellets. A further example is an immediate-release
tablet and a delayed-release tablet that are prepared separately
and encapsulated into an appropriate sized capsule shell. Or, for
example, a delayed-release tablet can be used as a core and the
immediate-release portion can be compressed as an outer layer using
a press coater or overcoated using a drug layering technique, both
techniques of which can be found in Gunsel and Dusel, Chapter 5,
"Compression-coated and layer tablets", in Pharmaceutical Dosage
Forms: Tablets, Second Edition, Volume 1, Edited by H. A.
Lieberman, L. Lachman, and J. B. Schwartz, Marcel Dekker, Inc. New
York and Basel (1990).
Multiparticulate Capsules
[0035] As a preferred embodiment, the IR/DR composition of
doxycycline is in the form of a capsule containing beadlets. At
present, it is preferred to have two different types of units in a
single form multiple-unit dosage form.
[0036] The first unit is an immediate release dosage form,
preferably in pellet form. This component can also be a powder if
desired or necessary. In either case, the dosage form may have a
surface-active agent such as sodium lauryl sulfate, sodium
monoglycerate, sorbitan monooleate, polyoxyethylene sorbitan
monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl
monobutyrate, any one of the Pluronic line of surface-active
polymers, or any other suitable material with surface active
properties or any combination of the above. Preferably, the
surface-active agent would be a combination of sodium monoglycerate
and sodium lauryl! sulfate. The concentration of these materials in
this component can range from about 0.05 to about 10.0% (W//W).
[0037] Other excipient materials that can be employed in making
drug-containing pellets are any of those commonly used in
pharmaceutics and should be selected on the basis of compatibility
with the active drug and the physicochemical properties of the
pellets. These include, for instance: binders such as cellulose
derivatives such as methylcellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer
and the like; disintegration agents such as cornstarch,
pregelatinized starch, cross-linked carboxymethylcellulose
(AC-DI-SOL.RTM.), sodium starch glycolate (EXPLOTAB.RTM.),
cross-linked polyvinylpyrrolidone (PLASDONE.RTM. XL), and any
disintegration agents used in tablet preparations, which are
generally employed in immediate release dosages such as the one of
the present invention; filling agents such as lactose, calcium
carbonate, calcium phosphate, calcium sulfate, microcrystalline
cellulose, dextran, starches, sucrose, xylitol, lactitol, mannitol,
sorbitol, sodium chloride, polyethylene glycol, and the like;
surfactants such as sodium lauryl sulfate, sorbitan monooleate,
polyoxyethylene sorbitan monooleate, bile salts, glyceryl
monostearate, the PLURONIC.RTM. line (BASF), and the like;
solubilizers such as citric acid, succinic acid, fumaric acid,
malic acid, tartaric acid, maleic acid, glutaric acid sodium
bicarbonate and sodium carbonate and the like; and stabilizers such
as any antioxidation agents, buffers, acids, and the like, can also
be utilized.
[0038] The pellet can be made by, for example, simple granulation,
followed by sieving; extrusion and marumerization; rotogranulation;
or any agglomeration process that results in a pellet of reasonable
size and robustness. For extrusion and marumerization, the drug and
other additives are granulated by addition of a binder solution.
The wet mass is passed through an extruder equipped with a certain
size screen, and the extrudates are spheronized in a marumerizer.
The resulting pellets are dried and sieved for further
applications. One may also use high-shear granulation, wherein the
drug and other additives are dry-mixed and then the mixture is
wetted by addition of a binder solution in a high
shear-granulator/mixer. The granules are kneaded after wetting by
the combined actions of mixing and milling. The resulting granules
or pellets are dried and sieved for further applications.
[0039] As stated earlier, it is also possible to have this
immediate release component as a powder, although the preferred
form is a pellet due to mixing and de-mixing considerations.
[0040] Alternatively, the immediate release beadlets or pellets of
the composition can be prepared by solution or suspension layering,
whereby a drug solution or dispersion, with or without a binder, is
sprayed onto a core or starting seed (either prepared or a
commercially available product) in a fluid bed processor or other
suitable equipment. The cores or starting seeds can be, for
example, sugar spheres or spheres made from microcrystalline
cellulose. The drug thus is coated on the surface of the starting
seeds. The drug-loaded pellets are dried for further
applications.
[0041] The second unit should have a delayed release (DR) profile,
and needs to be able to address the changing pH of the GI tract,
and its effect on the absorption of doxycycline or other
tetracycline. This pellet should have all of the ingredients as
mentioned for the first unit pellet, as well as optionally some
organic acid that will be useful to reduce the pH of the
microenvironment of the pellet, and thus facilitate dissolution.
These materials are, but not limited to, citric acid, lactic acid,
tartaric acid, or other suitable organic acids. These materials
should be present in concentrations of from about 0 to about 15.0%
(w/w); preferably these materials would be present in
concentrations of from about 5.0 to about 10.0 percent (w/w). The
process for manufacturing these pellets is consistent with the
process described above for the first unit pellet.
[0042] Unlike the first unit pellet, the second unit
delayed-release component has a controlling coat applied to the
surface of the pellet such that the release of the drug from the
pellet is delayed. This is accomplished by applying a coating of
enteric materials. "Enteric materials" are polymers that are
substantially insoluble in the acidic environment of the stomach,
but are predominantly soluble in intestinal fluids at specific pHs.
The enteric materials are non-toxic, pharmaceutically acceptable
polymers, and include, for example, cellulose acetate phthalate
(CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl
acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate
succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl
methylcellulose succinate, cellulose acetate succinate, cellulose
acetate hexahydrophthalate, cellulose propionate phthalate,
copolymer of methylmethacrylic acid and methyl methacrylate,
copolymer of methyl acrylate, methylmethacrylate and methacrylic
acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez
ES series), ethyl
methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl
acrylate copolymer, natural resins such as zein, shellac and copal
collophorium, and several commercially available enteric dispersion
systems (e.g., EUDRAGIT.RTM. L30D55, EUDRAGIT.RTM. FS30D,
EUDRAGIT.RTM. L100, KOLLICOAT.RTM. EMM30D, ESTACRYL.RTM.30D,
COATERIC.RTM., and AQUATERIC.RTM.). The foregoing is a list of
possible materials, but one of skill in the art would recognize
that it is not comprehensive and that there are other enteric
materials that would meet the objectives of the present invention
of providing for a delayed release profile. These coating materials
can be employed in coating the surfaces in a range of from about
1.0% (w/w) to about 50% (w/w) of the pellet composition. Preferably
these coating materials should be in a range of from about 20 to
about 40 percent (w/w). The pellets may be coated in a fluidized
bed apparatus or pan coating, for example.
[0043] With the enteric coated pellets, there is no substantial
release of doxycycline in the acidic stomach environment of
approximately below pH 4.5. The doxycycline becomes available when
the pH-sensitive layer dissolves at the greater pH of the small
intestine; after a certain delayed time; or after the unit passes
through the stomach. The preferred delay time is in the range of
two to six hours.
[0044] As a variation of this embodiment, the DR pellet contains
layers of the doxycycline, separated by protective layers, and
finally an enteric coating, resulting in a "repeat-action" dosage
delivery. Such a dosage form may meet the blood level requirements
of the release profile of the present invention if the release of
the doxycycline, or other tetracycline, in all of the layers is
within the absorption window for the drug.
[0045] An overcoating layer can further optionally be applied to
the IR/DR pellets of the present invention. OPADRY.RTM., OPADRY
II.RTM. (Colorcon) and corresponding color and colorless grades
from Colorcon can be used to protect the pellets from being tacky
and provide colors to the product. The suggested levels of
protective or color coating are from 1 to 6%, preferably 2-3%
(w/w).
[0046] Many ingredients can be incorporated into the overcoating
formula, for example to improve the coating process and product
attributes, such as plasticizers: acetyltriethyl citrate, triethyl
citrate, acetyltributyl citrate, dibutylsebacate, triacetin,
polyethylene glycols, propylene glycol and others; lubricants:
talc, colloidal silica dioxide, magnesium stearate, calcium
stearate, titanium dioxide, magnesium silicate, and the like.
[0047] The delayed release and immediate release units are combined
in the dosage form (in this instance, the different pellets are put
into capsules) in a predetermined ratio, preferably about 70:30 to
about 80:20, most preferably 75:25 (IR/DR), which will achieve the
desired steady state blood serum levels with only once-daily
dosing.
[0048] The composition, preferably in beadlet form, can be
incorporated into hard gelatin capsules, either with additional
excipients, or alone. Typical excipients to be added to a capsule
formulation include, but are not limited to: fillers such as
microcrystalline cellulose, soy polysaccharides, calcium phosphate
dihydrate, calcium sulfate, lactose, sucrose, sorbitol, or any
other inert filler. In addition, there can be flow aids such as
fumed silicon dioxide, silica gel, magnesium stearate, calcium
stearate or any other material imparting flow to powders. A
lubricant can further be added if necessary by using polyethylene
glycol, leucine, glyceryl behenate, magnesium stearate or calcium
stearate.
[0049] The composition may also be incorporated into a tablet, in
particular by incorporation into a tablet matrix, which rapidly
disperses the particles after ingestion. In order to incorporate
these particles into such a tablet, a filler/binder must be added
to a table that can accept the particles, but will not allow their
destruction during the tableting process. Materials that are
suitable for this purpose include, but are not limited to,
microcrystalline cellulose (AVICEL.RTM.), soy polysaccharide
(EMCOSOY.RTM.), pre-gelatinized starches (STARCH.RTM. 1500,
NATIONAL.RTM. 1551), and polyethylene glycols (CARBOWAX.RTM.). The
materials should be present in the range of 5-75% (w/w), with a
preferred range of 25-50% (w/w).
[0050] In addition, disintegrants are added in order to disperse
the beads once the tablet is ingested. Suitable disintegrants
include, but are not limited to: cross-linked sodium carboxymethyl
cellulose (AC-DI-SOL.RTM.), sodium starch glycolate (EXPLOTAB.RTM.,
PRIMOJEL.RTM.), and cross-linked polyvinylpolypyrrolidone
(Plasone-XL). These materials should be present in the rate of
3-15% (w/w), with a preferred range of 5-10% (w/w).
[0051] Lubricants are also added to assure proper tableting, and
these can include, but are not limited to: magnesium stearate,
calcium stearate, stearic acid, polyethylene glycol, leucine,
glyceryl behenate, and hydrogenated vegetable oil. These lubricants
should be present in amounts from 0.1-10% (w/w), with a preferred
range of 0.3-3.0% (w/w).
[0052] Tablets are formed, for example, as follows. The particles
are introduced into a blender along with AVICEL.RTM., disintegrants
and lubricant, mixed for a set number of minutes to provide a
homogeneous blend which is then put in the hopper of a tablet press
with which tablets are compressed. The compression force used is
adequate to form a tablet; however, not sufficient to fracture the
beads or coatings.
[0053] It will be appreciated that the multiple dosage forms of the
present invention can deliver dosages of pharmaceutically active
doxycycline, or other tetracycline, to achieve the desired levels
of the drug in a recipient over the course of about 24 hours at
steady state with a single daily oral administration.
[0054] The present invention also provides a method for treating a
mammal with doxycycline, or other tetracycline. The method involves
administering a doxycycline, or other tetracycline, composition
according to the present invention to a mammal, preferably a human,
in need of the anti-collagenase or anti-inflammatory activity of
doxycycline or other tetracycline substantially without
accompanying antibiotic activity. Systemic administration is
preferred, and oral administration is most preferred.
[0055] Using the compositions of the present invention, the steady
state blood levels of doxycycline or other tetracycline of a
minimum of about 0.1 .mu.g/ml, preferably about 0.3 .mu.g/ml and a
maximum of about 1.0 .mu.g/ml, more preferably about 0.8 .mu.g/ml,
can be achieved to treat diseases with increased collagenase
production, such as periodontal, skin diseases and the like, as
well as inflammatory states. Indeed, any disease state treatable
with sub-antimicrobial blood levels of a tetracycline given in
multiple daily dosages can also be treated using the corresponding
once-daily formulations of the present invention.
[0056] The invention will now be illustrated by the following
examples, which are not to be taken as limiting.
EXAMPLES
Example 1: Preparation of Layered IR Pellets Containing Doxycycline
Monohydrate
[0057] A dispersion of doxycycline monohydrate was prepared as
follows: To 5.725 kilograms of deionized water were added 0.113
kilogram hydroxypropyl methylcellulose and 1.5 kilograms of
doxycycline monohydrate, followed by moderate mixing, using a
stirring paddle for 30 minutes. The drug dispersion was sprayed
onto sugar seeds (30/35 mesh) in a 9'' Wurster Column of a GPCG-15
fluid bed processor. Until the entire dispersion was applied, the
pellets were dried in the column for 5 minutes. The drug-loaded
pellets were discharged from the Wurster Column and passed through
a 20 mesh screen. A protective coat (e.g., OPADRY.RTM. beige) also
can be applied onto the IR beads to provide color or physical
protection. FIG. 1 shows a typical dissolution profile for
doxycycline monohydrate immediate-release beads.
Example 2: Preparation of Enteric Coated Pellets Containing
Doxycycline Monohydrate
[0058] The EUDRAGIT.RTM. L30D55 coating dispersion was prepared by
adding 0.127 kilogram of triethyl citrate into 3.538 kilograms of
EUDRAGIT.RTM. L30D55 (solid content: 1.061 kilograms) and stirring
for at least 30 minutes. Talc 0.315 kilogram was dispersed into
2.939 kilograms of deionized water. The plasticized EUDRAGIT.RTM.
L30D55 was combined with the talc dispersion and screened through a
60 mesh screen. The resulting combined dispersion was sprayed onto
drug-loaded pellets (3.5 kilograms) prepared according to Example 1
in a 9'' Wurster Column of a GPCG-15 fluid bed processor. A
protective coat (e.g., OPADRY.RTM. beige) may be applied onto the
DR beads to provide color or physical protection. FIG. 2 shows a
typical dissolution profile for doxycycline monohydrate
delayed-release beads.
Example 3: Encapsulation of Drug-Loaded Pellets and Enteric Coated
Pellets
[0059] Capsules can be prepared by filling the drug-loaded pellets
and enteric coated pellets individually into appropriate sized
capsule shells. The ratio between the drug-loaded pellets and
enteric-coated pellets can be 100:0 to 70:30. For example, at the
ratio of 75:25, the fill weight of drug-loaded pellets can be
calculated based on the actual potency of the drug-loaded pellets
to deliver 30 mg doxycycline; the fill weight of enteric-coated
pellets also can be calculated based on the actual potency of the
enteric-coated pellets to deliver 10 mg doxycycline. Romoco CD5 or
MG-2 pellet filling machine can be used to accurately fill the
pellets into the desired capsule shells. FIG. 3 shows the typical
dissolution profile for the composite capsules with 75% of
immediate-release beads and 25% of delayed-release beads.
Example 4: Preparation of Delayed Tablet Containing Doxycycline
Monohydrate
[0060] Doxycycline monohydrate 0.5625 kilogram was blended with
3.15 kilograms of microcrystalline cellulose in a V-shaped blender
for 15 minutes and the powder blend was lubricated with magnesium
stearate (0.0375 kilogram) for additional 5 minutes. Doxycycline
monohydrate (0.2 kilogram) was granulated with EUDRAGIT.RTM. L100
powder (1.280 kilograms) and microcrystalline cellulose powder (0.5
kilograms) using isopropyl alcohol as a granulating fluid. The wet
granulation was dried in a fluid bed dryer and the dried
granulations were blended with magnesium stearate (0.020 kilogram)
in a V-shaped blender for 5 minutes. Doxycycline powder blend and
granulation were put on a belayed tablet press to compress into a
belayed tablet with target weights of 200 mg and 100 mg for the
powder blend and granulation layers, respectively.
Example 5: Preparation of Immediate-Release Tablet Containing
Doxycycline Monohydrate
[0061] Doxycycline monohydrate 1.0 kilogram was blended with 2.225
kilogram of microcrystalline cellulose (AVICEL.RTM. PH 102) in a
V-shaped blender for 5 minutes. The remaining microcrystalline
cellulose (1.75 kilogram of AVICEL.RTM. PH 202) is then added to
the powder blend in the V-shaped blender and mixed for additional
30 minutes. The powder blend was then lubricated with magnesium
stearate (0.025 kilogram) for 5 minutes. The lubricated powder
blend was compressed into a tablet with the target weight of 200
mg. The tablets can be further coated with a polymeric protective
layer.
Example 6
[0062] The simulated blood levels-time profiles at steady state for
various treatments (e.g., 40 mg once-a-day IR formula, 40 mg
once-a-day IR and DR combinations at 70:30 and 80:20 ratios, and
twice-a-day 20 mg doxycycline treatment) were determined by in
silico modeling, and are shown in FIG. 4. Using the unique dose
(i.e., <50 mg, preferably 40 mg) and composition (IR beads or
IR/DR combinations), the steady state blood levels of doxycycline
of a minimum of about 0.1 .mu.g/ml, preferably about 0.3 .mu.g/ml
and a maximum of about 1.0 .mu.g/ml, more preferably about 0.8
.mu.g/ml, can be achieved to treat such conditions as periodontal
and skin diseases.
Example 7
[0063] Size 0 capsules containing a ratio of 75:25 of drug-loaded
IR pellets to enteric coated DR pellets were prepared as follows.
The IR and DR pellets were prepared as set forth in Examples 1 and
2. From the assay value of the doxycycline used to make the
pellets, it was determined that 41.26 mg potency of the capsules
would correspond to an actual strength of 40 mg. doxycycline. The
potency of the IR pellets was 194 mg doxycycline per gram of
pellets (mg/g), and for the DR pellets was 133 mg/g. Accordingly,
it was calculated that for each capsule the fill weight of IR beads
would be 159.5 mg, and for DR beads 77.6 mg, corresponding to 75:25
of IR:DR of a 40 mg capsule.
Example 8
[0064] A pharmacokinetic (PK) study was conducted in human subjects
to compare a first group taking the extended release doxycycline
capsule (see Example 7) (75/25 IR/DR 40 mg) administrated orally
once daily versus a second group taking Periostat.RTM. tablets (20
mg) administrated orally twice daily, twelve hours apart.
[0065] Pharmacokinetic blood draws were collected on Nominal Study
Day 1 for first and second groups, and on Day 7 for the first group
as follows: 0 (pre dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12
(before the post-morning dose, if applicable), 12.5, 13, 13.5, 14,
14.5, 15, 16, 18, 20, and 24 hours after the morning dose.
[0066] The data from this study were shown in the following Table
1.
TABLE-US-00001 TABLE 1 75/25 IR/DR 75/25 IR/DR Periostat .RTM. Day
1 Day 7 steady state Day 1 T.sub.max 2.2 2.3 1.9/11.9 C.sub.max 562
602 100/333 AUC.sub.0-24(Hr*ng/ml) 5388 7230 4280
[0067] Mean C.sub.max at Day 1 from the 75/25 IR/DR 40 mg capsules
is comparable to that from the Periostat.RTM. tablets, and well
below the potential antibiotic effect concentration (1000 ng/ml).
The mean C.sub.min (177 ng/ml at 24-hour time point) is well above
the minimum effective plasma concentration (100 ng/ml). Individual
pharmacokinetic data from both 75/25 IR/DR 40 mg capsules and
Periostat.RTM. 20 mg tablets show that 75/25 IR/DR 40 mg capsules
provide more consistent in vivo performance in terms of less
frequency of high peak plasma concentration (>1000 ng/ml) and
low plasma concentration (<100 ng/ml) at the end of each
dosing.
[0068] FIGS. 5 and 6 show two aspects of results obtained from the
study. FIG. 5 compares the PK profiles of 75:25 IR:DR 40 mg
doxycycline formulations over a 24 hour period on Day 1 and also on
Day 7 (steady state). FIG. 6 compares the PK profiles of the 75:25
40 mg once daily dosage form and the Periostat.RTM. 20 mg (twice
daily) dosage forms.
* * * * *
References