U.S. patent application number 14/140791 was filed with the patent office on 2014-06-26 for tacrolimus for improved treatment of transplant patients.
This patent application is currently assigned to Veloxis Pharmaceuticals A/S. The applicant listed for this patent is Veloxis Pharmaceuticals A/S. Invention is credited to Robert D. Gordon, Per Holm, Anne-Marie Lademann, Tomas Norling.
Application Number | 20140179731 14/140791 |
Document ID | / |
Family ID | 39766919 |
Filed Date | 2014-06-26 |
United States Patent
Application |
20140179731 |
Kind Code |
A1 |
Gordon; Robert D. ; et
al. |
June 26, 2014 |
Tacrolimus For Improved Treatment Of Transplant Patients
Abstract
An extended release oral dosage form comprising as active
substance tacrolimus or a pharmaceutically active analogue thereof
for a once daily immunosuppressive treatment of a patient in need
thereof, preferable a kidney or liver transplant patient. The
dosage form releases the active substance over an extended period
of time. It also provides improved pharmacokinetic parameters due
to an extended and constant in vivo release including substantial
decreased peak concentrations, despite increased bioavailability,
substantial extended times for maximal concentration, and higher
minimal concentrations when compared with conventional immediate
release dosage forms and a recent modified release tacrolimus
dosage form.
Inventors: |
Gordon; Robert D.; (Sandy
Springs, GA) ; Holm; Per; (Vanlose, DK) ;
Lademann; Anne-Marie; (Klampenborg, DK) ; Norling;
Tomas; (Lyngby, DK) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Veloxis Pharmaceuticals A/S |
Horsholm |
|
DK |
|
|
Assignee: |
Veloxis Pharmaceuticals A/S
Horsholm
DK
|
Family ID: |
39766919 |
Appl. No.: |
14/140791 |
Filed: |
December 26, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13167420 |
Jun 23, 2011 |
8664239 |
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14140791 |
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12499034 |
Jul 7, 2009 |
8685998 |
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13167420 |
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PCT/DK2008/050130 |
May 30, 2008 |
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12499034 |
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61079015 |
Jul 8, 2008 |
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Current U.S.
Class: |
514/291 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61K 9/2027 20130101; A61P 37/06 20180101; Y10S 514/885 20130101;
A61K 9/2013 20130101; A61K 9/1652 20130101; A61K 9/1641 20130101;
A61K 9/2077 20130101; A61K 9/4891 20130101; A61K 9/0053 20130101;
A61K 47/10 20130101; A61K 9/2031 20130101; A61P 37/00 20180101;
A61K 31/436 20130101; A61K 9/1617 20130101; A61K 9/2846 20130101;
A61K 9/284 20130101 |
Class at
Publication: |
514/291 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/436 20060101 A61K031/436 |
Foreign Application Data
Date |
Code |
Application Number |
May 30, 2007 |
DK |
PA200700783 |
Nov 7, 2007 |
DK |
PA200701573 |
Claims
1-95. (canceled)
96. A method of suppressing kidney rejection in a kidney transplant
patient comprising orally administering once daily in the evening
to the kidney transplant patient an extended release pharmaceutical
composition comprising tacrolimus, wherein the in vivo release of
the extended release pharmaceutical composition after oral
administration takes place substantially in the colon.
97. The method of claim 96, wherein the in vivo release of the
extended release pharmaceutical composition after oral
administration takes place substantially in one or more of the
colon ascendens, colon transversum and colon descendens.
98. The method of claim 96, wherein the extended release
pharmaceutical composition provides a zero order release
profile.
99. The method of claim 96, where the extended release
pharmaceutical composition further comprises a modifying release
agent.
100. The method of claim 96, wherein the oral administration of the
composition results in a plasma concentration of about 5 ng/mL to
about 20 ng/mL for at least about 24 hours.
101. The method of claim 96, wherein (i) the pharmaceutical
composition provides a substantially zero order release profile and
(ii) less than 62% of the tacrolimus in the composition within 15
hours, when subjected to an in vitro dissolution test using the USP
II Paddle method at a rotation speed of 50 ppm in a 900 mL aqueous
dissolution medium at pH 4.5 with 0.005%
hydroxypropylcellulose.
102. The method of claim 96, wherein the pharmaceutical composition
is administered once daily for at least 7 days.
103. The method of claim 96, wherein the pharmaceutical composition
administered comprises from 0.1 to 15 mg of tacrolimus.
104. The method of claim 96, wherein the pharmaceutical composition
administered comprises from 0.5 to 5 mg of tacrolimus.
105. The method of claim 96, wherein the pharmaceutical composition
administered comprises 1 mg of tacrolimus.
106. The method of claim 96, wherein the pharmaceutical composition
is orally administered without simultaneous food intake.
107. The method of claim 96, wherein the patient is a de novo
kidney transplant patient.
108. The method of claim 96, wherein the tacrolimus in the
pharmaceutical composition is present in a hydrophilic or
water-miscible vehicle.
109. The method of claim 108, wherein the vehicle is selected from
a polyethylene glycol, a polyoxyethylene oxide, poloxamer,
polyoxyethylene stearate, poly-epsilon caprolactone, polyglycolized
glycerides, polyvinylpyrrolidone, polyvinyl-polyvinylacetate
copolymer, polyvinyl alcohol, polymethacrylic polymer hydroxypropyl
methylcellulose, hydroxypropyl cellulose, methylcellulose, sodium
carboxymethylcellulose, hydroxyethyl cellulose, a pectin, a
cyclodextrin, galactomannan, alginate, carragenate, xanthan gum,
and mixtures thereof.
110. The method of claim 108, wherein the vehicle comprises
poloxamer.
111. The method of claim 108, wherein the vehicle comprises a
mixture of polyethylene glycol and poloxamer.
112. A method of suppressing kidney rejection in a kidney
transplant patient comprising prescribing an extended release
pharmaceutical composition comprising tacrolimus for once daily
oral administration without restriction as to the time of day of
administration, wherein the in vivo release of the extended release
pharmaceutical composition after oral administration takes place
substantially in the colon.
113. A method of suppressing kidney rejection in a kidney
transplant patient comprising orally administering once daily an
extended release pharmaceutical composition comprising tacrolimus
without restriction as to the time of day of administration,
wherein (i) the pharmaceutical composition was prescribed without
restriction as to the time of day of administration, and (ii) the
in vivo release of the extended release pharmaceutical composition
after oral administration takes place substantially in the colon.
Description
RELATED U.S. APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/079,015, filed Jul. 8, 2008, which is hereby
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to an extended release oral
dosage form comprising as active substance tacrolimus or a
pharmaceutically active analogue thereof for use in a once daily
immunosuppressive treatment of a patient in need thereof which
dosage form releases the active substance over an very extended
period of time and which in vivo provides a high bioavailability
and an improved pharmacokinetic profile compared to conventional
dosage forms.
BACKGROUND OF THE INVENTION
[0003] Tacrolimus, also known as FK-506 or FR-900506, is the active
ingredient of Prograf.RTM., Protopic.RTM., and Advagraf.RTM.
approved by the European Agency for the Evaluation of Medicinal
Products (EMEA) at 23 Apr. 2007. During development of
Advagraf.RTM. the product has been known as MR4. Details of
Advagraf is described in the EPARs (European Public Assessment
Reports) for authorised medicinal products for human use including
the Scientific Discussion paper made public by EMEA on approval and
the Product Information (label, 25/01/2008 Advagraf-H-C-7,2-T-03)
which is hereby incorporated by reference. Tacrolimus
(Prograf.RTM.) was approved by the FDA in April of 1994 under NDA
No. 050708 for the prophylaxis of organ rejection in patients
receiving allogeneic liver transplants. It is also approved in the
European Union, Japan, Canada and Switzerland and a variety of
other countries under the same brand name. It is approved for the
prophylaxis of organ rejection in patients receiving allogeneic
liver, kidney or heart transplants. It has been estimated that 72%
of all kidney and 89% of all liver transplant recipients are
receiving tacrolimus.
[0004] Tacrolimus, administered as Prograf.RTM. capsules, exhibits
a large inter- and intra-individual variability of its absorption
and metabolism. Because of this variability, standard dosing is not
an accurate predictor of concentration. In clinical use, tacrolimus
dose-adjustments are frequently required based on monitoring of
tacrolimus trough blood concentrations. Tacrolimus appears in the
form of white crystals or crystalline powder. It is practically
insoluble in water, freely soluble in ethanol and very soluble in
methanol and chloroform.
[0005] The preparation of tacrolimus is described in EP-A-0 184 162
and analogues of tacrolimus are disclosed e.g. in EP-A-0 444 659
and U.S. Pat. No. 6,387,918, which are both hereby incorporated by
reference.
[0006] Tacrolimus is a macrolide compound with useful
immunosuppressive activity, antimicrobial activity and other
pharmacological activities and is of value for the treatment or
prevention of rejection reactions by transplantation of organs or
tissues, graft versus host diseases, autoimmune diseases and
infectious diseases.
[0007] Tacrolimus inhibits T-lymphocyte activation, although the
exact mechanism of action is unknown. Experimental evidence suggest
that tacrolimus binds to an intracellular protein, FKBP-12. A
complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin
is then formed and the phosphatase activity of calcineurin
inhibited. This effect may prevent the dephosphorylation and
translocation of nuclear factor of activated T-cells, a nuclear
component thought to initiate gene transcription for the formation
of lymphokines. The net result is the inhibition of T-lymphocyte
activation, i.e. immunosupression.
[0008] Tacrolimus is extensively metabolized by the CYP3A4
isoenzyme in the gut wall and liver. CYP3A4 isoenzyme is present or
expressed in all segments of the gastrointestinal tract including
the colon. It has been observed that the absorption is negatively
influenced by the simultaneous ingestion of food. Thus, the rate
and extent of tacrolimus absorption were greatest under fasted
conditions.
[0009] Tacrolimus is known to induce significant side effects, of
nephro- or neuro-toxic origin, as well as GI side-effects and
others.
[0010] Absorption of tacrolimus from the gastrointestinal tract
after oral administration is rapid with a mean time-to-peak
concentration (t.sub.max) of approximately 1-2 hours after
administration to healthy subjects or kidney or liver transplanted
patients, but incomplete and variable. The bioavailability is
generally as low as at the most about 20% after oral
administration.
[0011] Frequently observed side effects are vomiting and nausea but
side effects like tremor, headache, hypertension, renal
dysfunction, hyperkalemia, hypomagnesaemia, hyperglycemia,
insomnia, diarrhea, constipation, abdominal pain, nephrotoxicity
and neurotoxicity are also observed.
[0012] For oral administration, tacrolimus is originally formulated
and marketed as soft gelatine capsules comprising the equivalent of
0.5, 1 or 5 mg anhydrous tacrolimus and marketed under the trade
name Prograf.RTM.. The recommended initial oral dose is from about
0.1 to 0.2 mg/kg/day in patients. The dose aims at a certain trough
plasma level from about 5 to about 20 ng/ml. Prograf.RTM. is
indicated for the prophylaxis of organ rejection in patients
receiving allogeneic liver or kidney transplants. Details of the
clinical pharmacology, pharmacokinetics, and clinical studies are
described in the label approved by FDA on Apr. 27, 2006 for
Prograf.RTM., NDA no 50708 which is hereby incorporated by
reference.
[0013] There remains a need for novel pharmaceutical compositions
and/or dosage forms comprising tacrolimus exhibiting enhanced
bioavailability and improved pharmacokinetic properties. An
increased bioavailability in combination with an extended release
formulation may allow a reduction in the dosage units taken by a
patient, e.g. down to a single dose daily without risk of lack of
clinical effect due to low doses in the last past of the dosing
interval. Furthermore, fluctuations in the plasma concentration
versus time profile may be significantly reduced. Further, enhanced
bioavailability may also result in a more reproducible (i.e., less
variable compared to that of Prograf.RTM.) release profile.
[0014] Sustained release tacrolimus formulations are described in
WO99/49863 (Fujisawa Pharmaceutical Co.) inter alia granted as U.S.
Pat. No. 6,440,458, U.S. Pat. No. 6,576,259 and U.S. Pat. No.
6,884,433 relating to a formulation where the time for dissolving
63.2% (T63.2% value) of the tacrolimus is between 0.7 and 15 hours.
However, a formulation where 63.2% is released in 42 minutes seems
to be only marginally different from the conventional immediate
release formulation of tacrolimus having 68.4% released in 30
minutes. It is clearly stated that when the formulation has a T63.6
value of more than 15 hours, the release of the active ingredient
will be so retarded that the active ingredient will be eliminated
from the body before the effective blood concentration is reached.
The most preferred embodiment is a sustained-release formulation
with a T63.6 value of 2-5 hours. The formulations prepared
according to the examples of the application all have a T63.6%
value of from 1.9 (the formulation with the fastest release) to 8.2
hours for the formulation with the slowest release. It is further
stated that the tacrolimus is excellently absorbed and variation of
its absorbability is suppressed with the sustained release
formulations. From the examples therein an improved bioavailability
is obtained with all the tested formulations. The T63.6% values
disclosed for these formulations are 3.0, 3.3, 2.0, and 2.5,
respectively.
[0015] Inventors of the present application have in the patent
application WO 2005/020993 also tested different formulations of
tacrolimus in Beagle dogs and minipigs, however demonstrating that
both a fast release tablet (Example 18) and a slow release tablet
(Example 19) can result in improved bioavailability compared with
Prograf.RTM.. This indicates that an improved bioavailability could
be linked to having tacrolimus in a dissolved state in the dosage
form which also appears from WO 2005/020994 by the same inventors
relating to solid dispersions comprising tacrolimus. The fast
release conventional product Prograf.RTM. comprises tacrolimus in a
physical mixture of HPMC, lactose, cross carmellose sodium as
described in Example 31 in WO99/49863 referred to above and owned
by Fujisawa Pharmaceutical Co. (now Astellas) who developed
Prograf.RTM..
[0016] One major problem with modified or extended release dosage
forms relies in the difficulty in obtaining a sufficient absorption
in the lower part of the gastrointestinal tract as oral dosage
forms entering the colon may easily be excreted before a
substantial release has taken place. The release is generally
decreased due to the lack of fluids and physical interaction of the
dosage forms with the increasingly more solid content of the colon.
In addition, the surface of absorption is several times smaller
than the absorbing surface of the small intestines and this factor
increases the time where the released active substance is subjected
to possible degradation and entrapment in the solids present in the
colon.
BRIEF SUMMARY OF THE INVENTION
[0017] It is generally accepted that extending the release too much
may seriously affect the bioavailability even with substances
expected to have a good permeation in the colon. For substances
being substrates for CYP3A4, an advantage of the smaller
concentration of the metabolizing enzymes in the lower GI can be
expected from a bioavailability point of view. On the other hand,
the relative higher concentration of the transporter system,
P-glycoprotein, in the lower GI tract including the colon normally
counteract the effect of the low concentration of CYP3A4 enzymes
because the molecules that have entered the enterocyte are
transported back into the intestinal lumen by the transporter.
Tacrolimus is a known substrate for these mechanisms, both the
CYP3A4 metabolism and the P-glycoprotein transporter system.
Accordingly, an increased bioavailability cannot be correlated to
an extension of a release in a simple linear way. The release may
be carefully tailored to level out several counteracting factors
of. These factors includes in the colon a lower area for
absorption, a lower content of fluids, higher content of solids,
bacterial degradation, higher impact from the P-glycoprotein
transporter system, lower motility, differences in mucosal barrier
and/or mucous composition and differences in pH along the colon
compared with the small intestines. Accordingly, the control and
timing of the in vivo release of the extended release dosage form
in order to obtain a predictable release under the various physical
conditions present along the GI tract is a challenge, especially
bearing in mind that immune suppressive treatment in transplant
patients requires blood concentrations within very narrow limits to
balance efficacy (lack of rejection) and side effects (infections,
nephrotoxicity, metabolic and cardiovascular disease, etc).
Providing an improved formulation for a once daily treatment where
the release is extended to the exact level where the resulting
pharmacokinetic parameters are fully optimized without jeopardizing
safety, i.e if intra- and inter-patient variance is high on
important pharmacokinetic parameters, if correlation between
minimal concentration and bioavailability is not present, a crucial
factor in the treatment with a narrow therapeutic index drug such
as tacrolimus where treatment failure is closely related to organ
rejection and dose adjustments needs to take place on a safe basis.
Further factors decreasing the risk of clinical success with a once
daily formulation in organ transplant includes high prevalence of
gastrointestinal complications having impact on the
gastrointestinal parameters including transit times, pH, bacterial
composition and other functions of the GI system. These
complications include nausea, vomiting, and very frequently
diarrhea.
[0018] Accordingly, the present inventors has surprisingly found
that a dosage form which releases tacrolimus over an very extended
and controlled period of time is capable of delivering tacrolimus
in vivo in such a way that the tacrolimus at the same time is
sufficiently absorbed to be understood in the way that tacrolimus
is not lost in the lower gastrointestinal tract, the release is
sufficiently slow to enable a very low absorption rate whereby the
maximum concentration is controlled at a lower value and the
minimum concentration is increased securing efficacy of the
treatment for the full dosing interval of 24 hour. Very
importantly, the minimum concentration obtained 24 hour after
administration with an extended release formulation of the present
invention is very predictable and can therefore be used as a marker
for the overall bioavailability because a high correlation is
achieved between the minimal concentration and the actual
bioavailability observed in the previous 24 hour before the
measurement of the minimal concentration. The minimal concentration
can therefore be used safely as a tool for dosing and adjustments
during the treatment.
[0019] It is believed that conventional in vitro dissolution
methods correlate to or at least reflect the actual in vivo
modified release profile in man. Accordingly, a difference in vitro
in release rate between two formulations tested under the same
conditions is expected to reflect a difference in the in vivo
release rate. However, exceptions may apply if for instance one
formulation has a pH dependent release and the other not, and the
actual pH values for testing are not chosen to detect such
difference. A clear example is when testing an enteric coated
formulation at high pH it provides an immediate release in vitro,
and a delayed release in vivo. Additionally, when comparing two
extended formulations with different release mechanisms, for
instance an osmotic driven release mechanism compared with an
erodible dependent release mechanism, the same in vitro release
profiles for the two products may in theory result in different in
vitro profiles, however decreasing or increasing the dissolution
rate will be reflected in vivo for each product. Accordingly,
unless evidence to the contrary, and provided the methods are
performed according to the prescriptions of the pharmacopeias, the
conventional dissolution methods are useful tools for
differentiating between formulations and the corresponding in vivo
properties. In accordance herewith, the present invention provides,
in its first aspect, an extended release oral dosage form
comprising as active substance tacrolimus or an pharmaceutical
active analogue thereof for a once daily immunosuppressive
treatment of a patient in need thereof which dosage form releases
the active substance over an very extended period of time. In a
further aspect, the release is characterized by a substantial zero
order release for a majority of the release.
[0020] Conventional in vitro dissolution methods includes the
methods described in The United States Pharmacopeia (USP) the
official public standards-setting authority for all prescription
and over-the-counter medicines in USA and similar pharmacopeias for
Europe and Japan. The preferred methods include the USP dissolution
method I (basket) and method II (paddle) at 50 rpm, use of HPC to
prevent adherence of drug to the equipment, and a pH of 4.5 for
stability reasons. As tacrolimus is not protonized, pH does not
affect solubility of the drug, however, a pH modification may be
relevant in case pH sensitive inactive excipients are used in the
formulation as a pH of 4.5 is not a pH generally present in the GI
tract. Accordingly, it can be relevant to describe the degree of
extension of the release with alternative dissolution methods. In
addition, the extended formulation accordingly may be further
characterized by additional dissolution methods, inter alia methods
with different rotation speeds, different pH values, use of
dissolution media simulating GI conditions (e.g simulation of the
fasted and fed state, FaSSIP and FeSSIP medias), use of additives
to the dissolution medium such as SLS to increase the wettability
or the solubility of tacrolimus whereby the overall dissolution
time measured is decreased (dissolution rate is increased).
[0021] The inventors have found that the bioavailability of
tacrolimus is significantly increased and pharmacokinetic
parameters substantially improved when tacrolimus is administered
to a mammal in a extended release composition where the release and
a timing of release of the active ingredient, i.e., an in vitro and
vivo release profile, is extended for more than 15 hours measured
by conventional dissolution methods used for tacrolimus dosage
forms and measured in vivo via pharmacokinetic parameters of
clinical relevance and relevant for proving extension of the
release in vivo. These pharmacokinetic parameters includes:
substantial extended time to reaching the maximal concentration;
low maximal concentrations; high minimal concentrations, extended
mean residence times and at the same time securing a surprisingly
high bioavailability and excellent correlation between minimal
concentrations and bioavailability.
[0022] The extended release is defined by a release of at the most
63.5% of the content of the active substance at the 12 hours time
point defined by in vitro dissolution and when tested according to
the USP II dissolution test (paddle) or USP I dissolution test
(basket) form in a medium at pH 4.5 and comprising 0.005%
hydroxypropylcellulose, and a rotation of 50 rpm. In a yet other
aspect, the at the most 63.5% release of the active substance at
the 12 hours time point is combined with a release of at least 8%
at 4 hours and/or at least 15% at hour 8 to secure a continuous
release throughout the dosing interval. If no release takes place
for several hours after administration, the patient is in the risks
that the tacrolimus blood concentration continues to fall to a
value below the desired therapeutic lower limit for several hours
of the 24 hours dosing interval.
[0023] In yet further aspects, the invention relates to use of the
extended release composition for a more safe immunosuppressive
treatment due to the improved pharmacokinetic profile obtained in
healthy subjects and patients and demonstrated by several single
dose and steady state pharmacokinetic trials in comparison with
conventional commercially available dosage forms. The safe
immunosuppressive treatment according to the invention also relates
to a specific dosing regimen for conversion from a treatment on a
twice daily Prograf.RTM. where the conversion is to be performed
with a dosage in a ratio of 1:0.66-0.80 (according to the closest
available tablet strength). Such dosage regimen resulting in
comparable average blood concentrations during the dosing interval
measured before and after the conversion as well similar
bioequivalent exposure to Prograf.RTM. on other parameters such as
AUC and minimum concentration.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] FIG. 1 shows the dissolution of an extended release
formulation according to the invention and tested according to the
USP II dissolution test (paddle) method in a medium at pH 4.5,
comprising 0.005% hydroxypropylcellulose, and a rotation of 50
rpm.
[0025] FIG. 2 is a scintigraphic evaluation of the location of
release by use of an extended release formulation according to the
parameter's of study 003. The figure demonstrates that the in vivo
release with a formulation according to the present invention is
extended to a degree where absorption takes place in the colon of
the individual.
[0026] FIG. 3 shows blood concentrations of tacrolimus in a single
dose study in fasted state of healthy volunteers. Closed triangles
denotes concentration with a 5 mg formulation according to the
present invention, stars denotes a Prograf.RTM. 5 mg formulation;
open circles denotes a 2 mg formulation according to the present
invention; closed squares denotes 2.times.2 mg treatment according
to the present invention; closed diamonds denotes a Prograf.RTM.
4.times.1 mg treatment; vertical line denotes Prograf.RTM.
2.times.1 mg treatment. The study is described in Table A herein,
as study 002.
[0027] FIG. 4 shows the dissolution of a preferred formulation of
the invention having a composition similar to the one described in
Example 20. Triangles depicts treatment with a 1 mg formulation,
squares with a 2 mg formulation. Further, the dissolution of the
commercial product Advagraf.RTM. used for comparison in Example 20
are present where stars relates to a 0.5 mg, cross to a 1 mg and
circles to a 5 mg Advagraf.RTM. product. The release is measured in
percentage dissolved over time disclosed in hours. The dissolution
method used is USP II dissolution test (paddle) method in a medium
adjusted to pH 4.5, comprising 0.005% hydroxypropylcellulose, and a
rotation of 50 rpm.
[0028] FIG. 5 discloses steady state blood profiles obtained before
conversion (Prograf.RTM. day 7 steady state) and after conversion
on day 14 and day 21 to the extended release formulation according
to the present invention in stable liver patients. Squares denote
Prograf.RTM. bid day 7, circles LCP-Tacro once daily on day 17, and
diamonds depict LCP tacro once daily on day 21. The details of the
study are disclosed herein in Example 19. The profiles show the
actual profiles after conversion to a lower dose with the
formulation according to the invention.
[0029] FIG. 6 shows the dose corrected steady state blood profiles
of FIG. 5.
[0030] FIG. 7 shows the PK profile of LCP-Tacro Tablets versus
Advagraf.RTM. Capsules in steady state, fasting conditions.
[0031] FIG. 8: Discloses the blood plasma concentrations after
administration of the same single dosage of tacrolimus as
Advagraf.RTM. 2.times.1 mg capsules open circles and as LCT-Tacro 2
mg tablet according to the present invention. The study is outlined
in Example 20.
[0032] FIG. 9: Discloses steady state blood profiles obtained
before conversion (Prograf.RTM. day 7 steady state) and after
conversion on day 14 and day 21 to the extended release formulation
according to the present invention in stable liver patients.
Squares denotes Prograf.RTM. bid day 7, circles LCP-Tacro once
daily on day 17, and diamonds LCP tacro once daily on day 21. The
details of the study are disclosed herein in Example 19. The
profiles disclose the actual profiles after conversion to a lower
dose with the formulation according to the invention.
[0033] FIG. 10: Discloses the does corrected steady state blood
profiles of FIG. 9.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0034] As used herein, the term "active ingredient" or "active
pharmaceutical ingredient" means any component that is intended to
furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of disease,
or to affect the structure or any function of the body of man or
other animals. The term includes those components that may undergo
chemical change in the manufacture of the drug product and are
present in the drug product in a modified form intended to furnish
the specified activity or effect.
[0035] In the present context, the term "hydrophilic" describes
that something `likes water`, i.e. a hydrophilic molecule or
portion of a molecule is one that typically is electrically
polarized and capable of forming hydrogen bonds with water
molecules, enabling it dissolve more readily in water than in oil
or other "non-polar" solvents.
[0036] In the present context, the term "amphiphilic" describes a
molecule (as a surfactant) having a polar water-soluble group
attached to a water-insoluble hydrocarbon chain. Thus, one end of
the molecule is hydrophilic (polar) and the other is hydrophobic
(non-polar).
[0037] In the present context, the term "hydrophobic" denotes a
compound tending to be electrically neutral and non-polar, and thus
preferring other neutral and nonpolar solvents or molecular
environments.
[0038] As used herein, the term "vehicle" means any solvent or
carrier fluid in a pharmaceutical product that has no
pharmacological role. For example, water is the vehicle for
xilocalne and propylene glycol is the vehicle for many
antibiotics.
[0039] In the present context, the term "solid dispersion" denotes
a drug or active ingredient or substance dispersed on a particulate
level in an inert vehicle, carrier, diluent or matrix in the solid
state, i.e. usually a fine particulate dispersion.
[0040] In the present context, the term "solid solution" denotes a
drug or active ingredient or substance dissolved on a molecular
level in an inert vehicle, carrier, diluent or matrix in the solid
state.
[0041] As used herein, the term "analogue" means a chemical
compound that is structurally similar to another.
[0042] The term "drug" means a compound intended for use in
diagnosis, cure, mitigation, treatment, or prevention of disease in
man or other animals.
[0043] In this context, the term "dosage form" means the form in
which the drug is delivered to the patient. This could be
parenteral, topical, tablet, oral (liquid or dissolved powder),
suppository, inhalation, transdermal, etc.
[0044] As used herein, the term "bioavailability" denotes the
degree means to which a drug or other substance becomes available
to the target tissue after administration.
[0045] As used herein, the term "bioequivalency" denotes a
scientific basis on which generic and brand name drugs are compared
with one another. For example, drugs are bioequivalent if they
enter circulation at the same rate when given in similar doses
under similar conditions. Parameters often used in bioequivalence
studies are t.sub.max, C.sub.max, AUC.sub.0-infinity, AUC.sub.0-t.
Other relevant parameters may be W.sub.50, W.sub.75 and/or MRT.
Accordingly, at least one of these parameters may be applied when
determining whether bioequivalence is present. Furthermore, in the
present context, two compositions are regarded as bioequivalent if
the value of the parameter used is within 80-125% of that of
Prograf.RTM. or a similar commercially available
tacrolimus-containing product used in the test.
[0046] In the present context "t.sub.max" denotes the time to reach
the maximal plasma concentration (c.sub.max) after administration;
AUC.sub.0-infinity denotes the area under the plasma concentration
versus time curve from time 0 to infinity; AUC.sub.0-t denotes the
area under the plasma concentration versus time curve from time 0
to time t; W.sub.50 denotes the time where the plasma concentration
is 50% or more of C.sub.max, W.sub.75 denotes the time where the
plasma concentration is 75% or more of C.sub.max; and MRT denotes
mean residence time for tacrolimus (and/or an analogue thereof).
Swing denotes (C.sub.max-C.sub.min)/C.sub.min and fluctuation
(C.sub.max-C.sub.min)/C.sub.average. The fluctuation is suitable
for the comparison of dosage forms providing different
bioavailability.
[0047] In this context, the term "medicine" means a compound used
to treat disease, injury or pain. Medicine is justly distributed
into "prophylactic," i.e. the art of preserving health, and
"therapeutic", i.e. the art of restoring health.
[0048] In the present context, the terms "controlled release" and
"modified release" are intended to be equivalent terms covering any
type of release of tacrolimus from a composition of the invention
that is appropriate to obtain a specific therapeutic or
prophylactic response after administration to a subject. A person
skilled in the art knows how controlled release/modified release
differs from the release of plain tablets or capsules. The terms
"release in a controlled manner" or "release in a modified manner"
have the same meaning as stated above. The terms include slow
release (that results in a lower C.sub.max and later t.sub.max, but
t.sub.1/2 is unchanged), extended release (that results in a lower
C.sub.max, later t.sub.max, but apparent t.sub.1/2 is longer);
delayed release (that result in an unchanged C.sub.max, but lag
time and, accordingly, t.sub.max is delayed, and t.sub.1/2 is
unchanged) as well as pulsatile release, burst release, sustained
release, prolonged release, chrono-optimized release, fast release
(to obtain an enhanced onset of action) etc. Included in the terms
is also e.g. utilization of specific conditions within the body,
e.g. different enzymes or pH changes in order to control the
release of the drug substance. The term extended release is chosen
as this term is believed to most correctly cover the in vivo
release of the product.
[0049] In this context, the term "erosion" or "eroding" means a
gradual breakdown of the surface of a material or structure, for
example of a tablet or the coating of a tablet. The term as used
herein generally denotes the dissolution of a polymer responsible
for extending the release being is faster than the dissolution of
the active substance whereby the polymer erodes faster than the
active substance is dissolved. In other words the release is
primarily controlled by the erosion and not by the dissolution of
the active substance in the polymer matrix system.
[0050] The present invention provides pharmaceutical products for
improved treatment of conditions that respond to tacrolimus
treatment, especially treatments where an immunosuppressive effect
is desired.
[0051] The active ingredient in the inventive compositions is
preferably tacrolimus or any analogue or derivative of tacrolimus,
which exhibits either a pharmacological or a therapeutical
activity, which is at least equivalent to that of tacrolimus
(FK-506 or FR-900506). However, within the scope of the present
invention is tacrolimus in any physical form (crystals, amorphous
powder, any possible polymorphs, any possible solvates including
the hydrate, anhydrate, complexes thereof etc.). Included is also
any analogue, derivative or active metabolite of tacrolimus,
pharmaceutically acceptable salts, solvates, complexes and prodrugs
thereof. However, it is contemplated that a smaller particle size
in micro and nano scale and preferable a molecular solution will
contribute to a predictable and constant in vivo release of
tacrolimus.
[0052] Thus, in a preferred embodiment, the present invention
provides an extended release oral dosage form comprising as active
substance tacrolimus or an pharmaceutical active analogue thereof
for a once daily immunosuppressive treatment of a patient in need
thereof which dosage form releases the active substance over an
extended period of time defined by a release of at the most 63.5%
of the content of the active substance at the 12 hours time point
defined by in vitro dissolution and when tested according to the
USP II dissolution test (paddle) or USP I dissolution test (basket)
form in a medium at pH 4.5 and comprising 0.005%
hydroxypropylcellulose, and a rotation of 50 rpm. It is generally
accepted that the basket dissolution apparatus may be more suitable
for capsules and the paddle dissolution apparatus is more suitable
for disintegration tablets. However, the most suitable dissolution
apparatus may be easily recognized via testing whether highest
conformity is obtained by the one or other apparatus.
[0053] In a further embodiment, at the most 63.5% of the active
substance is released at the 13 hours time point, more preferred at
the 14 hours time point, such as at the 15 hours time point. In a
preferred embodiment the in vitro release is taking place at a
constant rated whereby a substantial zero order release profile may
be obtained over an extended period of time. As a sufficient
release is required at a time where the dosage form may have
reached the colon such corresponding period where zero order
release is desired may be defined by the release from 8 hours to 15
hours when tested according to the USP II dissolution test (paddle)
or USP I dissolution test (basket) form in a medium at pH 4.5 and
comprising 0.005% hydroxypropylcellulose, and a rotation of 50 rpm.
As a solid dosage form may leave the stomach soon after ingestion
or may be retained there for several hours before reaching the GI
tract, it is also desired that the more initial release is well
controlled as measured by a in vitro release which is an
substantial zero order release profile over an extended period of
time defined by the release from 2 hours to 10 hours when tested
according to the USP II dissolution test (paddle) or USP I
dissolution test (basket) form in a medium at pH 4.5 and comprising
0.005% hydroxypropylcellulose, and a rotation of 50 rpm.
[0054] In another embodiment of the invention, the addition of a
surfactant to the release medium provides a release rate of the
substance whereby the release of at the most 80% of the active
substances is extended for a period of at least 7 hours, such as at
least 8 hours, such as at least 9 hours, such as at least 10 hours,
such as at least 11 hours, such as at least 12 hours such as at
least 13 hours when tested in vitro according to the USP II
dissolution test (paddle) or USP I dissolution test (basket) in a
medium at pH 4.5 and comprising 0.005% hydroxypropylcellulose and
further comprising 0.5% sodium lauryl sulfate (SLS), and a rotation
of 50 rpm
[0055] As mentioned previously, if the release is too extended the
dosage form may be excreted before it has released completely or
the release takes place too distally for a sufficient distribution.
Accordingly, the content of the dosage form should be released with
the rates indicated herein, however not be extended beyond a period
of at the most 24 hours, such as at the most 23 hours, such as at
the most 22 hours, such as at the most 21 hours such as at the most
21 hours, such as at the most 21 hours such as at the most 18 hours
such as at the most 17 hours such as at the most 16 hours
calculated for 80% of the content and with the addition of 0.5%
sodium lauryl sulfate (SLS) to the dissolution medium.
[0056] Alternatively, or additionally, the dosage form is
fulfilling the following condition wherein 63.5% of the release of
the active substance is extended for a period of at the most 20
hours such as at the most 18 hours. Shorter dissolution periods may
also be preferred as the upper limit such as at the most 16 hours
such as at the most 15.5 hours also when tested in vitro according
to the USP II dissolution test (paddle) or USP I dissolution test
(basket) form in a medium at pH 4.5 and comprising 0.005%
hydroxypropylcellulose, and a rotation of 50 rpm.
[0057] An extended release oral dosage wherein the release begins
within 120 min such as within 90 minutes, such as within 60 minutes
after deposition of the dosage form in the dissolution apparatus
when tested in vitro according to the USP II dissolution test
(paddle) or USP I dissolution test (basket) form in a medium at pH
4.5 and comprising 0.005% hydroxypropylcellulose, and a rotation of
50 rpm is indicative for a composition which will provide a
predictable release profile as long as the release in the initial
period, such as within the first 2 hours is not to fast. If no
release takes place shortly after administration, the patient is in
risk of to low concentrations. The patient is generally titrated
according to the blood concentrations observed immediately before
ingesting a daily dosage being the minimum concentration observed
during the day. A delay in release will provide a later unknown
minimal concentration.
[0058] The following release characteristics is regarded as within
the scope of the invention:
[0059] a) An extended release oral dosage form which releases at
the most about 20% w/w of the active substance within 1 hours, or
within 2 hour, or within 3 hours, or within 4 hours or within 5
hours, when tested in vitro according to the USP II dissolution
test (paddle) or USP I dissolution test (basket) form in a medium
at pH 4.5 and comprising 0.005% hydroxypropylcellulose, and a
rotation of 50 rpm.
[0060] b) An extended release oral dosage form which releases 40%
w/w of the active substance within 10 to 14 hours such as, e.g.,
within about 11 to 13 hours, when tested in vitro according to the
USP II dissolution test (paddle) or USP I dissolution test (basket)
form in a medium at pH 4.5 and comprising 0.005%
hydroxypropylcellulose, and a rotation of 50 rpm.
[0061] c) An extended release oral dosage form which releases 20%
w/w of the total amount of the active substance released within 6
to 10 hours such as, e.g., within about 7 to 9 hours, when tested
in vitro according to the USP II dissolution test (paddle) or USP I
dissolution test (basket) form in a medium at pH 4.5 and comprising
0.005% hydroxypropylcellulose, and a rotation of 50 rpm.
[0062] d) An extended release oral dosage form which releases 50%
w/w of the active substance within 13 to 17 hours such as, e.g.,
within about 14 to 16 hours, when tested in vitro according to the
USP II dissolution test (paddle) or USP I dissolution test (basket)
form in a medium at pH 4.5 and comprising 0.005%
hydroxypropylcellulose, and a rotation of 50 rpm.
[0063] e) An extended release oral dosage form wherein the release
profile is substantially linear in the period from 4 to 8 hours
defined as a gradient or slope being within 25% of the gradient or
slope measured at hour 6, such as within 15%, preferable within
10%.
[0064] f) An extended release oral dosage form wherein the release
profile is substantially linear in the period from 6 to 10 hours
defined as a gradient or slope being within 25% of the gradient or
slope measured at hour 8, such as within 15%, preferable within
10%.
[0065] g) An extended release oral dosage form wherein the release
profile is substantially linear in the period from 8 to 12 hours
defined as a gradient or slope being within 25% of the gradient or
slope measured at hour 10, such as within 15%, preferable within
10%.
[0066] h) An extended release oral dosage form wherein the release
profile is substantially linear in the release period from the time
point where 20% is released to the time point where 50% is released
defined as a gradient or slope at the 80% time point being within
25% of the gradient or slope measured at the 20% time point.
[0067] i) An extended release dosage form according to any of the
preceding claims wherein the release extending mechanism is not by
a permeation controlling coat.
[0068] It is believed that release profile characteristics defined
above significantly enhances the bioavailability of tacrolimus in
mammals, since all or a major part of the active ingredient is in
fact released in the gastrointestinal tract in such as manner that
CYP3A4 metabolism is substantially avoided or at least
significantly reduced. Further, it is contemplated that this effect
is correlated to or at least reflected to the in vitro dissolution
profile of the pharmaceutical composition and/or dosage forms of
the invention, which profile is easily found when subjecting the
composition and/or dosage form to a conventional in vitro
dissolution method specified.
[0069] The desired release profile of the pharmaceutical
composition may be provided by combining one or more of the
following possibilities. [0070] i) coating the composition with an
enteric coating; and/or [0071] ii) using a pharmaceutical
composition comprising a solid dispersion or solid solution of
active ingredient, i.e. tacrolimus or an analogue thereof, in a
hydrophilic or water-miscible vehicle and one or more modifying
release agents; and/or [0072] iii) using a pharmaceutical
composition comprising a solid dispersion or solid solution of
active ingredient, i.e. tacrolimus or an analogue thereof, in a
hydrophobic vehicle and optionally one or more modifying release
agents.
[0073] An entero-coated formulation may however have the
disadvantage of delaying the release without extending the release
and should therefore be used in combination with an extending
technology.
[0074] In another embodiment of the invention, and more preferred
there is provided a extended release tacrolimus-containing
pharmaceutical composition having the active ingredient dissolved
or dispersed in a hydrophobic vehicle as described herein,
preferably in an oil, an oily material, a wax or a fatty acid
derivative, more preferably a wax having a low melting point such
as for example glyceryl monostearate.
[0075] In yet another embodiment of the invention, there is
provided a extended release tacrolimus-containing pharmaceutical
composition having the active ingredient dissolved or dispersed in
a hydrophilic or water-miscible vehicle as described herein,
preferably a vehicle selected among polyethylene glycols,
polyoxyethylene oxides, poloxamers, polyoxyethylene stearates,
poly-epsilon caprolactone, polyglycolized glycerides such as
Gelucire.RTM., and mixtures thereof, more preferably polyethylene
glycol optionally in mixture with a poloxamer. A specific example
of a useful mixture is a mixture of 70 w/w % polyethylene glycol
6000 (PEG6000) and 30 w/w % poloxamer 188.
[0076] In a further aspect, the present invention relates to a
pharmaceutical composition in particulate form comprising
tacrolimus and/or an analogue thereof together with one or more
pharmaceutically acceptable excipients, wherein the composition
upon oral administration to a mammal in need thereof exhibits an
AUC/AUC.sub.Prograf.RTM. value of at least about 1.3, the AUC
values being determined under similar conditions.
[0077] As it appears from the examples herein that the
bioavailability obtained after administration of a composition
according to the invention is markedly improved. Thus, in specific
embodiments, the AUC/AUC.sub.Prograf.RTM. value is at least about
1.25 such as about 1.5 or more, about 1.8 or more, about 1.9 or
more, about 2.0 or more, the AUC values being determined under
similar conditions.
[0078] After oral administration of a pharmaceutical composition
according to the present invention it is contemplated that the
plasma concentration versus time profile show an extended period of
time in which the plasma concentration is maintained within the
therapeutic window (i.e., the plasma concentration leads to a
therapeutic effect) without leading to serious unwanted side
effects. Thus, a reduction in peak concentration is also observed.
Accordingly, the invention relates to a pharmaceutical composition
in particulate form comprising tacrolimus together with one or more
pharmaceutically acceptable excipient, wherein the composition upon
oral administration to a mammal in need thereof releases tacrolimus
in a controlled manner and exhibits a C.sub.max that is at the most
about 80% of that of C.sub.max for Prograf.RTM. tablets such as,
e.g., at the most about 75%, at the most about 70%, at the most
about 65%, at the most about 60%, at the most about 55%, at the
most about 50%, at the most about 45% or at the most about 40%.
[0079] In the present context the terms controlled release and
extended release are intended to be equivalent terms covering any
type of release of tacrolimus from a composition of the invention
that is appropriate to obtain a specific therapeutic or
prophylactic response after administration to a subject. A person
skilled in the art knows how controlled release/extended release
differs from the release of plain tablets or capsules. The terms
"release in a controlled manner" or "release in a extended manner"
have the same meaning as stated above.
[0080] The terms controlled release/extended release include slow
release (that results in a lower C.sub.max and later t.sub.max, but
t.sub.1/2 is unchanged), extended release (that results in a lower
C.sub.max, later t.sub.max, but apparent t.sub.1/2 is longer);
delayed release (that result in an unchanged C.sub.max, but lag
time and, accordingly, t.sub.max is delayed, and t.sub.1/2 is
unchanged) as well as pulsatile release, burst release, sustained
release, prolonged release, chrono-optimized release, fast release
(to obtain an enhanced onset of action) etc. Included in the terms
is also e.g. utilization of specific conditions within the body
e.g. different enzymes or pH changes in order to control the
release of the drug substance.
[0081] To be more specific, after oral administration to a mammal,
including a human, of a pharmaceutical composition according to the
present invention containing a dose of 5 mg tacrolimus, tacrolimus
is released in a controlled manner and will exhibit a C.sub.max
that is at the most about 30 ng/ml such as, e.g. at the most about
25 ng/ml or at the most about 20 ng/ml.
[0082] However, a reduction in peak concentration may not lead to a
decrease in therapeutic effect as long as the plasma concentration
of tacrolimus is maintained within the therapeutic window.
Accordingly, the present invention also relates to a pharmaceutical
composition, wherein W.sub.50 is at least about 2 hours, such as,
e.g., at least about 3 hours, at least about 4 hours, at least
about 5 hours, at least about 6 hours, at least about 7 hours, at
least about 8 hours, at least about 9 hours, about 10 hours or
more, about 11 hours or more, about 12 hours or more, about 13
hours or about 14 hours or more.
[0083] Furthermore or moreover, a composition according to the
invention has a C.sub.diff=[C.sub.max-C.sub.t (t=12 hours)] that is
less than that of Prograf.RTM. under the same conditions. If
C.sub.diff for Prograf.RTM. is set to 100 then C.sub.diff of a
composition according to the invention is normally 90 or less such
as, e.g., about 85 or less, about 80 or less, about 75 or less,
about 70 or less, about 65 or less, about 60 or less, about 55 or
less, about 50 or less, about 45 or less or about 40 or less.
[0084] More specifically, after oral administration to a mammal,
including a human, of a pharmaceutical composition of the invention
containing 5 mg of tacrolimus, tacrolimus is released in a
controlled manner and exhibits a C.sub.diff of about 20 ng/mL or
less such as, e.g., about 15 ng/mL or less, about 13 ng/mL or less
or about 10 ng/mL or less.
[0085] A pharmaceutical composition according to the invention
releases tacrolimus in a controlled manner in order to extend the
therapeutic action of tacrolimus. In one aspect the release may be
pH dependant, i.e. the release predominantly takes place after
passage of the stomach. Such a pH dependent release is mainly
provided by means of enteric coating material as described herein.
The release may also be pH independent, e.g., by providing the
composition with a controlled release coating such as, e.g. a
cellulose based coating like e.g. ethylcellulose or by providing
the composition in the form of a matrix composition such as, e.g.,
a hydrophilic cellulose polymer matrix type e.g. based on HPMC. A
combination may of course also be employed.
[0086] In general, the change in bioavailability and/or the changes
in other bioavailability related parameters are normally determined
by in vivo studies in a suitable animal model testing the
compositions in question together with e.g. Prograf.RTM. or a
similar commercially available tacrolimus-containing product. The
use of a dog model for establishing evidence of the bioavailability
of certain formulations is general practice in the pharmaceutical
industry.
[0087] The studies relevant for tacrolimus are non-radomized,
cross-over studies, where each dog is its own control. Four dogs,
and four treatments are normally applied. As no iv injections are
given, the bioavailabilities obtained are relative.
[0088] Further it has surprisingly been found that the need for
simultaneous food intake in order to secure a sufficient uptake of
tacrolimus is significantly reduced or even completely
abolished.
[0089] Thus, the pharmaceutical compositions according to the
invention provide significant higher bioavailability of tacrolimus,
which may reduce the number of daily administered dosage units, and
reduce or abolish the need for administration in connection with
food intake, which provide for a higher degree of freedom for the
recipient of the pharmaceutical compositions, and consequently the
patients acceptance and/or compliance may be significantly
improved. Furthermore, the compositions provide a significant
reduction in side effects, especially side effect related to a high
peak concentration (such as, e.g., nephro- and neuro-toxicity,
diarrhea, constipation, abdominal pain, nausea etc) and provide for
an extended release of tacrolimus leading to a better therapy.
[0090] A further advantage of an extended-release-dosage-form
invention is the possibility of obtaining an effective therapeutic
response with a decreased dosage compared to traditional oral
treatment. A similar bioavailability and an improved profile after
administration in a dose is that is at the about most about 85% w/w
such as, e.g., at the most about 80% w/w, at the most about 75%, at
the most about 70% w/w, at the most about 65% w/w, at the most
about 60% w/w, at the most about 55% w/w or at the most about 50%
w/w of the dose of tacrolimus administered in the form of
Prograf.RTM. or a similar commercially available
tacrolimus-containing product or as a commercial available extended
release product including Advagraf.RTM..
[0091] Parameters often used in bioequivalence studies are
t.sub.max, C.sub.max, AUC.sub.0-infinity, AUC.sub.0-t. Other
relevant parameters may be W.sub.50, W.sub.75 and/or MRT.
Accordingly, at least one of these parameters may be applied when
determining whether bioequivalence is present. Furthermore, in the
present context, two compositions are regarded as bioequivalent if
value of the parameter used is within 80-125% of that of
Prograf.RTM. or a similar commercially available
tacrolimus-containing product used in the test.
[0092] In the present context "t.sub.max" denotes the time to reach
the maximal plasma concentration (c.sub.max) after administration;
AUC.sub.0-infinity denotes the area under the plasma concentration
versus time curve from time 0 to infinity; AUC.sub.0-t denotes the
area under the plasma concentration versus time curve from time 0
to time t; W.sub.50 denotes the time where the plasma concentration
is 50% or more of C.sub.max, W.sub.75 denotes the time where the
plasma concentration is 75% or more of C.sub.max; and MRT denotes
mean residence time for tacrolimus (and/or an analogue
thereof).
[0093] Two other main disadvantages associated with treatment or
prophylaxis with tacrolimus is the relative high incidence of side
effects and a relatively high inter-individual variation. It is
envisaged that a composition according to the invention will lead
to a reduction in side effects. The reduction may be in terms of
reduced frequency or in terms of severity. The side effects in
question include e.g., nephro- and neuro-toxicity, diarrhea,
constipation, abdominal pain, nausea etc. In one aspect the
invention concerns a pharmaceutical composition in particulate form
comprising tacrolimus or an analogue thereof together with one or
more pharmaceutically acceptable excipient, wherein the composition
upon oral administration to a mammal in need thereof releases
tacrolimus or an analogue thereof in a controlled manner and
reduces side effects compared to those of Prograf.RTM. administered
under the same conditions and in a dose that provides an equivalent
therapeutic effect.
[0094] Increasing the bioavailability, the Area Under the Curve
(AUC), will normally reduce the intra- and inter-variability
related to absorption of a drug substance. This is particularly
true; whenever the low and impaired bioavailability is a
consequence of poor water solubility. It is contemplated that
compositions according to the invention will provide a CV
(Coefficient of Variation) on Area under Curve data that are
significantly smaller than with Prograf.RTM. and like products.
[0095] As mentioned herein, one of the basic features of the
present invention is that it is possible to obtain an improvement
in the bioavailability by oral administration of an extended
release dosage form according to the invention. Normally, a low
bioavailability of a drug substance after oral administration is a
barrier for design of a controlled or extended release composition
of the drug substance due to the fact that it is almost impossible
to obtain effective drug levels over a prolonged period of time.
However, with the present technology it is possible to obtain a
significantly improved bioavailability and thereby possible to
design controlled, extended or delayed release compositions.
[0096] Tacrolimus is extensively metabolized by the CYP3A4
isoenzyme in the gut wall and liver. Accordingly, a suitable
controlled release composition may be a composition that is
designed to release tacrolimus in a delayed manner so as to avoid
or reduce the CYP3A4 metabolism in the gastrointestinal tract.
[0097] Delayed release is mainly brought about by some kind of
enteric coating. Whereas semi-permeable coating will show some kind
of delayed release, it does not preciously enough "delay" release.
Additionally it requires a certain amount of time to release the
content. The coating sought for this invention, is a pH dependant
coating. This type of coating is very resistant to release of drug
until a certain pH is reached. Within very few 1/10th of pH, the
film alters properties and becomes permeable. Examples of
pH-sensitive polymers, which are relatively insoluble and
impermeable at the pH of the stomach, but which are more soluble
and permeable at the pH of the small intestine and colon include,
but not limited to polyacrylamides, phthalate derivatives such as
acid phthalates of carbohydrates, amylose acetate phthalate,
cellulose acetate phthalate, other cellulose ester phthalates,
cellulose ether phthalates, hydroxypropylcellulose phthalate,
hydroxypropylethylcellulose phthalate, hydroxypropylmethylcellulose
phthalate, methylcellulose phthalate, polyvinyl acetate phthalate,
polyvinyl acetate hydrogen phthalate, sodium cellulose acetate
phthalate, starch acid phthalate, styrene-maleic acid dibutyl
phthalate copolymer, styrene-maleic acid polyvinylacetate phthalate
copolymer, styrene and maleic acid copolymers, polyacrylic acid
derivatives such as acrylic acid and acrylic ester copolymers,
polymethacrylic acid and esters thereof, poly acrylic methacrylic
acid copolymers, shellac, and vinyl acetate and crotonic acid
copolymers.
[0098] pH-sensitive polymers of specific interest include shellac;
phthalate derivatives, particularly cellulose acetate phthalate,
polyvinylacetate phthalate, and hydroxypropylmethylcellulose
phthalate; polyacrylic acid derivatives, particularly polymethyl
methacrylate blended with acrylic acid and acrylic ester
copolymers; and vinyl acetate and crotonic acid copolymers.
[0099] The release of the active substance from a composition
having a delayed release coating could also be an enzymatic
reaction, if for example Zein or mono/di-glyceride mixtures are
employed as coating material.
[0100] Upon oral administration to a mammal, including a human, in
need thereof, a controlled release pharmaceutical composition
according to the present invention releases tacrolimus in such a
manner that a plasma concentration of at least about 5 ng/ml such
as, e.g., at least about 7.5 ng/mL or at least about 10 ng/mL for a
time period of at least about 24 hours is obtained. In a specific
aspect of the invention the difference between the peak plasma
concentration and plasma concentration measured 24 hours after
administration is at the most about 20 ng/mL such as, e.g., at the
most about 10 ng/ml, at the most about 7.5 ng/mL or at the most
about 5 ng/mL.
[0101] In a specific aspect, the invention provides a
pharmaceutical composition or a solid dosage form that releases
tacrolimus and/or an analogue thereof relatively fast so as to
enable a relatively fast onset of therapeutic effect. In one
aspect, the invention relates to a pharmaceutical composition in
particulate form comprising tacrolimus and/or an analogue thereof
together with one or more pharmaceutically acceptable excipient,
wherein the composition upon oral administration to a mammal in
need thereof in a controlled manner releases at least about 50% w/w
of the total amount of tacrolimus or an analogue thereof within
about 24 hours, such as, e.g., within about 22 hours, within about
20 hours, within about 18 hours, within about 15 hours or within
about 12 hours.
[0102] Furthermore or alternatively, at least about 50% w/w of the
total amount of tacrolimus and/or an analogue thereof is released
within about 24 hours, within about 22 hours, within about 20
hours, within about 18 hours, within 15 hours, within about 12
hours, when tested in an in vitro dissolution test and employing a
dissolution medium comprising a buffer having pH 7.5. Guidance for
a suitable dissolution test is described in the Examples herein,
but variations with respect to the specific method employed and the
ingredients contained in the dissolution medium etc. are within the
scope of the present invention. A person skilled in the art will
know how to carry out a suitable dissolution test e.g. with
guidance from USP, Ph.Eur. and the like including the FDA database
of Dissolution Method for Drug Products. Suitable conditions for
the in vitro dissolution test are employing USP dissolution test
(paddle method) and a buffer pH 7.5 containing 2.5% SDS and 1 g/mL
of pancreatin as dissolution medium.
[0103] In other embodiments, the following conditions are fulfilled
with respect to in vitro dissolution test:
[0104] In other embodiments, the following conditions are fulfilled
with respect to in vitro dissolution test performed under acidic
conditions: [0105] i) at the most about 30% w/w such as, e.g., at
the most about 25% w/w, at the most about 20% w/w, at the most
about 15% w/w or at the most about 10% w/w of tacrolimus or an
analogue thereof is released within 2 hours in an in vitro
dissolution test employing a dissolution medium having a pH of at
the most about 5 such as, e.g. at the most about 4.5, at the most
about 4, at the most about 3.5, at the most about 3, at the most
about 2 or at the most about 1.5; [0106] ii) at the most about 10%
w/w such as, e.g., at the most about 7.5% w/w, at the most about 5%
w/w or at the most about 2.5% w/w of tacrolimus or an analogue
thereof is released within 2 hours in an in vitro dissolution test
employing a dissolution medium having a pH of at the most about 5
such as, e.g. at the most about 4.5, at the most about 4, at the
most about 3.5, at the most about 3, at the most about 2 or at the
most about 1.5; [0107] iii) at the most about 60% w/w such as,
e.g., at the most about 50% w/w, at the most about 40% w/w or at
the most about 30% w/w of tacrolimus or an analogue thereof is
released within 15 hours such as, e.g., within about 12 hours, when
tested in an in vitro dissolution test employing a dissolution
medium having a pH of at the most about 4.5 such as, e.g. at the
most about 4.0, at the most about 3.5, at the most about 3, at the
most about 2 or at the most about 1.5; [0108] iv) at the most about
40% w/w such as, e.g., at the most about 30% w/w, at the most about
25% w/w or at the most about 20% w/w of tacrolimus or an analogue
thereof is released within 6 hours when tested in an in vitro
dissolution test employing a dissolution medium having a pH of at
the most about 4.5 such as, e.g. at the most about 4.0, at the most
about 3.5, at the most about 3, at the most about 2 or at the most
about 1.5, and/or [0109] v) at the most about 30% w/w such as,
e.g., at the most about 25% w/w, at the most about 20% w/w or at
the most about 15% w/w of tacrolimus or an analogue thereof is
released within 4 hours when tested in an in vitro dissolution test
employing a dissolution medium having a pH of at the most about 4.5
such as, e.g. at the most about 4.0, at the most about 3.5, at the
most about 3, at the most about 2 or at the most about 1.5.
[0110] Apart from tacrolimus, a composition of the invention may
also comprise a further therapeutically, prophylactically and/or
diagnostically active substance. Notably combinations of tacrolimus
with at least one of the following active substances are of
interest: Substances that are indicated for use in connection with
organ transplantation such as, e.g., steroids, calcineurin
inhibitors and/or anti-proliferative agents. Specific examples
include prednisone, prednisolone, methylprednisone, cyclosporin,
mycophenolate mofetil, azathioprine, sirolimus, everolimus,
mycophenolate sodium, and FTY720 (Novartis).
[0111] The pharmaceutical compositions may be prepared by any
convenient method such as, e.g., granulation, mixing, spray drying
etc. A particularly useful method is the method described in WO
03/004001. Herein is described a process for the preparation of
particulate material by a controlled agglomeration method, i.e. a
method, which enables a controlled growth in particle size. The
method involves spraying a first composition comprising e.g.
tacrolimus and a carrier, which has been melted, onto a second
solid carrier medium. Normally, the meltable carrier has a melting
point of at least 5.degree. C. but lower than the melting point of
tacrolimus. The melting point of the carrier may be in the range of
10.degree. C. to 150.degree. C., such as, e.g., in the range of
30.degree. C. to 100.degree. C. or in the range of 40.degree. C. to
50.degree. C. is most preferred.
[0112] It is within the skills of the average practioner to select
a suitable carrier being pharmaceutical acceptable, capable of
dissolving or at least partly dissolve tacrolimus and having a
melting point in the desired range using general knowledge and
routine experimentation. Suitable candidate for carriers are
described in WO 03/004001, which is herein incorporated by
reference.
[0113] In the present context, suitable carriers are e.g. those
mentioned as an oil or an oily-like material (as discussed later
herein) as well as those disclosed in WO 03/004001.
[0114] An advantage of using the controlled agglomeration method
described in WO 03/004001 is that it is possible to apply a
relatively large amount of a melt to a particulate material without
having an undesirable growth in particle size. Accordingly, in one
embodiment of the invention, the particulate material of a
pharmaceutical composition has a geometric weight mean diameter
d.sub.gw of .gtoreq.10 .mu.m such as, e.g. .gtoreq.20 .mu.m, from
about 20 to about 2000, from about 30 to about 2000, from about 50
to about 2000, from about 60 to about 2000, from about 75 to about
2000 such as, e.g. from about 100 to about 1500 .mu.m, from about
100 to about 1000 .mu.m or from about 100 to about 700 .mu.m, or at
the most about 400 .mu.m or at the most 300 .mu.m such as, e.g.,
from about 50 to about 400 .mu.m such as, e.g., from about 50 to
about 350 .mu.m, from about 50 to about 300 .mu.m, from about 50 to
about 250 .mu.m or from about 100 to about 300 .mu.m.
[0115] The particulate material obtained by the above-mentioned
method has suitable properties with respect to flowability and/or
compressibility and is therefore suitable for further processing
into pharmaceutical dosage forms.
Solid Dispersion and/or Solid Solution of Tacrolimus
[0116] The solid dispersion or solid dispersion used in a preferred
embodiment of the invention comprises an active ingredient selected
among tacrolimus and analogues thereof, which ingredient is
dispersed or dissolved in a hydrophilic or water-miscible vehicle
having a melting point (freezing point or pour point) of at least
20.degree. C. in a concentration of between about 0.01 w/w % and
about 15 w/w %, and which dispersion is forming a solid dispersion
or solid solution at ambient temperature (room temperature).
[0117] The concentration of the active ingredient in the
hydrophilic or water-miscible vehicle is at the most 15 w/w %,
preferably at the most 10 w/w %, preferably at the most 8 w/w %,
more preferably at the most 6 w/w %, even more preferably at the
most 5 w/w %, at the most 4% w/w, especially at the most 3 w/w %,
in particular at the most 2% w/w; and/or is at least about 0.05 w/w
%, preferably at least about 0.1 w/w %, more preferably at least
about 0.5 w/w %, especially at least about 0.7 w/w %, in particular
at least about 1 w/w %.
[0118] Physically, the combination of active ingredient and vehicle
may either form a solid dispersion, i.e. the active ingredient is
dispersed in the vehicle in particulate form, or may form a solid
solution, i.e. the active ingredient is dissolved in the vehicle at
a molecular level. The active ingredient and the vehicle may also
form a solid dispersion having therein a part of the active
ingredient dissolved at a molecular level. The physical state of
the dispersion and/or solution may be determined by using various
techniques such as Hot Stage Microscopy (HSM), Differential
Scanning calorimetry (DSC), Scanning Electron Microscopy (SEM)
optionally in combination with Energy Dispersive X-ray (EDX), and
X-ray powder diffraction. In a preferred embodiment, the active
ingredient is fully dissolved in the vehicle to form a solid
solution at ambient temperature.
[0119] The solid dispersion of the invention exhibits a very fast
immediate release of tacrolimus, when a composition comprising the
dispersion or solution is tested in a dissolution test according to
USP using an aqueous dissolution medium, and at least 50 w/w % of
the active pharmaceutical ingredient is released within about 30
minutes, preferably within 20 minutes, more preferably within 15
minutes; such as at least 75 w/w % of the active pharmaceutical
ingredient is released within about 40 minutes, or even better at
least 90 w/w % of the active pharmaceutical ingredient is released
within about 60 minutes, preferably within 45 minutes. For example,
the test may be carried out according to the any method and any
specifications cited in USP. Thus, the dissolution test may be
carried out in an aqueous dissolution medium at a neutral or
near-neutral pH, for example at pH 6.8, or at any acidic pH
simulating the pH conditions in the gastrointestinal tract.
However, variations with respect to the specific method employed
and the ingredients contained in the dissolution medium etc. are
within the scope of the present invention. A person skilled in the
art will know how to carry out a suitable dissolution test e.g.
with guidance from USP, Ph.Eur. and the like. Suitable conditions
for the in vitro dissolution test are employing USP dissolution
test (paddle method) and a buffer pH 7.5 containing 2.5% SDS and 1
g/mL of pancreatin as dissolution medium.
[0120] The hydrophilic or water-miscible vehicle to be used
according to the invention is preferably one having a melting point
(freezing point or pour point) of at least 20.degree. C., more
preferably at least 30.degree. C., more preferably at least
40.degree. C., more preferably at least 50.degree. C., even more
preferably at least 52.degree. C., even more preferably at least
55.degree. C., even more preferably at least 59.degree. C.,
especially at least 61.degree. C., in particular at least
65.degree. C.
[0121] Examples of useful hydrophilic or water-miscible vehicles to
be used according to this invention are selected from the group
consisting of polyethylene glycols, polyoxyethylene oxides,
poloxamers, polyoxyethylene stearates, poly-epsilon caprolactone,
polyglycolized glycerides such as Gelucire.RTM., and mixtures
thereof.
[0122] In a preferred embodiment of the invention, the vehicle is a
polyethylene glycol (PEG), in particular a PEG having an average
molecular weight of at least 1500, preferably at least 3000, more
preferably at least 4000, especially at least 6000. The
polyethylene glycol may advantageously be mixed with one or more
other hydrophilic or water-miscible vehicles, for example a
poloxamer, preferably in a proportion (on a weight/weight basis) of
between 1:3 and 10:1, preferably between 1:1 and 5:1, more
preferably between and 3:2 4:1, especially between 2:1 and 3:1, in
particular about 7:3. A specific example of a useful mixture is a
mixture of PEG6000 and poloxamer 188 in the ratio 7:3.
[0123] For polyethylene glycols (PEG), the melting point (freezing
point or pour point) increases as the average molecular weight
increases. For example, PEG 400 is in the range of 4-8.degree. C.,
PEG 600 is in the range of 20-25.degree. C., PEG1500 is in the
range of 44-48.degree. C., PEG2000 is about 52.degree. C., PEG 4000
is about 59.degree. C., PEG 6000 is about 65.degree. C. and PEG
8000 is about 61.degree. C.
[0124] Useful poloxamers (also denoted
polyoxypropylene-polyoxyethylene block copolymers) are for example
poloxamer 188, poloxamer 237, poloxamer 338 or poloxamer 407 or
other block copolymers of ethylene oxide and propylene oxide such
as the Pluronic.RTM. and/or Tetronic.RTM. series. Suitable block
copolymers of the Pluronic.RTM. series include polymers having a
molecular weight of about 3,000 or more such as, e.g. from about
4,000 to about 20,000 and/or a viscosity (Brookfield) from about
200 to about 4,000 cps such as, e.g., from about 250 to about 3,000
cps. Suitable examples include Pluronic.RTM. F38, P65, P68LF, P75,
F77, P84, P85, F87, F88, F98, P103, P104, P105, F108, P123, F123,
F127, 10R8, 17R8, 25R5, 25R8 etc. Suitable block copolymers of the
Tetronic.RTM. series include polymers having a molecular weight of
about 8,000 or more such as, e.g., from about 9,000 to about 35,000
and/or a viscosity (Brookfield) of from about 500 to about 45,000
cps such as, e.g., from about 600 to about 40,000. The viscosities
given above are determined at 60.degree. C. for substances that are
pastes at room temperature and at 77.degree. C. for substances that
are solids at room temperature.
[0125] In a preferred embodiment of the present invention, the
poloxamer is poloxamer 188, which has an average molecular weight
of about 8400 and a melting point of about 50-54.degree. C.
[0126] Other useful hydrophilic or water-miscible vehicles may be
polyvinylpyrrolidones, polyvinyl-polyvinylacetate copolymers
(PVP-PVA), polyvinyl alcohol (PVA), polymethacrylic polymers
(Eudragit RS; Eudragit RL, Eudragit NE, Eudragit E), cellulose
derivatives including hydroxypropyl methylcellulose (HPMC),
hydroxypropyl cellulose (HPC), methylcellulose, sodium
carboxymethylcellulose, hydroxyethyl cellulose, pectins,
cyclodextrins, galactomannans, alginates, carragenates, xanthan
gums and mixtures thereof.
[0127] "Polyglycolized glycerides" denotes a mixture of mono-, di-
and triglycerides and polyethylene glycol (PEG) mono- and diesters,
preferably of molecular weight between 200 and 600, where
appropriate of free glycerol and free PEG, whose HLB value is
adjusted by the length of the PEG chain, and whose melting point is
adjusted by the length of the chains of the fatty acids, of the PEG
and by the degree of saturation of the fatty chains, and hence of
the starting oil; examples of such mixtures are Gelucire.RTM..
Gelucire.RTM. compositions are inert semi-solid waxy materials
which are amphiphilic in character and are available with varying
physical characteristics. They are surface active in nature and
disperse or solubilize in aqueous media forming micelles,
microscopic globules or vesicles. They are identified by their
melting point/HLB value. The melting point is expressed in degrees
Celsius and the HLB (Hydrophile-Lipophile Balance) is a numerical
scale extending from 0 to approximately 20. Lower HLB values denote
more lipophilic and hydrophobic substances, and higher values
denote more hydrophilic and lipophobic substances. The affinity of
a compound for water or for oily substances is determined and its
HLB value is assigned experimentally. One or a mixture of different
grades of Gelucire.RTM. excipient may be chosen to achieve the
desired characteristics of melting point and/or HLB value. They are
mixtures of monoesters, diesters and/or triesters of glycerides of
long chain (C.sub.12 to C.sub.18) fatty acids, and PEG (mono-
and/or di) esters of long chain (C.sub.12 to C.sub.18) fatty acids
and can include free PEG. Gelucire.RTM. compositions are generally
described as fatty acid esters of glycerol and PEG esters or as
polyglycolized glycerides. Gelucire.RTM. compositions are
characterized by a wide range of melting points of from about
33.degree. C. to about 64.degree. C. and most commonly from about
35.degree. C. to about 55.degree. C., and by a variety of HLB
values of from about 1 to about 14, most commonly from about 7 to
about 14. For example, Gelucire.RTM. 50/13 designates a melting
point of approximately 50.degree. C. and an HLB value of about 13
to this grade of Gelucire.RTM..
Pharmaceutically Acceptable Excipients
[0128] Examples of suitable excipients for use in a composition or
solid dosage form according to the present invention include
fillers, diluents, disintegrants, binders, lubricants and the like
and mixtures thereof. As the composition or solid dosage form
according to the invention may be used for different purposes, the
choice of excipients is normally made taken such different uses
into considerations. Other pharmaceutically acceptable excipients
for suitable use are e.g. acidifying agents, alkalizing agents,
preservatives, antioxidants, buffering agents, chelating agents,
coloring agents, complexing agents, emulsifying and/or solubilizing
agents, flavors and perfumes, humectants, sweetening agents,
wetting agents and the like.
[0129] Examples of suitable fillers, diluents and/or binders
include lactose (e.g. spray-dried lactose, .alpha.-lactose,
.beta.-lactose, Tabletose.RTM., various grades of Pharmatose.RTM.,
Microtose.RTM. or Fast-Floc.RTM.), microcrystalline cellulose
(various grades of Avicel.RTM., Elcema.RTM., Vivacel.RTM., Ming
Tai.RTM. or Solka-Floc.RTM.), hydroxypropylcellulose,
L-hydroxypropylcellulose (low substituted), hydroxypropyl
methylcellulose (HPMC) (e.g. Methocel E, F and K, Metolose SH of
Shin-Etsu, Ltd, such as, e.g. the 4,000 cps grades of Methocel E
and Metolose 60 SH, the 4,000 cps grades of Methocel F and Metolose
65 SH, the 4,000, 15,000 and 100,000 cps grades of Methocel K; and
the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH),
methylcellulose polymers (such as, e.g., Methocel A, Methocel A4C,
Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium
carboxymethylcellulose, carboxymethylene,
carboxymethylhydroxyethylcellulose and other cellulose derivatives,
sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins,
starches or modified starches (including potato starch, maize
starch and rice starch), calcium phosphate (e.g. basic calcium
phosphate, calcium hydrogen phosphate, dicalcium phosphate
hydrate), calcium sulfate, calcium carbonate, sodium alginate,
collagen etc.
[0130] Specific examples of diluents are e.g. calcium carbonate,
dibasic calcium phosphate, tribasic calcium phosphate, calcium
sulfate, microcrystalline cellulose, powdered cellulose, dextrans,
dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol,
starch, pregelatinized starch, sucrose, sugar etc.
[0131] Specific examples of disintegrants are e.g. alginic acid or
alginates, microcrystalline cellulose, hydroxypropyl cellulose and
other cellulose derivatives, croscarmellose sodium, crospovidone,
polacrillin potassium, sodium starch glycolate, starch,
pregelatinized starch, carboxymethyl starch (e.g. Primogel.RTM. and
Explotab.RTM.) etc.
[0132] Specific examples of binders are e.g. acacia, alginic acid,
agar, calcium carrageenan, sodium carboxymethylcellulose,
microcrystalline cellulose, dextrin, ethylcellulose, gelatin,
liquid glucose, guar gum, hydroxypropyl methylcellulose,
methylcellulose, pectin, PEG, povidone, pregelatinized starch
etc.
[0133] Glidants and lubricants may also be included in the
composition. Examples include stearic acid, magnesium stearate,
calcium stearate or other metallic stearate, talc, waxes and
glycerides, light mineral oil, PEG, glyceryl behenate, colloidal
silica, hydrogenated vegetable oils, corn starch, sodium stearyl
fumarate, polyethylene glycols, alkyl sulfates, sodium benzoate,
sodium acetate etc.
[0134] Other excipients which may be included in a composition or
solid dosage form of the invention are e.g. flavoring agents,
coloring agents, taste-masking agents, pH-adjusting agents,
buffering agents, preservatives, stabilizing agents, anti-oxidants,
wetting agents, humidity-adjusting agents, surface-active agents,
suspending agents, absorption enhancing agents, agents for extended
release etc.
[0135] Other additives in a composition or a solid dosage form
according to the invention may be antioxidants like e.g. ascorbic
acid, ascorbyl palmitate, butylated hydroxyanisole, butylated
hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium
metabisulfite, propyl gallate, sodium formaldehylde sulfoxylate,
sodium metabisulfite, sodium thiosulfate, sulfur dioxide,
tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or
other tocopherol derivatives, etc. The carrier composition may also
contain e.g. stabilizing agents. The concentration of an
antioxidant and/or a stabilizing agent in the carrier composition
is normally from about 0.1% w/w to about 5% w/w.
[0136] A composition or solid dosage form according to the
invention may also include one or more surfactants or substances
having surface-active properties. It is contemplated that such
substances are involved in the wetting of the slightly soluble
active substance and thus, contributes to improved solubility
characteristics of the active substance.
[0137] Suitable excipients for use in a composition or a solid
dosage form according to the invention are surfactants such as,
e.g., amphiphillic surfactants as those disclosed in WO 00/50007 in
the name of Lipocine, Inc. Examples of suitable surfactants are
[0138] i) polyethoxylated fatty acids such as, e.g. fatty acid
mono- or diesters of polyethylene glycol or mixtures thereof such
as, e.g. mono- or diesters of polyethylene glycol with lauric acid,
oleic acid, stearic acid, myristic acid, ricinoleic acid, and the
polyethylene glycol may be selected from PEG 4, PEG 5, PEG 6, PEG
7, PEG 8, PEG 9, PEG 10, PEG 12, PEG 15, PEG 20, PEG 25, PEG 30,
PEG 32, PEG 40, PEG 45, PEG 50, PEG 55, PEG 100, PEG 200, PEG 400,
PEG 600, PEG 800, PEG 1000, PEG 2000, PEG 3000, PEG 4000, PEG 5000,
PEG 6000, PEG 7000, PEG 8000, PEG 9000, PEG 1000, PEG 10,000, PEG
15,000, PEG 20,000, PEG 35,000, [0139] ii) polyethylene glycol
glycerol fatty acid esters, i.e. esters like the above-mentioned
but in the form of glyceryl esters of the individual fatty acids;
[0140] iii) glycerol, propylene glycol, ethylene glycol, PEG or
sorbitol esters with e.g. vegetable oils like e.g. hydrogenated
castor oil, almond oil, palm kernel oil, castor oil, apricot kernel
oil, olive oil, peanut oil, hydrogenated palm kernel oil and the
like, [0141] iv) polyglycerized fatty acids like e.g. polyglycerol
stearate, polyglycerol oleate, polyglycerol ricinoleate,
polyglycerol linoleate, [0142] v) propylene glycol fatty acid
esters such as, e.g. propylene glycol monolaurate, propylene glycol
ricinoleate and the like, [0143] vi) mono- and diglycerides like
e.g. glyceryl monooleate, glyceryl dioleae, glyceryl mono- and/or
dioleate, glyceryl caprylate, glyceryl caprate etc.; [0144] vii)
sterol and sterol derivatives; [0145] viii) polyethylene glycol
sorbitan fatty acid esters (PEG-sorbitan fatty acid esters) such as
esters of PEG with the various molecular weights indicated above,
and the various Tween.RTM. series; [0146] ix) polyethylene glycol
alkyl ethers such as, e.g. PEG oleyl ether and PEG lauryl ether;
[0147] x) sugar esters like e.g. sucrose monopalmitate and sucrose
monolaurate; [0148] xi) polyethylene glycol alkyl phenols like e.g.
the Triton.RTM. X or N series; [0149] xii)
polyoxyethylene-polyoxypropylene block copolymers such as, e.g.,
the Pluronic.RTM. series, the Synperonic.RTM. series, Emkalyx.RTM.,
Lutrol.RTM., Supronic.RTM. etc. The generic term for these polymers
is "poloxamers" and relevant examples in the present context are
Poloxamer 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188,
212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333,
334, 335, 338, 401, 402, 403 and 407; [0150] xiii) sorbitan fatty
acid esters like the Span.RTM. series or Ariacel.RTM. series such
as, e.g. sorbinan monolaurate, sorbitan monopalmitate, sorbitan
monooleate, sorbitan monostearate etc.; [0151] xiv) lower alcohol
fatty acid esters like e.g. oleate, isopropyl myristate, isopropyl
palmitate etc.; [0152] xv) ionic surfactants including cationic,
anionic and zwitterionic surfactants such as, e.g. fatty acid
salts, bile salts, phospholipids, phosphoric acid esters,
carboxylates, sulfates and sulfonates etc.
[0153] When a surfactant or a mixture of surfactants is present in
a composition or a solid dosage form of the invention, the
concentration of the surfactant(s) is normally in a range of from
about 0.1-80% w/w such as, e.g., from about 0.1 to about 20% w/w,
from about 0.1 to about 15% w/w, from about 0.5 to about 10% w/w,
or alternatively, from about 0.10 to about 80% w/w such as, e.g.
from about 10 to about 70% w/w, from about 20 to about 60% w/w or
from about 30 to about 50% w/w.
[0154] In a specific aspect of the invention, the at least one of
the one or more pharmaceutically acceptable excipient is selected
from the group consisting of silica acid or a derivative or salt
thereof including silicates, silicon dioxide and polymers thereof;
magnesium aluminosilicate and/or magnesium aluminometasilicate,
bentonite, kaolin, magnesium trisilicate, montmorillonite and/or
saponite.
[0155] Such materials are is especially useful as a sorption
material for oils or oily-like materials in pharmaceuticals,
cosmetics and/or foodstuff. In a specific embodiment, the material
is used as a sorption material for oils or oily-like materials in
pharmaceuticals. The material that has the ability to function as a
sorption material for oils or oily-like materials is also denoted
"oil sorption material". Furthermore, in the present context the
term "sorption" is used to denote "absorption" as well as
"adsorption". It should be understood that whenever one of the
terms is used it is intended to cover the phenomenon absorption as
well as adsorption.
[0156] Notably, the pharmaceutically acceptable excipient may
comprise a silica acid or a derivative or salt thereof such as,
e.g., silicon dioxide or a polymer thereof as a pharmaceutically
acceptable excipient. Dependent on the quality employed a silicon
dioxide may be a lubricant or it may be an oil sorption material.
Qualities fulfilling the latter function seem to be most
important.
[0157] In a specific embodiment, a composition or solid dosage form
according to invention comprises a pharmaceutically acceptable
excipient that is a silicon dioxide product that has properties
corresponding to Aeroperl.RTM. 300 (available from Degussa,
Frankfurt, Germany).
[0158] As it appears from the examples herein, a very suitable
material is Aeroperl.RTM. 300 (including materials with properties
like or corresponding to those of Aeroperl.RTM. 300).
[0159] Use of an oil sorption material in compositions or dosage
forms according to the invention is very advantageous for the
preparation of pharmaceutical, cosmetic, nutritional and/or food
compositions, wherein the composition comprises oil or an oily-like
material. One of the advantages is that is it possible to
incorporate a relatively large amount of oil and oily-like material
and still have a material that is solid. Thus, it is possible to
prepare solid compositions with a relatively high load of oil or
oily-like materials by use of an oil sorption material according to
the invention. Within the pharmaceutical field it is an advantage
to be able to incorporate a relatively large amount of an oil or an
oily-like material in a solid composition especially in those
situation where the active substance does not have suitable
properties with respect to water solubility (e.g. poor water
solubility), stability in aqueous medium (i.e. degradation occurs
in aqueous medium), oral bioavailability (e.g. low bioavailability)
etc., or in those situations where it is desired to modify the
release of an active substance from a composition in order to
obtain a controlled, delayed, sustained and/or pulsed delivery of
the active substance. Thus, in a specific embodiment it is used in
the preparation of pharmaceutical compositions.
[0160] In an important embodiment of the invention, at least a part
of tacrolimus and/or an analogue thereof is present in the
composition in the form of a solid solution including a molecular
dispersion and a solid dispersion. Normally, 10% or more such as,
e.g., 20% or more, 30% or more, 40% or more, 50% or more, 60% or
more, 70% or more, 80% or more, 90% or more such as, e.g., 95% or
more or about 100% w/w of tacrolimus and/or an analogue thereof is
present in the composition in the form of a solid dispersion.
[0161] A solid dispersion may be obtained in different ways e.g. by
employing organic solvents or by dispersing or dissolving the
active substance in another suitable medium (e.g. an oil or an
oily-like material that is in liquid form at room temperature or at
elevated temperatures).
[0162] Solid dispersions (solvent method) may for example be
prepared by dissolving a physical mixture of the active substance
(e.g. a drug substance) and the carrier in a common organic
solvent, followed by evaporation of the solvent. The carrier is
often a hydrophilic polymer. Suitable organic solvents include
pharmaceutical acceptable solvent in which the active substance is
soluble such as methanol, ethanol, methylene chloride, chloroform,
ethylacetate, acetone or mixtures thereof.
[0163] Suitable water soluble carriers include polymers such as
polyethylene glycol, poloxamers, polyoxyethylene stearates,
poly-.epsilon.-caprolactone, polyvinylpyrrolidone (PVP),
polyvinylpyrrolidone-polyvinylacetate copolymer PVP-PVA (Kollidon
VA64), poly-methacrylic polymers (Eudragit.RTM. RS, Eudragit.RTM.
RL, Eudragit.RTM. NE, Eudragit.RTM. E) and polyvinyl alcohol (PVA),
hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose
(HPMC), methyl cellulose, and poly(ethylene oxide) (PEO).
[0164] Polymers containing acidic functional groups may be suitable
for solid dispersions, which release the active substance in a
preferred pH range providing acceptable absorption in the
intestines. Such polymers may be one ore more selected from the
group comprising hydroxypropyl methylcellulose phtalate (HMPCP),
polyvinyl acetate phtalate (PVAP), hydroxypropylmethylcellulose
acetate succinate (HPMCAS), alginate, carbomer,
carboxymethylcellulose, methacrylic acid copolymer (Eudragit L,
Eudragit S), shellac, cellulose acetate phthalate (CAP), starch
glycolate, polacrylin, methyl cellulose acetate phtalate,
hydroxypropyulcellulose acetate phthalate, cellulose acetate
terephtahalate, cellulose acetate isophthalate and cellulose
acetate trimellitate.
[0165] Relative to the amount of the active substance and the
polymer in the solid dispersion, the weight ratio of active
substance to polymer may be in a range of from about 3:1 to about
1:20. However, narrower ranger of from about 3:1 to about 1:5, such
as, e.g., from about 1:1 to about 1:3 or about may also be
used.
[0166] The solid dispersion is preferably formed by spray drying
techniques, controlled agglomeration, freeze-drying or coating on
carrier particles or any other solvent removal process. The dried
product contains the active substance present in the form of a
solid dispersion including a molecular dispersion and a solid
solution.
[0167] As an alternative to the use of organic solvents the drug
and polymer may be co-grinded or extruded at elevated temperatures
(melt extrusion).
[0168] The pharmaceutical compositions comprising tacrolimus at
least partly in form of a solid dispersion or solution may in
principle be prepared using any suitable procedure for preparing
pharmaceutical compositions known within the art.
[0169] Apart from using the organic solvent based method, solid
dispersion or solid solutions of tacrolimus and/or an analogue
thereof may be obtained by dispersing and/or dissolving tacrolimus
in the carrier composition used in the controlled agglomeration
method. Stabilizing agents etc. may be added in order to ensure the
stability of the solid dispersion/solution.
[0170] In another aspect, the invention relates to a method for the
preparation of a pharmaceutical composition according to the
invention. In general, any suitable method within the
pharmaceutical field may be employed. However, in order to enable
incorporation of a relatively high amount of an oil or an oily-like
material especially the method described in WO 03/004001 has proved
useful. WO 03/004001 is hereby incorporated by reference. The
method comprises spraying a first composition in liquid form, said
composition comprising a first vehicle or carrier and having a
melting point above 5.degree. C. onto a second composition
comprising a second support or carrier material, said second
composition e.g. being in the fluidized state and having a
temperature below the melting point of the first vehicle or
carrier. The active substance may be present in the first vehicle
or carrier composition and/or in the second support or carrier
composition. However, in those cases where tacrolimus and/or an
analogue thereof are present, at least partly, in the form of as a
solid dispersion, it is advantageous to incorporate or dissolve
tacrolimus and/or an analogue thereof in the first vehicle or
carrier composition. WO05020993A1 and WO05020994A1 of the present
inventors additionally describe tacrolimus compositions by use of
the technology and with extended release formulations thereof and
are hereby incorporated by reference.
Solid Dosage Forms
[0171] The pharmaceutical composition according to the invention is
in particulate form and may be employed as such. However, in many
cases it is more convenient to present the composition in the form
of granules, pellets, microspheres, nanoparticles and the like or
in the form of solid dosage forms including tablets, capsules and
sachets and the like.
[0172] A solid dosage form according to the invention may be a
single unit dosage form or it may in the form of a poly-depot
dosage form contain a multiplicity of individual units such as,
e.g., pellets, beads and/or granules.
[0173] A solid dosage form according to the present invention
comprises a pharmaceutical composition in particulate form as
described above. The details and particulars disclosed under this
main aspect of the invention apply mutatis mutandis to the other
aspects of the invention. Accordingly, the properties with respect
to increase in bioavailability, changes in bioavailability
parameters, lack of diurnal effect as well as release of tacrolimus
and/or an analogue thereof, etc., described and/or claimed herein
for pharmaceutical compositions in particulate form, are analogous
for a solid dosage form according to the present invention.
[0174] The recommended dosage range for Prograf.RTM. is 0.1 to 0.2
mg/kg/day given every 12 hours in two divided doses. Importantly,
the blood levels have to be monitored.
[0175] The typical level for 1-3 months is 7-20 ng/mL and 4-12
months the levels should be 5-15 ng/mL. This is only guiding values
and may vary from types of transplant and ethnicity.
[0176] The following was found for kidney transplant patients.
TABLE-US-00001 Caucasian n = 114 Black n = 56 Trough Trough Time
After Dose Concentrations Dose Concentrations Transplant (mg/kg)
(ng/mL) (mg/kg) (ng/mL) Day 7 0.18 12.0 0.23 10.9 Month 1 0.17 12.8
0.26 12.9 Month 6 0.14 11.8 0.24 11.5 Month 12 0.13 10.1 0.19
11.0
[0177] The expected dosage recommendation for products of the
present invention will be from 0.02 mg/kg/day to 0.15 mg/kg/day,
dosed once a day. Suitable dosage forms (strength) range from 0.1
mg to 15 mg of tacrolimus, preferably a strength selected from 0.5
mg, 1 mg, 2 mg and 5 mg.
[0178] As demonstrated herein by scintigraphy and shown in FIG. 2,
the release according to the present invention can take place even
in the distal part of the colon and still being distributed to the
mucosa and absorbed. The absorption of the extended release dosage
form according to the invention is one where the in vivo release
after oral administration to a subject takes place substantially in
the colon such as release in one or more of the locations of colon
ascendens, colon transversum and colon decendens.
[0179] Different embodiments of the invention relating to preferred
pharmacokinetic parameters obtained with the extended release
dosage form according to present invention are listed below.
[0180] In one embodiment, the invention relates to an extended
release dosage form which when administered to a subject or a
number of subjects provides an intra subject and/or an inter
subject variability of the mean blood T.sub.max of tacrolimus which
relative to that obtained from administration of the commercial
product Advagraf.RTM. (MR4) dosage form or a bioequivalent extended
release dosage form is decreased with at least 10%, such as at
least 15%, such as at least 17.5%, such as at least 20%, such as at
least 22.5%, such as at least 25%, such as at least 27.5% such as
at least 30% when being determined under similar conditions and
administered in similar molecular dosages of the tacrolimus.
[0181] In one embodiment, the invention relates to an extended
release dosage form which when administered to a subject or a
number of subjects provides an intra subject and/or an inter
subject variability of the mean blood C.sub.max and/or
AUC.sub.(0-.infin.) of tacrolimus which relative to that obtained
from administration of the commercial product Advagraf.RTM. (MR4)
or a bioequivalent extended release dosage form is decreased with
at least 10%, such as at least 15%, such as at least 17.5%, such as
at least 20%, such as at least 22.5%, such as at least 25%, such as
at least 27.5% such as at least 30% when being determined under
similar conditions and administered in similar molecular dosages of
the tacrolimus.
[0182] In one embodiment, the invention relates to an extended
release dosage form, which when administered to a subject or a
number of subjects provides a decreased C.sub.max value relative to
that obtained by administration of the commercial product
Advagraf.RTM. (MR4) or a bioequivalent extended release dosage form
of at least about 10%, or at least about 15%, or at least about
20%, or at least about 30%, or at least about 35%, or at least
about 40 or more, or at least about 45%, or at least about 50%, or
at least about 55%, the C.sub.max values being determined under
similar conditions and administered in similar molecular dosages of
the tacrolimus.
[0183] In one embodiment, the invention relates to an extended
release dosage form form which when administered to a subject or a
number of subjects provides an increased bioavailability relative
to that obtained by administration of the commercially product
Advagraf.RTM. (MR4) or a bioequivalent extended release dosage form
of at least about 20%, or at least about 25%, or at least about
30%, or at least about 35%, or at least about 40%, or at least
about 45%, or at least about 50%, or at least about 55%, or at
least about 60%, such as at least 65%, the bioavailability being
determined as AUC(0-.infin.) and under similar conditions and
administered in similar molecular dosages of the tacrolimus.
[0184] In one embodiment, the invention relates to an extended
release dosage form which when administered to a subject or a
number of subjects provides an intra subject and/or an inter
subject variability of the mean blood T.sub.max of tacrolimus which
relative to that obtained by administration of the commercially
available Prograf.RTM. dosage form or a bioequivalent immediate
release tacrolimus dosage form is decreased with at least 10%, such
as at least 15%, such as at least 17.5%, such as at least 20%, such
as at least 22.5%, such as at least 25%, such as at least 27.5%
such as at least 30% when being determined under similar conditions
and administered in similar molecular dosages of the
tacrolimus.
[0185] In one embodiment, the invention relates to an extended
release dosage form which when administered to a subject or a
number of subjects provides an intra subject and/or an inter
subject variability of the mean blood C.sub.max and/or
AUC.sub.(0-.infin.) of tacrolimus which relative to that obtained
by administration of the commercially available Prograf.RTM. dosage
form or a bioequivalent immediate release dosage form is decreased
with at least 10%, such as at least 15%, such as at least 17.5%,
such as at least 20%, such as at least 22.5%, such as at least 25%,
such as at least 27.5% such as at least 30% when being determined
under similar conditions and administered in similar molecular
dosages of the tacrolimus.
[0186] In one embodiment, the invention relates to an extended
release dosage form which when administered to a subject or a
number of subjects provides a decreased C.sub.max value relative to
that obtained by administration of the commercially available
Prograf.RTM. dosage form or a bioequivalent immediate release
dosage form of at least about 20%, or at least about 30%, or at
least about 35%, or at least about 40%, or at least about 45%, or
at least about 50% or more, or at least about 55%, or at least
about 60%, or at least about 65%, when being determined under
similar conditions and administered in similar molecular dosages of
the tacrolimus.
[0187] In one embodiment, the invention relates to an extended
release dosage form which when administered to a subject or a
number of subjects provides an increased bioavailability relative
to that obtained by administration of commercially available
Prograf.RTM. dosage form or a bioequivalent immediate release
dosage form of at least about 10%, or at least about 15%, or at
least about 20%, or at least about 30%, or at least about 35%, or
at least about 40 or more, or at least about 45%, or at least about
50%, or at least about 55%, the bioavailability being determined as
AUC(0-.infin.) and under similar conditions and administered in
similar molecular dosages of the tacrolimus.
[0188] In one embodiment, the invention relates to an extended
release dosage form which when administered to a subject or a
number of subjects after at least 4 hours fasted state in the
evening provides an bioavailability which relative to that obtained
after administration of the dosage form in the morning after at
least 4 hours fasted state is at least 70%, such as at least 80%,
preferable at least 85% more preferable at least 90% and preferable
at least 95% of the value measured after administration in the
morning.
[0189] In one embodiment, the invention relates to an extended
release dosage form which when administered to a subject or a
number of subjects after at least 4 hours fasted state in the
evening provides a C.sub.max which relative to that obtained after
administration of the dosage form in the morning after at least 4
hours fasted state is at least 70%, such as at least 80%,
preferable at least 85% more preferable at least 90% and preferable
at least 95% value measured after administration in the
morning.
[0190] In one embodiment, the invention relates to an extended
release dosage form wherein the bioavailability is independent of
the dosing time of the day and thereby is suitable for a bedtime
dosing regimen.
[0191] In one embodiment, the invention relates to an extended
release dosage form which when comprising 5 mg of tacrolimus and
when administered as a single dose to at least 6 healthy subjects
in fasted state provides a mean maximal concentration (C.sub.max)
of tacrolimus of at the most 15 ng/mL, such as at the most 13 ng/mL
and a mean AUC(0-96 h) of at least 45 mgh/L, such as at least 55
mgh/L, such as at least 60 mgh/L.
[0192] In one embodiment, the invention relates to an extended
release dosage form according to wherein the blood concentration 24
after administration of tacrolimus is at least 2 ng/mL such as at
least 3 ng/mL such as at least 4 ng/mL.
[0193] In one embodiment, the invention relates to an extended
release dosage form which when administered once daily in steady
state to a healthy subject or a patient, the swing of the blood
concentrations of tacrolimus measured as
(C.sub.max-C.sub.min)/C.sub.min is less than the swing observed
when administering the Advagraf.RTM. dosage form or a bioequivalent
extended release dosage form of tacrolimus in a once daily regimen
and being determined under similar conditions and administered in
similar molecular daily dosages of the tacrolimus. The decrease is
preferable at least 10%, such as at least 20%, preferable at least
30%, such as at least 40%, more preferred at least 50%.
[0194] In one embodiment, the invention relates to an extended
release dosage form which when administered once daily in steady
state to a healthy subject or a patient, the swing of the blood
concentrations for total and/or free tacrolimus measured as
(C.sub.max-C.sub.min)/C.sub.min is less than the swing observed
when administering the Prograf.RTM. dosage form or a bioequivalent
immediate release composition of tacrolimus in a twice daily
regimen and being determined under similar conditions and
administered in similar molecular daily dosages of the tacrolimus.
The decrease is preferable at least 10%, such as at least 20%,
preferable at least 30%, such as at least 40%, more preferred at
least 50%.
[0195] In one embodiment, the invention relates to an extended
release dosage form which when administered once daily in steady
state to a healthy subject or a patient, the fluctuation of the
blood concentrations for total and/or free tacrolimus measured as
(C.sub.max-C.sub.min)/C.sub.average is less than the fluctuation
observed when administering the Advagraf.RTM. dosage form or a
bioequivalent extended release dosage form of tacrolimus in a once
daily regimen and being determined under similar conditions and
administered in similar molecular daily dosages of the tacrolimus.
The decrease is preferable at least 10%, such as at least 20%,
preferable at least 30%, such as at least 40%, more preferred at
least 50%.
[0196] In one embodiment, the invention relates to an extended
release dosage form which when administered once daily in steady
state to a healthy subject or a patient, the fluctuation of the
blood concentrations for total tacrolimus measured as
(C.sub.max-C.sub.min)/C.sub.average is less than the fluctuation
observed when administering the Prograf.RTM. dosage form or a
bioequivalent immediate release composition of tacrolimus in a
twice daily regimen and being determined under similar conditions
and administered in similar molecular daily dosages of the
tacrolimus. The decrease is preferable at least 10%, such as at
least 20%, preferable at least 30%, such as at least 40%, more
preferred at least 50%.
[0197] In one embodiment, the invention relates to an extended
release dosage form which when administered to at least 6 healthy
subjects in fasted state, the mean residence time, MRT, of
tacrolimus measured in blood is at least 10% longer than the mean
residence time measured under bioequivalent conditions with the
Advagraf.RTM. dosage form or a similar extended release dosage form
of tacrolimus. Preferable the MRT is increased by at least 20% such
as by 25%.
[0198] In one embodiment, the invention relates to an extended
release dosage form which when administered to at least 6 healthy
subjects in fasted state, the mean residence time tacrolimus
measured in blood is at least 35% longer than the mean residence
time measured under similar conditions with the Prograf.RTM. dosage
form or a bioequivalent immediate release dosage form of
tacrolimus.
[0199] In a yet further aspect the present invention provides for a
method for providing immunosuppressive treatment of a patient in
need thereof in a once daily regimen by administration of an
extended release formulation as described herein an providing one
or more of decreased C.sub.max, decreased swing, decreased
fluctuation, increased AUC, increased MRT, longer time to
T.sub.max, and a higher C.sub.min. Additionally, the methods
provides for a C.sub.min which correlates to the bioavailability
with a correlation factor of at least 0.75 to 1, such as at least
0.80, preferably 0.85, more preferred 0.90, still more preferred at
least 0.95, and even more preferred of at least 0.97.
[0200] In a preferred embodiment the difference in bioavailability
is substantially independent of the time of the day the dosage is
administered. This provides the possibility of a once daily dosage
regimen at bedtime or in the evening in addition to the normal
morning dosing. However more importantly, the risk of decreased
exposure if the patient actually ingest the dosage form on a
different time than prescribed and expected (non compliance by the
patient), the risk for the patient is decreased for reduced
exposure and thereby increased risk of e.g., a transplant
rejection.
[0201] In a further aspect the invention provides for a conversion
form a bid regimen with a higher dosage. One method for such
conversion from inter alia Prograf.RTM. to once daily regimen is
decreasing the daily dosage of the tacrolimus immediate release
regimen with between 25% to 50%, such as with between 30% to 40%,
preferable with approximately 33%. The reduction is to the extend
possible by use of extended release once daily dosage forms
selected from 0.5 mg 1 mg, 2 mg and 5 mg once daily dosage forms.
Accordingly, a conversion ratio of 1:0.66 to 0.80 dependent on the
available dosage strengths as mentioned. Furthermore, the present
invention relates to a conversion from Advagraf.RTM. with a ratio
of 1:0.30 to 0.75, such as 1:0.33 to 0.7 according to the available
dosage strengths selected from 0.5 mg, 1 mg, 2 mg and 5 mg of the
extended release formulations according to the present
invention.
[0202] An especially important aspect of the invention is the
substantial reduced peak concentrations which provide for a
decrease in peak concentration related side effects. Such effect
can however be difficult to measure due to the inter- and
intra-subject variation of the present tacrolimus treatments and
the nature of the side effects which are often of a subjective
character or may require tissue biopsies to determine. Careful
questionnaires and high number of patients will be needed for
comparison studies to demonstrate such effect with significance.
However, it is contemplated that treatment with a extended release
formulation according to the present invention may reduce some
possible peak concentration related side effects including side
effects of a neurological origin such as tremor and headache.
[0203] In a preferred embodiment the decrease in side effect is
related to the risk of prolonged QTc interval due to an affect on
ventricular repolarization. Other toxicities included which is
contemplated to be decreased is development of kidney damage, the
development of diabetes as well as development of hypertension.
[0204] Especially, the accumulation occurring in some organs may be
associated with organ damage, especially as the accumulation or the
individual tacrolimus concentration may not decrease during the
period with the low blood concentration during the later times of
the dosing interval. This lack of clearance from an organ may be
related to the high affinity of tacrolimus to that organ overcoming
the otherwise expected clearance of such highly vascularized
organs. Accordingly, the high peaks of the present available
commercial dosage forms may contribute to tacrolimus being
accumulated in these organs which organs may comprise as high as
nearly 30 times the concentration of the blood in steady state with
conventional dosage forms.
[0205] De novo transplanted patient may be extremely sensitive to
high concentrations due to general bad state of the body, low
levels of plasma proteins further increasing the fraction of
tacrolimus free to enter the organs. Especially in these patients
the high blood concentrations during titration are avoided by use
of the dosage form according to the invention which has the
potential to decrease the magnitude of accumulation or extending
the time before high concentrations are reached in organs where
tacrolimus is toxic. Accordingly, the invention also relates to a
method of treating patients in risk of organ toxicity form
tacrolimus. The organs known to accumulate tacrolimus include the
adrenal gland, lung, heart, liver, gastrointestinal tract and
kidney. However, according to the present invention it is further
believed that the pancreas and especially the islet of Langerhans
may be sensitive for high concentrations, especially during the
initiation of tacrolimus, whereby the risk of developing diabetes
on a later time may be substantially increased. Other organs
correlated with toxicity are the central nervous system. Many
patients withdraw from treatment due to headache and tremor, side
effects which is likely to be decreased with the treatment
according to the present invention. Especially tremor is a side
effect related to toxic effect on the central nervous system as
caused by tacrolimus crossing the blood brain barrier. It is
according to the present invention comtemplated that high
concentrations may facilitate trapping of tacrolimus in the central
nervous system as a higher concentration difference is present over
the blood brain barrier when the concentrations is high in the
systemic circulation which may result in increased transport into
the brain compared with a situation where a steady and lower
concentration is provided as with the extended release formulation
according to the present invention.
[0206] According to a further aspect of the invention, the extended
release formulation according to the present invention provides for
a treatment safety profile allowing treatment from the time of
transplantation as soon as the patient is sufficient well to be
treated with an oral formulation. Accordingly, the patient will not
need a first titration with a conventional twice daily formulation
such as Prograf.RTM. followed by a conversion to a treatment
according to the present invention, but can initiate the oral
immunosuppressive treatment with tacrolimus with a once daily
formulation according to the present invention.
[0207] In a further embodiment, treatment of de novo transplant
patients are provided as the formulation according to the present
invention is capable of securing a sufficient systemic exposure
even in the first 24 hours after initiation whereby a method of
treatment is provided where the same dosage form may used for the
initiation of tacrolimus oral treatment as well as for the
continuous treatment including maintenance treatment. It is
believed that the number of dose corrections may be reduced, the
compliance will be increased due to the once daily treatment of the
present invention with a tablet formulation of reduced size
compared with other available tacrolimus products.
[0208] It is observed that the use of Advagraf.RTM. in the first 24
hours provides a systemic exposure which is approximately 30% and
50% lower when compared with administration of the Prograf.RTM.
formulation administered to de novo kidney and de novo liver
transplant patients, respectively. The general explanation for this
reduced bioavailability is according to the Scientific Discussion
as disclosed in connection with the approval of Advagraf.RTM. by
the European Agency for the Evaluation of Medicinal Products (EMEA)
at 23 Apr. 2007 attributed to an absence of diurnal effect on the
absorption of tacrolimus for Prograf.RTM. formulation administered
in the evening relative to the morning on the first day
post-transplant. However, according to the present inventors, the
lower exposure of the Advagraf.RTM. product may primarily be
related to a relative higher impact of the gastrointestinal
metabolism possibly in combination with a lower absorption rate
which facilitates a higher first passage extraction fraction by the
liver. In liver transplant patients the GI metabolism may have even
higher impact as the liver metabolism may be reduced early after
transplantation. Accordingly, by providing an extended formulation
according to the present invention, the impact of the GI metabolism
is less as the formulation primarily releases tacrolimus in the
lower ileum and colon where metabolism is less and at the same time
releases tacrolimus in a way that absorption actually takes place,
i.g releasing the tacrolimus in a improved way such as in molecular
form or substantially molecular form.
[0209] Accordingly, a method for initial treatment of a de novo
liver transplant patient with tacrolimus is provided comprising
administering a tacrolimus oral dosage form once a day having an
extended release profile which when measured in vitro demonstrates
a release where less than 50% of the tacrolimus content in the oral
dosage form is released after 10 hours measured according to the
dissolution method disclosed for Program by the FDA database of
Dissolution Methods For Drug Products and the oral dosage form
provides a systemic exposure on day 1 which is at least 50% of the
exposure obtained at day 1 after administration of the same daily
dose however administered as an immediate release oral dosage form
administered twice a day.
[0210] Similarly, a method for initial treatment of a de novo
kidney transplant patient with tacrolimus comprising administering
a tacrolimus oral dosage form once a day having an extended release
profile which when measured in vitro demonstrates a release where
less than 50% of the tacrolimus content in the oral dosage form is
released after 10 hours measured according to the FDA method for
Prograf.RTM. and the oral dosage form provides a systemic exposure
on day 1 which is at least 70% of the exposure obtained at day 1
after administration of the same daily dose however administered as
an immediate release oral dosage form administered twice a day.
[0211] The method also related to initial treatment of a de novo
liver transplant patient with tacrolimus comprising administering a
tacrolimus oral dosage form once a day having an extended release
profile which when measured in vitro demonstrates a release where
less than 50% of the tacrolimus content in the oral dosage form is
released after 10 hours measured according to the FDA method for
Prograf.RTM. and the oral dosage form provides a systemic exposure
on day 1 which is at least 100% of the exposure obtained at day 1
after administration of the same daily dose however administered as
an extended release oral dosage form releasing more than 30% of the
tacrolimus within 5 hours.
[0212] Similarly a method for initial treatment of a de novo kidney
transplant patient with tacrolimus is provided comprising
administering a tacrolimus oral dosage form once a day having an
extended release profile which when measured in vitro demonstrates
a release where less than 50% of the tacrolimus content in the oral
dosage form is released after 10 hours measured according to FDA
method for Prograf.RTM. and the oral dosage form provides a
systemic exposure on day 1 which is at least 100% of the exposure
obtained at day 1 after administration of the same daily dose
however administered as an extended release oral dosage form
releasing more than 30% of the tacrolimus within 5 hours.
[0213] A solid dosage form according to the invention may also be
coated in order to obtain suitable properties e.g. with respect to
controlled release of the active substance. The coating may be
applied on single unit dosage forms (e.g. tablets, capsules) or it
may be applied on a poly-depot dosage form or on its individual
units.
[0214] Suitable coating materials are e.g. methylcellulose,
hydroxypropylmethylcellulose, hydroxypropylcellulose, acrylic
polymers, ethylcellulose, cellulose acetate phthalate, polyvinyl
acetate phthalate, hydroxypropyl methylcellulose phthalate,
polyvinylalcohol, sodium carboxymethylcellulose, cellulose acetate,
cellulose acetate phthalate, gelatin, methacrylic acid copolymer,
polyethylene glycol, shellac, sucrose, titanium dioxide, carnauba
wax, microcrystalline wax, glyceryl monostearate, zein.
[0215] Plasticizers and other ingredients may be added in the
coating material. The same or different active substance may also
be added in the coating material.
[0216] In preferred embodiments of the invention, the solid dosage
forms are designed to release tacrolimus and/or an analogue thereof
in a controlled manner. In the present context, the term
"controlled manner" is intended to include all types of release
which differ from the release obtained from plain tablets. Thus,
the term includes so-called "controlled release", "extended
release", "sustained release", "pulsed release", "prolonged
release", burst release", "slow release", "extended release", as
well as the terms "delayed release" and pH dependant release.
However, a specific aspect of the invention relates to a delayed
release composition or dosage form, which in this context is
intended to denote a composition or dosage form that at the most
releases 10% w/w of the active substance within the first 2 hours
after administration and/or after start of a dissolution test
employing a dissolution medium having a pH of at the most about
3.
Extended Release Systems
[0217] A first extended release system includes matrix systems, in
which tacrolimus is embedded or dispersed in a matrix of another
material that serves to retard the release of tacrolimus into an
aqueous environment (i.e., the luminal fluid of the GI tract). When
tacrolimus is dispersed in a matrix of this sort, release of the
drug takes place principally from the surface of the matrix. Thus
the drug is released from the surface of a device, which
incorporates the matrix after it diffuses through the matrix or
when the surface of the device erodes, exposing the drug. In some
embodiments, both mechanisms can operate simultaneously. The matrix
systems may be large, i.e., tablet sized (about 1 cm), or small
(<0.3 cm). The system may be unitary (e.g., a bolus), may be
divided by virtue of being composed of several sub-units (for
example, several capsules which constitute a single dose) which are
administered substantially simultaneously, or may comprise a
plurality of particles, also denoted a multiparticulate. A
multiparticulate can have numerous formulation applications. For
example, a multiparticulate may be used as a powder for filling a
capsule shell, or used per se for mixing with food to ease the
intake.
[0218] In a specific embodiment, a matrix multiparticulate,
comprises a plurality of tacrolimus-containing particles, each
particle comprising tacrolimus and/or an analogue thereof e.g. in
the form of a solid solution/dispersion with one or more excipients
selected to form a matrix capable of controlling the dissolution
rate of the tacrolimus into an aqueous medium. The matrix materials
useful for this embodiment are generally hydrophobic materials such
as waxes, some cellulose derivatives, or other hydrophobic
polymers. If needed, the matrix materials may optionally be
formulated with hydrophobic materials, which can be used as binders
or as enhancers. Matrix materials useful for the manufacture of
these dosage forms such as: ethylcellulose, waxes such as paraffin,
modified vegetable oils, carnauba wax, hydrogenated castor oil,
beeswax, and the like, as well as synthetic polymers such as
poly(vinyl chloride), poly(vinyl acetate), copolymers of vinyl
acetate and ethylene, polystyrene, and the like. Water soluble or
hydrophilic binders or release modifying agents which can
optionally be formulated into the matrix include hydrophilic
polymers such as hydroxypropyl cellulose (HPC), hydroxypropyl
methyl cellulose (HPMC), methyl cellulose,
poly(N-vinyl-2-pyrrolidinone) (PVP), poly(ethylene oxide) (PEO),
poly(vinyl alcohol) (PVA), xanthan gum, carrageenan, and other such
natural and synthetic materials. In addition, materials, which
function as release-modifying agents include water-soluble
materials such as sugars or salts. Preferred water-soluble
materials include lactose, sucrose, glucose, and mannitol, as well
as hydrophillic polymers like e.g. HPC, HPMC, and PVP.
[0219] In a specific embodiment, a multiparticulate product is
defined as being processed by controlled agglomeration. In this
case tacrolimus is dissolved or partly dissolved in a suitable
meltable carrier and sprayed on carrier particles comprising the
matrix substance.
Suitable Meltable Carriers are Mentioned Previously Herein.
[0220] Alternatively, tacrolimus is dissolved in an organic solvent
together with the matrix substance and spray dried or applied to
carrier particles, cf. below. Solvents typically employed for the
process include acetone, ethanol, isopropanol, ethyl acetate, and
mixtures of two or more.
[0221] Once formed, tacrolimus matrix multiparticulates may be
blended with compressible excipients such as lactose,
microcrystalline cellulose, dicalcium phosphate, and the like and
the blend compressed to form a tablet. Disintegrants such as sodium
starch glycolate or crosslinked poly(vinyl pyrrolidone) are also
usefully employed. Tablets prepared by this method disintegrate
when placed in an aqueous medium (such as the GI tract), thereby
exposing the multiparticulate matrix, which releases tacrolimus
therefrom.
[0222] In a further embodiment, the matrix system is in the form of
a hydrophilic matrix tablet containing tacrolimus and/or an
analogue thereof (e.g. in the form of a solid dispersion) as a
multiparticulate product and an amount of hydrophilic polymer
sufficient to provide a useful degree of control over the
tacrolimus dissolution. Hydrophilic polymers useful for forming the
matrix include hydroxypropylmethyl cellulose (HPMC), hydroxypropyl
cellulose (HPC), poly(ethylene oxide), poly(vinyl alcohol), xanthan
gum, carbomer, carrageenan, and zooglan. A preferred material is
HPMC. Other similar hydrophilic polymers may also be employed. In
use, the hydrophilic material is swollen by, and eventually
dissolves in, water. The tacrolimus is released both by diffusion
from the matrix and by erosion of the matrix. The tacrolimus
dissolution rate of these hydrophilic matrix tablets may be
controlled by the amount, molecular weight and gel strengths of the
hydrophilic polymer employed. In general, using a greater amount of
the hydrophilic polymer decreases the dissolution rate, as does
using a higher molecular weight polymer. Using a lower molecular
weight polymer normally increases the dissolution rate. A matrix
tablet typically comprises about 20 to 90% by weight of tacrolimus
and about 80 to 10% by weight of polymer.
[0223] A preferred matrix tablet comprises, by weight, about 30% to
about 80% solid dispersion containing tacrolimus and/or an analogue
thereof about 15% to about 35% matrix former (such as, e.g., HPMC),
0% to about 35% lactose, 0% to about 20% microcrystalline
cellulose, and about 0.25% to about 2% lubricant (such as, e.g.,
magnesium stearate).
[0224] The matrix systems as a class often exhibit non-constant
release of the drug from the matrix. This result may be a
consequence of the diffusive mechanism of drug release, and
modifications to the geometry of the dosage form can be used with
advantage to make the release rate of the drug more constant.
[0225] A second class of tacrolimus controlled-release dosage forms
of this invention includes membrane-moderated or reservoir systems.
In this class, a reservoir of tacrolimus e.g. in a solid
solution/dispersion as a multiparticulate product is surrounded by
a rate-limiting membrane. The tacrolimus traverses the membrane by
mass transport mechanisms well known in the art, including but not
limited to dissolution in the membrane followed by diffusion across
the membrane or diffusion through liquid-filled pores within the
membrane. These individual reservoir system dosage forms may be
large, as in the case of a tablet containing a single large
reservoir, or multiparticulate, as in the case of a capsule or
poly-depot tablets containing a plurality of reservoir particles,
each individually coated with a membrane. The coating can be
non-porous, yet permeable to tacrolimus (for example tacrolimus may
diffuse directly through the membrane), or it may be porous. As
with other embodiments of this invention, the particular mechanism
of transport is not believed to be critical.
[0226] Sustained release coatings as known in the art may be
employed to fabricate the membrane, especially polymer coatings,
such as a cellulose ester or ether, an acrylic polymer, or a
mixture of polymers. Preferred materials include ethyl cellulose,
cellulose acetate and cellulose acetate butyrate. The polymer may
be applied as a solution in an organic solvent or as an aqueous
dispersion or latex. The coating operation may be conducted in
standard equipment such as a fluid bed coater, a Wurster coater, or
a rotary fluid bed coater.
[0227] If desired, the permeability of the coating may be adjusted
by blending of two or more materials. A particularly useful process
for tailoring the porosity of the coating comprises adding a
pre-determined amount of a finely-divided water-soluble material,
such as sugars or salts or water-soluble polymers to a solution or
dispersion (e.g., an aqueous latex) of the membrane-forming polymer
to be used. When the dosage form is ingested into the aqueous
medium of the GI tract, these water soluble membrane additives are
leached out of the membrane, leaving pores which facilitate release
of the drug. The membrane coating can also be modified by the
addition of plasticizers, as known in the art.
[0228] A particularly useful variation of the process for applying
a membrane coating comprises dissolving the coating polymer in a
mixture of solvents chosen such that as the coating dries, a phase
inversion takes place in the applied coating solution, resulting in
a membrane with a porous structure.
[0229] In general, a support for mechanically strengthening the
membrane is not required.
[0230] The morphology of the membrane is not of critical importance
so long as the permeability characteristics enumerated herein are
met. The membrane can be amorphous or crystalline. It can have any
category of morphology produced by any particular process and can
be, for example, an interfacially-polymerized membrane (which
comprises a thin rate-limiting skin on a porous support), a porous
hydrophilic membrane, a porous hydrophobic membrane, a hydrogel
membrane, an ionic membrane, and other such materials which are
characterized by controlled permeability to tacrolimus.
[0231] In one embodiment of the invention it is an aim to reduce
the exposure of the upper GI tract to high concentrations of
tacrolimus. Accordingly, suitable dosage forms include those forms,
which incorporate a specific delay before the onset of controlled
release of tacrolimus. An exemplary embodiment can be illustrated
by a tablet (or a particulate material) comprising a core
containing tacrolimus coated with a first coating of a polymeric
material of the type useful for sustained release of tacrolimus and
a second coating of the type useful for delaying release of drugs
when the dosage form is ingested. The first coating is applied over
and surrounds the tablet or individual particles. The second
coating is applied over and surrounds the first coating.
[0232] A tablet can be prepared by techniques well known in the art
and contains a therapeutically useful amount of tacrolimus plus
such excipients as are necessary to form the tablet by such
techniques.
[0233] The first coating may be a sustained release coating as
known in the art, especially polymer coatings, to fabricate the
membrane, as previously discussed for reservoir systems, or it
could be a controlled release matrix core, which are coated a
second time with a delayed release material.
[0234] Materials useful for preparing the second coating on the
tablet include polymers known in the art as enteric coatings for
delayed-release of pharmaceuticals. These most commonly are
pH-sensitive materials such as cellulose acetate phthalate,
cellulose acetate trimellitate, hydroxypropyl methyl cellulose
phthalate, poly(vinyl acetate phthalate), and acrylic copolymers
such as Eudragit L-100 (Rohm Pharma) and related materials, as more
fully detailed below under "Delayed Release". The thickness of the
delayed-release coating is adjusted to give the desired delay
property. In general, thicker coatings are more resistant to
erosion and, consequently, yield a longer and more effective delay.
Preferred coatings range from about 30 .mu.m in thickness to about
3 mm in thickness.
[0235] When using a hydrophobic matrix material like glyceryl
monostearate, no delay coating is necessary. The tablet will not
release tacrolimus until an area of enzymatic degradation has been
reached, more specifically after the duodenum.
[0236] When ingested, the twice-coated tablet passes through the
stomach, where the second coating prevents release of the
tacrolimus under the acidic conditions prevalent there. When the
tablet passes out of the stomach and into the small intestine,
where the pH is higher, the second coating erodes or dissolves
according to the physicochemical properties of the chosen material.
Upon erosion or dissolution of the second coating, the first
coating prevents immediate or rapid release of the tacrolimus and
modulates the release so as to prevent the production of high peak
concentrations, thereby minimizing side-effects.
[0237] A further preferred embodiment comprises a multiparticulate
wherein each particle is dual coated as described above for
tablets, first with a polymer designed to yield sustained release
of the tacrolimus and then coated with a polymer designed to delay
onset of release in the environment of the GI tract when the dosage
form is ingested.
[0238] The rate of tacrolimus release from the
sustained-release-coated multiparticulates (i.e., the
multiparticulates before they receive the delayed-release coating)
and methods of modifying the coating are also controlled by the
factors previously discussed for reservoir system tacrolimus
multiparticulates.
[0239] The second membrane or coating for dual coated
multiparticulates is a delayed-release coating which is applied
over the first sustained-release coating, as disclosed above for
tablets, and may be formed from the same materials. It should be
noted that the use of the so-called "enteric" materials to practice
this embodiment differs significantly from their use to produce
conventional enteric dosage forms. With conventional enteric forms,
the object is to delay release of the drug until the dosage form
has passed the stomach and then to deliver the dose in the
duodenum. Dosing of tacrolimus directly and completely to the
duodenum may be undesirable, however, due to the side effects
sought to be minimized or avoided by this invention. Therefore, if
conventional enteric polymers are to be used to practice this
embodiment, it may be necessary to apply them significantly more
thickly than in conventional practice, in order to delay drug
release until the dosage form reaches the lower GI tract. However,
it is also possible to effect a sustained or controlled delivery of
tacrolimus after the delayed-release coating has dissolved or
eroded, therefore the benefits of this embodiment may be realized
with a proper combination of delayed-release character with
sustained-release character, and the delayed-release part alone may
or may not necessarily conform to USP enteric criteria. The
thickness of the delayed-release coating is adjusted to give the
desired delay property. In general, thicker coatings are more
resistant to erosion and, consequently, yield a longer delay.
[0240] A first delayed release embodiment according to the
invention is a "pH-dependent coated dosage form" such as, e.g., a
tablet or a capsule. In the case of a tablet it comprises a tablet
core comprising tacrolimus e.g. in a solid solution/dispersion as a
multiparticulate product, a controlled release matrix of e.g. HPMC,
a disintegrant, a lubricant, and one or more pharmaceutical
carriers, such core being coated with a material, preferably a
polymer, which is substantially insoluble and impermeable at the pH
of the stomach, and which is more soluble and permeable at the pH
of the small intestine. Preferably, the coating polymer is
substantially insoluble and impermeable at pH<5.0, and
water-soluble at pH>5.0. The tablet core may be coated with an
amount of polymer sufficient to assure that substantially no
release of tacrolimus from the dosage form occurs until the dosage
form has exited the stomach and has resided in the small intestine
for about 15 minutes or greater, preferably about 30 minutes or
greater, thus assuring that minimal tacrolimus is released in the
duodenum. Mixtures of a pH-sensitive polymer with a water-insoluble
polymer may also be employed. Tablets are coated with an amount of
polymer comprising from about 10% to about 80% of the weight of the
tacrolimus-containing tablet core. Preferred tablets are coated
with an amount of polymer comprising about 15% to about 50% of the
weight of the tacrolimus tablet core.
[0241] pH-sensitive polymers which are very insoluble and
impermeable at the pH of the stomach, but which are more soluble
and permeable at the pH of the small intestine and colon include
polyacrylamides, phthalate derivatives such as acid phthalates of
carbohydrates, amylose acetate phthalate, cellulose acetate
phthalate, other cellulose ester phthalates, cellulose ether
phthalates, hydroxypropylcellulose phthalate,
hydroxypropylethylcellulose phthalate, hydroxypropylmethylcellulose
phthalate, methylcellulose phthalate, polyvinyl acetate phthalate,
polyvinyl acetate hydrogen phthalate, sodium cellulose acetate
phthalate, starch acid phthalate, styrene-maleic acid dibutyl
phthalate copolymer, styrene-maleic acid polyvinylacetate phthalate
copolymer, styrene and maleic acid copolymers, polyacrylic acid
derivatives such as acrylic acid and acrylic ester copolymers,
polymethacrylic acid and esters thereof, poly acrylic methacrylic
acid copolymers, shellac, and vinyl acetate and crotonic acid
copolymers.
[0242] Preferred pH-sensitive polymers include shellac; phthalate
derivatives, particularly cellulose acetate phthalate,
polyvinylacetate phthalate, and hydroxypropylmethylcellulose
phthalate; polyacrylic acid derivatives, particularly polymethyl
methacrylate blended with acrylic acid and acrylic ester
copolymers; and vinyl acetate and crotonic acid copolymers.
[0243] The delay time before release of tacrolimus, after the
"pH-dependent coated tablet" dosage form has exited the stomach,
may be controlled by choice of the relative amounts of
Eudragit-L.RTM. and Eudragit-S.RTM. in the coating, and by choice
of the coating thickness. Eudragit-L.RTM. films dissolve above pH
6.0, and Eudragit-S.RTM. films dissolve above 7.0, and mixtures
dissolve at intermediate pH's. Since the pH of the duodenum is
approximately 6.0 and the pH of the colon is approximately 7.0,
coatings composed of mixtures of Eudragit-L.RTM. and
Eudragit-S.RTM. provide protection of the duodenum from tacrolimus.
If it is desired to delay release of tacrolimus until the
tacrolimus-containing "pH-dependent coated tablet" has reached the
colon, Eudragit-S.RTM. may be used as the coating material, as
described by Dew et al. (Br. J. Clin. Pharmac. 14 (1982) 405-408).
In order to delay the release of tacrolimus for about 15 minutes or
more, preferably 30 minutes or more, after the dosage form has
exited the stomach, preferred coatings comprise from about 9:1 to
about 1:9 Eudragit-L.RTM./Eudragit-S.RTM., more preferably from
about 9:1 to about 1:4 Eudragit-L.RTM./Eudragit-S.RTM.. The coating
may comprise from about 3% to about 70% of the weight of the
uncoated tablet core. Preferably, the coating comprises from about
5% to about 50% of the weight of the tablet core.
Uses
[0244] A solid dispersion and/or solution may be used for the
preparation of an extended release solid oral dosage form such as
tablets, capsules or sachets; or for the preparation of granules,
pellets microspheres or nanoparticles.
[0245] A further advantage of the extended release dosage form of
the present invention is the possibility of obtaining an effective
therapeutic response with a decreased dosage compared to
traditional oral treatment. Thus it is contemplated that the solid
dosage form of the invention, when orally administered to a mammal
in need thereof in a dose that is at the most about 85% w/w such
as, e.g., at the most about 80% w/w, at the most about 75%, at the
most about 70% w/w, at the most about 65% w/w, at the most about
60% w/w, at the most about 55% w/w or at the most about 50% w/w of
the dose of tacrolimus administered in the form of Prograf.RTM. or
a similar commercially available tacrolimus-containing product, is
essentially bioequivalent with Prograf.RTM. or a similar
commercially available tacrolimus-containing product.
[0246] Any of the tacrolimus-containing dosage forms, compositions,
dispersions or solutions of the invention may improved treatment of
conditions that respond to tacrolimus treatment.
[0247] Tacrolimus is indicated (or has been suggested) for the
treatment of diseases such as, e.g., rejection reactions by
transplantation of organs or tissues such as the heart, kidney,
liver, bone marrow, skin, cornea, lung, pancreas, small intestine,
limb, muscle, nerve, intervertebral disc, trachea, myoblast,
cartilage, etc.; graft-versus-host reactions following bone marrow
transplantation; autoimmune diseases such as rheumatoid arthritis,
systemic lupus erythematosus, Hashimoto's thyroiditis, multiple
sclerosis, myasthenia gravis, type I diabetes, etc.; infections
caused by pathogenic microorganisms (e.g. Aspergillus fumigatus,
Fusarium oxysporum, Trichophyton asteroides, etc.); inflammatory or
hyperproliferative skin diseases or cutaneous manifestations of
immunologically mediated diseases (e.g. psoriasis, atopic
dermatitis, contact dermatitis, eczematoid dermatitis, seborrheic
dermatitis, lichen planus, pemphigus, bullous pemphigoid,
epidermolysis bullosa, urticaria, angioedema, vasculitides,
erythema, dermal eosinophilia, lupus erythematosus, acne, and
alopecia areata); autoimmune diseases of the eye (e.g.
keratoconjunctivitis, vernal conjunctivitis, uveitis associated
with Behcet's disease, keratitis, herpetic keratitis, conical
keratitis, corneal epithelial dystrophy, keratoleukoma, ocular
premphigus, Mooren's ulcer, scleritis, Graves' ophthalmopathy,
Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry
eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine
ophthalmopathy, etc.); reversible obstructive airways diseases
[asthma (e.g. bronchial asthma, allergic asthma, intrinsic asthma,
extrinsic asthma, and dust asthma), particularly chronic or
inveterate asthma (e.g. late asthma and airway
hyper-responsiveness) bronchitis, etc.; mucosal or vascular
inflammations (e.g. gastric ulcer, ischemic or thrombotic vascular
injury, ischemic bowel diseases, enteritis, necrotizing
enterocolitis, intestinal damages associated with thermal burns,
leukotriene B4-mediated diseases); intestinal
inflammations/allergies (e.g. coeliac diseases, proctitis,
eosinophilic gastroenteritis, mastocytosis, Crohn's disease and
ulcerative colitis); food-related allergic diseases with
symptomatic manifestation remote from the gastrointestinal tract
(e.g. migraine, rhinitis and eczema); renal diseases (e.g.
intestitial nephritis, Goodpasture's syndrome, hemolytic uremic
syndrome, and diabetic nephropathy); nervous diseases (e.g.
multiple myositis, Guillain-Barre syndrome, Meniere's disease,
multiple neuritis, solitary neuritis, cerebral infarction,
Alzheimer's diseases Parkinson's diseases, amyotrophic lateral
sclerosis (ALS) and radiculopathy); cerebral ischemic disease
(e.g., head injury, hemorrhage in brain (e.g., subarachnoid
hemorrhage, intracerebral hemorrhage), cerebral thrombosis,
cerebral embolism, cardiac arrest, stroke, transient ischemic
attack (TIA), hypertensive encephalopathy, cerebral infarction);
endocrine diseases (e.g. hyperthyroidism, and Basedow's disease);
hematic diseases (e.g. pure red cell aplasia, aplastic anemia,
hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune
hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic
anemia, and anerythroplasia); bone diseases (e.g. osteoporosis);
respiratory diseases (e.g. sarcoidosis, pulmonary fibrosis, and
idiopathic interstitial pneumonia); skin diseases (e.g.
dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris,
photosensitivity, and cutaneous T-cell lymphoma); circulatory
diseases (e.g. arteriosclerosis, atherosclerosis, aortitis
syndrome, polyarteritis nodosa, and myocardosis); collagen diseases
(e.g. scleroderma, Wegener's granuloma, and Sjogren's syndrome);
adiposis; eosinophilic fasciitis; periodontal diseases (e.g. damage
to gingiva, periodontium, alveolar bone or substantia ossea
dentis); nephrotic syndrome (e.g. glomerulonephritis); male pattern
alopecia, alopecia senile; muscular dystrophy; pyoderma and Sezary
syndrome; chromosome abnormality-associated diseases (e.g. Down's
syndrome); Addison's disease; active oxygen-mediated diseases [e.g.
organ injury (e.g. ischemic circulation disorders of organs (e.g.
heart, liver, kidney, digestive tract, etc.) associated with
preservation, transplantation, or ischemic diseases (e.g.
thrombosis, cardial infarction, etc.)); intestinal diseases (e.g.
endotoxin shock, pseudomembranous colitis, and drug- or
radiation-induced colitis); renal diseases (e.g. ischemic acute
renal insufficiency, chronic renal failure); pulmonary diseases
(e.g. toxicosis caused by pulmonary oxygen or drugs (e.g. paracort,
bleomycin, etc.), lung cancer, and pulmonary emphysema); ocular
diseases (e.g. cataracta, iron-storage disease (siderosis bulbi),
retinitis, pigmentosa, senile plaques, vitreous scarring, corneal
alkali burn); dermatitis (e.g. erythema multiforme, linear
immunoglobulin A bullous dermatitis, cement dermatitis); and other
diseases (e.g. gingivitis, periodontitis, sepsis, pancreatitis, and
diseases caused by environmental pollution (e.g. air pollution),
aging, carcinogen, metastasis of carcinoma, and hypobaropathy)];
diseases caused by histamine release or leukotriene C4 release;
restenosis of coronary artery following angioplasty and prevention
of postsurgical adhesions; autoimmune diseases and inflammatory
conditions (e.g., primary mucosal edema, autoimmune atrophic
gastritis, premature menopause, male sterility, juvenile diabetes
mellitus, pemphigus vulgaris, pemphigoid, sympathetic ophthalmitis,
lens-induced uveitis, idiopathic leukopenia, active chronic
hepatitis, idiopathic cirrhosis, discoid lupus erythematosus,
autoimmune orchitis, arthritis (e.g. arthritis deformans), or
polychondritis); Human Immunodeficiency Virus (HIV) infection,
AIDS; allergic conjunctivitis; hypertrophic cicatrix and keloid due
to trauma, burn, or surgery.
[0248] In addition, tricyclic macrolides like e.g. tacrolimus have
liver regenerating activity and/or activities of stimulating
hypertrophy and hyperplasia of hepatocytes. Therefore, the extended
release dosage form of the present invention is useful for
increasing the effect of the therapy and/or prophylaxis of liver
diseases [e.g. immunogenic diseases (e.g. chronic autoimmune liver
diseases such as autoimmune hepatic diseases, primary biliary
cirrhosis or sclerosing cholangitis), partial liver resection,
acute liver necrosis (e.g. necrosis caused by toxins, viral
hepatitis, shock, or anoxia), hepatitis B, non-A non-B hepatitis,
hepatocirrhosis, and hepatic failure (e.g. fulminant hepatitis,
late-onset hepatitis and "acute-on-chronic" liver failure (acute
liver failure on chronic liver diseases))].
[0249] Furthermore, a extended release dosage form according to the
present invention is useful for increasing the effect of the
prevention and/or treatment of various diseases because of the
useful pharmacological activity of the tricyclic macrolides, such
as augmenting activity of chemotherapeutic effect, activity of
cytomegalovirus infection, anti-inflammatory activity, inhibiting
activity against peptidyl-prolyl isomerase or rotamase,
antimalarial activity, antitumor activity and so on.
[0250] The present invention is further illustrated by reference to
the Examples below. However, it should be noted that these
Examples, like the embodiments described above, are illustrative
and are not to be construed as restricting the enabled scope of the
invention in any way.
EXAMPLES
Materials and Methods
Materials
[0251] Tacrolimus (supplied by Eurotrade); batch no RD 03-111
Lactose monohydrate 200 mesh (from DMV) Granulated silicium oxide,
Aeroperl.RTM. 300, (Degussa) Polyethylene glycol 6000,
Pluracol.RTM. E6000 (from BASF) Poloxamer 188, Pluronic.RTM. F-68
(from BASF) Glyceryl monostearate, Rylo.RTM. MD50, (from Danisco
Cultor), Ph.Eur.; batch no. 4010056276 Avicel PH200
(microcrystalline cellulose) (from FMC) Lactose DCL 11 (from DMV)
Magnesium stearate Croscarmellose sodium, Ac-Di-Sol.RTM. (from FMC)
Eudragit.RTM. L30D.55 (from Degussa) Triethyl citrate (from Merck)
Anti-foam emulsion (from Unikem) Micro talc HPMC refers to Metolose
90SH (type 2910, 2208) or Metolose 60SH (type 2910) from ShinEtsu
available in various degrees of polymerization (viscosity 3-100,000
cP).
[0252] Tablets, capsules or granules might be enteric coated with
different types of polymers such as hydroxypropylmethylcellulose
acetate succinate (Aqoat), cellulose acetate phthalate CAP,
hydroxypropylmethylcellulose phtalate HPMCP or methacrylic acid
copolymers such as Eudragit L30D, Eudragit 100/S, Eudragit
100/L.
Comparison Prior Art Tacrolimus Formulation for In Vivo
Studies:
[0253] Prograf.COPYRGT. Hard Gelatin Capsules, manufactured by
Fujisawa Ireland Ltd.
TABLE-US-00002 Ingredients mg Tacrolimus, anhydr. 1.0 Gelatin 6.9
Hypromellose 1.0 Lactose monohydrate 24.7 Magnesium stearate 0.3
Shellac q.s. Soybean lecitine q.s. Iron oxide red (E172) q.s.
Titanium dioxide (E171) q.s. Dimeticone (E900) q.s.
Methods
Determination of Weight Variation
[0254] The tablets prepared in the Examples herein were subjected
to a test for weight variation performed in accordance with Ph.
Eur.
Determination of Average Tablet Hardness
[0255] The tablets prepared in the Examples herein were subjected
to at test for tablet hardness employing Schleuniger Model 6D
apparatus and performed in accordance with the general instructions
for the apparatus.
Determination of Disintegration Time
[0256] The time for a tablet to disintegrate, i.e. to decompose
into particles or agglomerates, was determined in accordance with
Ph. Eur.
Determination of Geometric Weight Mean Diameter d.sub.gw
[0257] The geometric weight mean diameter was determined by
employment of a method of laser diffraction dispersing the
particulate material obtained (or the starting material) in air.
The measurements were performed at 1 bar dispersive pressure in
Sympatec Helos equipment, which records the distribution of the
equivalent spherical diameter. This distribution is fitted to a log
normal volume-size distribution.
[0258] When used herein, "geometric weight mean diameter" means the
mean diameter of the log normal volume-size distribution.
In Vitro Dissolution Tests
[0259] The following test methods were applies to the compositions
and dosage forms of the present invention.
[0260] Test 1:
[0261] In vitro dissolution test according to USP Method A, delayed
release articles (USP paddle method; rotation speed: 50 rpm;
37.degree. C.; after 2 hours in acidic medium, the medium is
changed to phosphate buffer pH 6.8).
[0262] Test 2:
[0263] In vitro dissolution test in aqueous dissolution medium
adjusted to pH 4.5 (900 ml water with 0.005% HPC
(hydroxypropylcellulose) adjusted to pH4.5; 37.degree. C.; USP
Paddle method; rotation speed: 50 rpm).
[0264] The following examples serve the purpose of illustration of
the invention and are not intended to limiting the scope of the
present invention.
[0265] Pharmaceutical compositions and dosage forms which can be
optimized to provide the desired release profile according to the
invention is exemplified in examples 1-16 which formulations are
disclosed in the patent application WO 2005/020993 hereby
incorporated by reference. The dissolution profiles disclosed
therein and in Example 17 of the present application may however be
further optimized for providing release profiles fulfilling the
extended release parameters according to the present invention. The
optimization may include formulation changes including changes in
grades of excipients, change in ratios of excipients, manufacturing
changes such as change in punch pressure, change in hardness or
disintegration time. As a molecular solution is preferred, relevant
changes includes use of excipients preventing degradation of the
active substance as well as use of specific excipients less prone
to interact with the active substance and/or degradation products
thereof.
Example 1
Modified Release Poly-Depot Capsule Based on Swelling Hydrocolloid
Matrix of Hydroxypropylcellulose
TABLE-US-00003 [0266] Substance % mg Tacrolimus 0.50 1.00 HPMC
20.00 40.00 Lactose 200 mesh 30.00 60.00 PEG 6000 34.65 69.30
Poloxamer 188 14.85 29.70 Total 100.00 200.00
[0267] Tacrolimus was dissolved in polyethylene glycol 6000 and
poloxamer 188 (70:30 w/w ratio) at 70.degree. C. The solution was
sprayed on a mixture of 150 g lactose and 100 g HPMC in a fluid bed
Strea-1. The granular product was sieved through sieve 0.7 mm and
filled into hard gelatine capsules (200 mg).
Example 2
Modified Release Poly-Depot Capsule Based on Swelling Hydrocolloid
Matrix of Hydroxypropylcellulose
TABLE-US-00004 [0268] Substance % mg Tacrolimus 0.50 1.00 HPMC 2910
3 cp 20.00 40.00 Lactose 200 mesh 30.00 60.00 Glyceryl monostearate
49.50 99.00 Total 100.00 200.00
[0269] Tacrolimus was dissolved in glyceryl monostearate at
70.degree. C. The solution was sprayed on a mixture of 150 g
lactose and 100 g HPMC in a fluid bed Strea-1. The granular product
was sieved through sieve 0.7 mm and filled into hard gelatine
capsules (200 mg).
Example 3
Extended Release Matrix Tablet Based on Swelling Hydrocolloid
Matrix of Hydroxypropylcellulose
TABLE-US-00005 [0270] Substance % mg Tacrolimus 0.50 1.00 HPMC
19.90 40.00 Lactose 200 mesh 29.85 60.00 PEG 6000 34.48 69.30
Poloxamer 188 14.78 29.70 Magnesium stearate 0.50 1.01 Total 100.00
201.01
[0271] Tacrolimus was dissolved in polyethylene glycol 6000 and
poloxamer 188 (70:30 w/w ratio) at 70.degree. C. The solution was
sprayed onto 250 g lactose in a fluid bed Strea-1. The resulting
granular product was sieved through sieve 0.7 mm and blended with
HPMC and magnesium stearate for 0.5 min in a Turbula mixer.
[0272] The mixture was compressed into 8 mm tablets of 1 mg active
ingredient (200 mg tablet) with compound cup shaped.
[0273] Mean disintegration time: 20 min. Hardness: 45 N
Example 4
Modified Release Matrix Tablet Based on Lipophilic Matrix of
Glyceryl Monostearate
TABLE-US-00006 [0274] Substance % mg Tacrolimus 0.50 1.00 Lactose
200 mesh 49.75 100.00 Glyceryl monostearate 49.25 99.00 Magnesium
stearate 0.50 1.01 100.00 201.01
[0275] Tacrolimus was dissolved in glyceryl monostearate at
70.degree. C. The solution was sprayed onto 250 g lactose in a
fluid bed Strea-1. The granular product was sieved through sieve
0.7 mm and blended with magnesium stearate for 0.5 minutes in a
Turbula mixer.
[0276] The resulting mixture was compressed into 8 mm tablets of 1
mg active ingredient (200 mg tablet) with compound cup shape.
[0277] Mean disintegration time: 20 min. Hardness: 45 N
Example 5
Modified Release Polydepot Capsule Based on Lipophilic Matrix of
Glyceryl Monostearate
TABLE-US-00007 [0278] Substance % mg Tacrolimus 0.50 1.00 Lactose
200 mesh 49.75 100.00 Glyceryl monostearate 49.25 99.00 Magnesium
stearate 0.50 1.01 100.00 201.01
[0279] Tacrolimus was dissolved in glyceryl monostearate at
70.degree. C. The solution was sprayed onto 250 g lactose in a
fluid bed Strea-1. The granular product was sieved through sieve
0.7 mm and filled into hard gelatine capsules (200 mg).
Example 6
Modified Release Poly-Depot Tablet Based on Lipophilic Matrix of
Gelucire.RTM. 44/14
TABLE-US-00008 [0280] Substance % mg Tacrolimus 0.50 1.00 Aeroperl
.RTM. 300 49.75 100.00 Gelucire .RTM. 44/14 49.25 99.00 Magnesium
stearate 0.50 1.01 100.00 201.01
[0281] Tacrolimus was dissolved in Gelucire.RTM. at 70.degree. C.
The solution was sprayed onto 250 g Aeroperl.RTM. in a fluid bed
Strea-1. The granular product was sieved through sieve 0.7 mm and
filled into hard gelatine capsules (200 mg).
[0282] The resulting granulate was compressed into 8 mm tablets of
1 mg active ingredient (tablet weight 200 mg). Tablets were cup
shaped.
[0283] Mean disintegration time: 25 minutes. Hardness: 43 N.
Example 7
Enteric Coating
[0284] Capsules and tablets of examples 1, 2, 3, 5 and 6 were
subsequently coated with the following enteric coating in order to
obtain a delayed release of active ingredient after
administration.
TABLE-US-00009 Ingredients % Eudragit .RTM. L30D 40 Purified water
52 Triethyl acetylcitrate 1.8 Anti-foam emulsion 0.2 Talc 6 Total
100
[0285] The coating suspension was prepared by mixing triethyl
acetylcitrate, antifoam emulsion and purified water in Ultra Turrax
apparatus at 9500 rpm for 30 min. After 1 minute talc was added.
The mixture was passed through sieve no. 300 and stirred by a
magnet stirrer. Eudragit was passed through sieve no. 300 and added
the mixture, which was stirred for 5 minutes.
[0286] The process conditions of the coating process were the
following an inlet temperature of 40.degree. C., an outlet
temperature of 31.degree. C., air inlet of 140 cbm per hour and a
coating time of approx. 50 minutes (300 g of coating material).
Approximately 400 g of tablets, or 200 g of capsules were
coated.
[0287] The film coated tablets and capsules were cured for 48 hours
at 30.degree. C. before dissolution testing.
Example 8
Modified Release Matrix Tablet Based on Lipophilic Matrix of
Glycerol Monostearate
TABLE-US-00010 [0288] Substance % mg Tacrolimus 0.95 2.00 HPMC,
Pharmacoat 606 6.75 14.29 Lactose monohydrate, lactose 125 mesh
6.75 14.29 Glycerol monostearate, Rylo .RTM. MD50 30.56 64.67
Magnesium Stearate 0.5 1.06 Talc 4.5 9.52 Lactose monohydrate,
Pharmatose DCL 14 50.00 105.8 100.00 211.64
[0289] Tacrolimus was dissolved in glycerol monostearate at a
temperature above 80.degree. C. The solution was sprayed by feed
unit Phast FS1.7 onto 60 g lactose and 60 g HPMC in a fluid bed
Phast FB100. The granular product was hardened in a heating oven
for 4 hours at 50.degree. C. The resulting granular product was
sifted through sieve 0.71 mm and blended with lactose for 3 minutes
in a Turbula mixer.
[0290] Magnesium stearate and talc was sifted through sieve no. 300
and mixed in a Turbula mixer for 3 minutes. The granulate was mixed
with the mixture of magnesium stearate and talc (1:9) for 0.5
minutes in a Turbula mixer.
[0291] The final mixture was compressed into 8 mm tablets of 2 mg
active ingredient (210 mg tablet) with compound cup shape.
[0292] Mean disintegration time: 2 hours. Hardness: 50 N
Example 9
Enteric Coated Tablet with Core Based on PEG 6000/Poloxamer 188 and
Enteric Coating Based on Eudragit L30D 55
Tablet Core Composition:
TABLE-US-00011 [0293] Substance % mg Tacrolimus 1.98 2.00 Lactose
monohydrate, Lactose 200 mesh 40.50 40.91 PEG 6000 33.26 33.60
Poloxamer 188, Lutrol 68 14.40 14.40 Magnesium Stearate 0.50 0.51
Talc 4.50 4.55 Croscarmellose sodium, Ac-di-sol 5.00 5.05 100.00
101.01
[0294] The tacrolimus tablet core was produced by dissolving in PEG
6000 at a temperature above 80.degree. C. Poloxamer 188 was added,
and the solution was heated to a temperature above 80.degree. C.
The solution was sprayed by feed unit Phast FS1.7 on 200 g lactose
monohydrate in a fluid bed Phast FB100. The resulting granulate was
sifted through a Comill sieve 1397, 4500 rpm, and blended with
croscarmellose sodium for 3 minutes in a Turbula mixer.
[0295] Magnesium stearate and talc was sifted through sieve no. 300
and mixed in a Turbula mixer for 3 minutes. The granulate was mixed
with magnesium stearate and talc (1:9) for 0.5 minutes in a Turbula
mixer.
[0296] The resulting mixture was compressed into 6 mm tablets of 2
mg active ingredient (100 mg tablet) with compound cup shape.
[0297] Mean disintegration time: 7 minutes. Hardness: 65 N
Enteric Coating:
[0298] The enteric coating is based on an acrylic polymer Eudragit
L30D-55. Eudragit L30D is supplied as an aqueous latex suspension
creating a water insoluble film when the water is evaporated during
coating. The polymer is insoluble at pH-values below 5.0 and
readily soluble at pH-values over 6.0. The film coating composition
is:
TABLE-US-00012 Substance w/w % Eudragit L30D-55 40 Water 52
Triethyl citrate 1.8 Anti-foam emulsion 0.2 Talc (micro) 6 Total
100
[0299] The amount of applied film polymer (Eudragit) was based on a
calculation of mg film polymer per cm.sup.2 tablet surface. The
thickness of the enteric coating was 80 .mu.m. A verification of
the film thickness applied was based on measuring the increase in
tablet height with a digital micrometer. The film coating process
was performed in a Phast FB100 fluid bed equipped with a Wurster
like insert. The process conditions were: Inlet air temperature
50.degree. C.; Inlet air flow 100 m.sup.3 per hour; Product
temperature 38.degree. C.; Feed rate 15 g/min.
[0300] After coating, proper film formation requires curing of the
coated tablets i.e. at 30.degree. C. for 48 hours in an oven.
Alternatively the coated tablets more efficiently could be cured at
40.degree. C. in 24 hours.
Example 10
Controlled Release PEG 6000/Poloxamer 188 Tablet Based on a HPMC
Matrix
Tablet Composition:
TABLE-US-00013 [0301] Substance % mg Tacrolimus 1.21 2.00 Lactose
monohydrate, Lactose 200 mesh 24.75 40.91 PEG 6000 20.33 33.60
Poloxamer 188, Lutrol 68 8.71 14.40 Magnesium Stearate 0.50 0.83
Talc 4.50 7.44 Hydroxypropyl methylcellulose, Metolose 90SH 15000
40.00 66.12 100.00 165.29
[0302] Tacrolimus was dissolved in PEG 6000 at a temperature above
80.degree. C. Poloxamer 188 is added and the solution is heated to
a temperature above 80.degree. C. The solution is sprayed by feed
unit Phast FS1.7 on 200 g lactose monohydrate in a fluid bed Phast
FB100. The granular product is sieved through a Comill, sieve 1397,
4500 rpm, and blended with Hydroxypropyl methylcellulose for 3 min
in a Turbula mixer.
[0303] Magnesium stearate and talc is sifted through sieve 300 and
mixed in a Turbola mixer for 3 min. The granulate is mixed with
Magnesium Stearate:Talc (1:9) for 0.5 min in a Turbula mixer. The
mixture is compressed into 8 mm tablets with strength of 2 mg (165
mg tablet with compound cup shape). Mean disintegration time: 2
hours 34 minutes, Hardness: 50 N
Example 11
Enteric Coated Tablet Formulation
Wet Granulation and Enteric-Coated Tablets
Tablet Composition:
TABLE-US-00014 [0304] Ingredient mg Tacrolimus 2 Lactose 80 Sodium
lauryl sulfate 10 Kollidon VA64 3 Avicel PH200 30 Magnesium
stearate 0.5 Total 125.5
[0305] The tablet formulation was based on wet granulation in a
high shear mixer Pellmix 1/8. 16 g Micronized tacrolimus was mixed
with 640 g lactose 125 mesh and 80 g natrium lauryl sulfate in the
high shear mixer. A 15% aqueous solution of binder Kolllidon VA64
was pumped to the mixture at an impeller speed of 500 rpm at a feed
rate of 20 g/min. and subsequently kneaded for 3 minutes at the
equal speed. The granulate was dried in a tray dryer and sieved
through sieve size 0.7 mm.
[0306] The granulate was mixed with 240 g Avicel PH200 for 3
minutes and for and after addition of 4 g magnesium stearate for
further 0.5 minute. The mixture was compressed into tablets on a
single punch tabletting machine Diaf TM20.
[0307] Tablet diameter: 6 mm. Tablet shape: round, compound
cup.
[0308] The tablets were subsequently coated with an enteric coating
of acrylic type as described in example 9.
[0309] The amount of applied film polymer (Eudragit) should be
based on a calculation of mg film polymer per cm.sup.2 tablet
surface. The thickness of the enteric coating should be 50-80
.mu.m. A verification of the film thickness applied is based on
measuring the increase in tablet height with a digital micrometer.
The film coating process is performed in a Stre-1 fluid bed
equipped with a Wurster insert at the following process
conditions:
TABLE-US-00015 Process parameter Process value Product load, g 400
Inlet air temperature, .degree. C. 40 Inlet air flow, m.sup.3 per
hour 140 Outlet air temperature, .degree. C. 31 Feed rate g/min
5
[0310] After coating, proper film formation requires curing of the
coated tablets, i.e. 30.degree. C. in 48 hours in an oven.
Alternatively the coated tablets more efficiently could be cured at
40.degree. C. for 24 hours.
Example 12
Controlled Release Tablet Formulation Based on Eroding HPMC
Matrix
[0311] HPMC added as part of the extragranular phase. Wet
granulation.
Tablet Composition:
TABLE-US-00016 [0312] Ingredients mg Tacrolimus 2 Lactose 80 Sodium
lauryl sulfate 10 Kollidon VA64 3 Avicel PH200 30 Metolose SH 90 60
Magnesium stearate 1 Total 186
[0313] The tablet formulation was based on wet granulation in a
high shear mixer Pellmix 1/8. 16 g Micronized tacrolimus was mixed
with 640 g lactose 125 mesh and 80 g natrium lauryl sulfate in the
high shear mixer. A 15% aqueous solution of binder Kolllidon VA64
was pumped to the mixture at an impeller speed of 500 rpm at a feed
rate of 20 g/min and subsequently kneaded for 3 minutes at equal
impeller speed. The granulate was dried in a tray dryer and sieved
through sieve size 0.7 mm.
[0314] The granulate was mixed with 240 g Avicel PH200 and 480 g
hydroxypropylmethylcellulose Metolose SH 90 100 cP for 3 minutes
and for and after addition of 8 g magnesium stearate for further
0.5 minute. The mixture was compressed into tablets on a single
punch tabletting machine Diaf TM20.
[0315] Tablet diameter: 7 mm. Tablet shape: round, compound
cup.
Example 13
Controlled Release Tablet Formulation Based on Eroding HPMC
Matrix
[0316] HPMC added as part of the intragranular phase. Wet
granulation.
Tablet Composition:
TABLE-US-00017 [0317] Ingredient mg Tacrolimus 2 Lactose 80 Sodium
lauryl sulfate 10 Metolose SH 90 80 Avicel PH200 60 Magnesium
stearate 2 Total 234
[0318] The tablet formulation was based on wet granulation in a
high shear mixer Pellmix 1/8. 16 g Micronized tacrolimus was mixed
with 640 g lactose 125 mesh and 80 g natrium lauryl sulfate and 640
g hydroxypropylmethylcellulose Metolose SH 90 15.000 cP in the high
shear mixer. Purified water was pumped to the mixture at an
impeller speed of 500 rpm at a feed rate of 20 g/min. and
subsequently kneaded for 3 minutes. The granulate was dried in a
tray dryer and sieved through sieve size 0.7 mm.
[0319] The granulate was mixed with 480 g Avicel PH200 for 3
minutes and for and after addition of 16 g magnesium stearate for
further 0.5 minute. The mixture was compressed into tablets on a
single punch tabletting machine Diaf TM20.
[0320] Tablet diameter: 8 mm. Tablet shape: round, compound
cup.
Example 14
Controlled Release Tablet Formulation Based on Eroding HPMC
Matrix
[0321] HPMC added as part of the intragranular phase. Melt
granulation
Tablet Composition:
TABLE-US-00018 [0322] Ingredient mg Tacrolimus 2 Lactose 80 PEG
6000 15 Poloxamer 188 6 Metolose SH 90 80 Avicel PH200 60 Magnesium
stearate 2 Total 245
[0323] The tablet formulation was based on melt granulation in a
high shear mixer Pellmix 1/8. 16 g Micronized tacrolimus was mixed
with 640 g lactose 125 mesh and 120 g Polyethylene glycol 6000, 48
g Poloxamer 188 and 640 g hydroxypropylmethylcellulose Metolose SH
90 15.000 cP in the high shear mixer. The jacket of the mixer bowl
was heated to 80.degree. C. and the blend was heated at an impeller
rotation speed of 1000 rpm until melting point of PEG and
Poloxamer. After melting the kneading was continued for 4 minutes
at 800 rpm. The granulated was sieved through sieve size of 0.7 mm
and cooled on a tray. The granulate was mixed with 480 g Avicel
PH200 for 3 minutes and for and after addition of 16 g magnesium
stearate for further 0.5 minute. The mixture was compressed into
tablets on a single punch tabletting machine Diaf TM20. Tablet
diameter: 8 mm. Tablet shape: round, compound cup.
Example 15
Controlled Release Tablet Formulation Based on Eroding Kollidon SR
Matrix Added as Part of the Extragranular Phase
Tablet Composition:
TABLE-US-00019 [0324] Ingredient mg Tacrolimus 2 Lactose 80 Sodium
lauryl sulfate 10 Kollidon VA64 3 Lactose DC lac14 50 Kollidon SR
60 Magnesium stearate 1 Total 206
[0325] The tablet formulation was based on wet granulation in a
high shear mixer Pellmix 1/8. 16 g Micronized tacrolimus was mixed
with 640 g lactose 125 mesh and 80 g natrium lauryl sulfate in the
high shear mixer. A 15% aqueous solution of binder Kolllidon VA64
(Kollidon SR is a mixture of polyvinyl acetate and
polyvinylpyrrolidon 80:20) was pumped to the mixture at an impeller
speed of 500 rpm at a feed rate of 20 g/min and subsequently
kneaded for 3 minutes. The granulate was dried in a tray dryer and
sieved through sieve size 0.7 mm. The granulate was mixed with 400
g lactose DC Lac 14 and 480 g Kollidon SR for 3 minutes and for and
after addition of 8 g magnesium stearate for further 0.5 minute.
The mixture was compressed into tablets on a single punch
tabletting machine Diaf TM20.
[0326] Tablet diameter: 8 mm. Tablet shape: round, compound
cup.
Example 16
Enteric Coated Tablet Formulation
Melt Granulation and Enteric-Coated Tablets
Tablet Composition:
TABLE-US-00020 [0327] Ingredient mg Tacrolimus 2 Lactose 80 PEG
6000 15 Poloxamer 188 6 Avicel PH200 60 Magnesium stearate 2 Total
165
[0328] The tablet formulation was based on melt granulation in a
high shear mixer Pellmix 1/8. 16 g Micronized tacrolimus was mixed
with 640 g lactose 125 mesh and 120 g Polyethylene glycol 6000, 48
g Poloxamer 188 in the high shear mixer. The jacket of the mixer
bowl was heated to 80.degree. C. and the blend was heated at a
impeller rotation speed of 1000 rpm until melting point of PEG and
Poloxamer. After melting the kneading was continued for 4 minutes
at 800 rpm. The granulated was sieved through sieve size of 0.7 mm
and cooled on a tray. The granulate was mixed with 480 g Avicel
PH200 for 3 minutes and for and after addition of 16 g magnesium
stearate for further 0.5 minute. The mixture was compressed into
tablets on a single punch tabletting machine Diaf TM20. Tablet
diameter: 7 mm. Tablet shape: round, compound cup. Enteric coating
of the tablets is performed in accordance with the procedure
described in Example 11.
Example 17
In Vitro Dissolution Data
[0329] Compositions and dosage forms according to the previous
examples were subjected to in vitro dissolution tests using two
different dissolution media/tests. [0330] A. Using the dissolution
medium/test: 900 ml aqueous medium with 0.005% HPC
(hydroxypropylcellulose) adjusted to pH=4.5 (USP paddle method;
rotation speed: 50 rpm), the following dissolution profiles were
found:
TABLE-US-00021 [0330] % Release Time Ex. 8 Ex. 9 - EC Ex. 10
(hours) Ex. 1 Ex. 3 Ex. 4 (Rsd %) (Rsd %) (Rsd %) 0 0 0 0 0 (0) 0
(0) 0 (0) 0.5 2 1 4 1.5 0 0 2 0 0 3 6 4 1 3 7.8 (11.1) 0.8 (32.3)
7.4 (9.8) 5 6 3 4 8 5 7 17 17.0 (8.3) 0.4 (61.1) 13.3 (16.5) 10 20
14 15 40 32.2 (4.8) 11.0 (17.3) 36.0 (5.8) 16 38 17 35.1 (9.6) 13.2
(12.1) 44.5 (5.4) 20 24 37
[0331] Dissolution profile for tablet cores of Example 9 in
dissolution media: 900 ml, aqueous media with 0.005% HPC
(hydroxypropylcellulose) adjusted to pH=4.5. USP paddle method.
Rotation speed: 50 rpm:
TABLE-US-00022 Time (minutes) % release Rsd % 0 0 0 5 27.2 15.1 10
49.1 10.9 20 80.7 8.0 35 98.9 5.4 42 102.7 3.6 52 104.9 2.0
[0332] Dissolution profile for enteric coated tablets example 9 in
dissolution medium accord. to USP Method A, delayed release
articles. USP Paddle method. Rotation speed: 50 rpm:
TABLE-US-00023 Time (minutes) % release Rsd % 0 0 NA 120 0 NA 155
84.8 12.8 165 102.9 NA 175 101.0 3.5
Example 18
List of Stability Improving Measures for Improving and Optimizing
an Extended Release Tacrolimus Formulation Comprising Tacrolimus in
a Solid Solution
[0333] Tacrolimus in solubilized form is prone to degradation and
several degradation products may be produced during storage.
Stability improving measurements tested for improving the stability
of tacrolimus are disclosed in the following list.
Vehicles, Antioxidant formulations addition of 1000 ppm Propyl
gallate
500 ppm .alpha.-Tocopherol+500 ppm Lipoid
[0334] 500 ppm Ascorbyl palmitate
1000 ppm .alpha.-Tocopherol
500 ppm .alpha.-Tocopherol
50 ppm .alpha.-Tocopherol
[0335] 1000 ppm Ascorbyl palmitate+1000 ppm .alpha.-Tocopherol 500
ppm Ascorbyl palmitate+500 ppm .alpha.-Tocopherol 250 ppm Ascorbyl
palmitate+250 ppm .alpha.-Tocopherol 50 ppm Ascorbyl palmitate+50
ppm .alpha.-Tocopherol Removal of impurities in a poloxamer by
filtering through Al2O3 (Compalox)
Addition of Dimethicon
Addition of BHT
[0336] Addition of organic acids including Tartaric acid 0.01%
Tartaric acid, 0.05% Tartaric acid, 0.10% Tartaric acid, 0.20%
Tartaric acid, 0.40% Tartaric acid, 0.50% Tartaric acid, 0.60%
Tartaric acid, 0.75% Tartaric acid, 1% Tartaric acid, 5% Tartaric
acid Variation of Tartaric acid around 0.15%, with 200 ppm
.alpha.-Tocopherol Tablets, dried with N2 at 25.degree. 4 h dried
by N2, low heat 65.degree. C. low heating time, 25.degree. 24 h
dried by N2, low heat 65.degree. C. low heating time, 40.degree. 4
h dried by N2, low heat 65.degree. C. low heating time, 40.degree.
24 h dried by N2, low heat 65.degree. C. low heating time Tablets,
open storage in different controlled humidities, 11% humidity by
LiCl 32% humidity by MgCl2, 48% humidity by K2CO3, 75% humidity by
NaCl 89% humidity by KNO3
Example 19
A Clinical Study Comparing an Extended Release Formulation
According to the Present Invention with Prograf.RTM. in Stable
Kidney and Liver Transplant Patients, Respectively
[0337] Blood concentration profiles are disclosed in FIGS. 5 and 6
for stable kidney patients.
Study Title:
[0338] A Phase II, Open-Label, Multi-Center Prospective, Conversion
Study in Stable Kidney Transplant Patients to Compare the
Pharmacokinetics of LCP-Tacro Tablets Once-A-Day to Prograf.RTM.
Capsules Twice-A-Day. LCP-Tacro 1 mg, 2 mg, 5 mg Tablets
[0339] Active Ingredient: Tacrolimus.
[0340] Indications: Tacrolimus (Prograf.RTM.) is used to prevent
rejection of liver, kidney and heart transplants.
[0341] Study Design and Phase of Development: 3-sequence,
open-label, prospective, multicenter, conversion trial (Phase
II).
[0342] Title of Study: A Phase II, Open-Label, Multi-Center
Prospective, Conversion Study in Stable Kidney Transplant Patients
to Compare the Pharmacokinetics of LCP-Tacro Tablets Once-A-Day to
Prograf.RTM. Capsules Twice-A-Day
[0343] Objectives: To evaluate tacrolimus exposure (AUC0-24) and
trough levels (C24) in stable kidney transplant recipients
converted from Prograf.RTM. Capsules (tacrolimus, Astellas Pharma
US, Inc.) to LCP-Tacro tablets in a three sequence study design,
and to evaluate the safety of LCP-Tacro compared to Prograf.
[0344] Main Criteria for Inclusion: Men and women 18-65 years of
age who were recipients of a renal transplant at least 6 months
prior to enrollment.
[0345] Test Products/Investigational Products and Modes of
Administration: LCP-Tacro 1 mg, 2 mg, 5 mg Tablets, administered
orally once daily in the morning.
[0346] Reference Product, Lot Number and Mode of Administration:
Prograf.RTM. 0.5 mg, 1 mg, 5 mg Capsules, administered b.i.d. in
two equally divided doses, once in the morning and once in the
evening.
[0347] Methodology: A three sequence, open-label, multi-center,
prospective, study in stable kidney transplant patients to assess
and compare the pharmacokinetics (Cmax, C24, and AUC), and safety
of LCP-Tacro (tacrolimus) tablets versus Prograf.RTM. (tacrolimus)
capsules.
[0348] Stable kidney transplant patients who fulfilled all
inclusion/exclusion (I/E) criteria were enrolled and kept on
Prograf.RTM. for 7 days. Following a 24-hour PK study on Day 7 to
determine pharmacokinetics for Prograf.RTM., all patients were
converted to once daily LCP-Tacro (Ratio 1:0.66-0.80) for 7 days
with no dose changes allowed. On Day 14 a 24-hour LCP-Tacro PK
study was performed. On Day 15 one predefined dose change was
allowed if there was more than 25% change in the mean of 3 trough
levels measured on Days 10.+-.1, 12.+-.1 (separated by at least 48
hours from the previous sample) and 14 compared to the mean of 3
trough levels measured on Days 0, 7 and 8 for each individual
patient.
[0349] Patients remained on the dose determined on Day 14 for
another 7 days with no dose changes allowed. Another 24-hour
LCP-Tacro PK study was performed on Day 21. On Day 22 patients were
converted back to their original twice-daily dose of Prograf.RTM.
for a safety follow-up period of 30 days ending with a safety
assessment at Day 52. An interim PK analysis was preformed after 10
patients complete Day 21, before continuing enrollment.
[0350] Blood Draw Timepoints: The following blood samples were
drawn during this study:
For LCP-Tacro: Blood sampling points included: 0.00 (pre-dose),
0.50, 1.00, 1.50, 2.00, 3.00, 4.00, 6.00, 8.00, 12.00, 14.00,
16.00, 20.00 and 24.00 hours post dose, on Days 14 and 21. For
Prograf.RTM.: Blood sampling points included: 0.00 (pre-dose),
0.50, 1.00, 1.50, 2.00, 3.00, 4.00, 6.00, 8.00, 12.00, 12.50,
13.00, 13.50, 14.00, 15.00, 16.00, 20.00 and 24.00 hours after the
morning dose, on Day 7.
[0351] Criteria for Evaluation: The pharmacokinetic analysis was
performed on 47 patients. The safety assessment was performed on
all patients who received at least 1 dose during the course of the
study.
[0352] Pharmacokinetics (PK): The following pharmacokinetic
parameters for tacrolimus were calculated by standard
non-compartmental methods: AUC.tau. (.tau.=24), Cmax, Cmin, Cave,
Tmax, % Fluctuation, % Swing and Cmax/Cmin.
[0353] Statistical Methods: All demographic data, pharmacokinetic
parameters, laboratory data and AEs were summarized using
descriptive statistics. For continuous data, the mean, standard
deviation, median, minimum and maximum were reported. For
categorical data, percent and frequency were reported.
[0354] Non-compartmental pharmacokinetic parameters [AUC.tau.
(.tau.=24), Cmax, Cmin, Cave, Tmax] were calculated from blood
concentration-time data.
[0355] Statistical Methods Using GLM procedures in SAS, ANOVA was
performed on natural logarithmic (In) transformed parameters
AUC.tau., Cmax, Cmin, and Cavg and on untransformed parameters %
fluctuation, % swing, and Cmax/Cmin. The model included treatment
as a factor. The ratio of geometric LSMs along with the 90% CI was
calculated according to the following three comparisons for
AUC.tau., Cmax, and Cmin:
Day 14 Prograf versus Day 7 LCP-Tacro Day 21 Prograf versus Day 7
LCP-Tacro Day 21 LCP-Tacro versus Day 14 LCP-Tacro
[0356] The parameter Tmax was analyzed using nonparametric methods.
The Wilcoxon signed-rank test for pairwise treatments comparisons
was used. The mean shift between 2 treatments (as described above)
was estimated by the median unbiased Hodges-Lehmann estimate and
90% exact confidence interval.
[0357] The degree of correlation between AUC.tau. and Cmin was
quantified by calculating a correlation coefficient and presenting
graphical displays of the data on Days 7, 14, and 21. Both
parameters were In-transformed prior to correlation analysis.
Statistical analysis of subgroup race (Blacks vs. Non-Blacks) was
performed as a suitable split was obtained between the two
groups.
TABLE-US-00024 Summary of Pharmacokinetic Results: Pharmacokinetic
Parameters Of For Tacrolimus In All Patients: Geometric Mean (% CV)
Arithmetic Mean .+-. SD Dose Uncorrected Data Dose Corrected Data
Prograf .RTM. Capsules LCP-Tacro Tablets Prograf .RTM. Capsules
LCP-Tacro Tablets b.i.d. orally q.d. orally b.i.d. orally q.d.
orally Pharmacokinetic Day 7 Day 14 Day 21 Day 7 Day 14 Day 21
Parameters (n = 47) (n = 47) (n = 46) (n = 47) (n = 47) (n = 46)
AUC.tau. # 212.12 (25.59) 206.79 (29.27) 209.05 (31.30) 34.81
(52.08) 47.73 (57.25) 48.30 (56.46) (ng hr/mL) 218.82 .+-. 55.99
215.71 .+-. 63.14 218.03 .+-. 68.23 39.89 .+-. 20.78 56.83 .+-.
32.54 56.90 .+-. 32.13 Cmax (ng/mL) 17.66 (42.59) 12.64 (36.02)
13.05 (41.91) 2.90 (41.11) 2.92 (47.24) 3.02 (47.92) 19.14 .+-.
8.15 13.45 .+-. 4.84 13.94 .+-. 5.84 3.18 .+-. 1.31 3.29 .+-. 1.56
3.44 .+-. 1.65 Cmin (ng/mL) 6.82 (22.01) 6.59 (33.41) 6.64 (31.70)
1.12 (66.74) 1.52 (64.87) 1.53 (70.71) 7.00 .+-. 1.54 6.96 .+-.
2.32 6.94 .+-. 2.20 1.35 .+-. 0.90 1.91 .+-. 1.24 1.92 .+-. 1.35
Cavg (ng/mL) 8.84 (25.59) 8.62 (29.27) 8.71 (31.29) 1.45 (52.08)
1.99 (57.25) 2.01 (56.46) 9.12 .+-. 2.33 8.99 .+-. 2.63 9.08 .+-.
2.84 1.66 .+-. 0.87 2.37 .+-. 1.36 2.37 .+-. 1.34 Tmax (hr)* 1.82
6.00 6.00 1.82 6.00 6.00 (0.50-24.00) (1.00-16.00) (1.50-16.00)
(0.50-24.00) (1.00-16.00) (1.50-16.00) Degree of 127.41 .+-. 57.28
73.24 .+-. 44.96 77.04 .+-. 50.59 127.41 .+-. 57.28 73.24 .+-.
44.96 77.04 .+-. 50.59 Fluctuation (%) Degree of 174.55 .+-. 93.72
102.80 .+-. 75.24 110.07 .+-. 89.23 174.55 .+-. 93.72 102.80 .+-.
75.24 110.07 .+-. 89.23 Swing (%) Cmax/Cmin 2.75 .+-. 0.94 2.03
.+-. 0.75 2.10 .+-. 0.89 2.75 .+-. 0.94 2.03 .+-. 0.75 2.10 .+-.
0.89 Summary of Pharmacokinetic Results Pharmacokinetic Parameters
Of For Tacrolimus In Black Patients: Geometric Mean (% CV)
Arithmetic Mean .+-. SD Dose Uncorrected Data Dose Corrected Data
Prograf .RTM. Capsules LCP-Tacro Tablets Prograf .RTM. Capsules
LCP-Tacro Tablets b.i.d. orally q.d. orally b.i.d. orally q.d.
orally Pharmacokinetic Day 7 Day 14 Day 21 Day 7 Day 14 Day 21
Parameters (n = 20) (n = 20) (n = 19) (n = 20) (n = 20) (n = 19)
AUC.tau. # 242.19 (24.78) 204.13 (32.48) 216.93 (39.32) 26.35
(74.70) 31.57 (84.23) 32.50 (84.71) (ng hr/mL) 250.12 .+-. 61.98
214.78 .+-. 69.77 231.41 .+-. 90.99 31.41 .+-. 23.47 38.13 .+-.
32.11 39.17 .+-. 33.18 Cmax (ng/mL) 21.72 (41.29) 13.89 (41.05)
14.48 (48.92) 2.36 (46.02) 2.15 (60.56) 2.17 (64.07) 23.73 .+-.
9.80 15.20 .+-. 6.24 15.91 .+-. 7.78 2.61 .+-. 1.20 2.46 .+-. 1.49
2.53 .+-. 1.62 Cmin (ng/mL) 7.43 (21.57) 6.21 (37.53) 6.68 (38.83)
0.81 (107.31) 0.96 (99.20) 1.00 (120.04) 7.62 .+-. 1.64 6.62 .+-.
2.49 7.09 .+-. 2.75 1.07 .+-. 1.15 1.26 .+-. 1.25 1.34 .+-. 1.61
Cavg (ng/mL) 10.09 (24.78) 8.51 (32.49) 9.04 (39.32) 1.10 (74.70)
1.32 (84.22) 1.35 (84.70) 10.42 .+-. 2.58 8.95 .+-. 2.91 9.64 .+-.
3.79 1.31 .+-. 0.98 1.59 .+-. 1.34 1.63 .+-. 1.38 Tmax (hr)* 1.91
4.00 6.00 1.91 4.00 6.00 (0.50-24.00) (1.00-12.00) (1.50-16.00)
(0.50-24.00) (1.00-12.00) (1.50-16.00) Degree of 145.87 .+-. 60.72
94.99 .+-. 54.11 91.42 .+-. 63.47 145.87 .+-. 60.72 94.99 .+-.
54.11 91.42 .+-. 63.47 Fluctuation (%) Degree of 212.69 .+-. 108.38
138.16 .+-. 91.69 135.87 .+-. 114.34 212.69 .+-. 108.38 138.16 .+-.
91.69 135.87 .+-. 114.34 Swing (%) Cmax/Cmin 3.13 .+-. 1.08 2.38
.+-. 0.92 2.36 .+-. 1.14 3.13 .+-. 1.08 2.38 .+-. 0.92 2.36 .+-.
1.14 *median (min-max); #: .tau. = 24 hours
TABLE-US-00025 Pharmacokinetic Parameters Of For Tacrolimus In
Non-Black Patients Geometric Mean (% CV) Arithmetic Mean .+-. SD
Dose Uncorrected Data Dose Corrected Data Prograf .RTM. Capsules
LCP-Tacro Tablets Prograf .RTM. Capsules LCP-Tacro Tablets b.i.d.
orally q.d. orally b.i.d. orally q.d. orally Pharmacokinetic Day 7
Day 14 Day 21 Day 7 Day 14 Day 21 Parameters (n = 27) (n = 27) (n =
27) (n = 27) (n = 27) (n = 27) AUC.tau. # 192.28 (19.32) 208.78
(27.32) 203.68 (21.98) 42.79 (35.25) 64.82 (36.10) 63.83 (36.26)
(ng hr/mL) 195.64 .+-. 37.79 216.40 .+-. 59.11 208.62 .+-. 45.86
46.18 .+-. 16.28 70.69 .+-. 25.52 69.37 .+-. 25.15 Cmax (ng/mL)
15.15 (27.81) 11.79 (24.56) 12.14 (27.91) 3.37 (34.44) 3.66 (33.56)
3.80 (33.35) 15.74 .+-. 4.38 12.14 .+-. 2.98 12.55 .+-. 3.50 3.60
.+-. 1.24 3.92 .+-. 1.31 4.08 .+-. 1.36 Cmin (ng/mL) 6.41 (19.98)
6.88 (30.70) 6.60 (25.79) 1.43 (39.02) 2.14 (41.92) 2.07 (42.40)
6.54 .+-. 1.31 7.20 .+-. 2.21 6.84 .+-. 1.76 1.56 .+-. 0.61 2.40
.+-. 1.01 2.32 .+-. 0.98 Cavg (ng/mL) 8.01 (19.31) 8.70 (27.32)
8.49 (21.98) 1.78 (35.25) 2.70 (36.10) 2.66 (36.26) 8.15 .+-. 1.57
9.02 .+-. 2.46 8.69 .+-. 1.91 1.92 .+-. 0.68 2.95 .+-. 1.06 2.89
.+-. 1.05 Tmax (hr)* 1.52 6.00 7.87 1.52 6.00 7.87 (0.50-13.48)
(2.00-16.00) (1.53-12.05) (0.50-13.48) (2.00-16.00) (1.53-12.05)
Degree of 113.74 .+-. 51.53 57.13 .+-. 28.34 66.92 .+-. 37.20
113.74 .+-. 51.53 57.13 .+-. 28.34 66.92 .+-. 37.20 Fluctuation (%)
Degree of 146.30 .+-. 70.76 76.61 .+-. 46.88 91.92 .+-. 62.46
146.30 .+-. 70.76 76.61 .+-. 46.88 91.92 .+-. 62.46 Swing (%)
Cmax/Cmin 2.46 .+-. 0.71 1.77 .+-. 0.47 1.92 .+-. 0.62 2.46 .+-.
0.71 1.77 .+-. 0.47 1.92 .+-. 0.62 Dose Uncorrected Data Dose
Corrected Data Intra- Intra- Ratio of Subject Ratio of Subject
Parameter 90% C.I. Means CV 90% C.I. Means CV Summary of
Pharmacokinetic Results Relative Bioavailability Assessments For
Day 14 versus Day 7 For Tacrolimus In All Patients: AUC.tau.*
88.63% to 107.23% 97.49% 28.44% 111.97% to 167.84% 137.09% 64.84%
Cmax 63.09% to 81.23% 71.59% 38.29% 84.52% to 119.91% 100.67%
54.74% Cmin 87.33% to 106.70% 96.53% 29.97% 107.43% to 171.51%
135.74% 77.33% Relative Bioavailability Assessments For Day 21
versus Day 7 For Tacrolimus In All Patients: AUC.tau.* 89.55% to
108.46% 98.55% 28.44% 113.19% to 170.03% 138.73% 64.84% Cmax 65.11%
to 83.95% 73.93% 38.29% 87.29% to 124.08% 104.07% 54.74% Cmin
87.91% to 107.53% 97.23% 29.97% 108.17% to 173.12% 136.84% 77.33%
Relative Bioavailability Assessments For Day 21 versus Day 14 For
Tacrolimus In All Patients: AUC.tau.* 91.86% to 111.26% 101.09%
28.44% 82.56% to 124.03% 101.20% 64.84% Cmax 90.96% to 117.27%
103.28% 38.29% 86.71% to 123.25% 103.38% 54.74% Cmin 91.07% to
111.40% 100.72% 29.97% 79.69% to 127.54% 100.81% 77.33% Correlation
Between AUC.tau. and Cmin For Tacrolimus: Day 7 Day 14 Day 21
AUC.tau. Cmin AUC.tau. Cmin AUC.tau. Cmin Parameter (ng hr/mL)
(ng/mL) (ng hr/mL) (ng/mL) (ng hr/mL) (ng/mL) Dose Uncorrected Data
Mean 5.35716 1.92049 5.33171 1.88517 5.34260 1.89238 Standard
0.25141 0.23353 0.29591 0.33707 0.28751 0.29989 Deviation
Correlation 0.78656 0.91380 0.86471 p-value <.0001 <.0001
<.0001 Dose Corrected Data Mean 3.55001 0.11346 3.86547 0.41903
3.87736 0.42713 Standard 0.54311 0.62557 0.62680 0.72963 0.60442
0.69479 Deviation Correlation 0.97266 0.99092 0.98176 p-value
<.0001 <.0001 <.0001 *median (min-max); #: .tau. = 24
hours *.tau. = 24 hours
Conclusion:
[0358] The primary objective of this study was to evaluate steady
state tacrolimus exposure (AUC.tau.) and trough levels (Cmin) in
stable kidney transplant recipients converted from Prograf.RTM.
(tacrolimus, Astellas Pharma US, Inc.) to LCP-Tacro in a three
sequence study design.
[0359] Following dose correction, the systemic exposure of
tacrolimus at steady-state (AUC.tau.) and the trough tacrolimus
levels (Cmin) were significantly higher when LCP-Tacro tablets q.d.
were administered compared to therapy with Prograf.RTM. Capsules
b.i.d. in kidney transplant patients. The systemic exposure
(AUC.tau. and Cmin) over the period of 24 hours of LCP-Tacro 2 mg
Tablets (q.d.) was .about.38% and .about.36% higher than that of
Prograf.RTM. Capsules (b.i.d). The average concentration of the
drug over the dosing interval, Cavg, was significantly higher for
the LCP-Tacro therapy compared to Prograf.RTM..
[0360] Also, there were no statistically significant differences in
the peak systemic exposure (Cmax) of tacrolimus between
Prograf.RTM. therapy and when LCP-Tacro was given on Days 14 and
21. In addition, the treatment with Prograf.RTM. showed a
significantly higher degree of fluctuation and swing compared to
LCP-Tacro. There was a greater correlation between AUC.tau. and
Cmin on days 14 and 21 (LCP-Tacro therapy) compared to Prograf.RTM.
(Day 7); however, the magnitude of difference was not high. There
were no significant differences in the overall systemic exposure,
trough tacrolimus levels or degree of fluctuation and swing when
comparing LCP-Tacro given on Day 14 compared to when it was given
on Day 21.
[0361] A sub-group analysis of blacks versus non-blacks who are
either on Prograf.RTM. or LCP-Tacro therapy, shows that there were
statistical differences in the peak and systemic exposure of
tacrolimus as well as the trough tacrolimus levels indicating the
necessity for caution when dosing the black population.
[0362] The results from this study show that following conversion
from Prograf to LCP-Tacro, LCP-Tacro therapy shows a significantly
higher systemic exposure and a less degree of fluctuation and swing
of tacrolimus at steady state when compared to when Prograf.RTM.
therapy is given to stable kidney transplant patients. In addition,
the peak exposure of tacrolimus is similar upon comparing the
different treatments; however the average concentration over the
dosing interval was higher for LCP-Tacro.
[0363] Discussion and Overall Conclusions: The primary objective of
this study was to evaluate steady state tacrolimus exposure
(AUC.tau.) and trough levels (Cmin) in stable kidney transplant
recipients converted from Prograf.RTM. (tacrolimus, Astellas Pharma
US, Inc.) to LCP-Tacro in a three sequence study design.
[0364] Following dose correction, the systemic exposure of
tacrolimus at steady-state (AUC.tau.) and the trough tacrolimus
levels (Cmin) were significantly higher when LCP-Tacro tablets q.d.
were administered compared to therapy with Prograf.RTM. Capsules
b.i.d. in kidney transplant patients. The systemic exposure
(AUC.tau. and Cmin) over the period of 24 hours of LCP-Tacro 2 mg
Tablets (q.d.) was .about.38% and .about.36% higher than that of
Prograf.RTM. Capsules (b.i.d). The average concentration of the
drug over the dosing interval, Cavg, was significantly higher for
the LCP-Tacro therapy compared to Prograf.RTM.. Also, there were no
statistically significant differences in the peak systemic exposure
(Cmax) of tacrolimus between Prograf.RTM. therapy and when
LCP-Tacro was given on Days 14 and 21. In addition, the treatment
with Prograf.RTM. showed a significantly higher degree of
fluctuation and swing compared to LCP-Tacro. There was a greater
correlation between AUC.tau. and Cmin on days 14 and 21 (LCP-Tacro
therapy) compared to Prograf.RTM. (Day 7); however, the magnitude
of difference was not high. There were no significant differences
in the overall systemic exposure, trough tacrolimus levels or
degree of fluctuation and swing when comparing LCP-Tacro given on
Day 14 compared to when it was given on Day 21.
[0365] A sub-group analysis of blacks versus non-blacks who are
either on Prograf.RTM. or LCP-Tacro therapy, shows that there were
statistical differences in the peak and systemic exposure of
tacrolimus as well as the trough tacrolimus levels indicating the
necessity for caution when dosing the black population.
[0366] The results from this study show that following conversion
from Prograf to LCP-Tacro, LCP-Tacro therapy shows a significantly
higher systemic exposure and a less degree of fluctuation and swing
of tacrolimus at steady state when compared to when Prograf.RTM.
therapy is given to stable kidney transplant patients. In addition,
the peak exposure of tacrolimus is similar upon comparing the
different treatments; however the average concentration over the
dosing interval was higher for LCP-Tacro.
Results from Study in Stable Liver Transplant Patients
[0367] Summary statistics of dose uncorrected pharmacokinetic
parameters of tacrolimus in male and female stable liver transplant
patients on days 7, 14, and 21
TABLE-US-00026 Day 7 Day 14 Day 21 Parameter Mean .+-. SD Mean .+-.
SD Mean .+-. SD AUCtau{circumflex over ( )} 205.09 .+-. 61.28
194.93 .+-. 58.99 215.52 .+-. 79.43 (ng hr/mL) 196.35 (29.88)*
185.34 (30.26)* 202.15 (36.85)* Cmax 18.46 .+-. 7.77 12.49 .+-.
4.08 13.70 .+-. 5.95 (ng/mL) 16.87 (42.07)* 11.80 (32.66)* 12.62
(43.39)* Cmin 6.72 .+-. 2.07 6.37 .+-. 2.38 6.85 .+-. 2.63 (ng/mL)
6.40 (30.76)* 5.91 (37.38)* 6.37 (38.44)* Tmax (hr) 3.18 .+-. 4.53
6.31 .+-. 3.47 5.92 .+-. 3.31 1.82 (142.58)* 5.32 (55.07)* 5.05
(55.84)* Cavg 8.55 .+-. 2.55 8.12 .+-. 2.46 8.98 .+-. 3.31 (ng/mL)
8.18 (29.88)* 7.72 (30.26)* 8.42 (36.85)* Degree of 133.46 .+-.
56.19 79.21 .+-. 47.10 76.60 .+-. 40.97 Fluctuation 121.09 (42.10)*
67.02 (59.47) 65.34 (53.48)* (%) Degree of 175.02 .+-. 80.68 112.44
.+-. 83.36 107.97 .+-. 67.32 Swing (%) 154.73 (46.10)* 87.59
(74.14)* 86.44 (62.35)* Cmax/Cmin 2.75 .+-. 0.81 2.12 .+-. 0.83
2.08 .+-. 0.67 2.63 (29.34)* 2.00 (39.24)* 1.98 (32.37)* *Geometric
Mean (% CV) N = 56 on day 21, N = 57 on day 7 and day 14
{circumflex over ( )}tau = 24 hrs. Day 7 - Prograf .RTM. capsules
b.i.d. orally Day 14 - LCP-Tacro tablets q.d. orally Day 21 -
LCP-Tacro tablets q.d. orally
[0368] Comparison of dose uncorrected pharmacokinetic parameters of
tacrolimus in male and female patients between day 7 and day 14
TABLE-US-00027 AUCtau{circumflex over ( )} Cmax Cmin 90% Geometric
C.I.* 85.12% to 61.81% to 82.12% to 104.67% 79.23% 103.69% Ratio of
Means** 94.39% 69.98% 92.28% CV*** 34.31% 41.75% 39.0 {circumflex
over ( )}tau = 24 hrs. 90% Geometric Confidence Interval using
log-transformed data. **Calculated using geometric means according
to the formula: e((test drug) - (reference drug)) .times. 100%.
***Coefficient of variation for log-transformed pharmacokinetic
parameter. Day 14 - LCP-Tacro tablets q.d. orally Day 7 - Prograf
.RTM. capsules b.i.d. orally
[0369] Comparison of dose uncorrected pharmacokinetic parameters of
tacrolimus in male and female patients between day 7 and day 21
TABLE-US-00028 AUCtau{circumflex over ( )} Cmax Cmin 90% Geometric
C.I.* 92.80% to 66.04% to 88.45% to 114.22% 84.75% 111.79% Ratio of
Means** 102.95% 74.81% 99.44% CV*** 34.3 41.75% 39.00% {circumflex
over ( )}tau = 24 hrs. 90% Geometric Confidence Interval using
log-transformed data. **Calculated using geometric means according
to the formula: e((test drug) - (reference drug)) .times. 100%.
***Coefficient of variation for log-transformed pharmacokinetic
parameter. Day 21 - LCP-Tacro tablets q.d. orally Day 7 - Prograf
.RTM. capsules b.i.d. orally 1
[0370] Comparison of dose uncorrected pharmacokinetic parameters of
tacrolimus in male and female patients between day 14 and day
21
TABLE-US-00029 AUCtau{circumflex over ( )} Cmax Cmin 90% Geometric
C.I.* 98.31% to 94.37% to 95.85% to 121.00% 121.11% 121.15% Ratio
of Means 109.07% 106.91% 107.76% CV*** 34.31% 41.75% 39.00%
{circumflex over ( )}tau = 24 hrs. *90% Geometric Confidence
Interval using log-transformed data. **Calculated using geometric
means according to the formula: e((test drug) - (reference drug))
.times. 100%. ***Coefficient of variation for log-transformed
pharmacokinetic parameter. Day 21 - LCP-Tacro tablets q.d. orally
Day 14 - LCP-Tacro tablets q.d. orally
[0371] Summary statistics of dose corrected pharmacokinetic
parameters of tacrolimus in male and female stable liver transplant
patients on days 7, 14, and 21
TABLE-US-00030 Day 7 Day 14 Day 21 Parameter Mean .+-. SD Mean .+-.
SD Mean .+-. SD AUCtau{circumflex over ( )} 38.13 .+-. 16.45 50.85
.+-. 21.96 51.12 .+-. 22.14 (ng hr/mL) 34.99 (43.13)* 45.87 (43.1
.sup. 46.85 (43.31)* Cmax 3.36 .+-. 1.65 3.19 .+-. 1.29 3.13 .+-.
1.23 (ng/mL) 3.01 (49.16) 2.92 (40.31 .sup. 2.92 (39.25)* Cmin 1.25
.+-. 0.54 1.68 .+-. 0.84 1.68 .+-. (ng/mL) 1.14 (43.57)* 1.46
(50.08)* 1.48 (52.17)* Tmax (hr) 3.18 .+-. 4.53 6.31 .+-. 3.47 5.92
.+-. 3.31 1.82 (142.58)* 5.32 (55.07)* 5.05 (55.84)* Cavg 1.59 .+-.
0.69 2.12 .+-. 0.92 2.13 .+-. 0.92 (ng/mL) 1.46 (43.13)* 1.91
(43.19)* 1.95 (43.31)* Degree of 133.46 .+-. 56.19 79.21 .+-. 47.10
76.60 .+-. 40.97 Fluctuation 121.09 (42.10)* 67.02 (59.47)* 65.34
(%) Degree of 175.02 .+-. 80.68 112.44 .+-. 83.36 107.97 .+-. 67.32
Swing (%) 154.73 (46.10 .sup. 87.59 (74.14 .sup. 86.44 (62.35)*
Cmax/Cmin 2.75 .+-. 0.81 2.12 .+-. 0.83 2.08 .+-. 0.67 2.63
(29.34)* 2.00 (39.24)* 1.98 (32.37)* *Geometric Mean (% CV)
{circumflex over ( )}tau = 24 hrs. Day 7 - Prograf .RTM. capsules
b.i.d. orally Day 14 - LCP-Tacro tablets q.d. orally Day 21 -
LCP-Tacro tablets q.d. orally
[0372] Comparison of dose corrected pharmacokinetic parameters of
tacrolimus in male and female patients between day 7 and day 14
TABLE-US-00031 AUCtau{circumflex over ( )} Cmax Cmin 90% Geometric
C.I.* 114.35% to 85.04% to 109.63% to 150.28% 111.06% 149.81% Ratio
of Means** 131.09% 97.19% 128.16 CV*** 46.33% 45.15% 53.77%
{circumflex over ( )}tau = 24 hrs. *90% Geometric Confidence
Interval using log-transformed data. **Calculated using geometric
means according to the formula: e((test drug) - (reference drug))
.times. 100%. ***Coefficient of variation for log-transformed
pharmacokinetic parameter. Day 14 - LCP-Tacro tablets q.d. orally
Day 7 - Prograf .RTM. capsules b.i.d. orally
[0373] Comparison of dose corrected pharmacokinetic parameters of
tacrolimus in male and female patients between day 7 and day 21
TABLE-US-00032 AUCtau{circumflex over ( )} Cmax Cmin 90% Geometric
C.I.* 116.73% to 85.09% to 110.56% to 153.59% 111.26% 151.29% Ratio
of Means** 133.90% 97.30% 129.33% CV*** 46.33% 45.15% 53.77%
{circumflex over ( )}tau = 24 hrs. *90% Geometric Confidence
Interval using log-transformed data. **Calculated using geometric
means according to the formula: e((test drug) - (reference drug))
.times. 100%. ***Coefficient of variation for log-transformed
pharmacokinetic parameter. Day 21 - LCP-Tacro tablets q.d. orally
Day 7 - Prograf .RTM. capsules b.i.d. orally
[0374] Comparison of dose corrected pharmacokinetic parameters of
tacrolimus in male and female patients between day 14 and day
21
TABLE-US-00033 AUCtau{circumflex over ( )} Cmax Cmin 90% Geometric
C.I.* 89.04% to 87.56% to 87.56% to 117.16% 114.48% 114.48% Ratio
of Means** 102.14% 100.12% 100.92% CV*** 46.33% 45.15% 53.77%
{circumflex over ( )}tau = 24 hrs. *90% Geometric Confidence
Interval using log-transformed data. **Calculated using geometric
means according to the formula: e((test drug) - (reference drug))
.times. 100%. ***Coefficient of variation for log-transformed
pharmacokinetic parameter. Day 21 - LCP-Tacro tablets q.d. orally
Day 14 - LCP-Tacro tablets q.d. orally
[0375] As appears from the results of the stable liver transplant
patients the following is obtained: Approximately 31% improvement
in bioavailability; approximately 30 reduction in dose achieved
bioequivalence for AUC(0-24) and C(min24); reduced Cmax:Cmin ratio
and high AUC:Cmin correlation.
Example 20
Comparison of a Formulation According to the Invention (LCP-Tacro)
Against a Commercial Available Extended Release Tacrolimus
Formulation for Once Daily Dosing, Advagraf.RTM.
[0376] The primary objective of this study is to determine and
compare the rate and extent of absorption of tacrolimus from a test
formulation of LCP-Tacro 2 mg Tablets taken once daily (q.d.)
versus the reference Advagraf.RTM. 2.times.1 mg Capsules (q.d.)
under multiple-dose, fasting conditions.
[0377] Advagraf.RTM. is manufactured by Astellas Pharma GmbH
Munich, Germany
Study Synopsis
TABLE-US-00034 [0378] Experimental A randomized, two-way crossover,
open-label, multiple-dose, fasting Design design. Population Thirty
normal, healthy, non-smoking Caucasian male subjects. Study Drugs
LCP-Tacro 2 mg Tablets Advagraf .RTM. 1 mg Capsules Treatments
Subjects will receive 1 of the following treatments on Days 1 to 10
of each study period, according to a randomization scheme:
Treatment A: 1 LCP-Tacro 2 mg Tablet (q.d.) (Daily treatment dose =
2 mg) Treatment B: 2 Advagraf .RTM. 1 mg Capsules (q.d.) (Daily
treatment dose = 2 mg) Duration of This study consists of 2
sixteen-day periods (with a follow-up visit 30 to Treatment 35 days
after the last dose of Period II) separated by at least a two-week
washout period from the last dose of Period I to the first dose of
Period II. Subjects will be institutionalized from the day before
Day 1 dosing until 24 hours after Day 10 dosing for each study
period. Subjects are required to return for subsequent blood draws.
Blood Pharmacokinetics (PK): Collection A total of 50 blood samples
(4 mL each) will be drawn in each period according to the following
schedule: Day 1: 0.00 (pre-dose), 0.50, 1.00, 1.50, 2.00, 3.00,
4.00, 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 12.00, 14.00, 16.00,
20.00 and 24.00 (pre- dose for Day 2 dosing) hours post-dose. Days
5, 6, 7, 8, and 9: 0.00 (pre-dose) and 12.00 hours post-dose. Day
10: 0.00 (pre-dose), 0.50, 1.00, 1.50, 2.00, 3.00, 4.00, 5.00,
6.00, 7.00, 8.00, 9.00, 10.00, 12.00, 14.00, 16.00, 20.00, 24.00,
48.00, 72.00, 96.00 and 120.00 hours post-dose. Blood Biochemistry
Collection Samples will be drawn during this study as follows:
(Cont'd) Pre-Study: At the screening visit(s) Days 3 and 8: 0.00
hour (pre-dose) End-of-Study: After the last return blood draw
Post-Study Follow-up visit: Between Days 30 to 35 after the last
dose of Period II. 457.5 mL of blood will be taken from each
subject. PK: The PK parameters was calculated using
non-compartmental analysis for tacrolimus as follows: Day 1:
AUC.sub.0-24, Cmax, C24, and T.sub.max. Day 10: AUC.tau. (.tau. =
24), C.sub.max, C.sub.min, C.sub.avg, T.sub.max, t1/2, Kel, %
Fluctuation, % Swing, AUC.tau./Cmin, Cmax/Cmin and Accumulation
Ratio (R). Statistics: Descriptive statistics was calculated for
blood concentrations and for all PK parameters. The ratio
(Test/Reference) of geometric least square means (LSMs) and the 90%
confidence interval (CI) was calculated for natural logarithmic
(ln) transformed parameters AUC0-24, AUC.tau., Cmax, C24, Cmin,
Cavg and untransformed parameters % Fluctuation, % Swing, R,
Cmax/Cmin, AUC.tau./Cmin, Kel and t1/2. Tmax was analyzed using
nonparametric methods.
[0379] The following results were obtained demonstrating
significant higher bioavailability with a product according to the
invention and at the same time having a profile demonstrating a
much more extended absorption of the drug of almost 50%, much lower
fluctuation in concentrations during the dosing period and high
concentration by the end of the dosing interval where by a true
once daily effect is obtained and any toxicity or side effect
related to periods with high concentrations is eliminated to the
extend possible with an oral once daily formulation. The present
invention provided a formulation which with an 2 mg oral dosing in
the morning provides an average concentration for full 24 hours
which is above 4 ng/mL (according to results below a Cmin of 4.66
ng/mL is provided) which is substantially higher than with the
marketed once daily product Advagraf.RTM. (Cmin 2.80 ng/mL) with
the same administered dosage.
[0380] Pharmacokinetic parameters of tacrolimus in healthy
Caucasian male subjects for treatment A, on day 1
TABLE-US-00035 TABLE 20-1 Cmax AUC (0-24) C24 Tmax (ng/mL) (ng
hr/mL) (ng/mL) (hr) Mean 3.60 49.79 1.82 7.52 SD (.+-.) 1.04 13.26
0.56 3.08 Median 3.57 46.63 1.69 7.00 CV (%) 28.79 26.63 30.65
40.88 Geometric 3.46 48.19 1.73 6.99 Mean Range (min) 2.07 27.56
0.66 3.00 (max) 5.47 79.18 2.85 16.00 n = 21 21 21 21 Treatment A:
1 LCP-Tacro 2 mg Tablet (q.d.)
[0381] Pharmacokinetic parameters of tacrolimus in healthy
Caucasian male subjects for treatment B, on day 1
TABLE-US-00036 TABLE 20-2 Cmax AUC (0-24) C24 Tmax (ng/mL) (ng
hr/mL) (ng/mL) (hr) Mean 3.44 34.00 0.97 2.19 SD (.+-.) 0.99 9.41
0.37 0.77 Median 3.28 33.04 0.83 2.00 CV (%) 28.78 27.67 38.37
34.97 Geometric 3.31 32.92 0.91 2.07 Mean Range (min) 2.19 22.07
0.58 1.00 (max) 5.48 61.56 2.00 4.00 n = 21 21 21 21 Treatment B: 2
Advagraf .RTM. 1 mg Capsules (q.d.)
[0382] Pharmacokinetic parameters of tacrolimus in healthy
Caucasian male subjects for treatment A, on day 10
TABLE-US-00037 TABLE 20-3 AUC.sub.tau Cmax Cmin Tmax Cavg Kel T1/2
Fluctuation Cmax/ ng hr/mL ng/mL ng/mL (hr) (ng/mL) (hr{circumflex
over ( )}(-1)) (hr) (%) Swing R Cmin Mean 142.27 8.39 4.66 7.03
5.93 1.87E-02 37.97 64.72 85.45 2.85 1.85 SD (.+-.) 49.41 2.89 1.71
2.96 2.06 2.76E-03 5.83 22.97 37.62 0.64 0.38 CV (%) 34.73 34.51
36.60 42.11 34.73 1.84E-02 37.62 35.48 44.03 22.42 20.29 Median
136.31 7.68 4.51 8.00 5.68 1.48E+01 15.36 64.06 87.79 2.91 1.88
Geometric 133.99 7.93 4.35 6.03 5.58 1.85E-02 37.56 60.92 78.16
2.77 1.82 Mean Range 69.84 4.53 1.94 1.00 2.91 1.42E-02 29.03 31.46
36.05 1.52 1.36 (min) (Max) 236.75 14.30 7.61 12.00 9.86 2.39E-02
48.94 123.52 191.31 4.29 2.91 n = 20 20 20 20 20 20 20 20 20 20 20
Tau = m 24 hrs Treatment A: 1 LCP Tacro 2 mg Tablet (q.d.)
[0383] Pharmacokinetic parameters of tacrolimus in healthy
Caucasian male subjects for treatment B, on day 10
TABLE-US-00038 TABLE 20-4 AUC.sub.tau Cmax Cmin Tmax Cavg Kel T1/2
Fluctation Cmax/ ng hr/mL ng/mL ng/mL (hr) ng/mL (hr{circumflex
over ( )}(-1)) (hr) (%) Swing R Cmin Mean 94.15 7.00 2.80 2.40 3.92
1.83E-02 38.65 110.22 158.53 2.80 2.59 SD (.+-.) 28.24 2.04 0.98
1.21 1.18 2.85E-03 5.69 28.20 48.20 0.86 0.48 CV (%) 29.99 29.21
34.79 50.40 29.99 1.77E-02 39.26 25.58 30.40 30.85 18.64 Median
89.82 6.97 2.52 2.00 3.74 1.55E+01 14.71 116.55 169.20 2.59 2.69
Geometric 89.86 6.71 2.64 2.16 3.74 1.81E-02 38.24 106.46 150.98
2.70 2.54 Mean Range 49.14 4.32 1.39 1.0 2.05 1.40E-02 28.10 54.97
74.41 1.82 1.74 (min) (Max) 138.85 10.50 4.46 6.00 5.79 2.47E-02
49.39 161.17 238.80 5.56 3.39 n = 20 20 20 20 20 20 20 20 20 20 20
Treatment B: 2 Advagraf .RTM. 1 mg Capsules (q.d.)
[0384] Comparison of Tmax of tacrolimus in healthy Caucasian male
subjects between days 1 and 10, for treatments A and B
TABLE-US-00039 TABLE 20-5 Day 1 Day 10 Estimate, Treatment Median
(Range) Median (Range) 90% C.I.* p-value** A 7.00 (3.00, 16.00)
8.00 (1.00, 12.00) 0.00 (-2.00, 2.00) 0.901 B 2.00 (1.00, 4.00)
2.00 (1.00, 6.00) 0.00 (-0.50, 0.00) 0.776 *Hodges-Lehmann point
estimate and 90% exact CI for the treatment difference. **p-value
for treatment comparison based on the Wilcoxon-Mann-Whitney test.
Treatment A: 1 LCP Tacro 2 mg Tablet (q.d.) Treatment B: 2 Advagraf
.RTM. 1 mg Capsules (q.d.)
[0385] Summary statistics and comparison of pharmacokinetic
parameters of tacrolimus in healthy Caucasian male subjects,
between treatments A and B, on day 1
TABLE-US-00040 TABLE 20-6 Treatment A Treatment B Paramenter n Mean
.+-. SD n Mean .+-. SD AUC(0-24) 21 49.79 .+-. 13.26 21 34.00 .+-.
9.41 (ng hr/mL) 48.19 (26.63)* 32.92 (27.67)* C24 (ng/mL) 21 1.82
.+-. 0.56 21 0.97 .+-. 0.37 1.73 (30.65)* 0.91 (38.37)* Cmax
(ng/mL) 21 3.60 .+-. 1.04 21 3.44 .+-. 0.99 3.46 (28.79)* 3.31
(28.78)* Tmax (hr) 21 7.00 (3.00, 16.00)** 21 2.00 (1.00, 4.00)**
*Geometric mean (% CV) **Median (Range) Treatment A: 1 LCP Tacro 2
mg Tablet (q.d.) Treatment B: 2 Advagraf .RTM. 1 mg Capsules
(q.d.)
[0386] Summary statistics and comparison of pharmacokinetic
parameters of tacrolimus in healthy Caucasian male subjects,
between treatments A and B, on day 1
TABLE-US-00041 TABLE 20-7 AUC (0-24) C24 Cmax 90% Geometric C.I. 1
133.95% to 161.80% to 93.92 to 163.57% 222.46% 118.70% Ratio of
Means 2 148.02% 189.72% 105.59% Intra-Subject CV 3 18.69% 30.18%
21.97% Degree of Freedom 19 19 19 1. 90% Geometric Confidence
Interval using log-transformed data 2. Calculated using geometric
means according to the formula: e ((test drug) - (reference drug))
.times. 100% 3. Intra-subject coefficient of variation for
log-transformed pharmacokinetic parameter Test: Treatment A: 1 LCP
Tacro 2 mg Tablet (q.d.) Reference: Treatment B: 2 Advagraf .RTM. 1
mg Capsules (q.d.)
[0387] Summary statistics and comparison of pharmacokinetic
parameters of tacrolimus in healthy Caucasian male subjects,
between treatments A and B, on day 10
TABLE-US-00042 TABLE 20-8 Treatment A Treatment B Parameter n Mean
.+-. SD n Mean .+-. SD AUCTau{circumflex over ( )} 20 142.27 .+-.
49.41 20 94.15 .+-. 28.24 (ng hr/mL 133.99 (34.73)* 89.86 (29.99)*
Cmax 20 8.39 .+-. 2.89 20 7.00 .+-. 2.04 (ng/mL) 7.93 (34.51)* 6.71
(29.21)* Cmin 20 4.66 .+-. 1.71 20 2.80 .+-. 0.98 (ng/mL) 4.35
(36.60)* 2.64 (34.79)* Tmax (hr) 20 7.03 .+-. 2.96 20 2.40 .+-.
1.21 6.03 (42.11)* 2.16 (50.40)* Cavg 20 5.93 .+-. 2.06 20 3.92
.+-. 1.18 (ng/mL) 5.58 (34.73)* 3.74 (29.99)* Degree of 20 64.72
.+-. 22.97 20 110.22 .+-. 28.20 Fluctuation 60.92 (35.48)* 106.46
(25.58)* (%) Degree of 20 85.45 .+-. 37.62 20 158.53 .+-. 48.20
Swing (%) 78.16 (44.03)* 150.98 (30.40)* R 20 2.85 .+-. 0.64 20
2.80 .+-. 0.86 2.77 (22.42)* 2.70 (30.85)* Cmax/Cmin 20 1.85 .+-.
0.38 20 2.59 .+-. 0.48 1.82 (20.29)* 2.54 (18.64)* T1/2 (hr) 20
37.97 .+-. 5.83 20 38.65 .+-. 5.69 Kel (hr{circumflex over (
)}(-1)) 20 1.87E-02 .+-. 2.76E-03 20 1.83E-02 .+-. 2.85E-03
*Geometric mean (% CV) Treatment A: 1 LCP Tacro 2 mg Tablet (q.d.)
Treatment B: 2 Advagraf .RTM. 1 mg Capsules (q.d.)
[0388] Summary statistics and comparison of pharmacokinetic
parameters of tacrolimus in healthy Caucasian male subjects,
between treatments A and B, on day 10
TABLE-US-00043 TABLE 20-9 AUCtau{circumflex over ( )} Cmax Cmin 90%
Geometric C.I.* 137.43% to 105.33% to 152.29% to 161.12% 127.73%
180.25% Ratio of Means** 148.80% 115.99% 165.68% Intra-Subject
CV*** 13.98% 16.99% 14.83% Degree of Freedom 17 17 17 {circumflex
over ( )}tau = 24 hrs *90% Geometric Confidence Interval using
log-transformed data **Calculated using geometric means according
to the formula: e ((test drug) - (reference drug)) .times. 100%
***Intra-subject coefficient of variation for log-transformed
pharmacokinetic parameter. Treatment A: 1 LCP Tacro 2 mg Tablet
(q.d.) Treatment B: 2 Advagraf .RTM. 1 mg Capsules (q.d.)
TABLE-US-00044 Extended release composition, stabilized LCP-Tacro 2
mg Tacrolimus monohydrate (2.00 mg calculated on 2.0400 mg the
anhydrous basis) Excipients Butylated hydroxytoluene 10.200 .mu.g
Dimethicone 350 0.25500 .mu.g Hypromellose 2208 (15,000 cp) 62.866
mg Lactose monohydrate 41.727 mg Magnesium stearate 1.5716 mg
Opadry II white 85G18490 4.7232 mg Poloxamer 188 14.688 mg
Polyethylene glycol 6,000 34.272 mg Tartaric acid 255.00 .mu.g
Example 21
[0389] Table disclosing dissolution of a preferred embodiment of
the invention having a composition as demonstrated above in Example
20 and the dissolution of the commercial product Advagraf.RTM. used
for comparison in Example 20.
[0390] Release measured in percentage, dissolution method USP II
dissolution test (paddle) method in a medium adjusted to pH 4.5 and
comprising 0.005% hydroxylpropylcellulose, and a rotation of 50
rpm. The dissolution are disclosed in FIG. 4.
TABLE-US-00045 Dissolution Extended Formulation Batch no. 0988/2006
0989/2006 0990/2006 1 mg 2 mg 5 mg Time, hrs assay RSD assay RSD
Assay RSD 1 1.1 31.5 5 12.9 6.8 14.2 2 7.2 7.9 7.9 10.6 10.1 14.5 3
10.1 15.4 10.8 12.3 13.4 18.2 5 18.1 10.6 15.4 23.5 20.4 19.5 9
30.4 13.2 33.8 33.5 35.6 16.1 12 45.3 9.9 48 18.4 43.3 13.2 15 61.4
9.1 59.6 10.2 45.3 10 20 74 2.6 68.4 5.8 47 9.3 24 80.9 3.5 72.2
3.7 47.5 7.6 Formulation Advagraf Batch no. OM4001A 1M6002A 5M4002A
0.5 mg 1 mg 5 mg Time, hrs assay RSD assay RSD assay RSD 1 15.9 4.6
21.2 24.5 13.6 19.1 2 27.2 11.3 30.9 29.4 29.2 9.6 3 37.3 15 39.2
24.9 36.2 7 5 48.5 13 45.8 21.5 46 7.4 9 61.2 7.3 58 16.8 57.1 7.1
12 65 9.3 63 15.7 60.2 4.4 15 70.4 9.9 66.6 14.7 63.6 7.8 20 71.3
9.7 69.3 13.4 67 6.4 24 74.1 7.4 68.1 15.3 69.3 6.6
[0391] As appears from the dissolution, the extended release
formulation according to the present invention provides a much
longer and more extended profile with considerable lower release
initially, for instance demonstrated by lower than 25% release at
the 5 hour time point, despite a release at 3 hours which are at
least 10%. Additionally, the curve profile according to the present
invention has a substantial zero order release and a very extended
release. The latter being clearly demonstrated by a less than 50%
release at the 12 hour time point, and less than 62% release at the
15 hour time point. As appears from Example 20, the pharmacokinetic
parameters are substantially improved with the extended release
formulation according to invention in comparison with the
commercially available Advagraf.RTM. product.
[0392] In addition, the extended release formulation according to
the present invention may be provided in a much smaller tablet
compared with Advagraf.RTM. as appears from the table below.
TABLE-US-00046 Dosage from and Volume of dosage form, Ratio
Advagraf:LCP- strengts mm3 Tacro (same strengts) Advagraf .RTM. 0.5
mg 180 Advagraf .RTM. 1 mg 244 1.7 Advagraf .RTM. 5 mg 927 2.7
LCP-Tacro .TM. 1 mg 140 LCP-Tacro .TM. 2 mg 140 LCP-Tacro .TM. 5 mg
346
Example 22
Extended Release Tacrolimus in De Novo Kidney Transplant
Patients
[0393] De novo kidney transplant patients were randomized (1:1
ratio) within 12 hours after transplantation (Study Day 0) to
receive either: 1) LCP-Tacro tablets (as outlined in Example 20 and
the dissolution demonstrated in Example 21) orally once daily in
the morning, with an interval of 24.+-.1 hours between doses,
starting at 0.14 mg/kg (the starting daily dose for Black patients
was 0.17 mg/kg), or 2) Prograf capsules in two equally divided
doses, starting at 0.1 mg/kg every 12 hours (0.2 mg/kg total daily
dose) as currently recommended in the U.S. Prescribing Information
(Astellas Pharma US, April 2006, NDA no. 050708). A 24-hour
pharmacokinetic (PK) assessment was performed on Study Days 1, 7
and 14. Study Day 1 was defined as the day on which the first
morning (AM) dose of study drug was given, which had to be within
48 hours of transplantation. Results are shown in table 22.
TABLE-US-00047 TABLE 22 LCP-Tacro .TM. Prograf .RTM. Parameter Day
n Mean .+-. SD n Mean .+-. SD C.sub.max 1 31 11.56 .+-. 6.83 30
23.41 .+-. 11.10 (ng/mL) 9.52 (59.11) 20.83 (47.41)* 7 29 27.41
.+-. 17.53 28 24.12 .+-. 12.78 23.11 (63.95)* 20.97 (52.99)* 14 28
28.21 .+-. 13.68 28 20.27 .+-. 6.49 25.65 (48.51)* 19.15 (32.04)*
Cmin 1 31 5.80 .+-. 3.73 30 9.22 .+-. 4.35 (ng/mL) 4.90 (64.20)*
8.27 (47.18)* 7 29 10.58 .+-. 7.18 28 10.35 .+-. 5.16 8.92 (67.90)*
9.39 (49.92)* 14 28 10.37 .+-. 4.24 28 8.12 .+-. 3.13 9.51 (40.84)*
7.45 (38.57)* Tmax 1 31 11.97 (4.02, 24.00)** 30 4.00 (0.98,
24.00)** (hr) 7 29 6.00 (1.52, 12.10)** 28 1.61 (0.50, 24.00)** 14
28 4.00 (1.33, 8.07)** 28 1.88 (0.50, 14.05)** Cavg 1 30 5.47 .+-.
3.20 29 10.59 .+-. 4.43 (ng/mL) 7 27 13.31 .+-. 5.16 28 11.90 .+-.
4.09 14 28 14.55 .+-. 4.66 28 10.61 .+-. 3.34 Degree of 1 30 89.90
.+-. 65.56 29 137.61 .+-. 77.01 fluctua- 7 27 135.95 .+-. 121.44 28
107.74 .+-. 76.92 tion (%) 14 28 131.10 .+-. 98.50 28 122.60 .+-.
59.98 Degree of 1 31 118.07 .+-. 110.07 30 181.76 .+-. 126.72 swing
(%) 7 29 215.52 .+-. 244.56 28 152.79 .+-. 135.61 14 28 210.18 .+-.
182.42 28 174.49 .+-. 100.91 AUCR 1-7 26 4.30 .+-. 7.03 27 1.32
.+-. 0.69 Day 7 to Day 1 AUCR 1-14 28 4.37 .+-. 5.26 28 1.19 .+-.
0.59 Day 14 to Day 1 AUCR 7-14 27 1.21 .+-. 0.51 28 1.04 .+-. 0.56
Day 14/ Day 7 *Geometric mean (% CV) **Median (Range) AUCR is the
accumulation ratio of AUC.tau. on the day shown to day 1
[0394] The AUC.sub.0-.tau. for LCP-Tacro is significantly lower
than that for Prograf.RTM. for the first day after transplantation
(The dose uncorrected LCP-Tacro AUC.sub.0-.tau. on Day 1 in the
present was 131.11.+-.76.78 versus 253.45.+-.106.58 (nghr/mL)).
However, for reduction of initial overimmunesuppression this is
considered an advantage especially if the patients receives
induction therapy and corticosteroids. According to the present
invention, a target through value of 5-10 ng/mL (immunoassay
method) is considered an optimal treatment compared with the
extended release formulation according to the invention. Preferable
in combination with a mycophenolate regimen with 1 gram twice daily
administered in the form of mycophenolate mofetil (CellCept.RTM.)
NDA no. 050722 and 050723 or a dosage form with an equivalent
amount of mycophenolic acid such as Myfortic.RTM. NDA no 050791
(including generics thereto)
[0395] Examples of immunoassays for tacrolimus trough value
measurements:
TABLE-US-00048 Tacrolimus Trough Method Microparticle Enzyme
Immunoassay (MEI) (Abbott) Cedia Cloned Enzyme Donor Immunoassay
Siemens Dimension methodology Enzyme immunoassay Abbott IMX
Microparticle Enzyme Immunoassay (MEI) (Abbott)
TABLE-US-00049 [0396] ARCHITEC tacrolimus assay - chemiluminescent
immunoassay (CMIA) Abbott Imx Cedia Cloned Enzyme Donor
Immunoassay
[0397] From the below Table (Table 23) it appears that a higher
proportion of the patients obtain the target trough concentration
according to the present invention of 5-10 ng/mL.
[0398] The table also shows that approximately two-thirds of the
patients treated with LCP-Tacro are within the 5-7 ng/mL range
after the first dose of LCP-Tacro and by Day 3 over 80% of the
patients treated with LCP-Tacro were above the minimum 5 ng/mL
level.
TABLE-US-00050 TABLE 23 Proportion of patients within and outside
of a target concentration of 5-10 ng/mL (No (%)) Trough (ng/mL)
Study drug Day 2 Day 3 Day 4 Day 7 Day 10 Day 12 Day 14 <5
LCP-Tacro 8 (26.7) 6 (20.0) 5 (1.7) 3 (9.7) 0 (0.0) 0 (0.0) 1 (3.4)
Prograf .RTM. 1 (3.6) 2 (6.7) 2 (7.7) 2 (6.5) 0 (0.0) 1 (3.7) 2
(6.9) 5-10* LCP-Tacro 14 (46.7) 13 (43.3) 11 (36.7) 12 (38.7) 6
(24.0) 5 (25.0) 7 (24.1) Prograf .RTM. 12 (42.9) 9 (30.0) 8 (30.8)
9 (29.0) 10 (38.5) 6 (22.2) 11 (37.9) >10 LCP-Tacro 8 (26.7) 11
(36.7) 14 (46.7) 16 (51.6) 19 (76.0) 15 (75.0) 21 (72.4) Prograf
.RTM. 15 (53.6) 19 (63.3) 16 (61.5) 20 (64.5) 16 (61.5) 20 (74.1)
16 (55.2)
Example 23
Clinical Studies with an Extended Release Formulation According to
the Present Invention
Table A
[0399] Table A is a list of initial Clinical studies with an
extended release formulation according to the present invention.
The list includes the improved pharmacokinetic parameters obtained
with an extended release formulation according to the present
invention and claimed herein.
TABLE-US-00051 TABLE A Cmax Cmin12 Cmin24 Kel Tmax T1/2 LCP Fasted
Study 002 10.05 .+-. 3.99 6.92 4.32 0.0217 8.55 .+-. 2.72 31.95
Study 003 3.62 NA NA NA 6.71 (0.5-12) 39.04 Study 004 2.82 .+-.
0.96 2.42 .+-. 0.87 1.83 .+-. 0.72 NA 9.69 .+-. 4.90 NA Study 005
14.31 .+-. 4.29 6.504 .+-. 2.58 4.09 .+-. 1.70 2.07E-02 5.17 .+-.
1.68 35.14 .+-. 8.37 Prograf .RTM. Fasted Study 002 32.75 .+-. 9.65
3.508 2.268 0.0208 1.63 .+-. 0.43 33.16 Study 003 NA NA NA NA NA NA
Study 004 5.26 .+-. 1.28 0.63 .+-. 0.18 NA NA 1.38 .+-. 0.42 NA
Study 005 31.76 .+-. 8.81 4.24 .+-. 1.73 3.13 .+-. 1.14 2.05E-02
1.38 .+-. 0.34 34.86 .+-. 7.04
[0400] Plasma profiles from the studies shown in Tables A and B are
shown in FIG. 3.
TABLE-US-00052 TABLE B Subjects Title Study 002 12 2-way
cross-over; single-dose, fasting; LCP- Tacro tablets 2 .times. 2 mg
modified release vs. Prograf capsules 4 .times. 1 mg (tacrolimus)
Study 003 6 2-way replicated design; single-dose, fasting,
colon-absorption study on LCP-Tacro 2 mg Study 004 13 2-way
crossover, multi-dose, fasting, relative bioavailability study;
LCP-Tacro tablets 2 mg q.d. vs. Prograf capsules 2 .times. 1 mg
b.i.d.
Single-Dose, Comparative PK Study (Study 002):
[0401] Study 002, a single-dose comparative pharmacokinetic study
of LCP-Tacro 4 mg (2.times.2 mg tablets) vs. Prograf.RTM. 4 mg
(4.times.1 mg capsules) demonstrated comparable AUC for both
products when administered under fasting conditions. However, they
differ in their rate of absorption when administered in the fasted
condition, being slower and more sustained for the test
formulation, LCP-Tacro. The longer T.sub.max for LCP-Tacro tablets
(test; HPMC) vs. Prograf.RTM. capsules (tacrolimus; reference)
(8.55 h vs. 1.63 h) combined with the lower C.sub.max (10.05 ng/ml
vs. 32.75 ng/ml) and lower AUC(0->24) (122.4 ng*h/mL vs. 157.95
ng*h/mL), supports a once-a-day dosing for LCP-Tacro tablets
compared to Prograf.RTM. capsules (tacrolimus)
Study 003:
[0402] Study 003 was designed as a replicate scintigraphic
absorption study in 8 healthy volunteers to evaluate the transit
time, pharmacokinetic profile and site of release of LCP-Tacro 2 mg
tablets, radiolabelled with a maximum of 1 MBq 153 Sm. In this
study, an extended release profile could be demonstrated with a
T.sub.max of .about.6.7 hours. LCP-Tacro was well tolerated.
Overall, this study demonstrated an in vivo extended release
profile of LCP-Tacro tablets with release in all parts of the
colon, and absorption of tacrolimus from distal parts of the
gastrointestinal tract. The scintigraphic pictures are disclosed in
FIG. 2 where pictures are taken 0.02, 0.53, 4.32, 4.57, 11.23, and
23.32 hours post-dose respectively.
Multi-Dose, Steady-State, Comparative PK Study (Study 004):
[0403] Study 004 is a multi-dose, steady-state comparative
pharmacokinetic study of LCP-Tacro 2 mg q.d. vs. Prograf.RTM.
2.times.1 mg b.i.d in 14 healthy volunteers. This study
demonstrated clearly a once-a-day profile of LCP-Tacro versus
Prograf.RTM. b.i.d. In addition, this study demonstrated superior
bioavailability of LCP-Tacro tablets given once-a-day compared to
Prograf.RTM. capsules given twice-a-day. Upon administration of
LCP-Tacro 2 mg tablets (q.d.) and Prograf.RTM. 1 mg capsules
(b.i.d.) for 10 successive days, there were no significant
differences observed in the morning pre-dose concentrations between
Days 7, 8, 9, and 10, therefore steady state was maintained since
Day 7. At steady state, the systemic exposure over the period of 24
hours of LCP-Tacro 2 mg Tablets (q.d.) was about 50% higher than
that of Prograf 1 mg capsules (b.i.d.). The time to peak
concentration between the single and multiple doses of LCP-Tacro 2
mg q.d. and Prograf.RTM. 2.times.1 mg b.i.d was similar for both
treatments. As expected due to the extended release profile
according to the invention, the LCP-Tacro 2 mg tablets (q.d.) had
higher C.sub.min values and lower degree of fluctuation than that
of the immediate-release Prograf.RTM. 1 mg capsules (b.i.d.). There
was no significant difference observed in C.sub.max between the 2
treatments, as shown below in table 25.
TABLE-US-00053 TABLE 25 Pharmacokinetic Parameter Summary of Study
004 Geometric Mean (% CV) Arithmetic Mean .+-. SD LCP-Tacro Prograf
.RTM. 2 mg Tablets 1 mg Capsules (A; n = 13) (B; n = 13) AUC.tau.
(ng hr/mL) (34.98) (34.26) 115.07 .+-. 40.25 43.65 .+-. 14.95
AUC.sub.0-24 (ng hr/mL) Not applicable 72.95 (34.40) 76.93 .+-.
26.46 C.sub.max (ng/mL) 6.42 (36.55) 6.71 (31.30) 6.80 .+-. 2.49
7.02 .+-. 2.20 C.sub.min (ng/mL) 3.12 (35.20) 2.00 (40.51) 3.31
.+-. 1.17 2.14 .+-. 0.87 T.sub.max (hr)* 8.00 (6.00-10.02) 1.50
(1.00-2.00) t.sub.1/2 (hr) 32.93 .+-. 2.66 32.59 .+-. 4.08.dagger.
C.sub.max/C.sub.min 2.12 .+-. 0.51 3.43 .+-. 0.75 *median
(min-max); .dagger.n = 12
TABLE-US-00054 TABLE C List of additional Studies Study No/ Phase
Subjects Title Study 1011 30 A two-way crossover single-dose study
of LCP-Tacro 5 mg tablet vs. Prograf 5 mg capsule Study 1012 25 A
two-way crossover, open-label, multi-dose, fasting relative
bioavailability study of LCP- Tacro 2 mg q.d. vs. Prograf 1 mg
b.i.d. .times. 10 days Study 1013 25 A single-dose, dose-linearity
study of LCP- Tacro 5 mg vs. 7 mg vs. 10 mg Study 1014 26 A
single-dose chrono-pharmaco-kinetic study of LCP-Tacro 2 mg tablets
administered morning vs. evening Study 1015 17 A single-dose
relative bioavail-ability study of LCP-Tacro 1 mg tablet vs.
Prograf 1 mg capsule Study 1016 28 A two-way crossover, open-label,
multi-dose, fasting relative bioavailability study of LCP- Tacro 2
mg q.d. vs. Prograf 1 mg b.i.d. .times. 10 days
Multi-Dose, Steady-State, Comparative PK Study (Study 1012):
[0404] This study evaluated and compared the bioavailability of
tacrolimus from a test formulation of LCP-Tacro 2 mg tablets taken
once daily (q.d.) in group A versus the reference Prograf 1 mg
capsules taken twice daily (b.i.d.) in group B, under
multiple-dose, fasting conditions. The study population consisted
of 30 healthy volunteers receiving study treatment for a period of
10 days followed by a two-week wash-out and subsequent crossover
between study groups. Twenty five patients were evaluable for this
study. The pharmacokinetics of tacrolimus on Day 10 are summarized
in Tables 26-27 below.
TABLE-US-00055 TABLE 26 Pharmacokinetic parameters for tacrolimus
on Day 10 (Study 1012) Geometric Mean (% CV) Arithmetic Mean .+-.
SD LCP-Tacro Prograf .RTM. Pharmacokinetic 2 mg Tablets 1 mg
Capsules Parameters (A; q.d.; n = 25) (B; b.i.d.; n = 25) AUC0-12
70.71 (27.94) 48.98 (44.05) (ng hr/mL) 73.65 .+-. 20.58 54.22 .+-.
23.88 AUC12-24 54.81 (31.10) 36.48 (43.15) (ng hr/mL) 57.72 .+-.
17.95 40.28 .+-. 17.38 Cmax (ng/mL) 7.49 (31.74) 8.06 (40.91) 7.85
.+-. 2.49 8.72 .+-. 3.57 C12 (ng/mL) 5.68 (31.88) 2.47 (46.73) 6.00
.+-. 1.91 2.78 .+-. 1.30 Cavg (ng/mL) 5.24 (29.04) 3.57 (42.80)
5.47 .+-. 1.59 3.94 .+-. 1.68 Tmax (hr)* 6.00 (1.00-10.00) 1.50
(1.00-13.00) AUC0-12/C12 (hr) 12.44 (13.44) 19.82 (11.53) 12.54
.+-. 1.68 19.94 .+-. 2.30 AUC.tau./Cmin (hr) 32.00 (6.83) 32.14
(11.25) 32.07 .+-. 2.19 32.34 .+-. 3.64 AUC12-24/Cmin (hr) 13.96
(5.70) 13.69 (13.13) 13.98 .+-. 0.80 13.80 .+-. 1.81 *median
(min-max)
TABLE-US-00056 TABLE 27 Relative bioavailability assessments for
tacrolimus on Day 10 (Study 1012) Ratio of Intra- Parameter 90%
C.I. Means Subject CV AUC.tau. 131.49% to 162.84% 146.33% 22.31%
Cmin 131.27% to 163.97% 146.71% 23.22%
TABLE-US-00057 TABLE 28 Summary of pharmacokinetic parameters for
study 1013 (Dose proportionality, NHV, n = 25). Treatment B
Treatment A 1 .times. 5 mg + Treatment C 1 .times. 5 mg 1 .times. 2
mg 2 .times. 5 mg AUC0-12 88.23 .+-. 32.87 125.33 .+-. 44.96 186.15
.+-. 56.81 (ng hr/mL) AUC0-24 143.00 .+-. 54.23 212.69 .+-. 77.30
307.05 .+-. 98.07 (ng hr/mL) AUC0-t 303.55 .+-. 133.60 449.63 .+-.
173.51 648.81 .+-. 224.20 (ng hr/mL) AUC0-inf 324.46 .+-. 143.52
473.40 .+-. 182.86 687.68 .+-. 241.22 (ng hr/mL) Cmax 12.21 .+-.
4.84 16.73 .+-. 5.22 24.91 .+-. 7.15 (ng/mL) Tmax (hr) 5.18 .+-.
2.36 5.63 .+-. 2.53 5.76 .+-. 1.39 C24 3.91 .+-. 1.74 6.11 .+-.
2.57 8.63 .+-. 3.43 (ng/mL)
[0405] Study 1014 (Diurnal Variability, NHV):
[0406] This study investigated the pharmacokinetic profile of
tacrolimus after administration of LCP-Tacro 2 mg in the morning
vs. evening in 26 male and female healthy volunteers under fasting
conditions. The study consisted of two eight-day periods separated
by at least a two-week washout period between treatments. The mean
pharmacokinetic parameters are summarized in Table 29 below.
TABLE-US-00058 TABLE 29 Summary of Pharmacokinetic Parameters from
study 1014 Evening Dose Morning Dose 1 .times. 2 mg, n = 26 1
.times. 2 mg, n = 25 AUC.sub.0-t (ng hr/mL) 61.65 .+-. 24.31 113.10
.+-. 41.89 AUC.sub.0-12 (ng hr/mL) 28.18 .+-. 8.28 29.85 .+-. 9.20
AUC.sub.0-24 (ng hr/mL) 50.51 .+-. 14.74 54.50 .+-. 16.80
AUC.sub.0-inf (ng hr/mL) 106.74 .+-. 35.11 124.78 .+-. 42.82
C.sub.max (ng/mL) 4.39 .+-. 1.21 4.20 .+-. 1.46 T.sub.max (hr) 6.77
.+-. 2.69 6.66 .+-. 2.79 C24 (ng/mL) 1.34 .+-. 0.52 1.69 .+-.
0.67
TABLE-US-00059 TABLE 30 Study 1014 - Diurnal variability, NHV Ratio
of means (%) Intra-subject CV (%) AUC0-t 86.93 39.48 AUC0-12 97.95
26.91 AUC0-24 95.67 26.67 AUC0-inf 87.64 35.56 Cmax 109.65
29.49
Study 1015
[0407] This study compared the rate and extent of absorption of
tacrolimus after LCP-Tacro 1 mg tablet vs. Prograf.RTM.
(tacrolimus) 1 mg capsule under fasting conditions in 17 normal
healthy male or female subjects. The study consisted of two
eight-day periods separated by at least a two-week washout period
between treatments. Pharmacokinetic results are summarized in Table
below. The longer T.sub.max for LCP-Tacro tablets (8.78 h vs. 1.39
h) combined with the lower C.sub.max (2.54 ng/mL vs. 7.04 ng/mL)
and lower AUC(0-inf) (71.82 ng*h/mL vs. 50.18 ng*h/mL), supports a
once-a-day dosing for LCP-Tacro tablets compared to Prograf.RTM.
capsules (tacrolimus).
TABLE-US-00060 LCP-Tacro vs. Prograf, NHV, n = 17 LCP-Tacro Prograf
.RTM. 1 .times. 1 mg tablet 1 .times. 1 mg capsule AUC0-t (ng
hr/mL) 61.65 .+-. 24.31 36.15 .+-. 22.71 AUC0-12 (ng hr/mL) 16.43
.+-. 5.98 22.93 .+-. 10.64 AUC0-24 (ng hr/mL) 31.21 .+-. 8.90 28.77
.+-. 13.75 AUC0-inf (ng hr/mL) 71.82 .+-. 26.52 50.18 .+-. 28.38
Cmax (ng/mL) 2.54 .+-. 1.03 7.04 .+-. 3.56 Tmax (hr) 8.78 .+-. 5.05
1.39 .+-. 0.50 C24 (ng/mL) 1.04 .+-. 0.36 0.46 .+-. 0.25 Study 1015
- Diurnal variability, NHV, n = 17 Ratio of means (%) Intra-subject
CV (%) AUC0-t 187.29 58.06 AUC0-12 74.89 42.87 AUC0-24 116.97 40.10
AUC0-inf 154.08 50.73 Cmax 37.63 51.81
[0408] Exposure to tacrolimus is significantly higher after
LCP-Tacro tablets than after Prograf capsules, with reduced
peak/trough fluctuation and delayed Tmax in NHV. The results are
consistent with other PK data obtained with the extended release
formulation according to the present invention.
[0409] The release time for the extended release dosage forms
according to the invention used in the clinical trials described
herein all provides an extended release profile where less than
63.5% is released within 15 hours. A relevant release profile in
this respect is demonstrated in FIG. 1 tested according to the USP
II dissolution test (paddle) in a medium at pH 4.5 and comprising
0.005% hydroxypropylcellulose, and a rotation of 50 rpm.
Example 24
[0410] A phase 1, two-way crossover, open label, multidose,
bioequivalence study comparing the pharmacokinetics (Cmax, C24, and
AUCtau), and safety of LCP-Tacro Tablets versus Advagraf.RTM.
Capsules in steady state, fasting conditions was conducted.
[0411] Twenty healthy male volunteers were randomized to receive
either one LCP-Tacro 2 mg tablet or two Advagraf.RTM. 1 mg Capsules
daily for 10 days. After a two week washout period, each subject
then received the alternative treatment. The PK profile after 10
days of each treatment is illustrated in the FIG. 7 and demonstrate
that LCP-Tacro Tablets provide approximately 50% greater
bioavailability of tacrolimus than a comparable dose of
Advagraf.RTM.. The PK profile of the LCP-Tacro Tablets also
supports once-a-day administration.
[0412] Patents, patent applications, publications, product
descriptions, and protocols which are cited throughout this
application are incorporated herein by reference in their
entireties.
[0413] The embodiments illustrated and discussed in this
specification are intended only to teach those skilled in the art
the best way known to the inventors to make and use the invention.
Nothing in this specification should be considered as limiting the
scope of the present invention. Modifications and variation of the
above-described embodiments of the invention are possible without
departing from the invention, as appreciated by those skilled in
the art in light of the above teachings. It is therefore understood
that, within the scope of the claims and their equivalents, the
invention may be practiced otherwise than as specifically
described.
* * * * *