U.S. patent application number 16/531707 was filed with the patent office on 2019-11-21 for transmucosal administration system for a pharmaceutical drug.
The applicant listed for this patent is LTS Lohmann Therapie-Systeme AG, Santhera Pharmaceuticals (Schweitz) AG. Invention is credited to Judith DUBACH-POWELL, Rudolf HAUSMANN, Keith JENSEN, Markus KRUMME.
Application Number | 20190350872 16/531707 |
Document ID | / |
Family ID | 47559517 |
Filed Date | 2019-11-21 |
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United States Patent
Application |
20190350872 |
Kind Code |
A1 |
KRUMME; Markus ; et
al. |
November 21, 2019 |
Transmucosal Administration System for a Pharmaceutical Drug
Abstract
The invention generally relates to transmucosal administration
systems for administering quinones, benzoquinones, and especially
1,4-benzoquinones, via the oromucosal route. The present invention
more specifically relates to methods of treatment for Duchenne
Muscular Dystrophy that includes administering to a patient a dose
in the form of one or more transmucosal administration systems.
Inventors: |
KRUMME; Markus; (Neuwied,
DE) ; JENSEN; Keith; (Clifton, DE) ;
DUBACH-POWELL; Judith; (Oberwil, DE) ; HAUSMANN;
Rudolf; (Basel, US) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LTS Lohmann Therapie-Systeme AG
Santhera Pharmaceuticals (Schweitz) AG |
Andernach
Liestal |
|
DE
CH |
|
|
Family ID: |
47559517 |
Appl. No.: |
16/531707 |
Filed: |
August 5, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14372878 |
Jul 17, 2014 |
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PCT/EP2013/050822 |
Jan 17, 2013 |
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16531707 |
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13354714 |
Jan 20, 2012 |
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14372878 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 3/00 20180101; A61P
21/00 20180101; A61P 27/06 20180101; A61K 47/38 20130101; A61P
17/06 20180101; A61P 35/00 20180101; A61K 31/122 20130101; A61P
25/16 20180101; A61K 9/7007 20130101; A61P 29/00 20180101; A61P
43/00 20180101; A61P 19/02 20180101; A61K 47/32 20130101; A61P 3/04
20180101; A61P 9/10 20180101; A61P 9/00 20180101; A61P 25/08
20180101; A61P 21/04 20180101; A61K 9/006 20130101; A61K 9/0056
20130101; A61P 25/14 20180101; A61P 27/02 20180101; A61P 13/12
20180101; A61P 11/00 20180101; A61P 25/10 20180101; A61P 25/00
20180101; A61P 11/06 20180101; A61P 25/28 20180101; A61P 37/02
20180101; A61P 3/10 20180101; A61P 25/18 20180101; A61P 21/02
20180101 |
International
Class: |
A61K 9/70 20060101
A61K009/70; A61K 9/00 20060101 A61K009/00; A61K 31/122 20060101
A61K031/122; A61K 47/32 20060101 A61K047/32; A61K 47/38 20060101
A61K047/38 |
Claims
1. A method of treatment for Duchenne Muscular Dystrophy ("DMD")
comprising administering to a patient a dose consisting of one or
more transmucosal administration systems consisting of a
polymer-based film by attaching said film in the oral cavity of a
patient with subsequent release of a pharmaceutical active
ingredient to the mucosa, the system containing 0.01to 80% by
weight of idebenone as active ingredient and a carrier material
comprising polyalcohol and/or a cellulose derivative, the system is
a mucoadhesive wafer which dissolves in the mouth, with the
idebenone primarily absorbed through the mucosa, the system
exhibits an AUC.sub.0-360/mg of the active ingredient concentration
in the patient's blood that is greater than that exhibited through
administering the active ingredient through the oral route on a
dose normalized basis.
2. The method of treatment as claimed in claim 1, wherein said
administering step comprises administering the polymer-based film
onto the oral mucosa on or under the tongue in the buccal cavity or
any other location in the oral cavity.
3. The method of treatment as claimed in claim 1, wherein said
administration system further comprises a second therapeutic
agent.
4. The method of treatment as claimed in claim 3, wherein said
second therapeutic agent is selected from glucocorticosteroids,
deflazacort and any medicament used to treat DMD-associated
cardiomyopathy.
5. The method of treatment as claimed in claim 4, wherein said
glucocorticosteroid is 6a-methylprednisolone-21 sodium succinate
and the medicament used to treat DMD-associated cardiomyopathy is
an ACE-inhibitor, beta-blocker, diuretic or HMG-CoA reductase
inhibitor.
6. The method of treatment as claimed in claim 1, wherein said
active ingredient is either dissolved in the carrier material
thereby forming a molecularly dispersed solid solution or is
present as a micronized suspension within the carrier material.
7. The method of treatment as claimed in claim 2, wherein a
mucoadhesive wafer containing 15 mg of said molecularly dispersed
active ingredient exhibits an AUC.sub.0-360/mg of the active
ingredient in the blood that is 4.75 times higher than the
AUC.sub.0-360/mg of said mucoadhesive wafer containing 30 mg of
suspended micronized pharmaceutical active ingredient after dose
normalization per mg.
8. The method of treatment as claimed in claim 1, wherein the
idebenone is administered in a dosage of equal to or less than 60
mg/kg/day.
9. The method of treatment as claimed in claim 1, wherein the
idebenone is administered in a dosage ranging from 0.01 mg/kg/day
to 20 mg/kg/day.
10. The method of treatment as claimed in claim 3, wherein the
idebenone is administered in a dosage ranging from 0.01 mg/kg/day
to 10 mg/kg/day.
11. The method of treatment as claimed in claim 1, wherein the film
dissolves completely in a period of less than 30 minutes in the
mouth.
12. The method of treatment as claimed in claim 1, wherein a
maximum concentration of the active ingredient in the blood is
reached in a period of less than 240 minutes after application.
13. The method of treatment as claimed in claim 11, wherein a
maximum concentration of the active ingredient in the blood is
reached at a period of between 5 and 30 min after application.
14. The method of treatment as claimed in claim 1, wherein said
wherein the transmucosal administration system comprises optional
excipient consisting of one or more of flavorings, colorants,
sweeteners, fillers, plasticizers, surface-active substances,
solubilizers, liquid excipient, disintegrants, solubility enhancers
and absorption enhancers.
15. The method of treatment as claimed in claim 1, wherein the
carrier material comprises cellulose, cellulose derivatives,
polyvinyl-alcohol, poly-N-vinylpyrrolidones, vinylpyrrolidone-vinyl
acetate copolymers, starch, starch derivatives, gelatin, gelatin
derivatives, and combinations thereof.
16. The method of treatment as claimed in claim 15, wherein the
cellulose derivative is methylcellulose, ethylcellulose,
hydroxypropylcellulose, hydroxyethylcellulose,
hydroxypropylmethylcellulose, carboxymethylcellulose or
combinations thereof.
17. The method of treatment as claimed in claim 1, wherein said
system comprises 50% by weight of active ingredient and 40% by
weight polyvinyl alcohol and 10% by weight of sodium
carboxymethyl-cellulose as carrier material, or said system
comprises 10% by weight of active ingredient and 90% by weight of
hydroxypropylmethylcellulose as carrier material.
18. The method of treatment as claimed in claim 1, wherein said
patient has swallowing difficulties.
19. The method of treatment as claimed in claim 1, wherein the
system has a monolayer or double-layer construction.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This Continuation Application claims priority to U.S. patent
application Ser. No. 14/372,878, filed Jul. 17, 2014, which claims
priority to International Application No. PCT/EP2013/050822, filed
Jan. 17, 2013, which claims priority to pending parent application
U.S. patent application Ser. No. 13/354,714, filed Jan. 20, 2012.
Each of U.S. patent application Ser. No. 14/372,878; International
Application No. PCT/EP2013/050822 and U.S. patent application Ser.
No. 13/354,714 are hereby incorporated herein in their
entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to a transmucosal
administration system to administer quinones, benzoquinones, and
especially 1,4-benzoquinones via the oromucosal route to a patient.
Specifically, the present invention relates to a transmucosal
administration system to administer
2,3-dimethoxy-5-metriyl-6-(10-hydroxydecyl)-1,4-benzoquinone
(idebenone) and its analogues via a film formulation (oral
wafer).
BACKGROUND OF THE INVENTION
[0003] Idebenone is a synthetic analogue of coenzyme Q10 (CoQ10), a
vital cell membrane antioxidant and essential constituent of the
adenosine-triphosphate (ATP) producing mitochondrial electron
transport chain (ETC). Up to now, idebenone has been used in a
variety of medical applications. Similar to coenzyme Q10, idebenone
undergoes reduction/oxidation cycles in living organisms and
reduced idebenone is an antioxidant and radical scavenger (A.
Mordente, G. E. Martorana, G. Minotti, B. Giardina, Chem. Res.
Toxicol. 11 (1998), 54-63). It is known that idebenone protects
cell membranes and mitochondria from oxidative damage because of
its ability to inhibit lipid peroxidation (M. Suno, M. Shibota, A.
Nagaoka, Arch. Gerontol. Geriatr. 8 (1989), 307-311). Idebenone
also interacts with the ETC, preserving ATP formation in ischemic
states. It has been shown that the compound stimulates nerve growth
factor, a characteristic that could be important for the treatment
of Alzheimer's and other neurodegenerative diseases (K. Yamada, A.
Nitta, T. Hasegawa, K. Fuji, M. Hiramatsu, T. Kameyama, Y.
Furukawa, K. Hayashi, T. Nabeshima, Behav. Brain Res. 83 (1997),
117-122). The compound has also been suggested for the treatment of
Friedreich's Ataxia and other mitochondrial and neuromuscular
diseases (A. O. Hausse, Y. Aggoun, D. Bonnet, D. Sidi, A. Munnich,
A. Rotig, P. Rustin, Heart 87 (2002), 346-349; Di Prospero N. A.,
Baker A., Jeffries N, Fischbeck K. H. Lancet Neurol 6 (2007)
878-886).
[0004] As a lipophilic compound idebenone is well absorbed in the
gastrointestinal tract after conventional oral administration,
which is the normal route for administering said compound. Dosage
forms such as tablets or capsules have been used in clinical trials
and as marketed product. In the course of our investigations on the
pharmacological profile of idebenone, we discovered that the
compound, after being absorbed in the gut, is metabolized very
quickly during its first passage through the liver
("first-pass-effect"). Experiments showed that more than 98% of the
idebenone is metabolized during its first passage through the
liver. Hepatic metabolism of idebenone results in side chain
oxidation, reduction of the quinone ring, sulphate and glucuronide
conjugation and subsequent renal excretion. The high liver
metabolism greatly reduces the potentially high plasma levels of
the pharmacologically active idebenone. Because of this strong
first pass metabolism, oral administration of idebenone requires
high doses of the compound to achieve pharmacologically efficacious
plasma levels in the body. Said high doses can result in unwanted
side effects such as diarrhea.
[0005] In addition, the requirement for oral formulations of
idebenone to be swallowed inflicts difficulties in the practical
administration to patients with swallowing problems, e.g. a patient
with a serious neuromuscular disease such as Duchenne Muscular
Dystrophy or Friedreich's Ataxia, elderly or young patients.
SUMMARY OF ADVANTAGEOUS EMBODIMENTS OF THE INVENTION
[0006] A solution to this problem is presented in this invention
which is based on data obtained with a specific type of
transmucosal administration system consisting of especially a thin
polymer-based film that when attached to the oral mucosa releases
the active ingredient directly to the mucosa or partly into the
saliva in the oral cavity, esophagus and stomach. The active
ingredient is absorbed through the mucosa primarily in the oral
cavity, esophagus and stomach, thus avoiding the first-pass
metabolism observed after conventional oral administration and
gastrointestinal absorption. This dosage form is also described as
oral wafer.
[0007] The principle of this system is also applicable to analogues
of idebenone, such as other benzoquinones or quinones, having a
reversibly reducible quinone ring, with a lipophilic side chain.
The term "ubiquinone analogues", as used herein, encompasses
natural ubiquinones (coenzyme Q-n) as well as their structural
analogs having a reversibly reducible quinone ring with a
lipophilic side chain, for example idebenone or
decylubiquinone.
[0008] Said object has been achieved by the use of a preferably
thin film formulation (oral wafer) containing especially idebenone.
Surprisingly it has been shown (see Figure) that the plasma levels
of idebenone after oromucosal administration of wafer A (containing
30 mg), wafer B (containing 15 mg as a solid solution) are
significantly higher compared to oral administration (300 mg/kg as
microemulsion) in the same Beagle dogs (n=3).
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 is a graphical illustration of the mean plasma
concentrations versus time of free idebenone after single
administrations of various exemplary formulations (oral and thin
wafer) in female Beagle dogs.
DETAILED DESCRIPTION OF ADVANTAGEOUS EMBODIMENTS OF THE
INVENTION
[0010] The present invention relates to a transmucosal formulation,
which comprises an effective amount of an active ingredient of the
general structural formula (I) wherein R.sup.1 is a lower alkyl
group; R.sup.2 is a hydrogen atom or an alkyl or alkenyl group
which may be substituted; R.sup.3 and R.sup.4 each independently
means a lower alkyl or lower alkoxy group or, taken together, mean
a butadienylene group.
##STR00001##
[0011] Referring to the above general formula (I), the lower alkyl
group R.sup.1 is a lower alkyl group of 1 to 4 carbon atoms, such
as methyl, ethyl, propyl, butyl and so on. The alkyl moiety of the
unsubstituted or substituted alkyl group R.sup.2 includes acyclic
hydrocarbon residues of 1 to 22 carbon atoms, such as methyl,
ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,
undecyl, dodecyl, tridecyl, pentadecyl, heptadecyl, eicosyl,
docosyl and so on. Among them, an alkyl having 8 to 13 carbon atoms
is preferable.
[0012] The alkenyl moiety of the unsubstituted or substituted
alkenyl group R.sup.2 include acyclic hydrocarbon residues of 2 to
15 carbon atoms, such as ethenyl, 1-propenyl, 3-methyl-2-butenyl,
3,7-dimethyl-2,6-octadienyl, etc., wherein the number of double
bonds may generally range from 1 to 3 and these double bonds may be
conjugated. Examples of substituents on the alkyl and alkenyl
groups R.sup.2 include hydroxy, carboxy, alkoxycarbonyl (e.g. C1-4
alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl,
propionyloxycarbonyl, butoxycarbonyl, etc.), aryl (e.g. phenyl,
1-naphthyl, 2-naphthyl, indanyl, etc.), heterocyclic groups (e.g.
2-pyridyl, 3-pyridyl, 2-thienyl, 3-thienyl, etc.) and halogen (e.g.
fluorine, chlorine, bromine and iodine). Where the substituent
group is such an aryl group or a heterocyclic group, the group may
be nuclearly substituted by one or more substituents in optional
positions of the ring structure. The substituents mentioned just
above include, but are not limited to, unsubstituted C1-4 alkyl
groups (e.g. methyl, ethyl, propyl, butyl, etc.), hydroxy, carboxy,
and C2-5 alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, butoxycarbonyl, etc.). The position of
substitution on the alkyl or alkenyl group R.sup.2 is optional but
preferably 1-position or .omega.-position. The lower alkyl group,
represented by R.sup.3 and R.sup.4, may be a C1-6 alkyl group, such
as methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl,
t-butyl, amyl, hexyl, etc. and preferably a C1-3 alkyl group. These
lower alkyl groups may have substituents such as hydroxy, halogen
(fluorine, chlorine, bromine and iodine), nitro, trifluoromethyl,
carboxy, C2-5 alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,
etc.), 3-pyridyl, 1-imidazolyl, 5-thiazolyl and so on. The lower
alkoxy group, represented by R.sup.3 and R.sup.4, may be a C1-3
alkoxy group such as methoxy, ethoxy, propoxy, i-propoxy and so on.
Where R.sup.3 and R.sup.4 mean a butadienylene group, they
constitute a benzene ring in association with the carbon atoms to
which R.sup.3 and R.sup.4 are respectively attached, and the
benzene ring so constituted may have 1 to 3 substituent groups in
optional positions, which substituent groups include, among others,
lower (C1-3) alkyl groups (e.g. methyl, ethyl, propyl, etc.), lower
(C1-3) alkoxy groups (e.g. methoxy, ethoxy, propoxy, etc.),
hydroxy, nitro and halogen.
[0013] The present invention relates also to the use of quinone or
benzoquinone, especially idebenone (International Nonproprietary
Name (INN): idebenone; Chemical name:
2-(10-Hydroxydecyl)-5,6-dimethoxy-3-methyl-2,5-cyclohexadiene-1,4-dione;
Chemical Abstracts Service (CAS) registry number: 58186-27-9) and
its analogues for the preparation of a preferably thin film
formulation that when attached to the oral mucosa releases the
active ingredient directly to the mucosa or partly into the saliva
in the oral cavity (also called oral wafer) and is used for
transmucosal administration to human beings or animals. This type
of system results in much higher plasma levels of the compound
compared to the oral route of administration. The preferred
transmucosal administration system for a pharmaceutical active
ingredient as thin film (oral wafer) formulations comprising as an
active ingredient idebenone together with additives and excipients
in conjunction with an appropriate manufacturing process used for
this type of formulations are further described herein.
[0014] Idebenone has the following chemical structural formula
(II):
##STR00002##
[0015] 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone,
idebenone Idebenone, a member of the quinone family, has been
promoted commercially as a synthetic analog of Coenzyme Q10, and
has been indicated to be suitable for treating a number of diseases
and/or conditions. Moreover, it has been made the subject of
various medical studies investigating its efficacy in the treatment
of, for example, neuromuscular diseases such as Friedreich's Ataxia
or neurological diseases such as Alzheimer's disease. Idebenone has
also been used in topical applications to treat wrinkles.
Therefore, idebenone may be regarded as toxicologically safe which
means that it can be used as a pharmaceutical active agent in a
medication. The toxicological safety of Idebenone has been
confirmed in a clinical study with 536 patients that have been
treated with up to 360 mg of idebenone t.i.d. (ter in die).
Compared to the placebo treated control group, no treatment
emergent adverse events except some gastrointestinal irritations as
well as a slight increase in orthopedic events were observed (L. J.
Thal, M. Grundman, J. Berg, K. Ernstrom, R. Margolin, E. Pfeiffer,
M. F. Weiner, E. Zamrini, R. G. Thomas, Neurology 61 (2003),
1498-1502).
[0016] It has now been observed that, after conventional oral
administration and absorption in the gut, idebenone is rapidly
metabolized during its first passage through the liver. The major
metabolites are idebenone conjugates such as glucuronates and
sulphates as well as derivatives where the side chain of the parent
compound has been oxidized. The metabolites of idebenone are
pharmacologically not significantly active and they are rapidly
excreted. Due to this strong first pass metabolism, oral
administration of idebenone requires high doses in order to reach
pharmacologically active plasma levels. These high doses result in
unwanted effects such as diarrhea and gastrointestinal (GI) tract
disturbances which are frequently observed in clinical
applications.
[0017] Using the preferred thin film formulation (oral wafer) it
has surprisingly been found that even with a 20-fold lower dose
compared to the oral administration route, a more than 5-fold AUC
can be achieved which, on a dose-normalized level, leads to a
>100-fold AUC (see Table 4). Moreover, this opens up
possibilities to achieve plasma levels of the pharmacologically
active molecule that are far above those achievable via the oral
route of administration.
[0018] By use of this system and the transmucosal route of
administration, the high first pass metabolism observed after
conventional oral administration of idebenone can very effectively
be circumvented.
[0019] Circumvention of the strong first-pass metabolism of
idebenone by using the thin film formulation (oral wafer) enables;
[0020] a) similarly high plasma levels of this active ingredient to
be obtained whilst significantly reducing the dose that has to be
administered. Lower active ingredient exposure is generally
believed to be associated with a reduced risk of adverse side
effects and offers a medical advantage leading to improved
compliance by the patient. In the particular case of idebenone, the
described GI side effects that can be avoided; [0021] b)
significantly higher plasma levels compared to those achievable
with an oral formulation of the active ingredient being absorbed
via the gastrointestinal route. This may lead to extension of the
use of idebenone to additional, new indications in the field of
neuromuscular diseases that require high concentrations e.g. in
order to cross the blood-brain-barrier; [0022] c) increased patient
convenience as the film formulation (oral wafer) is thin, easy to
handle and one unit is able to replace swallowing of several large
tablets; and [0023] d) administration of a thin film formulation
(oral wafer) to patients with swallowing difficulties, such as
patients suffering from certain neuromuscular diseases or children
below the age of 8, could increase compliance and convenience of
use.
[0024] In the present invention, "thin film formulations" or "oral
wafer" means a formulation that is intended to be applied and/or
administered to the oral mucosa of a patient and where the active
ingredient is absorbed into the body through the mucosa. According
to the invention, such formulation constitutes the basis of
medication containing idebenone for this specific route of
administration. The oral mucosa comprise the mucosa in the entire
oral and connecting cavities including but not limited to the
sublingual, buccal, gingival, lingual, as well as the esophageal
mucosa. The system has preferably a monolayer or double-layer
construction.
[0025] The objective upon which the present invention is based is
achieved through a transmucosal administration system which
dissolves in the mouth of a patient and which comprises 0.01 to 80%
by weight, preferably 2-70% by weight, of at least one quinone and
20-99.99% by weight, preferably 30-98% by weight, of a carrier
material. Suitable carrier materials are in particular cellulose
and derivatives thereof, such as methylcellulose, ethylcellulose,
hydroxypropyl-cellulose, hydroxyethyl cellulose,
hydroxypropylmethyl-cellulose (HPMC), carboxymethylcellulose (CMC);
poly-alcohols such as poly-vinyl-alcohol (PVA);
poly-N-vinylpyrrolidones; vinyl-pyrrolidone-vinyl acetate
copolymers; starch; starch derivatives; gelatin; gelatin
derivatives; SOLUPLUS.RTM. (a polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol graft copolymer); KOLLICOAT.RTM.; (a
polyvinyl alcohol-polyethylene glycol graft copolymer) and
combinations thereof. The administration system releases the
quinone contained therein with a high bioavailability. Preferably,
the system will be able to achieve high bioavailability without the
addition of permeation enhancers.
[0026] An administration system containing a suspension of the
active ingredient would preferably comprise 30-60% by weight,
particularly preferably 40-50% by weight, of a quinone--especially
of an 1,4-benzoquinone--and 40-70% by weight of a carrier
material--especially a poly-alcohol and/or a cellulose derivative
wherein the active ingredient is preferably micronized.
Micronisation involves the reduction of particles to a size of
preferably less than 100 .mu.m, particularly preferably less than
10 .mu.m.
[0027] An administration system containing an amorphous
presentation (or amorphous composition) of the active ingredient
would preferably comprise 3-20% by weight, particularly preferably
5-10% by weight of a quinone--especially of a 1,4-benzoquinone--and
80-97% by weight of a carrier material--especially a suitably
substituted carbohydrate or other water soluble polymer.
[0028] An administration system containing an emulsion of the
active ingredient would preferably comprise 3-50% by weight,
particularly preferably 5-30% by weight of a quinone--especially of
a 1,4-benzoquinone--and 50-97% by weight of a carrier
material--especially a cellulose derivative.
[0029] One particularly preferred administration system comprises
50% by weight of a 1,4-benzoquinone of the group consisting of
idebenone, idebenone analogues, ubiquinone, or ubiquinone analogues
and 40% by weight of poly-vinyl alcohol (PVA) and 10% by weight of
sodium carboxymethyl-cellulose carrier material.
[0030] Another particularly preferred administration system
comprises 10% by weight of a 1,4-benzoquinone of the group
consisting of idebenone, idebenone analouges, ubiquinone, or
ubiquinone analouges and 90% by weight of HPMC carrier
material.
[0031] It is preferred for the present invention that the
administration systems which dissolves in the mouth to be in film
form. These administration systems in film form are also referred
to as "strips" or "wafers". The inventive administration systems in
film form can, in a particular embodiment, be designed such that it
has mucoadhesion. By this, it is meant that the property of
adhering to a mucous membrane of a patient, specifically in such a
manner that it is difficult or impossible to detach the
administration system from the mucous membrane subsequent to the
application.
[0032] For the present invention, it is preferred that the film
administration system have a high surface area to weight ratio. It
is also preferred that the administration system is in or forms a
gel-like consistency in the oral cavity upon swelling in
saliva.
[0033] The administration systems in film form of the present
invention have an area of between 1 and 10 cm.sup.2, preferably
between 2 and 8 cm.sup.2 and particularly preferably between 5 and
7 cm.sup.2. They, moreover, have a weight per unit area between 50
and 250 g/m.sup.2, preferably between 100 and 150 g/m.sup.2. The
latter approximately correlates with a thickness of between 40 and
300 .mu.m, preferably between 50 and 100 .mu.m.
[0034] The administration system dissolves in the mouth of a
patient preferably in a period of less than 30 min, particularly
preferably in a period of less than 15 min. The quinone which
enters the bloodstream transmucosally from the administration
system leads to a rapid rise in the concentration of this quinone
in the blood. In this case, a maximum concentration of the quinone
in the blood is reached preferably in a period of less than 60
min--particularly preferably in a period of between 5 and 30
min--after application.
[0035] It is possible with the administration system to achieve a
relatively high bioavailability, as measured by the AUC of the
active ingredient concentration in the blood, of at least a factor
of 5 times (500%) greater, preferably of at least a factor of 10
(1000%) greater than that of the quinone in tablet form (or
simulated tablet form), when adjusted for the dose administered. A
particularly preferred increase in bioavailability would be a
factor of 20 (2000%) greater.
[0036] The administration system in film form may, besides the
carrier material and the quinone, comprise further substances, for
example flavorings, colorants, sweeteners, fillers, plasticizers,
surface-active substances, liquid--preferably
lipophilic--excipients which are able to dissolve the quinone and
form a second phase in the--preferably hydrophilic--carrier
material, solubilizers, pH stabilizers, disintegrants, solubility
enhancers, absorption enhancers, and or permeation enhancers.
[0037] Quinones according to the present invention may be
1,4-hydroquinones and related compounds. The preferred
1,4-hydroquinones are idebenone, idebenone analouges, and
ubiquinone and their related compounds. The term "ubiquinone and
their related compounds", as used herein, encompasses natural
ubiquinones (coenzyme Q-n) as well as their structural analogs
having a reversibly reducible quinone ring with a lipophilic side
chain.
[0038] The transmucosal administration system of 1,4-hydroquinones
and related compounds according to the present invention can be
used in the treatment of patients suffering from various diseases
and/or conditions, including mitochondrial, neuromuscular or
neurological diseases. Examples of diseases to be treated include,
but are not limited to, Friedreich's Ataxia, Duchenne Muscular
Dystrophy, Becker Muscular Dystrophy, Alzheimer's Disease, Leber's
Hereditary Optic Neuropathy, MELAS (mitochondrial myopathy,
encephalopathy, lactic acidosis with stroke-like episodes),
Parkinson's Disease and mitochondrial myopathies. In addition,
there is preliminary evidence that the 1,4-benzoquinone, Coenzym
Q10 or CoQ10, may be effective in treating coronary heart disease,
Myoclonic epilepsy and ragged-red fibers, Kearns-Sayre syndrome,
progressive external ophthalmoplegia, Diabetes mellitus and
deafness, Leigh syndrome, subacute sclerosing encephalopathy, NARP
(Neuropathy, ataxia, retinitis pigmentosa, and ptosis), and
Myoneurogenic gastrointestinal encephalopathy, migraines, cancer,
hypertension, age-related macular degeneration, Alzheimer's
disease, Anthracycline chemotherapy heart toxicity, asthma and many
others. Another particular application is the co-administration of
1,4-benzoquinone with statins and beta blockers to patients.
[0039] In a preferred embodiment in combination with any of the
above or below embodiments, the administration system is for use in
the treatment of a mitochondrial disease, preferably selected from
the group consisting of Leber's hereditary optic neuropathy (LHON),
autosomal dominant optic atrophy (DOA), macular degeneration,
glaucoma, retinopathy, cataract, optic disc drusen (ODD),
mitochondrial myopathy, encephalomyopathy, lactic acidosis,
stroke-like symptoms (MELAS), myoclonic epilepsy with ragged red
fibers (MERRF), myoneurogenic gastrointestinal encephalomyopathy
(MNGIE) Kearns-Sayre syndrome, CoQ10 deificieny, and mitochondrial
complex deficiencies (1-5, CPEO);
[0040] a neurodegenerative disease, preferably selected from the
group consisting of Friedreich's ataxia (FRDA), amyotrophic lateral
sclerosis (ALS) Parkinson's disease, Alzheimer's disease,
Huntington's disease, stroke/reperfusion injury, and dementia;
[0041] a neuromuscular disease, preferably selected from the group
consisting of Duchenne muscular dystrophy (DMD), Becker muscular
dystrophy (BMD), Limb-Girdle muscular dystrophy (LGMD), X-linked
dilated cardiomyopathy (XLDCM), Pantothenate kinase-associated
neurodegeneration (PKAN), spinal muscular atrophy (SMA), multiple
sclerosis, relapsing remitting multiple sclerosis (RR-MS), primary
progressive multiple sclerosis (PP-MS), secondary progressive
multiple sclerose (SP-MS), Kugelberg-Welander disease, and
Werdnig-Hoffmann disease;
[0042] a psychiatric disorder, preferably selected from the group
consisting of schizophrenia, major depressive disorder, bipolar
disorder, and epilepsy;
[0043] a metabolic disorder, preferably elected from the group
consisting of ageing-related physical decline, obesity, overweight,
type II diabetes, and metabolic syndrome;
[0044] cancer; multiple sclerosis; or
[0045] immune dysfunction, preferably selected from the group
consisting of arthritis, psoriasis, and rheumatoid arthritis.
[0046] In a preferred embodiment in combination with any of the
above or below embodiments, the administration system if for use in
the treatment of a mitochondrial disease. Preferably, the
mitochondrial disease is selected from the group consisting of
Leber's hereditary optic neuropathy (LHON), autosomal dominant
optic atrophy (DOA), macular degeneration, glaucoma, retinopathy,
cataract, optic disc drusen (ODD), mitochondrial myopathy,
encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS),
myoclonic epilepsy with ragged red fibers (MERRF), myoneurogenic
gastrointestinal encephalomyopathy (MNGIE), Kearns-Sayre syndrome,
CoQ10 deficiency, and mitochondrial complex deficiencies (1-5,
CPEO).
[0047] In a preferred embodiment in combination with any of the
above or below embodiments, the administration system is for use in
the treatment of Leber's hereditary optic neuropathy (LHON).
[0048] In a preferred embodiment in combination with any of the
above or below embodiments, the thin film drug delivery system is
for use in the treatment of mitochondrial myopathy,
encephalomyopathy, lactic acidosis, stroke-like symptoms
(MELAS).
[0049] In a preferred embodiment in combination with any of the
above or below embodiments, the administration system is for use in
the treatment of a neurodegenerative disease. Preferably, the
neurogenerative disease is selected from the group consisting of
Friedreich's ataxia (FRDA), amyotrophic lateral sclerosis (ALS),
Parkinson's disease, Alzheimer's disease, Huntington's disease,
stroke/reperfusion injury, and dementia.
[0050] In a preferred embodiment in combination with any of the
above or below embodiments, the administration system is for use in
the treatment of a neuromuscular disease. Preferably, the
neuromuscular disease is selected from the group consisting of
Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD),
Limb-Girdle muscular dystrophy (LGMD), X-linked dilated
cardiomyopathy (LXDCM), Pantothenate kinase-associated
neurodegeneration (PKAN), spinal muscular atrophy (SMA), multiple
sclerosis and primary progressive multiple sclerosis (PP-MS),
Kugelberg-Welander disease, and Werdnig-Hoffmann disease.
[0051] In a preferred embodiment in combination with any of the
above or below embodiments, the administration system is for use in
the treatment of Duchenne muscular dystrophy (DMD).
[0052] In a preferred embodiment in combination with any of the
above or below embodiments, the administration system is for use in
the treatment of primary progressive multiple sclerosis
(PP-MS).
[0053] In a preferred embodiment in combination with any of the
above or below embodiments, the administration system is for use in
the treatment of a psychiatric disorder. Preferably, the
psychiatric disorder is selected from the group consisting of
schizophrenia, major depressive disorder, bipolar disorder, and
epilepsy.
[0054] In a preferred embodiment in combination with any of the
above or below embodiments, the administration system is for use in
the treatment of a metabolic disorder. Preferably, the metabolic
disorder is selected from the group consisting of ageing-related
physical decline, obesity, overweight, type II diabetes, and
metabolic syndrome.
[0055] In a preferred embodiment in combination with any of the
above or below embodiments, the administration system is for use in
the treatment of cancer.
[0056] In a preferred embodiment in combination with any of the
above or below embodiments, the administration system is for use in
the treatment of multiple sclerosis.
[0057] In a preferred embodiment in combination with any of the
above or below embodiments, the administration system is for use in
the treatment of primary progressive multiple sclerosis, relapsing
remitting multiple sclerosis and secondary progressive multiple
sclerosis, more preferably for use in the treamtnbe of primary
progressive multiple sclerosis.
[0058] In a preferred embodiment in combination with any of the
above or below embodiments, the administration system if for use in
the treatment of immune dysfunction. Preferably, the immune
dysfunction is selected from the group consisting of arthritis,
psoriasis and rheumatoid arthritis.
[0059] Compared to the efficacious dose of idebenone administered
via the conventional oral route of administration and absorption in
the gastrointestinal tract the efficacious dose of the formulation
described in this application is expected to be significantly
lower. On the other hand, it is expected that with this formulation
and depending on the actual dose applied, significantly higher
plasma levels and potentially increased clinical efficacy may be
achievable within patients. Moreover, due to the higher plasma
levels the use of idebenone can be extended to additional
indications in the field of neuromuscular diseases that require
high concentrations of drug substance e.g. in order to cross the
blood-brain-barrier within patients.
[0060] Suitable doses of the active ingredient administered by thin
film formulation (oral wafer) are 0.01 mg/kg/day to 60 mg/kg/day.
Preferably, for example idebenone is administered in a dosage of
0.01 mg/kg/day to 20 mg/kg/day, more preferably in a dosage of 0.01
mg/kg/day to 10 mg/kg/day and even more preferably in a dosage of
0.01 mg/kg/day to less than 5 mg/kg/day. Most preferably, the
dosage of the active ingredient idebenone is between 0.1 mg/kg/day
to 4 mg/kg/day. Studies have shown that, surprisingly, such low
dosages achieve the required plasma level of idebenone if it is
applied via the oral mucosa. The required dosage may be ascertained
readily by a person skilled in the art.
[0061] In a preferred embodiment, idebenone may be administered in
combination with a second therapeutic agent, wherein said second
therapeutic agent is preferably selected from glucocorticosteroids
such as 6a-methylprednisolone-21 sodium succinate (SOLUMEDROL.RTM.)
or deflazacort (CALCORT.RTM.) which are routinely used in DMD
patients for treatment of inflammation and muscle weakness.
Likewise, idebenone may be administered in combination with any
medicament used in DMD patients to treat DMD-associated
cardiomyopathy such as ACE-inhibitors, beta-blockers and diuretics
as well as HMG-CoA reductase inhibitors.
[0062] In a further preferred embodiment, idebenone may be
administered in combination with further therapeutic agents,
wherein said further therapeutic agents are preferably
erythropoietin, vitamin E, vitamin C, or mitoquinone (MitoQ; K. M.
Taylor, R. Smith, WO05019232A1).
[0063] Idebenone and other therapeutic agents can be used
simultaneously, separately or sequentially in order to treat or
prevent the disease symptoms. The therapeutic agents may be
provided in a single dosage form or as separate formulations, each
formulation containing at least one of the active agents.
[0064] The following examples illustrate the invention, but are not
intended to limit the scope of the invention.
EXAMPLE 1
[0065] 112 g of PVA is added to 720 mL of water and stirred until
dissolution is complete. The dissolution is assisted where
appropriate by application of heat. After cooling, 140 g of
idebenone is dispersed uniformly. Afterward, 28 g of CMC is added,
and the mixture is stirred until dissolution is complete.
[0066] The mixture is degassed, coated and dried. A thin opaque
film which is between 50 and 150 .mu.m thick is produced. Opaque
wafers with a content of 30 mg of idebenone are obtained by cutting
out samples of the appropriate size.
EXAMPLE 2
[0067] 28 g of idebenone are added to 720 mL of 75:25
methanol:water, which is stirred until the active ingredient has
completely dissolved. 250 g of HPMC are added and stirred until
dissolution is complete. Degassing of the mixture and coating are
followed by drying. A thin translucent film which is between 100
and 300 .mu.m thick is produced. Translucent wafers with a content
of 15 mg of idebenone are obtained by cutting out samples of the
appropriate size.
[0068] It may be noted that the dried systems of example 1 comprise
the benzoquinone as particles in a separate phase suspended in the
carrier material, whereas the benzoquinone in examples 2 is in the
form of a mono-molecular dispersion in the carrier material.
[0069] Experimental Data:
[0070] Pharmacokinetic Data After Oromucosal Delivery of
Idebenone
[0071] Plasma levels of idebenone were studied after the
administration of two different thin film formulations (oral
wafers) administered via the oromucosal route and compared to the
profile obtained when idebenone is dosed by the oral route (gavage)
in a micro-emulsion. The doses used in this study were 30 mg
oromucosal (oral wafer A, suspension type), 15 mg oromucosal (oral
wafer B, solid solution type) and 300 mg oral (TPGS/Miglyol
microemulsion administered by oral gavage). The study was a
three-way cross-over study with one week wash-out between
administrations. Formulations were administered to female Beagle
dogs under fasted conditions. The pharmacokinetic exposure of free
(unconjugated) idebenone and its total metabolites (total
idebenone, total QS10, total QS6, and total QS4) was determined for
each formulation.
[0072] Blood samples were collected at several time points over 6
hours after administration. Concentrations of idebenone in plasma
were measured by HPLC-MS/MS and pharmacokinetic parameters were
calculated.
[0073] For this, idebenone was separated and quantified by
HPLC-MS/MS: For HPLC, a SYNERGI.TM. 4.mu. MAX-RP (50.times.2 mm)
column (Phenomenex, Schlieren, Switzerland) was used. Column
temperature: 50.degree. C. Mobile phase A: water+30 mM NH.sub.4OAc;
mobile phase B: MeOH/H.sub.2O 100/3 (v/v)+30 mM NH.sub.4OAc,
gradient elution (table 4). Flow: 250 .mu.l/min and 400
.mu.l/min.
[0074] Once separated, idebenone was quantified by ESI-MS/MS (API
4000, Perkin-Elmer-Europe BV, Rotkreuz, Switzerland) in positive
mode.
TABLE-US-00001 TABLE 1 Pump-gradient program and time events for
separation and quantification of idebenone Time mobile phase B Flow
[min] [%] [.mu.l/min] Comments 0.01 50 250 start gradient, HPLC
eluent to MS 3.00 -- 250 -- 3.01 -- 400 -- 3.75 95 400 end gradient
4.50 95 400 -- 4.51 50 400 -- 5.90 50 400 -- 5.91 50 250 -- 29.99
50 250 pump shutdown 30.00 95 20
[0075] From times 0.01 to 3.75 min a linear gradient was used.
[0076] Idebenone conjugates such as glucuronates and sulphates have
been quantified after acidic hydrolysis as described by R. Artuch,
C. Colome, M. A. Vilaseca, A. Aracil. M. Pineda, J. Neurosci. Meth.
115 (2002), 63-66.
[0077] The pharmacokinetic analysis included maximum plasma
concentration (C.sub.max), the time when maximum plasma
concentration was observed (T.sub.max), and the area under the
plasma concentrations versus time curve from time 0 h to 360 min
(AUC.sub.0-360 min).The relative bioavailability of idebenone after
sublingual administration compared to the oral administration was
calculated for each dog from normalized (1 mg/kg) AUC values. The
AUC ratios of the metabolites were also calculated. In addition,
C.sub.max ratios, normalized to a 1 mg/kg dose, were
calculated.
[0078] The results obtained are shown in Table 2 below.
TABLE-US-00002 TABLE 2 Mean pharmacokinetic parameters of idebenone
after oromucosal (30 mg wafer A) and (15 mg wafer B) vs. oral (300
mg, microemulsion) administration in dogs. C.sub.max T.sub.max
AUC.sub.0-360 Dosing [ng/ml] [min] [min*ng/ml] 30 mg wafer A
(micronized 248 15 6152 suspension) 15 mg wafer B 404 25 13864
(solid solution) 300 mg oral gavage 111 7 2305 (microemulsion)
[0079] As shown in Table 2, the two wafer formulations of idebenone
administered via the oromucosal route, prepared according to
example 1 and 2, clearly lead to significantly higher plasma levels
of idebenone compared to conventional oral administration. Both
C.sub.max and AUC.sub.0-360 were superior to the oral
administration in both thin film (oral wafer) formulations. There
is also a marked difference between wafer A, which contains 30 mg
idebenone as micronized powder suspended in the polymer matrix, and
wafer B, which contains only 15 mg but in a solid solution, i.e.
molecularly dispersed state. The latter clearly dissolves much more
efficiently and is better absorbed.
[0080] FIG. 1 illustrates the mean plasma concentrations versus
time of free idebenone after single administrations of various
formulations (oral and thin wafer) in female Beagle dogs.
[0081] As shown in FIG. 1, wafer B (15 mg, solid solution type
wafer) showed the highest C.sub.max and the largest AUC compared to
the other treatment arms. Wafer A (30 mg, suspension type wafer)
shows a higher C.sub.max and a larger AUC compared to the oral
route (300 mg, microsuspension).
TABLE-US-00003 TABLE 3 Mean pharmacokinetic parameters of idebenone
after oromucosal (30 mg wafer A) and (15 mg wafer B) vs. oral (300
mg, microemulsion) administration in dogs after dose normalization
per mg. C.sub.max/mg AUC.sub.0-360/mg Dosing [ng/ml] [min*ng/ml] 30
mg wafer A (micronized 8.3 205 suspension) 15 mg wafer B 26.9 924
(solid solution) 300 mg oral gavage 0.4 7.7 (microemulsion)
[0082] As shown in Table 3: above, the magnitude of increase in
exposure obtained with the two wafer formulations of idebenone
administered via the oromucosal route (prepared according to
example 1 and 2) compared to the oral route of administration
becomes even more apparent after normalization for differences in
dose.
TABLE-US-00004 TABLE 4 Comparison of the mean pharmacokinetic
parameters of the different formulations after dose normalization
per mg. C.sub.max/mg AUC.sub.0-360/mg Dosing [ng/ml] [min*ng/ml]
Comparison 33 26 wafer A vs. oral gavage Comparison 144 121 wafer B
vs. oral gavage Comparison 3.62 4.75 wafer B vs. wafer A
[0083] As shown in Table 4: The comparison on a dose-normalized
basis shows that wafer A lead to a 26-fold higher AUC (33-fold
C.sub.max) than the oral formulation on a dose normalized level and
wafer B lead to a 121-fold higher AUC (144-fold C.sub.max) in
comparison to the oral route. The solid solution wafer B leads to
>4-fold higher exposure of idebenone compared to the suspension
type wafer A.
[0084] In summary it can be concluded that [0085] Oral-mucosal
administration of idebenone by a thin film formulation (oral wafer)
based on the solid-solution technology strongly improves the
relative bioavailability of idebenone by approximately 100 fold
over oral administration. The main reason for the increased
bioavailability is the initial bypass of the enterohepatic
circulation. [0086] On top of that, there is evidence that the
absorption of idebenone from this wafer is increased compared to an
oral administration of idebenone by gavage. [0087] A wafer, based
on the micronized suspension technology, also improves the relative
bioavailability of idebenone, though to a lesser extent [0088] The
metabolic spectrum of idebenone is comparable after oral
administration by gavage and the oral-mucosal application [0089]
The oral wafer formulation offers the following advantages over the
formulations administered via the oral route: [0090] Significant
dose reduction (less side effects) [0091] Higher plasma levels
achievable [0092] Increased patient convenience [0093]
Administration to patients with swallowing difficulties [0094] The
inventive systems may further comprise a polymer matrix and the
pharmaceutical active ingredient may be incorporated within the
polymer matrix as a suspension, a suspension after micronization,
an emulsion, a micro- or nano-emulsion, or in solubilised and/or
molecularly dispersed form.
* * * * *