U.S. patent application number 17/522200 was filed with the patent office on 2022-05-26 for oral thin film.
The applicant listed for this patent is LTS LOHMANN THERAPIE-SYSTEME AG. Invention is credited to Mario FICKER, Florian HAMMES, Michael LINN, Markus MULLER.
Application Number | 20220160646 17/522200 |
Document ID | / |
Family ID | 1000006182772 |
Filed Date | 2022-05-26 |
United States Patent
Application |
20220160646 |
Kind Code |
A1 |
MULLER; Markus ; et
al. |
May 26, 2022 |
ORAL THIN FILM
Abstract
Described is an oral thin film comprising at least one matrix
layer, wherein the at least one matrix layer comprises at least one
pharmaceutically active agent, at least one polyvinyl alcohol and
at least one polyvinyl alcohol-polyethylene glycol graft copolymer,
a method for producing same, and use thereof as a medicament.
Inventors: |
MULLER; Markus; (Troisdorf,
DE) ; FICKER; Mario; (Bonn, DE) ; LINN;
Michael; (Waldbockelheim, DE) ; HAMMES; Florian;
(Andernach, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LTS LOHMANN THERAPIE-SYSTEME AG |
Andernach |
|
DE |
|
|
Family ID: |
1000006182772 |
Appl. No.: |
17/522200 |
Filed: |
November 9, 2021 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/135 20130101;
A61K 9/7007 20130101; A61K 47/32 20130101 |
International
Class: |
A61K 9/70 20060101
A61K009/70; A61K 47/32 20060101 A61K047/32; A61K 31/135 20060101
A61K031/135 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 9, 2020 |
DE |
10 2020 129 394.1 |
Aug 11, 2021 |
DE |
10 2021 120 937.4 |
Claims
1. An oral thin film comprising at least one matrix layer, wherein
the at least one matrix layer comprises at least one
pharmaceutically active agent, at least one polyvinyl alcohol, and
at least one polyvinyl alcohol-polyethylene glycol graft
copolymer.
2. The oral thin film according to claim 1, wherein the at least
one pharmaceutically active agent comprises ketamine, preferably
(S)-ketamine or a pharmaceutically acceptable salt thereof.
3. The oral thin film according to claim 1, wherein the at least
one pharmaceutically active agent is provided in the matrix layer
in an amount of 45 to 70 wt. % in relation to the total weight of
the matrix layer.
4. The oral thin film according to claim 1, wherein the at least
one polyvinyl alcohol comprises a polyvinyl alcohol with a mean
molecular weight of approximately 25,000 to approximately 250,000
g/mol.
5. The oral thin film according to claim 1, wherein the at least
one polyvinyl alcohol comprises a polyvinyl alcohol with a mean
molecular weight of approximately 25,000 to approximately 35,000
g/mol and/or a polyvinyl alcohol with a mean molecular weight of
approximately 200,000 to 210,000 g/mol.
6. The oral thin film according to claim 1, wherein the at least
one polyvinyl alcohol-polyethylene glycol graft copolymer has a
polyethylene glycol main chain onto which there are grafted
polyvinyl alcohol units.
7. The oral thin film according to claim 1, wherein the at least
one polyvinyl alcohol-polyethylene glycol graft copolymer has a
polyethylene glycol main chain onto which there are grafted
polyvinyl alcohol units, wherein the molar ratio of polyethylene
glycol to polyvinyl alcohol is 1:3.
8. The oral thin film according to claim 1, wherein the at least
one polyvinyl alcohol-polyethylene glycol graft copolymer has a
polyethylene glycol main chain onto which there are grafted
polyvinyl alcohol units, wherein the polyvinyl alcohol-polyethylene
glycol graft copolymer has a mean molecular weight in the range of
40,000 to 50,000 g/mol.
9. The oral thin film according to claim 1, wherein the at least
one polyvinyl alcohol is provided in the matrix layer in an amount
of 5 to 40 wt. % in relation to the total weight of the matrix
layer.
10. The oral thin film according to claim 1, wherein the at least
one polyvinyl alcohol-polyethylene glycol graft copolymer is
provided in the matrix layer in an amount of 15 to 45 wt. % in
relation to the total weight of the matrix layer.
11. The oral thin film according to claim 1, wherein the oral thin
film further comprises at least one auxiliary substance selected
from the group comprising colouring agents, flavourings,
sweeteners, plasticisers, taste-masking agents, emulsifiers,
enhancers, pH regulators, humectants, preservatives and/or
antioxidants.
12. The oral thin film according to claim 1, wherein the area
density of the oral thin film is approximately 50 to 300
g/m.sup.2.
13. The oral thin film according to claim 1, wherein the at least
one pharmaceutically active agent comprises ketamine as a free base
in a total amount of 25 to 150 mg.
14. The oral thin film according to claim 1, wherein at least 40%
or at least 50% of the at least one pharmaceutically active agent
are released within the first minute following application, and/or
wherein at least 75% of the at least one pharmaceutically active
agent are released within the first two minutes following
application.
15. The oral thin film according to claim 1, wherein the puncture
strength is at least 0.15 N/mm.sup.2, with an areal density of 150
to 250 g/m.sup.2.
16. The oral thin film according to claim 1, wherein the matrix
layer comprises 60 wt. % of (S)-ketamine HCl, 10 wt. % of a
polyvinyl alcohol with a mean molecular weight of approximately
200,000 to 210,000 g/mol, and 20.1 wt. % of a polyvinyl
alcohol-polyethylene glycol graft copolymer, wherein the polyvinyl
alcohol-polyethylene glycol graft copolymer has a polyethylene
glycol main chain onto which there are grafted polyvinyl alcohol
units, and wherein the polyvinyl alcohol-polyethylene glycol graft
copolymer has a mean molecular weight in the range of 40,000 to
50,000 g/mol.
17. The oral thin film according to claim 1, wherein the maximum
plasma concentration of (S)-ketamine following administration of a
dose of 50 mg (S)-ketamine lies at 50 to 200 ng/mL, or wherein the
maximum plasma concentration of (S)-ketamine following
administration of a dose of 100 mg (S)-ketamine lies at 100 to 200
ng/mL.
18. The oral thin film according to claim 1, wherein the maximum
plasma concentration of the ketamine metabolite (S)-norketamine
following administration of a dose of 50 mg (S)-ketamine lies at
200 to 400 ng/mL, or wherein the maximum plasma concentration of
the ketamine metabolite (S)-norketamine following administration of
a dose of 100 mg (S)-ketamine lies at 300 to 500 ng/mL.
19. The oral thin film according to claim 1, wherein the maximum
plasma concentration of the ketamine metabolite
(S)-hydroxynorketamine following administration of a dose of 50 mg
(S)-ketamine lies at 50 to 150 ng/mL, or wherein the maximum plasma
concentration of the ketamine metabolite (S)-hydroxynorketamine
following administration of a dose of 100 mg (S)-ketamine lies at
100 to 250 ng/mL.
20. A method for producing an oral thin film according to claim 1,
comprising the steps of: a) producing a solution, dispersion or
melt comprising the at least one pharmaceutically active agent, the
at least one polyvinyl alcohol and the at least one polyvinyl
alcohol-polyethylene glycol graft copolymer; a1) optionally foaming
the solution, dispersion or melt from step a) by introducing a gas
or gas mixture, by chemical gas generation or by expansion of a
dissolved gas, b) spreading the solution, dispersion or melt from
step a) or the optionally foamed solution, dispersion or melt from
step a1.
21. A method for the treatment of pain and/or depression comprising
the administration of an effective amount of the active agent
included in the oral thin film of claim 1.
Description
[0001] The present invention relates to an oral thin film
containing at least one pharmaceutically active agent, a method for
producing same, and the use of such an oral thin film as a
medicament, especially in the treatment of pain and/or
depression.
[0002] Oral thin films are thin films containing at least one
pharmaceutically active agent that are placed directly in the oral
cavity or against the oral mucosa and dissolve or macerate there
and in so doing deliver the active agent. These films are,
especially, thin active agent-containing polymer-based films which,
when applied to a mucous membrane, especially the oral mucosa, can
deliver the active agent directly into same. The very good blood
supply to the oral mucosa ensures a rapid transfer of the active
agent into the bloodstream. This dosage system has the advantage
that the active agent is resorbed for the most part by the mucous
membrane, thus avoiding the first-pass effect, which occurs in the
case of the conventional dosage form of an active agent in tablet
form. The active agent may be dissolved, emulsified or dispersed in
the film.
[0003] As explained in greater detail further below, the oral thin
film according to the invention preferably contains ketamine as
pharmaceutically active agent and is preferably used for the
treatment or prevention of pain.
[0004] The repositioning of ketamine from a medicinal perspective
as an analgesic indicates the possibility of a new pain treatment
option. Ketamine has proven to be effective in the treatment of
moderate to severe pain and represents a useful alternative to
opioid analgesia. Ketamine has also been found to reduce
hyperalgesia (increased sensitivity to feeling pain), which occurs
in many pain conditions, more specifically also by the long-term
ingestion of opioids. In combination with opioids, ketamine also
has the effect of reducing the dosage amount of opioids, which is
necessary for achieving this analgesia.
[0005] The NMDA receptor antagonism of ketamine offers a
"non-opioid" treatment option for the treatment of pain, which
satisfies the unfulfilled requirements of the current therapy (for
example reduced severe side effects in conjunction with opioids).
(S)-ketamine, in comparison to the racemate, has approximately
twice the analgesic effect as well as an anti-depressive effect. In
contrast to opioids, the lethal dose of (S)-ketamine is very high
(lethal dose averaged at 4.2 g/70 kg, for example lethal dose of
fentanyl 2 mg/70 kg, oxycodone 40 mg/70 kg).
[0006] When administering some pharmaceutically active agents, high
active agent loads of the oral thin film are desirable. A high
active agent load in oral thin films is a known problem, since this
can lead to brittle films or can directly prevent a film formation
of the contained polymers. In order to achieve this nevertheless,
large oral thin films or oral thin films with very high layer
thicknesses are generally required. Large or thick oral thin films
have the disadvantage that they cause problems with the application
and may cause the patient to experience a sensation of a foreign
body and may lead to long dissolving times.
[0007] Depending on the application, however, long disintegration
times are undesirable.
[0008] In addition, known oral thin films with high active agent
load have the disadvantage that the maximum area density and thus
the amount of contained pharmaceutically active agent is determined
by the drying of the oral thin film during production thereof. The
greater is the area density of the oral thin film, the more
pharmaceutically active agent may be contained therein, however,
the drying time of the oral thin film is extended, as a result, to
a time that is no longer economical, and in addition the active
agent may be distributed inhomogeneously in the oral thin film.
BRIEF DESCRIPTION
[0009] The aim of the present invention lies in overcoming the
above-mentioned disadvantages of the prior art. Especially, the aim
of the present invention lies in providing an oral thin film for
administering a high amount of at least one pharmaceutically active
agent, wherein the oral thin film has an acceptable disintegration
time, and wherein the pharmaceutically active agent is distributed
relatively homogeneously in the oral thin film. Furthermore, the
oral thin film will have a preferably pleasant and soft texture and
therefore preferably will not trigger a sensation of a foreign body
for the patient. The oral thin film according to the invention will
also allow the greatest possible bioavailability of, for example,
more than 10% or more than 20% or more than 30% or more than 40% or
more than 50% or more than 60% or more than 70% or more than 80% or
more than 90% of the pharmaceutically active agent.
[0010] The oral thin film according to the invention preferably has
a bioavailability of 20 to 30% of the pharmaceutically active
agent.
[0011] In addition, the oral thin film according to the invention
will be designed such that approximately 40 to 60% of the contained
pharmaceutically active agent can be released within the first
minute following application, or approximately 75 to 90% of the
contained pharmaceutically active agent can be released after the
first two minutes following application.
[0012] In addition, once the oral thin film has been administered,
minimal side effects will occur, especially minimal psychedelic
effects (psychological and psychomimetic side effects).
[0013] In addition, it will be possible to produce the oral thin
film as easily and economically as possible.
[0014] Especially, the at least one pharmaceutically active agent
will comprise ketamine.
[0015] The above aim is addressed by an oral thin film according to
claim 1, which has at least one matrix layer, wherein the at least
one matrix layer comprises at least one pharmaceutically active
agent, especially ketamine, at least one polyvinyl alcohol, and at
least one polyvinyl alcohol-polyethylene glycol graft
copolymer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 is a graphical depiction of the results of a release
study for Formulation 15;
[0017] FIGS. 2A-I are graphical depictions showing a reduction in
pressure, electrical and heat pain;
[0018] FIGS. 3-5 show the plasma level of the metabolite
(S)-norketamine are higher following administration of an OTF as
compared to intravenous-administration of 20 mg (S)-ketamine;
[0019] FIGS. 6-8 show the plasma level of the metabolite
(S)-hydroxynorketamine are higher following administration of an
OTF as compared to intravenous administration of 20 mg
(S)-ketamine;
[0020] FIGS. 9-11 show the plasma levels of ketamine are higher for
intravenous administration than following administration of an
OTF;
[0021] FIGS. 12-15 show the data relating to the observed
psychedelic effects (phychological and psychomimetic side effects)
according to the Bowdle questionnaire;
[0022] FIGS. 16-31 show the data relating response to the Bond and
Lade questionnaire; and
[0023] FIG. 32 shows the results of the permeation study of Example
5.
DETAILED DESCRIPTION
[0024] It has been found that a polyvinyl alcohol-polyethylene
glycol graft copolymer can absorb a high amount of active
agent.
[0025] This has also been observed already in polyvinyl alcohols,
where this effect is even more pronounced in part. Films based on
polyvinyl alcohol alone, however, are hard and thus have a texture
that is unpleasant for the patient.
[0026] Films based on a polyvinyl alcohol-polyethylene glycol graft
copolymer alone, by contrast, have a softer texture since the
polymer itself forms softer films. These films, however, are not
quite so stable.
[0027] Due to the mixture of a polyvinyl alcohol-polyethylene
glycol graft copolymer and a polyvinyl alcohol, it has been
possible to achieve a film which, with a high active agent load,
has the soft texture of a polyvinyl alcohol-polyethylene glycol
graft copolymer film alongside a stability approaching that of a
polyvinyl alcohol film.
[0028] The polyvinyl alcohol-polyethylene glycol graft copolymer
preferably forms the basic structure and decisively determines the
film properties, and the polyvinyl alcohol acts as an additional
stabiliser.
[0029] A high active agent load with layer thicknesses and film
sizes in acceptable ranges can thus be achieved. The dissolving
times also lie in an acceptable range, the acceptable range
preferably comprising values of less than 1 min. In addition, such
an oral thin film is agreeable to the patient and can be produced
easily and economically.
[0030] Preferred embodiments are described in the dependent
claims.
[0031] In the present document, the word "comprising" can also mean
"consisting of".
[0032] The oral thin film according to the invention has at least
one matrix layer, wherein the at least one matrix layer comprises
at least one pharmaceutically active agent, especially ketamine, at
least one polyvinyl alcohol, and at least one polyvinyl
alcohol-polyethylene glycol graft copolymer.
[0033] The at least one pharmaceutically active agent is not
subject in principle to any limitation, but is preferably selected
from all pharmaceutically active agents that are suitable for oral
and/or transmucosal application.
[0034] According to the present invention, all pharmaceutically
acceptable salts and solvates of the particular pharmaceutically
active agent are also subsumed under the pharmaceutically active
agent.
[0035] Active agents are preferably selected from the group
comprising the active agent classes of analgesics, hormones,
hypnotics, sedatives, antiepiletics, analeptics, psychoneurotropic
drugs, neuro-muscle blockers, antspasmodics, antihistamines,
antiallergics, cardiotonics, antiarrhythmics, diuretics,
hypotensives, vasopressors, antidepressants, antitussives,
expectorants, thyroid hormones, sexual hormones, antidiabetics,
antitumour active agents, antibiotics, chemotherapeutics and
narcotics, however, this group is not conclusive.
[0036] Polyvinyl alcohols (abbreviated to PVA or PVAL, sometimes
also PVOH) are polymers of the general structure
##STR00001##
[0037] which can also contain small amounts (approximately 2%) of
structural units of the type
##STR00002##
[0038] They belong to the group of vinyl polymers.
[0039] Commercially customary polyvinyl alcohols, which are offered
in the form of white-yellow powder or granules, generally have a
degree of hydrolysis of 98 to 99 or 87 to 89 mol %, that is to say
also contain a residual content of acetyl groups. The polyvinyl
alcohols are characterised by the manufacturer by a specification
of the degree of polymerisation of the starting polymers or the
mean molecular weight, the degree of hydrolysis, the saponification
number or the solution viscosity.
[0040] Graft copolymers are branched polymers that contain
different monomer units in the main chain and the branched
chain.
[0041] The term "graft copolymers" is a common term.
[0042] The polyvinyl alcohol-polyethylene glycol graft copolymer
provided here preferably has a main chain, comprising polyethylene
glycol, onto which the polyvinyl alcohol units are grafted.
[0043] The oral thin film according to the invention is preferably
also characterised in that the at least one pharmaceutically active
agent comprises ketamine, preferably (S)-ketamine or a
pharmaceutically acceptable salt thereof.
[0044] The oral thin film according to the invention in another
embodiment is preferably characterised in that the at least one
pharmaceutically active agent comprises ketamine, preferably
R-ketamine or a pharmaceutically acceptable salt thereof.
[0045] Ketamine is preferably provided in the form of an HCl salt
or in the form of a free base.
[0046] In the present case, ketamine is understood to mean
(S)-(.+-.)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one,
(R)-(.+-.)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one, and
the racemate
(RS)-(.+-.)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one.
[0047] After administration, ketamine is metabolised to
norketamine, hydroxynorketamine and further substances.
[0048] Both (S)-ketamine and R-ketamine as well as a racemic
mixture of these two can be contained in the matrix layer of the
oral thin film according to the invention. However, (S)-ketamine in
the form of a free base or a pharmaceutically acceptable salt
thereof, especially (S)-ketamine HCl, is especially preferably
present as a single stereoisomer of ketamine, since the analgesic
and anaesthetic potency of (S)-ketamine is approximately three
times higher than that of the (R) form.
[0049] The oral thin film according to the invention is also
preferably characterised in that the at least one pharmaceutically
active agent, preferably ketamine, is provided in the matrix layer
in an amount of 45 to 70 wt. %, preferably of 50 to 65 wt. %, or of
55 to 65 wt. %, or of 55 to 60 wt. %, or of 60 to 65 wt. %, in
relation to the total weight of the matrix layer.
[0050] Especially, the oral thin film according to the invention is
preferably also characterised in that the at least one
pharmaceutically active agent, preferably ketamine, is present in
the matrix layer in an amount of 60 wt. %, in relation to the total
weight of the matrix layer.
[0051] The oral thin film according to the invention is preferably
also characterised in that the at least one pharmaceutically active
agent, preferably ketamine, is present in the form of
microcrystals.
[0052] Suitable mean crystal sizes of these microcrystals lie
preferably in the range of 1 to 1000 .mu.m or in the range of 5 to
500 .mu.m or in the range of 10 to 200 .mu.m. The mean crystal size
especially preferably lies in the range of 15 to 25 .mu.m,
especially in the range of 20 to 22 .mu.m. The crystal size can be
determined, for example, by means of light microscopy or by means
of micro computer tomography X-ray (micro-CT).
[0053] Unless stated otherwise, all cited molecular weights of
polymers relate to the weight-average molecular weight (Mw),
determined by means of gel permeation chromatography.
[0054] The oral thin film according to the invention is also
preferably characterised in that the at least one polyvinyl alcohol
comprises a polyvinyl alcohol with a mean molecular weight of
approximately 25,000 to approximately 250,000 g/mol.
[0055] The oral thin film according to the invention is also
preferably characterised in that the at least one polyvinyl alcohol
comprises a polyvinyl alcohol with a mean molecular weight of
approximately 25,000 to approximately 35,000 g/mol and/or a
polyvinyl alcohol with a mean molecular weight of approximately
200,000 to 210,000 g/mol.
[0056] According to the present invention, polyvinyl alcohols with
a mean molecular weight of approximately 31,000 (4-88) to
approximately 205,000 (40-88) g/mol are especially suitable.
[0057] According to the present invention, polyvinyl alcohols with
a mean molecular weight with approximately 31,000 (4-88) to
approximately 205,000 (40-88) g/mol are especially suitable.
[0058] According to the present invention, polyvinyl alcohols with
a viscosity of 3.4 to 4.6 mPas (4-88) to 34 to 46 mPas (40-88) mPas
in a 40 g/l aqueous solution, determined by the "falling ball
method" (Ph.Eur. 2.2.49), are also especially suitable, or mixtures
of two or more different ones of these PVA types.
[0059] According to the present invention, polyvinyl alcohols with
a viscosity of 3.4 to 4.6 mPas (4-88) or of 34 to 46 mPas (40-88)
mPas in a 40 g/l aqueous solution, determined by the "falling ball
method" (Ph.Eur. 2.2.49), are also especially suitable, or mixtures
of two or more different ones of these PVA types.
[0060] The oral thin film according to the invention is also
preferably characterised in that the at least one polyvinyl
alcohol-polyethylene glycol graft copolymer has a polyethylene
glycol main chain onto which there are grafted polyvinyl alcohol
units.
[0061] The oral thin film according to the invention is also
preferably characterised in that the at least one polyvinyl
alcohol-polyethylene glycol graft copolymer has a polyethylene
glycol main chain onto which there are grafted polyvinyl alcohol
units, wherein the molar ratio of polyethylene glycol to polyvinyl
alcohol is 1:3.
[0062] The oral thin film according to the invention is also
preferably characterised in that the at least one polyvinyl
alcohol-polyethylene glycol graft copolymer has a polyethylene
glycol main chain onto which there are grafted polyvinyl alcohol
units, wherein the polyvinyl alcohol-polyethylene glycol graft
copolymer has a mean molecular weight in the range of 40,000 to
50,000 g/mol, preferably of approximately 45,000 g/mol.
[0063] A suitable and preferred polyvinyl alcohol-polyethylene
glycol graft copolymer is known by the trade name Kollicoat IR
(BASF).
[0064] The oral thin film according to the invention is also
preferably characterised in that the at least one polyvinyl alcohol
is provided in the matrix layer in an amount of 5 to 40 wt. %,
preferably of 5 to 20 wt. %, of 5 to 19 wt. %, of 5 to 18 wt. %, of
5 to 17 wt. %, of 5 to 16 wt. %, of 5 to 15 wt. %, of 5 to 14 wt.
%, of 5 to 13 wt. %, of 5 to 12 wt. %, of 5 to 11 wt. % or of 5 to
10 wt. %, in relation to the total weight of the matrix layer.
[0065] The oral thin film according to the invention is also
preferably characterised in that the at least one polyvinyl
alcohol-polyethylene glycol graft copolymer is provided in the
matrix layer in an amount of 15 to 45 wt. %, preferably of 17 to 40
wt. %, or 20 to 30 wt. %, in relation to the total weight of the
matrix layer.
[0066] In another embodiment, the oral thin film according to the
invention is also preferably characterised in that the at least one
polyvinyl alcohol-polyethylene glycol graft copolymer is provided
in the matrix layer in an amount of 10 to 30 wt. %, preferably of
15 to 25 wt. %, of 17.5 to 22.5 wt. % or of 19 to 21 wt. %,
especially of approximately 19.5 to 20.5 wt. %, and especially
preferably of approximately 20 wt. % or of 20.1 wt. %, in relation
to the total weight of the matrix layer.
[0067] The oral thin film according to the invention is also
preferably characterised in that the matrix layer also comprises at
least one auxiliary substance selected from the group comprising
colouring agents, flavourings, sweeteners, softeners, taste-masking
agents, emulsifiers, enhancers, pH regulators, humectants,
preservatives and/or antioxidants.
[0068] Each of these auxiliary substances is preferably contained
in each case in an amount of 0.1 to 15 wt. %, preferably of 0.1 to
10 wt. %, or of 0.1 to 5 wt. %, in relation to the total weight of
the matrix layer.
[0069] Sweeteners, such as saccharin Na and/or sucralose are
preferably contained in the matrix layer in a total amount of 2 to
5 wt. %, especially approximately 3 wt. %, in relation to the total
weight of the matrix layer.
[0070] Apart from sweeteners, flavourings are preferably contained
in the matrix layer in a total amount of 2 to 5 wt. %, especially
approximately 3 wt. %, in relation to the total weight of the
matrix layer.
[0071] Colouring agents are preferably contained in the matrix
layer in a total amount of 0.1 to 1 wt. %, especially approximately
0.4 wt. %, in relation to the total weight of the matrix layer.
[0072] The oral thin film according to the invention is not
subjected to any limitations in respect of its structure.
[0073] The oral thin film according to the invention can thus be
provided in the form of a single-layer oral thin film and thus can
consist merely of the matrix layer as defined above.
[0074] In another embodiment, the oral thin film according to the
invention can thus be provided in the form of a multi-layer oral
thin film and thus can contain further layers in addition to the
matrix layer as defined above.
[0075] This plurality of layers can be laminated directly on top of
one another or can be connected to an adhesive layer arranged in
between.
[0076] An adhesive layer is understood to mean a layer that can act
as an adhesive, as defined in DIN EN 923:2016-03. A non-adhesive
layer therefore cannot act as an adhesive as defined above.
[0077] Especially, water-soluble adhesive layers as described in DE
10 2014 127 452 A1 are suitable as adhesive layers, and the content
of that document in this regard is hereby expressly incorporated
fully in the present disclosure.
[0078] For example, buffer layers for setting a pH value or slowly
dissolving or insoluble layers which protect the oral thin film
against premature erosion can be provided as further layers.
[0079] Alternatively, further matrix layers can be provided, which
contain other pharmaceutically active agents or flavourings or
taste-masking agents.
[0080] In one embodiment the oral thin film according to the
invention is characterised in that the matrix layer is in the form
of a smooth film. This means that the matrix layer, for example, is
not provided in the form of a foam.
[0081] A smooth film is preferably characterised in that a smooth
film has a volume fraction of 0 to 5%, in relation to the total
volume of the matrix layer, of bubbles or cavities. The cavities
are filled here preferably with air or a gas, preferably with an
inert gas, especially preferably with nitrogen, carbon dioxide,
helium or a mixture of at least two of these gases. The diameter of
the bubbles or cavities generally lies in the range of 0.01 to 350
.mu.m. The diameter of the bubbles or cavities especially
preferably lies in the range of 10 and 200 .mu.m.
[0082] In another embodiment the oral thin film according to the
invention is characterised in that the matrix layer is in the form
of a solidified film having cavities.
[0083] Especially, the infiltration of water or saliva or other
bodily fluids into the interior of the dosage form is facilitates
by the cavities and the associated larger surface of the films, and
therefore the dissolving of the dosage form and the active agent
release are accelerated.
[0084] In the case of a quickly resorbing active agent, the
transmucosal resorption can be improved additionally by the quick
dissolution of the matrix layer.
[0085] On the other hand, the wall thickness of said cavities is
preferably low, since these represent, for example, solidified
bubbles, and so these cavities dissolve or break down quickly.
[0086] A further advantage of this embodiment lies in the fact
that, due to the formulation as a foam, a quicker drying can be
provided than for a comparable, non-foamed composition, in spite of
the comparatively high area density.
[0087] The multi-layer oral thin film according to the invention is
preferably characterised in that the cavities are isolated from one
another and are preferably provided in the form of bubbles, wherein
the cavities are filled with air or a gas, preferably with an inert
gas, especially preferably with nitrogen, carbon dioxide, helium or
a mixture of at least two of these gases.
[0088] According to another embodiment it is provided that the
cavities are connected to one another preferably by forming a
cohesive channel system penetrating the matrix.
[0089] Said cavities preferably have a volume fraction of 5 to 98%,
preferably of 50 to 80%, in relation to the total volume of the
matrix layer. In this way, the advantageous effect of accelerating
the dissolving of the matrix layer is favourably influenced.
[0090] Furthermore, surface-active substances or surfactants can be
added to the matrix layer for foam formation or to the obtained
foam before or after the drying in order to improve the stability
of the foam before or after the drying.
[0091] A further parameter that influences the properties of the
dosage form according to the invention is the diameter of the
cavities or bubbles. The bubbles or cavities are preferably
produced with the aid of a foaming machine, with which the diameter
of the bubbles can be set within a wide range, almost arbitrarily.
The diameter of the bubbles or cavities can thus lie in the range
of 0.01 to 350 .mu.m. The diameter especially preferably lies in
the range of 10 and 200 .mu.m.
[0092] The oral thin film according to the invention preferably has
an area of 0.5 cm.sup.2 to 10 cm.sup.2, especially preferably of 2
cm.sup.2 to 8 cm.sup.2 or of 4 cm.sup.2 to 5 cm.sup.2.
[0093] The area density of the matrix layer or of a further layer
possibly provided is, in each case, preferably at least 10
g/m.sup.2, more preferably at least 20 g/m.sup.2 or at least 30
g/m.sup.2 or most preferably 50 g/m.sup.2, or less than or equal to
400 g/m.sup.2, more preferably less than or equal to 350 g/m.sup.2,
or less than or equal to 300 g/m.sup.2 or most preferably less than
250 g/m.sup.2. The area density is preferably 10 to 400 g/m.sup.2,
more preferably 20 to 350 g/m.sup.2, or 30 to 300 g/m.sup.2 and
most preferably 50 to 250 g/m.sup.2.
[0094] Each of the provided layers, especially the matrix layer,
preferably has in each case a layer thickness of preferably 10
.mu.m to 500 .mu.m, especially preferably of 20 .mu.m to 300
.mu.m.
[0095] If the various layers, especially the matrix layer, are
present in the form of a solidified foam, it is thus preferred that
each of the layers provided as a foam has, in each case, a layer
thickness of preferably 10 .mu.m to 3000 .mu.m, especially
preferably of 90 .mu.m to 2000 .mu.m.
[0096] The oral thin film according to the invention is also
preferably characterised in that the at least one pharmaceutically
active agent is present in the matrix layer in a total amount of 25
mg to 150 mg, preferably of 25 mg to 125 mg, especially of
approximately 50 mg to 150 mg.
[0097] The oral thin film according to the invention is especially
characterised in that the at least one pharmaceutically active
agent is present in the matrix layer in a total amount of 50 mg to
100 mg, preferably of approximately 50 mg or approximately 100
mg.
[0098] The oral thin film according to the invention is also
preferably characterised in that the at least one pharmaceutically
active agent comprises ketamine, preferably in the form of a free
base or ketamine HCl, in a total amount of 25 mg to 150 mg,
preferably of 25 mg to 125 mg, especially of approximately 50 mg to
150 mg.
[0099] The oral thin film according to the invention is especially
characterised in that the at least one pharmaceutically active
agent ketamine, preferably in the form of a free base or ketamine
HCl, is present in the matrix layer in a total amount of 50 mg to
100 mg, preferably of approximately 50 mg or approximately 100
mg.
[0100] The oral thin film according to the invention is also
preferably characterised in that the at least one pharmaceutically
active agent is present as ketamine, preferably in the form of a
free base or ketamine HCl, is present in the matrix layer in a
total amount of 25 mg to 150 mg, preferably of 25 mg to 125 mg,
especially of approximately 50 mg to 150 mg.
[0101] The oral thin film according to the invention is especially
characterised in that the at least one pharmaceutically active
agent as ketamine, preferably in the form of a free base or
ketamine HCl, is present in the matrix layer in a total amount of
50 mg to 100 mg, preferably of approximately 50 mg or approximately
100 mg.
[0102] The oral thin film according to the invention is also
preferably characterised in that the at least one pharmaceutically
active agent as ketamine, preferably in the form of a free base or
ketamine HCl, is present in the matrix layer in a total amount of 2
mg or 5 mg or 7 mg or 10 mg or 15 mg or 20 mg or 25 mg or 30 mg or
35 mg or 40 mg or 45 mg or 50 mg or 55 mg or 60 mg or 65 mg or 70
mg or 80 mg or 90 mg or 95 mg or 100 mg or 105 mg or 110 mg or 115
mg or 120 mg or 125 mg or 130 mg or 135 mg or 140 mg or 145 mg or
150 mg.
[0103] The oral thin film according to the invention is also
preferably characterised in that the puncture strength is at least
0.15 N/mm.sup.2, preferably at least 0.18 N/mm.sup.2, especially
preferably 0.20 N/mm.sup.2 or more. The area density here is
preferably 150 to 250 g/m.sup.2, especially preferably 180 to 220
g/m.sup.2.
[0104] The puncture strength is preferably determined as
follows:
[0105] Used test device: Sauter FH-20 force gauge.
[0106] Test area: round test area of diameter 5 mm.
[0107] Execution:
[0108] The force gauge is fixed and a 10 cm.sup.2 laminate specimen
is placed centrally on the test area of the device (round test area
of diameter 5 mm). The laminate specimen is fixed at the edges and
a force is exerted in the direction of the test specimen, which
force is increased until the laminate specimen is punctured. The
resultant maximum value of the force that was applied to the
specimen until puncture is measured. The measurement is performed
with n=3 laminate specimens per laminate batch.
[0109] The oral thin film according to the invention is also
preferably characterised in that the bioavailability of the at
least one pharmaceutically active agent, especially the ketamine,
preferably in the form of a free base or ketamine HCl, is at least
5% or at least 10% or at least 15% or at least 20% or at least 25%
or at least 30% or at least 35% or at least 40% or at least 45% or
at least 50% or at least 55% or at least 60% or at least 65% or at
least 70% or at least 75% or at least 80% or at least 85% or at
least 90% or at least 95% or at least 97% or at least 99%
[0110] The oral thin film according to the invention is also
preferably characterised by the following release rates, wherein
the release rate relates to the release of the at least one
pharmaceutically active agent, preferably the ketamine, after a
certain time following application of the oral thin film according
to the invention.
[0111] It is preferred if, after 1 min, at least 40% or at least
50% of the at least one pharmaceutically active agent, preferably
the ketamine, are released.
[0112] It is preferred if, after 2 min, at least 75% or at least
80% or at least 85% of the at least one pharmaceutically active
agent, preferably the ketamine, are released.
[0113] It is preferred if, after 15 s, approximately 5 to 10% of
the at least one pharmaceutically active agent, preferably the
ketamine, are released.
[0114] It is preferred if, after 30 s, approximately 20 to 25% of
the at least one pharmaceutically active agent, preferably the
ketamine, are released.
[0115] It is preferred if, after 45 s, approximately 30 to 40% of
the at least one pharmaceutically active agent, preferably the
ketamine, are released.
[0116] It is preferred if, after 1 min, approximately 50 to 60% of
the at least one pharmaceutically active agent, preferably the
ketamine, are released.
[0117] It is preferred if, after 1 min and 15 s, approximately 60
to 70% of the at least one pharmaceutically active agent,
preferably the ketamine, are released.
[0118] It is preferred if, after 1 min and 30 s, approximately 70
to 80% of the at least one pharmaceutically active agent,
preferably the ketamine, are released.
[0119] It is preferred if, after 1 min and 45 s, approximately 80
to 85% of the at least one pharmaceutically active agent,
preferably the ketamine, are released.
[0120] It is preferred if, after 2 min, approximately 82 to 88% of
the at least one pharmaceutically active agent, preferably the
ketamine, are released.
[0121] It is preferred if, after 2 min and 15 s, approximately 84
to 90% of the at least one pharmaceutically active agent,
preferably the ketamine, are released.
[0122] It is preferred if, after 2 min and 30 s, approximately 86
to 92% of the at least one pharmaceutically active agent,
preferably the ketamine, are released.
[0123] Hereinafter, preferred embodiments in respect of the maximum
plasma concentration (Cmax) of the active agent or metabolites
thereof will be described for the oral thin film according to the
invention, in which (S)-ketamine is used as pharmaceutically active
agent.
[0124] 100 mg (S)-ketamine can be administered here in one dose or
by means of two doses of 50 mg each of (S)-ketamine.
[0125] The oral thin film according to the invention is preferably
characterised in that the maximum plasma concentration of
(S)-ketamine following administration of a dose of 50 mg of
(S)-ketamine lies at 50 to 200 ng/mL.
[0126] The oral thin film according to the invention is also
preferably characterised in that the maximum plasma concentration
of the ketamine metabolite (S)-norketamine following administration
of a dose of 50 mg of (S)-ketamine lies at 200 to 400 ng/mL.
[0127] The oral thin film according to the invention is also
preferably characterised in that the maximum plasma concentration
of the ketamine metabolite (S)-hydroxynorketamine following
administration of a dose of 50 mg of (S)-ketamine lies at 50 to 150
ng/mL.
[0128] The oral thin film according to the invention is preferably
characterised in that the maximum plasma concentration of
(S)-ketamine following administration of a dose of 100 mg of
(S)-ketamine lies at 100 to 200 ng/mL.
[0129] The oral thin film according to the invention is also
preferably characterised in that the maximum plasma concentration
of the ketamine metabolite (S)-norketamine following administration
of a dose of 100 mg of (S)-ketamine lies at 300 to 500 ng/mL.
[0130] The oral thin film according to the invention is also
preferably characterised in that the maximum plasma concentration
of the ketamine metabolite (S)-hydroxynorketamine following
administration of a dose of 100 mg of (S)-ketamine lies at 100 to
250 ng/mL.
[0131] The oral thin film according to the invention is preferably
characterised in that the maximum plasma concentration of
(S)-ketamine following administration of a dose of 50 mg of
(S)-ketamine lies at 70 to 120 ng/mL.
[0132] The oral thin film according to the invention is also
preferably characterised in that the maximum plasma concentration
of the ketamine metabolite (S)-norketamine following administration
of a dose of 50 mg of (S)-ketamine lies at 200 to 300 ng/mL.
[0133] The oral thin film according to the invention is also
preferably characterised in that the maximum plasma concentration
of the ketamine metabolite (S)-hydroxynorketamine following
administration of a dose of 50 mg of (S)-ketamine lies at 70 to 120
ng/mL.
[0134] The oral thin film according to the invention is preferably
characterised in that the maximum plasma concentration of
(S)-ketamine following administration of a dose of 100 mg of
(S)-ketamine lies at 120 to 160 ng/mL.
[0135] The oral thin film according to the invention is preferably
characterised in that the maximum plasma concentration of the
ketamine metabolite (S)-norketamine following administration of a
dose of 100 mg of (S)-ketamine lies at 300 to 350 ng/mL.
[0136] The oral thin film according to the invention is preferably
characterised in that the maximum plasma concentration of the
ketamine metabolite (S)-hydroxynorketamine following administration
of a dose of 100 mg of (S)-ketamine lies at 150 to 220 ng/mL.
[0137] The oral thin film according to the invention is preferably
characterised in that the maximum plasma concentration of
(S)-ketamine following sublingual administration of a dose of 50 mg
of (S)-ketamine lies at 70 to 120 ng/mL.
[0138] The oral thin film according to the invention is preferably
characterised in that the maximum plasma concentration of the
ketamine metabolite (S)-norketamine following sublingual
administration of a dose of 50 mg of (S)-ketamine lies at 200 to
300 ng/mL.
[0139] The oral thin film according to the invention is preferably
characterised in that the maximum plasma concentration of the
ketamine metabolite (S)-hydroxynorketamine following administration
of a dose of 50 mg of (S)-ketamine lies at 70 to 120 ng/mL.
[0140] The oral thin film according to the invention is preferably
characterised in that the maximum plasma concentration of
(S)-ketamine following sublingual administration of a dose of 100
mg of (S)-ketamine lies at 120 to 160 ng/mL.
[0141] The oral thin film according to the invention is preferably
characterised in that the maximum plasma concentration of the
ketamine metabolite (S)-norketamine following sublingual
administration of a dose of 100 mg of (S) ketamine lies at 300 to
350 ng/mL.
[0142] The oral thin film according to the invention is preferably
characterised in that the maximum plasma concentration of the
ketamine metabolite (S)-hydroxynorketamine following sublingual
administration of a dose of 100 mg of (S)-ketamine lies at 150 to
220 ng/mL.
[0143] The oral thin film according to the invention is preferably
characterised in that the maximum plasma concentration of
(S)-ketamine following buccal administration of a dose of 50 mg of
(S)-ketamine lies at 80 to 160 ng/mL.
[0144] The oral thin film according to the invention is preferably
characterised in that the maximum plasma concentration of the
ketamine metabolite (S)-norketamine following buccal administration
of a dose of 50 mg of (S)-ketamine lies at 200 to 280 ng/mL.
[0145] The oral thin film according to the invention is preferably
characterised in that the maximum plasma concentration of the
ketamine metabolite (S)-hydroxynorketamine following buccal
administration of a dose of 50 mg of (S)-ketamine lies at 60 to 100
ng/mL.
[0146] The oral thin film according to the invention is preferably
characterised in that the maximum plasma concentration of
(S)-ketamine following buccal administration of a dose of 100 mg of
(S)-ketamine lies at 120 to 200 ng/mL.
[0147] The oral thin film according to the invention is preferably
characterised in that the maximum plasma concentration of the
ketamine metabolite (S)-norketamine following buccal administration
of a dose of 100 mg of (S)-ketamine lies at 400 to 500 ng/mL.
[0148] The oral thin film according to the invention is preferably
characterised in that the maximum plasma concentration of the
ketamine metabolite (S)-hydroxynorketamine following buccal
administration of a dose of 50 mg of (S)-ketamine lies at 120 to
200 ng/mL.
[0149] The oral thin film according to the invention is also
preferably characterised in that the matrix layer comprises 60 wt.
% of (S)-ketamine HCl, 10 wt. % of the polyvinyl alcohol 40-88 as
defined previously, and 20 wt. % or 20.1 wt. % of a polyvinyl
alcohol-polyethylene glycol graft copolymer as defined
previously.
[0150] The oral thin film according to the invention is also
preferably characterised in that the matrix layer comprises 60 wt.
% of (S)-ketamine HCl, 10 wt. % of the polyvinyl alcohol 40-88 as
defined previously, and 20.1 wt. % of a polyvinyl
alcohol-polyethylene glycol graft copolymer, preferably as defined
previously, 1.0 wt. % of saccharin Na, 2.0 wt. % of sucralose, 3.5
wt. % of glycerol, 3.0 wt. % of a pharmaceutically acceptable
flavouring and 0.4 wt. % of a pharmaceutically acceptable colouring
agent. Pure water is preferably used here as solvent.
[0151] In a very especially preferred embodiment the oral thin film
has a formulation according to formulation 15 in Table 3.
[0152] The oral thin film according to the invention can be
produced by conventional methods.
[0153] The above definitions in relation to the oral thin film
apply similarly for the method according to the invention.
[0154] A method for producing the oral thin film according to the
invention preferably comprises the steps of:
[0155] a) producing a solution, dispersion or melt comprising the
at least one pharmaceutically active agent, the at least one
polyvinyl alcohol and the at least one polyvinyl
alcohol-polyethylene glycol graft copolymer;
[0156] a1) optionally foaming the solution, dispersion or melt from
step a) by introducing a gas or gas mixture, by chemical gas
generation or by expansion of a dissolved gas,
[0157] b) the solution, dispersion or melt from step a) or the
optionally foamed solution, dispersion or melt from step at.
[0158] It is clear to a person skilled in the art that step at) is
necessary only if the matrix layer is to be provided in the form of
a solidified foam having cavities.
[0159] The bubbles or cavities are preferably produced with the aid
of a foaming machine, with which the diameter of the bubbles can be
set within a wide range, almost arbitrarily.
[0160] The present invention also relates to an oral thin film
obtainable by the method described above.
[0161] In addition, the present invention relates to an oral thin
film, as described above or obtainable by the above-described
method, as a medicament.
[0162] In addition, the present invention relates to an oral thin
film, as described above or obtainable by the above-described
method, as a medicament for sublingual and/or buccal
administration.
[0163] In addition, the present invention relates to an oral thin
film, as described above or obtainable by the above-described
method, as a medicament for use in the treatment of pain and/or
depression.
[0164] In addition, the present invention relates to an oral thin
film, as described above or obtainable by the above-described
method, as a medicament for use in the treatment of pain and/or
depression by sublingual and/or buccal administration of the oral
thin film.
[0165] The present invention additionally relates to an oral thin
film, as described above or obtainable by the above-described
method, wherein ketamine, preferably (S)-ketamine, or a
pharmaceutically acceptable salt thereof, is used as
pharmaceutically active agent in the matrix layer, for use in the
treatment of pain and/or depression, especially to reduce the risk
of suicide and/or for use as a general anaesthetic, preferably to
initiate and carry out general anaesthesia, or as a supplement in
the case of local anaesthesia and/or as an analgesic.
[0166] The present invention relates especially to an oral thin
film as described above or obtainable by the above-described
method, wherein ketamine, preferably (S)-ketamine, or a
pharmaceutically acceptable salt thereof is used as
pharmaceutically active agent in the matrix layer, for use in the
treatment of pain, preferably as defined hereinafter.
[0167] The term "pain" is generally understood to mean a feeling of
pain that is often caused by intense or noxious stimuli. Pain that
is chronic or ongoing is understood to be long-lasting, and pain
that disappears quickly is said to be acute.
[0168] Nociceptive pain is pain caused by the stimulation of
sensory nerve fibres which respond to stimuli approaching or
surpassing a noxious intensity (nociceptors) and can be classified
according to the mode of the noxious stimulation. The most common
categories are thermal, mechanical and chemical stimulation. Some
nociceptors respond to more than one modality and are therefore
termed as being polymodal.
[0169] Nociceptive pain can also be subdivided into "visceral",
"deep somatic" and "superficial somatic" pain.
[0170] Neuropathic pain is generally caused by an injury or illness
affecting a part of the nervous system involved in body sensation
(the somatosensory system).
[0171] Neuropathic pain can be subdivided into peripheral, central
or mixed (peripheral and central) neuropathic pain. Peripheral
neuropathic pain is often described as "burning", "tingling",
"electric" or "piercing".
[0172] The present invention also relates to a method for treating
pain and/or depression in a patient, comprising the application of
an oral thin film, as described above, to a mucous membrane of the
patient.
[0173] The method for treating pain and/or depression in a patient
is preferably characterised in that the mucous membrane comprises
the oral mucosa.
[0174] The method for treating pain and/or depression in a patient
is preferably characterised in that the oral thin film according to
the invention is applied sublingually or buccally.
[0175] The method for treating pain and/or depression in a patient
is preferably characterised in that the dosing of the at least one
pharmaceutically active agent, preferably ketamine, especially in
the form of a free base or ketamine HCl, is approximately 50 mg to
150 mg, preferably approximately 50 mg or approximately 100 mg.
[0176] The method for treating pain and/or depression in a patient
is preferably characterised in that the oral thin film preferably
is applied for a period of less than 2 min, especially of 30 s to
90 s, preferably of 30 s to 60 s and preferably dissolves during
this time.
[0177] The invention will be described in greater detail
hereinafter on the basis of non-limiting examples.
EXAMPLES
Example 1
[0178] The starting materials stated in Table 1 were used in the
following examples.
TABLE-US-00001 TABLE 1 Starting material Function (S)-ketamine HCl
API Polyvinyl alcohol Matrix polymer (PVA) 4-88 (35% solution)
Polyvinyl alcohol Matrix polymer (PVA) 40-88 (15%solution)
Kollicoat IR Matrix polymer (30% solution) Glycerol Plasticiser
Sucralose Sweetener Saccharin Na Sweetener Cherry Flavour
Flavouring M55394 (EU taste) FD&C Red 40 Colouring agent
Purified water Process solvent P 120 g/m.sup.2, PE2 Coating liner
AB1
[0179] A plurality of oral thin films were produced from these
starting materials by the method according to the invention and
were examined. The composition of these is stated in Table 2.
TABLE-US-00002 TABLE 2 1 2 3 4 5 6 7 8 9 10 Material [wt. %] [wt.
%] [wt. %] [wt. %] [wt. %] [wt. %] [wt. %] [wt. %] [wt. %] [wt. %]
(S)-ketamine HCl 55.0 50.0 50.0 60.0 60.0 55.0 60.0 65.0 60.0 60.0
PVA 4-88 35.0 -- -- 30.5 -- -- -- -- -- -- PVA 40-88 -- -- 9.9 --
7.6 8.8 9.9 6.4 -- 2.0 Kollicoat IR -- 39.5 29.6 -- 22.9 26.2 20.6
19.1 30.5 28.5 Saccharin Na 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
Sucralose 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Glycerol 4.0 4.0
4.5 3.5 3.5 4.0 3.5 3.5 3.5 3.5 Cherry Flavour 3.0 3.0 3.0 3.0 3.0
3.0 3.0 3.0 3.0 3.0 M55394 Solvent Aq. Pur. Aq. Pur. Aq. Pur. Aq.
Pur. Aq. Pur. Aq. Pur. Aq. Pur. Aq. Pur. Aq. Pur. Aq. Pur.
Foam/Film Foam Film Foam Foam Foam Foam Foam Foam Film Foam
[0180] All oral thin films according to the invention with the
compositions stipulated in Table 2 solve the problem addressed by
the invention.
[0181] Based on composition 2, further oral thin films were
produced having the composition according to Table 3 and were
tested.
TABLE-US-00003 TABLE 3 11 12 13 14 15 Material [wt. %] [wt. %] [wt.
%] [wt. %] [wt. %] (S)-ketamine 60.0 55.0 60.0 60.0 60.0 HCl PVA
4-88 -- -- 5.0 10.0 -- PVA 40-88 5.0 5.0 -- -- 10.0 Kollicoat IR
25.1 30.1 25.1 20.1 20.1 Saccharin Na 1.0 1.0 1.0 1.0 1.0 Sucralose
2.0 2.0 2.0 2.0 2.0 Glycerol 3.5 3.5 3.5 3.5 3.5 Cherry Flavour 3.0
3.0 3.0 3.0 3.0 M55394 FD&C Red 0.4 0.4 0.4 0.4 0.4 No, 40
Solvent Aq. Pur. Aq. Pur. Aq. Pur. Aq. Pur. Aq. Pur. Test Good Good
Good Good Very film, film, film, film, good small bubbles bubbles
small film, few particles visible, visible, particles bubbles,
visible rough rough visible very good surface surface tear
strength
[0182] All oral thin films with the compositions stipulated in
Table 3 solve the problem addressed by the invention.
[0183] Formulation 15 was examined in detail.
[0184] Formulation 15 is stable for 9 months at 25.degree. C./60
r.h. %-40.degree./r.h. 75%.
[0185] The residual water content of formulation 15 was determined
by means of Karl Fischer titration.
[0186] The residual water content of 6 samples was determined. The
determined residual water content was 4.40 wt. %, 3.82 wt. %, 4.02
wt. %, 4.51 wt. %, 4.91 wt. % and 4.57 wt. %.
[0187] This residual water content is acceptable.
[0188] The disintegration time of formulation 15 in a 1 L glass
beaker with 900 ml dimineralised water (temperature-controlled to
37.degree. C..+-.2.degree. C.) was determined.
[0189] The disintegration time of six samples was determined. The
determined disintegration time was 52 s, 55 s, 58 s, 56 s, 54 s and
55 s.
[0190] Formulation 15 thus has a good disintegration time.
[0191] The in vitro release of the active agent was also determined
from formulation 15.
[0192] With the in vitro release, (S)-ketamine is released from
(S)-ketamine HCl-containing oral thin films and is determined. The
active agent is released in phosphate buffer pH 6.8 USP and is then
determined by in situ fibre optic UV system. The quantification was
performed against an external standard.
[0193] The release is performed with Dissolution Apparatus
2--(Paddle over sinker) according to USP <711>,
TABLE-US-00004 TABLE 4 Stainless Steel Capsule Sinker with 10
Spirals, 31.0 .times. 11.0 mm Capacity Sinker: (Sotax Style)
Stirring speed: 50 rpm Distance between the vessel base and 25 mm
.+-. 2 mm the lower edge of the paddle: Temperature: 37.degree. C.
.+-. 0.5.degree. C. Release medium: Phosphate buffer pH 6.8 USP
Release medium volume: 500 mL Sample measurement intervals: Every 5
seconds (0 to 5 min) Every 10 seconds (5 to 10 min) Every 15
seconds (10 to 15 min)
[0194] The results of the release study are shown and FIG. 1 and
were as follows:
TABLE-US-00005 after 15s approx. 11% after 30s approx. 24% after
45s approx. 38% after 1 minute approx. 54% after 1 minute 15s
approx. 68% after 1 minute 30s approx. 78% after 1 minute 45s
approx. 83% after 2 minutes approx. 85% after 2 minutes 15s approx.
86% after 2 minutes 30s approx. 87%
Example 2
[0195] The formulations from Table 3 were examined in greater
detail in further studies.
[0196] 1. Measurement of the Puncture Strength
[0197] Execution of the measurement (test of the puncture strength
of the laminate):
[0198] Used test device: Sauter FH-20 force gauge.
[0199] Test area: round test area of diameter 5 mm.
[0200] The commercially obtainable product: "LISTERINE
POCKETPAKS.RTM. COOL MINT ORAL CARE FRESH BREATH STRIPS" was used
as comparison product. This contains pullulan, menthol, Acesulfame
potassium, copper gluconate, polysorbate 80, chondrus crispus gum
(Carrageenan), glyceryl oleate, thymol, eucalyptol, methyl
salicylate, Ceratonia siliqua gum (locust bean gum), propylene
glycol, xanthan gum, aroma (flavouring), FD&C Blue No. 1
(colouring agent) and FD&C Green No. 3 (colouring agent).
[0201] Execution:
[0202] The force gauge was fixed and a 10 cm.sup.2 laminate
specimen (for Listerine, a 32 mm.times.22 mm Listerine OTF was
used) was placed centrally on the test area of the device (round
test area of diameter 5 mm). The laminate specimen was fixed at the
edges and a force was exerted in the direction of the test
specimen; the force was increased until the laminate specimen was
punctured. The resultant maximum value of the force that was
applied to the test specimen until puncture was measured. The
measurement was performed with n=3 laminate specimens per laminate
batch (for Listerine, n=3 measurement with OTF).
[0203] The results are summarised in the following Table 5:
TABLE-US-00006 TABLE 5 Standard Puncture Average deviation Area
density strength Formulation [N] [N] [g/m.sup.2] [N/mm.sup.2] 2
1.96 0.09 150 0.10 3 2.22 0.10 130 0.11 5 1.85 0.06 157 0.09 5 2.88
0.19 206 0.15 7 2.92 0.08 167 0.15 8 1.27 0.12 145 0.06 9 1.55 0.12
190 0.08 10 1.79 0.15 156 0.09 11 2.68 0.20 188 0.14 12 2.63 0.05
172 0.13 13 2.04 0.05 184 0.10 14 2.26 0.11 180 0.12 15 4.00 0.15
206 0.20 Listerine 3.14 0.80 46.3 0.16 (comparison)
[0204] All shown examples have a good puncture strength (comparable
to the product Listerine as reference) in spite of high active
agent load.
Example 3
[0205] As stated in the description, the oral thin film according
to the invention is preferably characterised in that the at least
one pharmaceutically active agent, preferably ketamine, is present
in the form of microcrystals. Suitable mean crystal sizes of these
microcrystals lie preferably in the range of 1 to 1000 .mu.m or in
the range of 5 to 500 .mu.m or in the range of 10 to 200 .mu.m. The
crystal size can be determined, for example, by means of light
microscopy or by means of micro computer tomography X-ray
(micro-CT).
[0206] Micro computer tomography (micro CT) x-ray test method and
measurement conditions:
[0207] Instrument SkyScan 2211
[0208] X-ray energy 60 kV
[0209] Resolution 0.75 .mu.m/voxel
[0210] Reconstruction according to Feldkamp
[0211] The results are summarised in the following Table 6:
TABLE-US-00007 TABLE 6 Crystal size and Formulation standard
deviation 4 20.1 .mu.m +- 7.2 .mu.m 7 18.4 .mu.m +- 6.8 .mu.m 14
16.9 .mu.m +- 6.2 .mu.m 15 21.0 .mu.m +- 7.8 .mu.m
Example 4
[0212] Results of a clinical study with an OTF based on formulation
15 according to Table 3.
[0213] Aim:
[0214] Primary objective: Determination of the pharmacokinetic
profile of an oral thin film of (S)-ketamine with 50 mg
(S)-ketamine; Secondary objective: (1) Determination of the
pharmacodynamic profile of an oral thin film of (S)-ketamine with
50 or 100 mg (S)-ketamine with the end points antinociceptors and
psychomimetic side effects; (2) Determination of the safety and
compatibility of the (S)-ketamine oral thin film.
[0215] Study Design:
[0216] The study had an explorative, open, crossover and randomised
design. All test subjects were treated twice. The test subjects
received 50 mg (S)-ketamine OTF once and two 50 mg (S)-ketamine OTF
once (total dose thus 100 mg) in a random order. 15 test subjects
received the OTF sublingually; 5 further test subjects received the
OTF buccally.
[0217] Execution of the Study:
[0218] During one test run, the test subjects received an
individual 50 mg (S)-ketamine OTF either sublingually (n=15) or
buccally (n=5) During a further test run, the test subjects
received simultaneously two 50 mg (S)-ketamine OTFs sublingually
(n=15) or buccally (n=5) Six hours after the OTF administration, a
low (S)-ketamine dose (20 mg) was administered to the test subjects
intravenously. A wash-out phase of at least 2 days was provided
between the study days.
[0219] Blood Sampling:
[0220] For blood sampling, an arterial access was placed in the
left or right radial or brachial artery. Blood samples (4 ml) were
taken at the following intervals following OTF administration (t=0
min): 0, 5, 10, 20, 40, 60, 90, 120, 180, 240, 300, 360 min and at
the following intervals following the start of intravenous
administration: 2, 4, 10, 15, 20, 30, 40, 60, 75, 90 and 120
min.
[0221] Pain Tests:
[0222] Three pain tests were performed at intervals of 10 to 20
minutes (at intervals of 10 to 60 minutes
(0-10-20-30-40-60-80-100-120-150-180-240-300-360 minutes)
[0223] a) pressure pain,
[0224] b) electrical pain and
[0225] c) heat-induced pain.
[0226] a) The test subjects assessed their pressure pain threshold
in response to an increasing pressure stimulus using an FDN 200
Algometer from Wagner Instruments.
[0227] b) The test subject used a transcutaneous electrical pain
model to assess the pain threshold during a fixed stimulation of
the skin so that the pain value was 7 to 8.
[0228] c) A fixed heat stimulus that caused a pain value of 7 to 8
was applied to the skin using the Medoc Pathway System.
[0229] All pain assessments were performed using an 11-stage Likert
scale (Verbal Rating Scale, VRS), which ranged from 0 (no pain) to
10 (maximum pain imaginable).
[0230] Qualitative Results:
[0231] The taste of the film formulations was described by the test
subjects as being acceptable. No safety-relevant results were
reported. Neither the sublingual nor the buccal administration were
considered to be problematic.
[0232] Plasma Concentrations:
[0233] The plasma concentration was measured by means of liquid
chromatography coupled with QTOF-MS as detection method. The lower
detection limit was 6 ng/mL, 6 ng/mL and 4 ng/mL for (S)-ketamine,
(S)-norketamine and (S)-hydroxynorketamine respectively. The upper
detection limit was 1000, 500 and 200 ng/mL for (S)-ketamine,
(S)-norketamine and (S)-hydroxynorketamine respectively.
[0234] Questionnaires:
[0235] Immediately before the pain test, two questionnaires were
filled out with an interval of 30 minutes in between in order to
assess the effect of the medicinal treatment for psychological and
psychomimetic side effects (0-30-60-90--etc. from 0 to 360
minutes).
[0236] 1. Bowdle questionnaire: Based on the Bowdle questionnaire
(Bowdle et al "Psychedelic effects of ketamine in healthy
volunteers: relationship to steady-state plasma concentrations"
Anesthesiology 1998 January; 88(1): 82-8) it is possible to deduce
three factors of psychedelic effects: drug intoxication, internal
perception and external perception.
[0237] 2. Bond and Lader questionnaire: The Bond and Lader scales
are calculated from sixteen 100 mm visual analogue scales. The end
points are set to antonymous word pairs, such as `awake-sleepy`,
`well coordinated-clumsy`, `mentally slow-quickly attentive` and
`incompetent-professional`.
[0238] Results:
[0239] The results show the rapid onset of a powerful and
long-lasting reduction in pain (see FIG. 2). No dose dependency for
the pain relief was observed for the OTF formulation. This is
presumably due to the high concentration of the metabolite
norketamine, which brings about an anti-analgesic effect (see
Olofsen et al "Estimation of contribution of norketamine to
ketamine-induced acute pain relief and neurocognitive impairment in
healthy volunteers" Anesthesiology 2012; 117; Addendum 5).
[0240] A non-linear dose-dependent increase in the concentration of
ketamine and the metabolites norketamine and hydroxynorketamine was
observed for the OTF formulation.
[0241] The plasma level of the metabolites (S)-norketamine (see
FIGS. 3, 4 and 5) and (S)-hydroxynorketamine (FIGS. 6, 7 and 8) are
higher following administration of an OTF (see also Table 7 below)
as compared to intravenous administration of 20 mg
(S)-ketamine.
[0242] The plasma levels of ketamine are higher for intravenous
administration than following administration of an OTF (see FIGS.
9, 10, 11 and Table 7 below).
[0243] The examined film formulation is suitable for the treatment
of pain.
TABLE-US-00008 TABLE 7 Cmax plasma concentration (ng/ml) All data
All data Sublingually Sublingually Buccally Buccally 50 mg 2
.times. 50 mg 50 mg 2 .times. 50 mg 50 mg 2 .times. 50 mg
(S)-ketamine 101 143 95 138 117 158 (S)-Norketamine 254 330 258 323
242 450 (S)-Hydroxynorketamine 94 171 98 173 81 165
[0244] Following the administration of a film, the plasma values to
be achieved are preferably in the following ranges: cmax
((S)-ketamine)=50-200 ng/mL; cmax ((S)-norketamine)=200-400 ng/mL;
cmax ((S)-hydroxynorketamine)=50-150 ng/mL.
[0245] If two films are administered, the plasma values to be
achieved are preferably in the following ranges: cmax
((S)-ketamine)=100-200 ng/mL; cmax ((S)-norketamine)=300-500 ng/mL;
cmax (hydroxynorketamine)=100-250 ng/mL.
[0246] Oral Bioavailability
[0247] The oral bioavailability for (S)-ketamine OTF is
26.3%.+-.1.0%.
[0248] The oral bioavailability of 50 mg and 100 mg (S)-ketamine
OTF differs by approximately 20% (F1 50 mg=29%, F1 100 mg=23%), but
this does not reach the significance level (p 0.01).
[0249] Tmax, AUC data calculated using a PK model.
[0250] Data analysis of measured plasma concentrations of
(S)-ketamine and its metabolites to determine a pharmacokinetic
model was performed using NONMEM version 7.5.0 (ICON Development
Solutions, Hanover, Md., USA).
[0251] FOCI-I (first-order conditional estimation with interaction)
was used to calculate the pharmacokinetic model parameters. Based
on the created pharmacokinetic model, TMax data and AUC data of
(S)-ketamine and its metabolites were calculated and are shown in
Table 8.
TABLE-US-00009 TABLE 8 50 mg (S)-Ketamine OTF 100 mg (S)-Ketamine
OTF (S)-Ketamin Tmax (min) 18.8 (16.6 - 21.2) 19.1 (17.1 - 21.2)
AUC (0-6) 8.363 (7.263 - 9.464) 13.347 (11.933 - 14.760) (ng/mL
min) (S)-Norketamine Tmax (min) 61 (53-68) 78 (66-91) AUC (0-6)
38.497 (34.131 - 42.863) 67.959 (60.045 - 75.872) (ng/mL min)
(S)-Hydroxynorketannine Tmax (min) 81 (69-92) 109 (89 - 130) AUC
(0-6) 24.087 (20.694 - 27.480) 44.972 (38.563 - 51.382) (ng/mL
min)
[0252] Further results of the study are as follows:
[0253] 1. The OTF formulation according to the invention has an
analgesic effect in all three pain modalities, irrespective of the
localisation.
[0254] 2. None of the used pain tests showed a clear dose-effect
relationship.
[0255] 3. In the electrical and thermal pain test, the analgesic
effect is long-lasting and ranged from 2 to 6 hours, especially
following sub-lingual administration of the OTF.
[0256] 4. There are no obvious differences in the data obtained
during and after sublingual and buccal administration.
[0257] 5. The psychedelic effects for the administered OTF can be
considered to be very mild.
[0258] 6. Eighteen (18) test subjects reported at least one adverse
event. In total, there were 33 adverse events. None of these was a
serious adverse event (see Table 9 below for the prevalence of the
events). The adverse events were observed primarily for the
intravenous administration of 20 mg (S)-ketamine.
TABLE-US-00010 TABLE 9 20 mg (S)- 50 mg (S)- 100 mg (S)- ketamine
Side effect ketamine ketamine IV Blurred vision 1 -- -- Feeling of
drunkenness 2 -- -- Bradykinesia 1 1 -- Whistling noise in the ear
-- -- 1 Dizziness 1 3 4 Drowsiness -- -- 3 Nausea 1 1 2 Headache 1
2 3 Numbness of the tongue -- 2 -- High blood pressure -- -- 2
(SBP>180mm Hg) Sweating -- -- 1 Dry eyes -- -- 1 Total 7 9
17
[0259] The data relating to the observed psychedelic effects
(psychological and psychomimetic side effects) according to the
Bowdle questionnaire are summarised in FIGS. 12 to 15 and according
to the Bond and Lade questionnaire are summarised in FIGS. 16 to
31.
Example 5
[0260] The active agents R-ketamine and (S)-ketamine were
compared.
[0261] To this end, oral thin films with the composition according
to Table 10 were produced.
TABLE-US-00011 TABLE 10 15 16 Material [wt. %] [wt. %] S ketamine
HCl 60.0 -- R-ketamine HCl 60.0 PVA 4-88 -- -- PVA 40-88 10.0 10.0
Kollicoat IR 20.1 20.1 Saccharin Na 1.0 1.0 Sucralose 2.0 2.0
Glycerol 3.5 3.5 Cherry Flavour 3.0 3.0 M55394 FD&C Red No, 40
0.4 0.4 Solvent Aq. Pur. Aq. Pur. Area density 215.73 g/m.sup.2
221.4 g/m.sup.2
[0262] The active agent flux was determined below in the in vitro
model.
[0263] The active agent flux was performed within the scope of a
typical in vitro permeation by means of Franz diffusion cells
(volume 10 mL) at 37.degree. C. The used acceptor medium was
replaced completely for a new one at predetermined replacement
times, and the content of permeated active agent amount in these
acceptor solutions was determined by means of HPLC.
[0264] Phosphate buffer (pH 7.4) was used as acceptor medium.
[0265] Dermatomised skin from the oesophagus of a pig with a layer
thickness of 400 .mu.m was used as skin model.
[0266] The results of the permeation study are shown in FIG.
32.
* * * * *