NZ625022B2 - Liposomal corticosteroids for treatment of inflammatory disorders in humans - Google Patents
Liposomal corticosteroids for treatment of inflammatory disorders in humans Download PDFInfo
- Publication number
- NZ625022B2 NZ625022B2 NZ625022A NZ62502212A NZ625022B2 NZ 625022 B2 NZ625022 B2 NZ 625022B2 NZ 625022 A NZ625022 A NZ 625022A NZ 62502212 A NZ62502212 A NZ 62502212A NZ 625022 B2 NZ625022 B2 NZ 625022B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- corticosteroid
- treatment
- prednisolone
- dose
- liposomes
- Prior art date
Links
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Abstract
The disclosure relates to a pharmaceutical composition comprising liposomes composed of non-charged vesicle-forming lipids, optionally including not more than 10 mole percent of negatively charged vesicle- forming lipids and/or not more than 10 mole percent of PEGylated lipids, the liposomes having a selected mean particle diameter in the size range of 40-200 nm and comprising a first corticosteroid in water soluble form, for the site-specific treatment of inflammatory disorders in humans, providing in human patients a fast, strong, and durable anti-inflammatory effect for at least 2 weeks at a dose of at most 5 mg/kg body weight of prednisolone or an equipotent dose corticosteroid other than prednisolone at a treatment frequency of at most once per two weeks. Furthermore the present disclosure relates to the application of the above-mentioned pharmaceutical composition given as intervention therapy in inflammatory disorders such as rheumatic disease or a related inflammatory connective tissue disorder, inflammatory diseases of the kidney or inflammatory bowel disorders, in combination with chronic therapy with a second free corticosteroid formulation or in combination with chronic treatment with a disease- modifying agent such as methotrexate. a selected mean particle diameter in the size range of 40-200 nm and comprising a first corticosteroid in water soluble form, for the site-specific treatment of inflammatory disorders in humans, providing in human patients a fast, strong, and durable anti-inflammatory effect for at least 2 weeks at a dose of at most 5 mg/kg body weight of prednisolone or an equipotent dose corticosteroid other than prednisolone at a treatment frequency of at most once per two weeks. Furthermore the present disclosure relates to the application of the above-mentioned pharmaceutical composition given as intervention therapy in inflammatory disorders such as rheumatic disease or a related inflammatory connective tissue disorder, inflammatory diseases of the kidney or inflammatory bowel disorders, in combination with chronic therapy with a second free corticosteroid formulation or in combination with chronic treatment with a disease- modifying agent such as methotrexate.
Description
Title: Liposomal corticosteroids for treatment of inflammatory disorders in
humans
The invention relates to the field of medicine. More specifically the
invention relates to corticosteroid treatment of inflammatory disorders.
Inflammatory diseases like inflammatory connective tissue disorder, such
as rheumatoid arthritis (RA), inflammatory diseases of the kidney and inflammatory
bowel disorders (IBD) are chronic, progressive, and debilitating diseases often leading
to disability. Prednisolone and other corticosteroids can be effective in inflammatory
diseases, but their systemic application is limited because of a high incidence of
adverse effects (AE) including osteoporosis, hypothalamic-pituitary-adrenal axis
(HPA) suppression, muscle wasting, insulin resistance, easy skin bruising, increased
risk of serious bacterial infections, and cardiovascular events. In most cases the
severity of these AE depends on dose, duration of exposure and potency of the
prescribed agent. Besides a poor safety profile, also poor localization in inflamed areas
in the body limits the usefulness of corticosteroids in the patient, as this requires
frequent administration of corticosteroids to attain adequate therapeutic benefit.
In recent years, several lines of investigation have been pursued to
improve the therapeutic index of corticosteroids. These lines encompass for instance
the development of selective glucocorticoids (GC) receptor agonists (SEGRAs), the
combination of corticosteroids with drugs that potentiate their effects in activated
inflammatory cells, the development of controlled-release formulations, and the
design of advanced formulations that achieve targeted delivery of corticosteroids to
the actual sites of inflammation. Targeted delivery of corticosteroids can be realized
by encapsulation in long circulating liposomes (LCL) that circulate after i.v. injection
and at the same time extravasate at the sites of inflammation lesions by virtue of
increased vascular permeability, building local depots of corticosteroids selectively at
the target sites. This approach is for instance described in WO 02/45688 and WO
03/105805 and proved to be effective in preclinical studies with experimental animal
models of arthritis, and other inflammatory diseases.
Typically in these experiments PEG-liposomal prednisolone phosphate
(PLP) at a dose of 10 mg/kg of PLP results in resolution of the inflammation up to one
week after treatment, after which the inflammation slowly comes back. 20 mg/kg
PEG-liposomal prednisolone phosphate can lead to a resolution of the inflammation
still observable 2 weeks after treatment. Single treatment with an equal dose of free
prednisolone is not effective while repeated daily treatment with free prednisolone
only results in a short-lasting moderate effect as shown by the results of the study
under Example 1 (Figure 1 A and 1 B).
However, intravenous administration of liposomal corticosteroid at dose
levels of 10 and 20 mg/kg of a corticosteroid in humans is impractical. If a dose of 20
mg prednisolone per kg body weight is administered to an individual with a body
weight of 75 kg a total of 1.5 g of prednisolone is administered. The typical
prednisolone content of formulations with liposomal prednisolone is 1.5 mg of
prednisolone per mL. As a result, a dose of 20 mg prednisolone per kg body weight
would require one liter (1.5 g prednisolone / 1.5 mg/mL) of formulation per treatment.
Such amount of formulation then needs to be infused over more than 12 hours to
prevent infusion or hypersensitivity reactions, i.e. pseudoallergic reactions that can be
caused by intravenous administration of particles such as liposomes to humans.
Furthermore, these high prednisolone doses lead to the administration of enormous
quantities of liposomal components, such as phospholipid and cholesterol, to the
patient. Lower doses of liposomal corticosteroid would therefore be preferred for the
treatment of inflammatory disorders in humans, because in that case less of the
liposomal corticosteroid formulation needs to be administered and administration
times as long as 12 hours are not necessary. However, in animal studies, doses lower
than 10 mg/kg liposomal prednisolone have a much less durable effect as is for
instance demonstrated in Example 1 (Figure 2A and 2B). 1 mg/kg of prednisolone has
a limited effect during 4 days only. 2 mg/kg of prednisolone shows the same effect
duration although it is slightly more effective. Even at 5 mg/kg the therapeutic
activity lasts no longer than 1 week.
Similar observations have been described in prior publications. For
instance, WO 02/45688 describes that a dose of 10 mg/kg liposomal prednisolone
phosphate was effective in rats with adjuvant-induced arthritis. Although it is
mentioned that 1 mg/kg liposomal prednisolone phosphate was also effective, the
duration of the therapeutic effect is, however, not indicated. The analogous scientific
publication, Metselaar JM. et al. 2003, demonstrates that a dose of 1 mg/kg liposomal
prednisolone phosphate has a therapeutic activity in rats with adjuvant-induced
arthritis that lasts only 4 days (see figure 3A of Metselaar JM. et al.). A sustained
treatment with a dose of 1 mg/kg in rats would thus require administration of the
liposomal corticosteroid at least once every 4 days.
EP 2127639 describes the use of liposomal corticosteroid for treatment of
cardiovascular disease. As an example, treatment of rabbits with aortic
atherosclerotic plaques is described. The rabbits were treated with liposomal
prednisolone phosphate at a dose of 15 mg/kg body weight, which resulted in a
therapeutic effect lasting up to two weeks. Lower doses of liposomal corticosteroid
were not tested or described.
relates to the use of liposomal triamcinolone for
treatment of the respiratory tract. It is described that administration via a nebulizer
once every one to two weeks is allowed, without any indication as to the dose of the
liposomal triamcinolone. The experimental section of describes a
mouse model of asthma. Mice were treated once a week with liposomal triamcinolone.
Thus, the prior art teaches that administration of a dose of at least 10
mg/kg body weight may result in a therapeutic effect in animal models of
inflammatory disorders that lasts at least two weeks. Administration of a lower doses
of liposomal corticosteroid in these animals may only have a satisfying therapeutic
efficacy if treatment is given at a higher frequency, such as once every week or once
every 4 days. Therefore, based on experiments performed in rats, mice and rabbits
described in prior publications and in present Example 1, a person skilled in the art
would expect that to achieve an effective therapeutic response, treatment at dose
levels below 10 mg/kg of corticosteroid will need to be repeated at least within a week,
possibly even every four days. Before the present invention, it was expected that with
doses below 10 mg/kg of corticosteroid a lasting therapeutic response is not possible.
At most short effects were expected, which require multiple doses of liposomal
corticosteroid to be administered. In a clinical setting this means that at these low
dose levels – because liposomal corticosteroids will be applied in an outpatient setting
– the patient would need to go to the hospital every 4 to 7 days to receive a new
intravenous infusion, which is not practical. In order for liposomal corticosteroid
treatment to be feasible, a patient needs to achieve a lasting therapeutic response
that allows him/her to go home after the treatment without the need to repeat the
treatment, or at least without the need to come back to the hospital within the next 2
weeks or an even longer time period. Furthermore, the infusion time of the treatment
preferably does not take longer than approximately 4 hours and therefore treatment
need to be limited to maximally 200 mL of liposomal corticosteroid formulation.
Finally, the treatment preferably allows the patient to continue with his/her
maintenance therapy comprising for instance the relatively cheap and widely
available small-molecular disease modifying agents (e.g. methotrexate,
hydroxychloroquine, leflunomide, cyclophosphamide, 5-fluorouracil, a 5-ASA agent, 6-
mercaptopurine, or azathioprine). Such disease modifying agents are not effective in
and not used for suppressing a temporary exacerbation of inflammation but are
rather used to modify the long-term course of the disease. Clinical practice has
revealed that without an effective treatment of the short-term exacerbations of
inflammation a patient will be likely to cease his/her maintenance therapy with the
relatively cheap (generic) disease modifying agents and instead desire to commence
therapy with the relatively expensive biological products (e.g. infliximab, enbrel,
adalimumab, anakinra and related products). In contrast to disease modifying agents,
such biological products can be effective in an acute setting but need to be used, like
the disease modifying agents, as maintenance therapy. However, the costs of
maintenance therapy with such biological products is many times larger than the cost
of therapy with disease modifying agents and the tendency of patients to switch to
biologicals can eventually lead to an enormous increase of the burden of healthcare
costs.
It is an aim of the present invention to overcome the limitations mentioned
above by providing liposomal corticosteroid formulations that can be used to achieve a
long lasting and clinically meaningful therapeutic response in patients suffering from
an exacerbation or an active phase of inflammatory disorder, such as inflammatory
connective tissue disorders (notably rheumatoid arthritis), inflammatory diseases of
the kidney or inflammatory bowel disorders; and/or to provide the public with a useful
choice.
Accordingly in a first aspect, the invention provides a use of liposomes
composed of non-charged vesicle-forming lipids, optionally including not more than 10
mole percent of negatively charged vesicle-forming lipids and/or not more than 10
mole percent of PEGylated lipids, the liposomes having a selected mean particle
diameter in the size range of 40-200 nm and comprising a first corticosteroid in water
soluble form for the preparation of a medicament for the treatment of an
inflammatory disorder in a human at a dose of at most 5 mg/kg body weight of
prednisolone or an equipotent dose of a corticosteroid other than prednisolone,
wherein said treatment has a treatment frequency of at most once per two weeks.
In a second aspect the invention provides a kit of parts comprising:
a) a pharmaceutical composition comprising liposomes composed of non-charged
vesicle-forming lipids, optionally including not more than 10 mole percent of
negatively charged vesicle- forming lipids and/or not more than 10 mole percent of
PEGylated lipids, the liposomes having a selected mean particle diameter in the size
range of 40-200 nm and comprising a first corticosteroid in water soluble form,
comprising one or more dosage units, each dosage unit suitable for administration of
the liposomes comprising the corticosteroid at a dose of at most 5 mg/kg of
prednisolone or an equipotent dose of a corticosteroid other than prednisolone, and
b) a pharmaceutical composition comprising a second, free corticosteroid.
Also described is a method for the treatment of an inflammatory disorder
in a human comprising administering to a human in need thereof a pharmaceutical
composition comprising liposomes composed of non-charged vesicle-forming lipids,
optionally including not more than 10 mole percent of negatively charged vesicle-
forming lipids and/or not more than 10 mole percent of PEGylated lipids, the
liposomes having a selected mean particle diameter in the size range of 40-200 nm
and comprising a first corticosteroid in water soluble form in a dose of at most 5
mg/kg body weight of prednisolone or an equipotent dose of a corticosteroid other than
prednisolone, wherein said treatment has a treatment frequency of at most once per
two weeks. Also described is a use of liposomes composed of non-charged vesicle-
forming lipids, optionally including not more than 10 mole percent of negatively
charged vesicle-forming lipids and/or not more than 10 mole percent of PEGylated
lipids, the liposomes having a selected mean particle diameter in the size range of 40-
200 nm and comprising a first corticosteroid in water soluble form for the preparation
of a medicament for the treatment of an inflammatory disorder in a human at a dose
of at most 5 mg/kg body weight of prednisolone or an equipotent dose of a
corticosteroid other than prednisolone, wherein said treatment has a treatment
frequency of at most once per two weeks.
Liposomes composed of non-charged vesicle-forming lipids, optionally
including not more than 10 mole percent of negatively charged vesicle- forming lipids
and/or not more than 10 mole percent of PEGylated lipids, the liposomes having a
selected mean particle diameter in the size range of 40-200 nm and comprising a first
corticosteroid in water soluble form, are herein also referred to as "liposomes for use
in a method according to the invention" and "liposomes as defined herein".
A pharmaceutical composition comprising such liposomes is herein
referred to as "a pharmaceutical composition for use in a method according to the
invention" and "a pharmaceutical composition comprising liposomes as described
herein".
The present disclosure provides the insight that administration of
liposomal corticosteroid at a dose of at most 5 mg/kg body weight of prednisolone or an
equipotent dose of a corticosteroid other than prednisolone in humans suffering from
an inflammatory disorder leads to a surprisingly long lasting therapeutic effect of up
to 2 weeks or longer. As shown in Example 2, in rheumatoid arthritis (RA) patients a
fast, strong, and durable anti-inflammatory activity is shown with a relatively low
dose of 150 mg (roughly 2 mg/kg), which activity is comparable to the relatively new
intravenous anti-TNF alpha biologicals that are currently on the market for these
diseases (a drop of the EULAR DAS-28 score of 1.5 points). The long-lasting effect
observed at this lower (and therefore clinically more practical) dose level is new as
compared to the known preclinical study results at these dose levels in rats (see the
comparison in Figure 6 of the results from the preclinical study in rats under Example
1 with the results of the clinical study according to the present invention in humans
reported under Example 2). In clinical practice this means that when a patient
experiences an exacerbation or an active phase of an inflammatory disease, i.e. a
disease flare, a single treatment may suffice to keep the disease flare under control.
Alternatively, if repeated treatment is needed, a treatment frequency of once per two
weeks or lower, as long as the exacerbation or active disease phase lasts, will suffice
to keep the disease flare under control.
A pharmaceutical composition comprising liposomes for use in a method
described herein is advantageously combined with a second pharmaceutical
composition comprising a free corticosteroid. It was found by the present inventor that
treatment with intravenous liposomal corticosteroids is complementary to treatment
with intramuscular formulations of corticosteroid. As is demonstrated in Example 2,
the therapeutic activity of the liposomal corticosteroid in humans suffering from RA is
not only stronger as compared to an equipotent dose of free corticosteroid
(methylprednisolone in Example 2) administered intramuscularly, but also faster. As
is shown in figures 3-5, the liposomal corticosteroid provides a fast and strong
therapeutic response especially during the first weeks. It has its maximum
therapeutic activity, i.e. maximum reduction of EULAR disease activity scores, within
the first two weeks following administration, after which the scores gradually
increase again. On the other hand, an intramuscular formulation of free corticosteroid
leads to a moderate therapeutic response reached after some weeks. The therapeutic
activity gradually increases following administration and reaches its maximum
therapeutic activity at weeks three to seven following administration. Thus,
intramuscularly administered free corticosteroid functions as a depot formulation.
Combination of liposomal corticosteroid and free corticosteroid is therefore
particularly advantageous because both a strong direct therapeutic activity as well as
a strong therapeutic activity several weeks after administration are achieved. Thus, if
such a combination is used, liposomal corticosteroid serves as a direct treatment of
the inflammatory disorder and the free corticosteroid serves as a depot formulation,
i.e. as a more slowly establishing treatment. Giving these two treatments at the same
time therefore yields an efficacy profile over an even longer period of time (4 – 6 weeks
or longer) so that repeated treatment with the liposomal formulation can be avoided
for at least 4 weeks.
Also described is a method for the treatment of an inflammatory disorder
in a human comprising administering to a human in need thereof a pharmaceutical
composition comprising liposomes as described herein, and a pharmaceutical
composition comprising a second, free corticosteroid. A dose of at most 5 mg/kg body
weight of prednisolone or an equipotent dose of a corticosteroid other than
prednisolone, and a treatment frequency of liposomal corticosteroid of at most once
per two weeks are preferred.
Also described is a kit of parts comprising a pharmaceutical composition
comprising liposomes as herein described, and a pharmaceutical composition
comprising a second, free corticosteroid. Said kit of part further preferably comprises
instructions for a dosing regime for the first, liposomal, corticosteroid of at most 5
mg/kg body weight of prednisolone or an equipotent dose of a corticosteroid other than
prednisolone at a treatment frequency of at most once per two weeks, and, optionally,
for a dosing regime for the second, free corticosteroid of between 0.5 and 5 mg/kg body
weight of prednisolone or an equipotent dose of a corticosteroid other than
prednisolone. It is preferred that the kit of parts comprises an amount of liposomal
corticosteroid corresponding to the dosage regimen of at most 5 mg/kg body weight of
prednisolone or an equipotent dose of a corticosteroid other than prednisolone with a
treatment frequency of at most once per two weeks. Therefore, said kit of parts
preferably comprises one or more dosage units, each dosage unit suitable for
administration of the first, liposomal, corticosteroid at a dose of at most 5 mg/kg body
weight of prednisolone or an equipotent dose of a corticosteroid other than
prednisolone. Further, said kit of parts preferably comprises one or more dosage
units, each dosage unit suitable for administration of the second, free corticosteroid at
a dose of between 0.5 and 5 mg/kg body weight of prednisolone or an equipotent dose
of a corticosteroid other than prednisolone.
Further described is a combination of a pharmaceutical composition
comprising liposomes as described herein, and a pharmaceutical composition
comprising a second, free corticosteroid for use in a method for the treatment of an
inflammatory disorder in a human, preferably at a dose of at most 5 mg/kg body
weight of liposomal prednisolone or an equipotent dose of a liposomal corticosteroid
other than prednisolone, wherein said treatment has a treatment frequency of at most
once per two weeks.
"Free corticosteroid" as used herein refers to a corticosteroid that is not
incorporated in a microvesicle such as a liposome. Optionally said free corticosteroid is
coupled to a pharmaceutically acceptable carrier and/or present in a pharmaceutically
acceptable diluent, optionally in the presence of one or more pharmaceutically
acceptable additives. A second, free corticosteroid is preferably in fat soluble form and
can be identical to the first, liposomal, corticosteroid, or different. Preferably a second
free corticosteroid is a corticosteroid used in clinical practice for the treatment of
inflammatory disorders in a human, being typically prednisolone,
methylprednisolone, triamcinolone, dexamethasone, betamethasone, cortisone or their
respective derivatives, such as prednisolone acetate, methylprednisolone acetate,
triamcinolone acetate, betamethasone phosphate.
A pharmaceutical composition comprising said second free corticosteroid is
preferable administered orally, intra-articularly, intravenously, subcutaneously, or
most preferably, intramuscularly to a human in need thereof in a method described
herein. A pharmaceutical composition comprising liposomes as described herein is
preferably administered intravenously, more preferably by intravenous infusion.
If a combination treatment is used involving administration of liposomes
as described herein and a second, free corticosteroid, said treatment preferably
involves administration of a pharmaceutical composition comprising said liposomes at
a dose of at most 5 mg/kg body weight of prednisolone or an equipotent dose of a
corticosteroid other than prednisolone, at a treatment frequency of at most once per
two weeks. Said second, free corticosteroid is preferably administered at a dose of
between 0.5 and 5 mg/kg, preferably between 1 and 5 mg/kg, with a treatment
frequency of at most once every two weeks. Most preferably, said first, liposomal
corticosteroid and said second, free corticosteroid are administered concomitantly.
With “concomitantly” it is meant that the first and the second corticosteroid are
administered at the same time, or almost at the same time. The second, free
corticosteroid is preferably administered within one hour before administration of the
first liposomal corticosteroid is started, during administration of the first liposomal
corticosteroid, or within one hour after administration of the first liposomal
corticosteroid has finished, more preferably within 30 minutes before or after
administration of the first liposomal corticosteroid, even more preferably within 15
minutes before or after administration of the first liposomal corticosteroid or during
administration of the first liposomal corticosteroid.
A pharmaceutical composition comprising liposomes for use in a method
described herein is also advantageously combined with a pharmaceutical composition
comprising a disease modifying agent. Also described are pharmaceutical
compositions comprising liposomes for use in a method described herein, are
particularly suitable for counteracting an active episode of an inflammatory disorder.
Such pharmaceutical liposomal compositions provide an effective intervention therapy
when a patient, who has an otherwise rather stable disease course as a result of
sustained treatment with disease modifying agents, infrequently and unexpectedly
experiences an active episode or an exacerbation of inflammation. A dose of at most 5
mg/kg body weight of prednisolone or an equipotent dose of a corticosteroid other than
prednisolone, and a treatment frequency of liposomal corticosteroid of at most once
per two weeks are preferred.
Also described is a method for the treatment of an inflammatory disorder
in a human comprising administering to a human in need thereof a pharmaceutical
composition comprising liposomes as described herein, and a pharmaceutical
composition comprising a disease modifying agent. Said treatment comprises
maintenance therapy with said pharmaceutical composition comprising a disease
modifying agent and temporary therapy of an exacerbation of inflammation with a
pharmaceutical composition comprising liposomal corticosteroids.
Also described is a combination of a pharmaceutical composition
comprising liposomes as described herein, and a pharmaceutical composition
comprising a disease modifying agent for use in a method for the treatment of an
inflammatory disorder in a human.
As detailed in Example 2, it was found that patients suffering from
rheumatoid arthritis who receive maintenance therapy with methotrexate are more
sensitive to therapy with liposomal corticosteroid than patients who do not take
methotrexate or who take another disease modifying agent. In spite of the fact that
the treatment of corticosteroids in combination with methotrexate is not unheard of in
the literature, the clinical trial reported in Example 2 shows that patients who
received intramuscularly administered free corticosteroid in combination with
methotrexate did not show a better response than patients with intramuscularly
administered free corticosteroid without methotrexate (Figure 7). In contrast,
according to the present disclosure, a combination of liposomal corticosteroid and
methotrexate does provide better results as compared to liposomal corticosteroids
alone. Thus, a combination of liposomes as described herein with methotrexate
maintenance therapy is highly effective in reducing disease activity, whereas
treatment of such patients with a combination of free corticosteroid and methotrexate
is not. In clinical practice this means that patients, who are otherwise successfully
treated by maintenance therapy with relatively cheap oral disease modifying agents
like methotrexate and go through an active phase or an exacerbation of the disease
can now be very effectively treated with a single infusion, or only a few repeated
infusions, with liposomal corticosteroid. This allows patients with a low frequency of
disease flaring to quickly regain the low activity phase of the disease and to continue
with their relatively cheap disease modifying agent therapy without the desire or
need to switch to treatment with the more expensive biologicals that more recently
entered the field of inflammatory diseases. Besides the convenience for the patient,
this is also important from a health economics perspective as treatment which entails
the use of liposomal corticosteroid helps to keep the costs associated with treatment of
inflammatory diseases within limits.
Therefore, in a preferred embodiment, a human suffering from an
inflammatory disorder receives maintenance therapy with a pharmaceutical
composition comprising a disease modifying agent and receives temporary treatment
with a pharmaceutical composition comprising liposomes following a flare of said
inflammatory disorder.
The term "disease modifying agent" is known in the art and refers to a
small molecular drug used as maintenance therapy in inflammatory diseases, i.e. it is
taken by a patient for a prolonged period of time as to modulate the progression of the
disease, usually longer than one month but more typically longer than three months.
For instance, disease modifying agents used in the treatment of rheumatoid arthritis
are disease-modifying antirheumatic drugs (DMARDs). Such small molecular drug
used as maintenance therapy in inflammatory diseases preferably has a molecular
weight of at most 800 dalton. Preferably a disease modifying agent for use in a
method according to the invention is chosen from the group of relatively cheap disease
modifying agents given in clinical practice for the sustained treatment of
inflammatory diseases, such as methotrexate, hydroxychloroquine, leflunomide,
cyclophosphamide, 5-fluorouracil, a 5-ASA agent, 6-mercaptopurine, mycophenolate
mofetil, and azathioprine. In a particularly preferred embodiment, the disease
modifying agent is methotrexate. If the disease treated in accordance with the
methods described herein is a rheumatic disease or a related inflammatory connective
tissue disorder, said disease modifying agent is preferably selected from the group
consisting of methotrexate, hydroxychloroquine, leflunomide, cyclophosphamide, 5-
fluorouracil, a 5-ASA agent, 6-mercaptopurine, and azathioprine, most preferably said
disease modifying agent is methotrexate. If the disease treated in accordance with the
methods described herein is an inflammatory disease of the kidney, said disease
modifying agent is preferably selected from the group consisting of
hydroxychloroquine, mycophenolate mofetil, azathioprine and cyclophosphamide. If
the disease treated in accordance with the methods described herein is an
inflammatory bowel disorder, said disease modifying agent is preferably selected from
the group consisting of a 5-ASA agent, azathioprine, 6-mercaptopurine and
methotrexate.
"Maintenance therapy" as used herein refers to therapy which is received
by a patient for a prolonged period of time as to modulate the progression of the
disease, usually longer than one month but more typically longer than three months.
Typically, maintenance therapy involves administration of a daily dose of a
medicament, such as a disease modifying agent.
"Temporary treatment" as used herein refers to treatment which is
received by a patient via a single dose or a limited number of doses, i.e. less than 10,
preferably less than 5, such as two or three doses. "Temporary treatment" is used
herein to discriminate the treatment from "maintenance therapy", which, as indicated
above, entails treatment for a prolonged period of time.
"A flare" as used herein refers to a period during which an inflammatory
disorder enters into an active phase or exacerbates, and thus to an increase in
severity of the manifestations of the disorder.
Preferably, a pharmaceutical composition comprising a disease modifying
agent is administered orally, in the form of tablets, capsules or elixirs for oral
administration. A pharmaceutical composition comprising liposomes as described
herein is preferably administered intravenously, more preferably by intravenous
infusion. If a combination treatment is used involving administration of liposomes as
described herein and a disease modifying agent, said treatment preferably involves
administration of a pharmaceutical composition comprising said liposomes at a dose
of at most 5 mg/kg body weight of corticosteroid, at a treatment frequency of at most
once per two weeks.
The term “comprising” as used in this specification and claims means
“consisting at least in part of”. When interpreting statements in this specification,
and claims which include the term “comprising”, it is to be understood that other
features that are additional to the features prefaced by this term in each statement or
claim may also be present. Related terms such as “comprise” and “comprised” are to
be interpreted in similar manner.
"Treatment frequency" as used herein refers to the frequency of
administration of (a pharmaceutical composition comprising) liposomes for use in a
method described herein. For instance, a treatment frequency of once per two weeks
means that a pharmaceutical composition is administered to a patient once every two
weeks, i.e. administration of two different doses is separated by approximately two
weeks. In clinical practice, this may be two weeks plus or minus one or two days. A
treatment frequency of at most once per two weeks indicates that a pharmaceutical
composition is administered to a patient once every two weeks or often less, such as
once every three weeks, or once every four weeks. Thus, the time between two doses is
at least two weeks, or a second dose is not administered at all. A sole and single
administration of a pharmaceutical composition as described herein is also
encompassed within the term "treatment frequency of at most once per two weeks".
According to the present disclosure, the dose of a pharmaceutical
composition comprising liposomes for use in a method described herein is at most 5
mg/kg body weight of prednisolone or an equipotent dose of a corticosteroid other than
prednisolone. "Equipotent dose" as used herein is defined as the dose of a
corticosteroid required to produce the same pharmacological effect as compared to the
pharmacological effect of a given dose of prednisolone. For instance, if a dose of
prednisolone is 2.5 mg/kg, an equipotent dose of another corticosteroid is the dose that
has the same pharmacological effect as 2.5 mg/kg of prednisolone. The term
"pharmacological effect" refers to the effect of a corticosteroid on a human body,
preferably to a therapeutic effect. Methylprednisolone and triamcinolone have a
potency ratio of 1.25 as compared to prednisolone. "A potency ratio" as used herein
refers to the ratio of the pharmacological effect of a corticosteroid to that of
prednisolone, whereby the potency of prednisolone is set to 1. Thus, a corticosteroid
having a potency ratio of 1.25 indicates that a dose of 5/1.25 = 4 mg/kg of said
corticosteroid has an effect comparable to the effect of a dose of 5 mg/kg of
prednisolone. Said dose of 4 mg/kg is thus an equipotent dose of 5 mg/kg of
prednisolone. As said before, methylprednisolone and triamcinolone have a potency
ratio of 1.25 as compared to prednisolone. Therefore, in one embodiment, a liposome
for use in a method described herein comprises methylprednisolone or triamcinolone
and said dose is at most 4 mg/kg body weight of methylprednisolone or triamcinolone.
Dexamethasone and betamethasone have a potency ratio of 6.5 as compared to
prednisolone. Therefore, in another embodiment, a liposome for use in a method
described herein comprises dexamethasone or betamethasone and said dose is at most
0.8 mg/kg body weight of dexamethasone or betamethasone, because said dose is a
dose equipotent to 5 mg/kg body weight of prednisolone. As another example,
fludrocortisone acetate has a potency ratio of 3.5 as compared to prednisolone.
Therefore, in another embodiment, a liposome for use in a method described herein
comprises fludrocortisone acetate and said dose is at most 1.4 mg/kg body weight of
fludrocortisone acetate, because said dose is a dose equipotent to 5 mg/kg body weight
of prednisolone.
The dose may be typically 4 mg/kg of prednisolone or an equipotent dose of
a corticosteroid other than prednisolone, or lower, such as a dose of at most 3.5 mg/kg
of prednisolone or an equipotent dose of a corticosteroid other than prednisolone, or a
dose of at most 3 mg/kg of prednisolone or an equipotent dose of a corticosteroid other
than prednisolone. Doses of at most 2.5 mg/kg body weight of prednisolone or an
equipotent dose corticosteroid other than prednisolone are preferred. Examples of
preferred doses are 2.5 mg/kg, 2 mg/kg, 1.5 mg/kg and 1 mg/kg. In one embodiment, a
liposome for use in a method described herein comprises methylprednisolone or
triamcinolone and said dose is at most 2 mg/kg body weight of methylprednisolone or
triamcinolone. In another embodiment, a liposome for use in a method described
herein comprises dexamethasone or betamethasone and said dose is at most 0.4 mg/kg
body weight of dexamethasone or betamethasone. In yet another embodiment, a
liposome for use in a method described herein comprises fludrocortisone acetate and
(a pharmaceutical composition comprising) said dose is at most 0.7 mg/kg body weight
of fludrocortisone acetate. The above mentioned doses are all doses equipotent to 5
mg/kg body weight of prednisolone. Most preferably, said dose is at most 2.5 mg/kg
body weight of prednisolone.
Treatment may be repeated after two weeks, however treatment intervals
of three weeks, four weeks or longer are also possible. Alternatively, a single
treatment with a pharmaceutical composition for use in a method described herein
having a dose of at most 5 mg/kg of prednisolone or an equipotent dose corticosteroid
other than prednisolone is used if such single treatment is sufficient to overcome the
active episode or the exacerbation of the inflammatory disease in the human,
preferably said dose is at most 4 mg/kg, more preferably at most 3 mg/kg, more
preferably at most 2.5 mg/kg.
A pharmaceutical composition comprising liposomes, free corticosteroid or
a disease modifying agent for use in a method described herein preferably further
comprises a pharmaceutically acceptable carrier, diluent and/or excipient.
Liposomes for use in a method described herein have a mean particle
diameter of 40-200 nm as determined by Dynamic Light Scattering using Malvern
DLS measurement laser equipment. Preferably the liposomes have a diameter of
between 75 and 150 nm. The liposomes preferably have a rather low polydispersity
index, i.e. of below 0.2, which means that the particle size distribution is narrow.
Liposomes for use in a method described herein typically comprise non-
charged vesicle forming lipids from the group of phospholipids, that can be either
artificially synthesized or that originates from a natural source, optionally being
artificially modified. Preferably said non-charged vesicle forming lipids are partially
or wholly synthetic. Phosphatidylcholines (PC), including those obtained from natural
sources or those that are partially or wholly synthetic, or of variable lipid chain length
and unsaturation are suitable for use in the methods described herein. As used
herein, the term "partially synthetic or wholly synthetic vesicle- forming
phospholipids" means at least one vesicle-forming phospholipid which has either been
artificially made or which originates from a naturally occurring phospholipid, which
has been artificially modified. Preferred phospholipids contain saturated alkyl chains
yielding a bilayer with a relatively high transition temperature. Particularly
preferred are DiPaltmitoyl Phosphatidyl Choline (DPPC), Hydrogenated Soy Bean
Phosphatidyl Choline (HSPC), DiStearoyl Phosphatidyl Choline (DSPC), and
Hydrogenated Egg Phosphatidyl Choline (HEPC). Liposomes for use in a method
described herein comprise at most 10 mole % PEGylated lipids and/or at most 10 mole
% of negatively charged lipids. Preferred PEGylated lipids are composed of a PEG
polymer with a molecular mass between 200 and 20 000 dalton on the one end and a
lipophilic anchoring molecule on the other end. Typically anchoring molecules are
chosen from the group of phospholipids and sterols. Preferred PEGylated lipids are
PEG 2000-DiStearoyl Phosphatidyl Ethanolamine (PEG-DSPE) and PEG 2000-
cholesterol. Preferred negatively charged lipids are DiPalmitoyl Phosphatidyl Glycerol
(DPPG) and DiStearoyl Phosphatidyl Glycerol (DSPG). Liposomes for use in a method
described herein preferably comprise a sterol or steroid alcohol of synthetic or natural
origin which have a hydroxyl group in the 3-position of the A-ring. Of this group of
sterol compounds cholesterol is preferred.
The fraction of polymer lipid conjugates and negatively charged lipids is 0-
mol%, and preferably 1 – 10 mol%, more preferably 2.5 – 10 mol%, based upon the
total molar ratio of the vesicle forming lipids in the formulation. The presence of
negatively charged lipids and especially polymer-lipid-conjugates in the liposomal
formulation stabilizes the formulation and has a favourable effect on the circulation
time of the liposome. However, by carefully selecting specific lipid compositions at
physical specifications, suitable long circulation times can be obtained without using a
PEG-lipid-conjugate or negatively charged lipids. For example, 50-100 nm liposomes
of DSPC and cholesterol and/or sphingolipids like sphingomyelin are suitable for use
in a method described herein.
In a particularly preferred embodiment, described is a liposome for use in
a method described herein, wherein said liposome comprises 0-50 mol% of cholesterol,
50-90 mol% of non-charged partially synthetic or wholly synthetic vesicle-forming
lipids, 0-10 mol% of amphipatic vesicle-forming lipids coupled to polyethylene glycol,
and 0-10 mol% of a negatively charged vesicle-forming lipid. Such liposome is for
instance made in accordance with the methods described in WO 02/45688 or WO
03/105805. However, low doses and treatment frequencies in accordance with the
present disclosure are not described therein. Liposomes for use in a method described
herein preferably have a mean particle diameter size range of between about 75 and
150 nm. As stated before, said partially synthetic or wholly synthetic vesicle-forming
lipid is preferably selected from the group consisting of DSPC, DPPC, HSPC and
HEPC.
Specific examples of liposomes for use in a method described herein are:
liposomes composed of non-charged vesicle-forming lipids, including up to 10 mole
percent of an amphipathic vesicle-forming lipid derivatised with
polyethyleneglycol and optionally including not more than 10 mole percent of
negatively charged vesicle-forming lipids, which liposomes have a selected mean
particle diameter in the size range of 40-200 nm and containing a corticosteroid,
characterised in that the corticosteroid is present in a water soluble form;
liposomes composed of cholesterol and non-charged vesicle-forming lipids selected
from DSPC, HSPC, HEPC and DPPC, which liposomes have a selected mean
particle diameter in the size range of 40-200 nm and contain a corticosteroid
characterised in that the corticosteroid is present in a water soluble form;
liposomes composed of non-charged vesicle-forming lipids and not more than 5
mole percent of negatively charged dipalmitoyl phosphatidyl glycerol, which
liposomes have a selected mean particle diameter in the size range of 40-200 nm
and contain a corticosteroid characterised in that the corticosteroid is present in a
water soluble form;
liposomes composed of cholesterol and non-charged vesicle-forming lipids selected
from phospholipids that are partially or wholly synthetic, optionally including not
more than 5 mole percent of negatively charged vesicle-forming lipids, which
liposomes have a selected mean particle diameter in the size range of 40-200 nm
and contain a corticosteroid characterised in that the corticosteroid is present in a
water soluble form.
As said, liposomes used in accordance with the methods described herein
may be prepared according to methods used in the preparation of conventional
liposomes or PEG-liposomes, for instance such as disclosed in WO 02/45688 or WO
03/105805. Passive loading of the active ingredients into liposomes by dissolving the
corticosteroids in the aqueous phase is sufficient in order to reach sufficient
encapsulation, but other methods can also be used, so as to further increase the
encapsulation efficiency. The lipid components used in forming the liposomes may be
selected from a variety of vesicle-forming lipids, such as phospholipids, sphingolipids
and sterols. Substitution (complete or partial) of these basic components by e.g.
sphingomyelins and ergosterol appeared to be possible. For effective encapsulation of
the water-soluble corticosteroids in liposomes, thereby avoiding leakage of the drug
from the liposomes, especially phospholipid components having saturated, rigidifying
acyl chains have appeared to be useful.
A liposomal composition for use in a method described herein comprises a
water-soluble corticosteroid. The term "water-soluble" is defined herein as having a
solubility at a temperature of 25°C of at least 10 g/l water or water buffered at neutral
pH. Water soluble corticosteroids which can be advantageously used in accordance
with the present disclosure are alkali metal and ammonium salts prepared from
corticosteroids, having a free hydroxyl group, and organic acids, such as (C2 - C12)
aliphatic, saturated and unsaturated dicarbonic acids, and inorganic acids, such as
phosphoric acid and sulphuric acid. As alkaline metal salts the potassium and sodium
salts are preferred. Also other, positively or negatively charged, derivatives of
corticosteroids can be used. Specific examples of water soluble corticosteroids are
betamethasone sodium phosphate, desonide sodium phosphate, dexamethasone
sodium phosphate, hydrocortisone sodium phosphate, hydrocortisone sodium
succinate, methylprednisolone disodium phosphate, methylprednisolone sodium
succinate, prednisolone sodium phosphate, prednisolone sodium succinate,
prednisolamate hydrochloride, prednisone disodium phosphate, prednisone sodium
succinate, triamcinolone acetonide disodium phosphate and triamcinolone acetonide
disodium phosphate. Of these corticosteroids, prednisolone disodium phosphate,
prednisolone sodium succinate, methylprednisolone disodium phosphate,
methylprednisolone sodium succinate, dexamethasone disodium phosphate and
betamethasone disodium phosphate are preferred. The above-mentioned
corticosteroids normally are used in systemic treatment of anti- inflammatory
diseases and disorders. In one embodiment therefore, the first corticosteroid
comprises within a liposomes for use in a method described herein and/or the second,
free corticosteroid is a corticosteroid for systemic administration. As used herein "a
corticosteroid for systemic administration" means that said corticosteroid is in clinical
practice used in systemic treatment of anti- inflammatory diseases.
Since it has been proved that by using a water-soluble form of a
corticosteroid in long-circulating liposomes, having a mean particle diameter of 40-200
nm, effective targeting of the drug to inflammation sites occurs, the present disclosure
can also advantageously be applied to corticosteroids, which for a variety of reasons
normally are used for topical use. Such corticosteroids include for example
alclomethasone dipropionate, amcinonide, beclomethasone monopropionate,
betamethasone 17-valerate, ciclomethasone, clobetasol propionate, clobetasone
butyrate, deprodone propionate, desonide, desoxymethasone, dexamethasone acetate,
diflucortolone valerate, diflurasone diacetate, diflucortolone, difluprednate,
flumetasone pivalate, flunisolide, fluocinolone acetonide acetate, fluocinonide,
fluocortolone pivalate, fluormetholone acetate, fluprednidene acetate, halcinonide,
halometasone, hydrocortisone acetate, medrysone, methylprednisolone acetate,
mometasone furoate, parametasone acetate, prednicarbate, prednisolone acetate,
prednylidene, rimexolone, tixocortol pivalate and triamcinolone hexacetonide. Topical
corticosteroids of special interest are e. g. budesonide, flunisolide and fluticasone
propionate, which undergo fast, efficient clearance as soon as these drugs become
available in the general circulation. By preparing a water soluble form of these
steroids and encapsulating this into long-circulating liposomes in accordance with the
present disclosure it is now possible to systemically administer such corticosteroids in
order to reach site-specific drug delivery, thereby avoiding adverse effects associated
with systemic treatment and overcoming problems, which are inherent to the
corticosteroid, such as a fast clearance. In this respect budesonide disodium
phosphate has appeared to be a salt of great interest. In one embodiment therefore,
the first corticosteroid comprised within a liposome for use in a method described
herein and/or the second, free corticosteroid is a corticosteroid for topical application.
As used herein "a corticosteroid for topical application" means that said corticosteroid
is in clinical practice used in topical treatment of anti- inflammatory diseases, i.e. it is
applied body surfaces such as the skin or mucous membranes such as those from the
vagina, anus, throat and eyes.
Examples of inflammatory disorders that can be successfully treated with
the liposomal compositions in accordance with the present disclosure are
inflammatory connective tissue disorders, inflammatory diseases of the kidney and
inflammatory bowel disorders (IBD). Specific examples of inflammatory connective
tissue disorders are rheumatoid arthritis, systemic lupus erythomatosis (with for
instance lupus nephritis as one of its notable manifestations), alkylosing spondylitis,
osteoarthritis, and psoriatic arthritis. Preferably an inflammatory disorder treated
with a method according to the present disclosure is a rheumatic disease, more
preferably rheumatoid arthritis, or an inflammatory bowel disorder, or an
inflammatory disease of the kidney. Of the inflammatory bowel disorders, colitis
ulcerosa and Crohn’s disease are preferred inflammatory disorders treated in
accordance with the present disclosure. Preferred inflammatory diseases of the kidney
treated in accordance with the present invention are glomerulonephritis, lupus
nephritis, acute transplant rejection and arteriovenous fistula failure.
The invention is further explained in the following examples. These examples do not
limit the scope of the invention, but merely serve to clarify the invention.
Brief description of the drawings
Figure 1. Therapeutic activity of treatment with liposomal and free prednisolone
phosphate (PLP) in rats with adjuvant-induced arthritis.
A. Effect on macroscopic paw inflammation scores of a single treatment with 10 mg/kg
PLP–polyethylene glycol (PEG) liposomes (solid circles), 10 mg/kg free PLP (solid
squares), and saline control treatment (open squares).
B. Effect on scores of 20 mg/kg PLP–polyethylene glycol (PEG) liposomes (solid
circles), daily treatment with 20 mg/kg free PLP (solid squares) and saline control
(open squares). Bars show the mean and SEM of 5 rats. Treatment took place on day
Figure 2. Therapeutic activity of a single treatment with increasing dose levels of
prednisolone phosphate (PLP)-polyethylene glycol (PEG) liposomes in rats with
adjuvant-induced arthritis.
A. Effect on macroscopic paw inflammation scores of 1 mg/kg PLP–PEG liposomes
(grey circles), 10 mg/kg free PLP (solid squares), and saline control treatment (open
squares).
B. Effect on scores of 2 mg/kg PLP–PEG liposomes (grey circles), 5 mg/kg PLP–PEG
liposomes (solid squares), and saline control (open squares).
Bars show the mean and SEM of 3-5 rats. Treatment took place on day 14 (A) and day
13 (B).
Figure 3. Effect on EULAR Disease Activity Scores (DAS 28 scores) of 150 mg (2
mg/kg) PLP–PEG-liposomes (solid circles) and an equipotent dose of 120 mg (1.6
mg/kg) methylprednisolone (intramuscular depot formulation, open squares). Bars
show the mean and SEM of 7 human subjects in both treatment groups. The values
are expressed as % of the disease score at day of treatment (baseline), the baseline
defined as 100%.
Figure 4. Distribution of patients achieving a good, moderate or no EULAR response
after 150 mg (2 mg/kg) PLP–PEG-liposomes (test medication) or an equipotent dose of
120 mg (1.6 mg/kg) methylprednisolone (reference medication). Bars show the mean of
7 human subjects in both treatment groups.
Figure 5. Intensity of pain as determined by VAS score after 150 mg (2 mg/kg) PLP–
PEG-liposomes (test medication) or an equipotent dose of 120 mg (1.6 mg/kg)
methylprednisolone (reference medication).
Bars show the mean and SEM of 7 human subjects in both treatment groups. The
values are expressed as % of the VAS score at day of treatment.
Figure 6. Therapeutic activity of a single treatment with 2 mg/kg prednisolone
phosphate (PLP) PEG-liposomes in rats versus humans.
A. Effect in rats on macroscopic disease scores as a % of baseline (100%).
B. Effect in humans on EULAR Disease Activity Scores (DAS 28 scores) as a % of
baseline (100%).
Bars show the mean and SEM of 3-5 rats (A) and 7 humans (B).
Figure 7. Effect on EULAR Disease Activity Scores (DAS 28 scores) of a single
treatment of:
A. 150 mg (2 mg/kg) PLP–PEG-liposomes to patients who receive chronic
methotrexate therapy (solid circles, n=4) compared to patients who do not take
methotrexate (open squares, n=3).
B. An equipotent dose of 120 mg (1.6 mg/kg) methylprednisolone (intramuscular depot
formulation) to patients who receive chronic methotrexate therapy (solid circles, n=4)
compared to patients who do not take methotrexate (open squares, n=3).
Bars show the mean and SEM. The values are expressed as % of the disease score at
day of treatment (baseline), the baseline defined as 100%.
Examples
Example 1: rat experimental arthritis study
Formulation
Prednisolone phosphate-containing PEG-liposomes were composed of 750 mg of
dipalmitoyl phosphatidylcholine (DPPC), 250.8 mg of cholesterol and 267.6 mg of
PEG-distearoylphosphatidylethanol-amine (PEG-DSPE). These components were
weighed and mixed in a 100 ml round-bottom flask. The lipids were dissolved in about
ml of ethanol and thereafter evaporated to dryness in a Rotavapor during 1 hour
under vacuum at 40°C. 1200 mg of prednisolon disodium phosphate was weighed and
dissolved in 12 ml of sterilized water. The solution was added to the dry lipid film and
shaken during one hour in the presence of glass beads in order to enable complete
hydration of the lipid film. The liposomal suspension was transferred to an extruder
(Avestin, maximum volume 15 ml) and extruded under pressure, using nitrogen gas,
using polycarbonate filters with pore sizes below 100 nm. Subsequently the liposomal
suspension was dialyzed against sterile saline. The mean particle size of the
liposomes was determined by dynamic light scattering and was found to be 93.1 ± 1.2
nm, the polydispersity index being 0.095 ± 0.024. The encapsulation efficiency of the
prednisolone phosphate was determined by means of a HPLC method and was found
to be between 3 and 4%. The suspension of liposomes was stored in a nitrogen
atmosphere at 4°C and found to be stable for more than a year.
Rats, experimental arthritis and study protocol
Lewis rats were immunized subcutaneously at the tail base with heat-inactivated
Mycobacterium tuberculosis in incomplete Freund’s adjuvant. Paw inflammation
started between 9 and 12 days after immunization, reached maximum severity
approximately after 20 days, and then gradually resolved. Assessment of the disease
was performed by visually scoring paw inflammation severity, maximum score 4 per
paw, and measuring disease-induced body weight loss. The therapeutic efficacy of
liposomal prednisolone phosphate on these variables was compared with equal doses
unencapsulated drug. Rats were treated when the average score > 6 (at day 14 or 15
after disease induction).
Results
A complete remission of the inflammation in 4 out of 5 rats was observed within 3
days after treatment with a single dose of liposomal prednisolone phosphate at 10
mg/kg of prednisolone phosphate (figure 1A). Unencapsulated prednisolone phosphate
did not significantly alter the course of the disease as a single injection. Therefore it
was decided to inject an even higher dose of 20 mg/kg unencapsulated prednisolone
daily for 7 days. This treatment regimens reduced inflammation scores from an
average of 6.5 (day 14) to average values around 5.0 from day 15 until day 21 (control
treatment with daily saline reached a maximum of 10.6 on day 20, Figure 1B).
However, a single injections of the same dose of 20 mg/kg liposomal prednisolone
phosphate at day 14 resulted in disappearance of adjuvant arthritis (AA) symptoms
until day 20.
Also dose levels lower than 10 mg/kg liposomal prednisolone were tested in the rat
adjuvant arthritis model. The efficacy at these dose levels proved to be short lasting. 1
mg/kg liposomal prednisolone has a limited effect during 4 days only (Figure 2A),
while 2 mg/kg shows the same effect duration albeit slightly more effective (Figure
2B). Even at 5 mg/kg the therapeutic activity lasts no longer than 1 week (Figure 2B).
Example 2: human RA study
Formulation
Prednisolone containing polyethylene glycol (PEG) liposomes are composed of a lipid
bilayer enclosing an aqueous compartment in which the water-soluble disodium
phosphate derivative of prednisolone is entrapped. Each mL of formulation contains
1.5 mg/mL prednisolone sodium phosphate, 30 mg palmitoyl phosphatidyl choline
(DPPC), 9 mg distearoyl phosphatidyl ethanolamine-PEG2000 (PEG-DSPE), and 8
mg cholesterol. The liposomes are dispersed in 10% sucrose buffered with phosphate
buffer at a pH of 7.4.
The formulation is prepared by mixing the lipid constituents with an aqueous solution
of the corticosteroid followed by repeated high-shear homogenization to reduce the
size of the formed vesicles. Unencapsulated corticosteroid is removed by tangential
flow filtration. Sterilization takes place by dead-end filtration using 0.2 micrometer
filter membranes.
The formulation is subject to the following characterization and quality controls:
particle size and polydispersity index (100 nm and <0.1 respectively as measured by
dynamic light scattering), content of prednisolone and lipid excipients as measured by
HPLC assays, sterility and pyrogenicity (the latter determined with the LAL assay
(Biowhittaker, Walkersville, MD)), and solvent residual testing. All raw material
purchased is GMP-certified and the liposome manufacturing is performed under GMP
conditions.
Patients
To evaluate the therapeutic activity of the prednisolone PEG-liposomal formulation in
inflammatory disease, 16 consenting patients with active RA were enrolled in a
clinical trial, in which 8 patients were treated once with 150 mg intravenously infused
prednisolone-PEG-liposomes (approximately 2 mg/kg body weight of prednisolone)
and 8 patients with an equipotent dose of 120 mg methylprednisolone depot
formulation (intramuscular). Criteria for eligibility were as follows: age ≥ 18 years,
RA according to the revised 1987 ARA criteria (Arnett FC, et al. 1988), active disease
as defined by a Modified Disease Activity Score (DAS 28, Prevoo ML, et al. 1995) ≥ 3.2
at the screening visit.
Exclusion criteria included abnormal renal, liver or hematological tests, current
pregnancy, breastfeeding, infections or malignancies, clinically severe or unstable
medical conditions and endocrine disorders. Oral GCs were not permitted within 2
weeks prior to study entry, intra-articular or intramuscular GCs were not allowed
within 8 weeks prior to baseline and therapy with disease modifying anti-rheumatic
drugs (DMARD) had to be stable within 12 weeks prior to trial initiation.
Study protocol
After satisfying the in- and exclusion criteria, the administration of the study
medication was planned. On day 1, patients were admitted to the ward where they
received prednisolone PEG-liposomes/placebo or methylprednisolone / placebo.
After baseline, patients were assessed weekly for up to 12 weeks. Each visit included
clinical evaluation, assessment of the disease activity, vital signs, safety assessments,
and blood sampling. The disease activity was measured by the same assessor using
the Disease Activity Score (DAS28), and the response to therapy using the European
League Against Rheumatism (EULAR) criteria (Zandbelt MM, et al. 2001; Van Gestel
AM, et al. 1996). Disease flare was defined by an increase of the DAS28 of > 1.2 or an
increase of the DAS of 0.6-1.2 if this resulted in a DAS28 of > 5.1, on the weekly
assessments (Den Broeder AA, et al. 2002).
Data analysis
The DAS 28 score was the primary outcome measure to test the efficacy of the trial
intervention. Type I error was controlled at a significance level of 0.05 for the analysis
of the primary outcome. Several secondary efficacy measures were analyzed to
confirm the findings of the primary measure. These included the individual
components of the DAS, the patient assessment for pain, the physician assessment for
disease activity. As this was a trial with a limited number of patients, most analyses
were descriptive only. Where statistical analysis could be applied the two sample t-
test was used.
Results
Out of 16 patients, 14 patients (7 in each group) were evaluated for efficacy. A
pronounced therapeutic improvement was found during the first weeks after
treatment in the test medication (prednisolone PEG-liposomes) group during the first
weeks after treatment. In the reference medication group (intramuscular
methylprednisolone) a slower and more moderate therapeutic improvement is visible
(Figure 3).
The test medication group shows a higher percentage of responders according to the
EULAR definition of therapeutic response. Interestingly, only patients in the test
medication group experienced a good EULAR response (Figure 4). In the reference
medication the responses that were observed are only moderate. The intensity of pain
was measured on a 100mm line ranging from “no pain” to “extreme pain”. The pain
improved better and decreased more rapidly in the LCLP group (Figure 5). A
significantly better efficacy of the trial medication at the level of the “Investigator’s
evaluation of RA activity” was found as compared to the control medication.
The safety analysis showed comparable pattern of adverse events in both treatment
groups. There was one serious adverse event (a mild infusion reaction) probably
related to the trial medication. The trial medication did not raise further toxicity
concerns.
Interestingly the efficacy of 2 mg/kg prednisolone PEG-liposomes in the human study
proved to be much more prolonged as compared to the efficacy of the same dose in rat
experimental arthritis, which did not last longer than a few days. Figure 6A shows
the efficacy of a single treatment with 2 mg/kg liposomal prednisolone in rat arthritis
and figure 6B shows the effect at the level of arthritic inflammation in humans (for
the purpose of comparison the baseline value at the day of treatment was defined as
100%).
Figure 7 shows the therapeutic effects of test medication and reference medication for
patients receiving chronic therapy with methotrexate and patients not receiving such
therapy. Patients who are under chronic therapy with methotrexate are more
sensitive to the therapy with liposomal prednisolone than patients that do not take
methotrexate or other disease modifying agents (Figure 7A). However, patients who
received reference medication (intramuscular methylprednisolone) did not show a
better response in combination with methotrexate than patients with reference
medication without methotrexate (Figure 7B).
Example 3: human inflammatory bowel disorder study
Formulation
Prednisolone containing PEG liposomes were prepared as described in Example 2.
Patients
Twenty subjects between the ages of 18 and 75 with active ulcerative colitis
(UC) were selected during a 14-day screening phase according to the following main
inclusion/exclusion criteria: ≥ 18 to 75 years of age, documented history of UC (at least
6 months) as assessed by endoscopy and confirmed by histological measurements, a
Mayo score ≥ 5 with endoscopic sub-score of ≥ 2 and rectal bleeding sub-score ≥1 and
stable medications (6-MP/azathioprine, 5-ASA, MTX, biologicals, and in good physical
and mental health (other than the disease under study) as determined by medical
history and physical examination.
Study protocol
When a subject was randomized in the arm of investigational product, single infusions
of 150 mg PEG-liposomal prednisolone sodium phosphate (Nanocort) IV in 250 mL
saline over at least 1 hour were administered on Day 1 and at Day 15 (approximately
2 mg/kg body weight of prednisolone). When a subject was randomized in the placebo
arm, single infusions of 250 mL saline (without Nanocort) over at least 1 hour were
administered on Day 1 and at Day 15.
After baseline, patients were assessed weekly for up to 8 weeks. Each visit included
clinical evaluation, assessment of the disease activity, vital signs, safety assessments,
and blood sampling. The disease activity was measured as the % of subjects achieving
clinical remission or response at Day 15, 29, 57 and 85 as measured by partial Mayo
score in Nanocort versus placebo group, and by scoring the histopathological
assessments on biopsies by microscopic evaluation (acute inflammation score and
grading scale of inflammation) in Nanocort versus placebo group.
Results
7 patients have been enrolled so far. In the majority of the patients rapid and
substantial beneficial therapeutic effects are seen.
References
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA,
Kaplan SR, Liang MH, Luthra HS, et al. The American Rheumatism Association 1987
revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;
31: 315-324.
Den Broeder AA, Creemers MC, van Gestel AM, van Riel PL. Dose titration using the
Disease Activity Score (DAS28) in rheumatoid arthritis patients treated with anti-
TNF-alpha. Rheumatology (Oxford) 2002;41:638-642.
Metselaar JM, Wauben MH, Wagenaar-Hilbers JP, Boerman OC, Storm G. Complete
remission of experimental arthritis by joint targeting of glucocorticoids with long-
circulating liposomes. Arthritis Rheum 2003; 48(7):2059-66.
Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel
PL. Modified disease activity scores that include twenty-eight-joint counts.
Development and validation in a prospective longitudinal study of patients with
rheumatoid arthritis. Arthritis Rheum 1995; 38: 44-48.
Van Gestel AM, Prevoo ML, van 't Hof MA, van Rijswijk MH, van de Putte LB, van
Riel PL. Development and validation of the European League Against Rheumatism
response criteria for rheumatoid arthritis. Comparison with the preliminary
American College of Rheumatology and the World Health Organization/International
League Against Rheumatism Criteria. Arthritis Rheum 1996;39:34-40.
Zandbelt MM, Welsing PM, van Gestel AM, van Riel PL. Health Assessment
Questionnaire modifications: is standardisation needed? Ann Rheum Dis 2001; 60:
841-845.
In this specification where reference has been made to patent
specifications, other external documents, or other sources of information, this is
generally for the purpose of providing a context for discussing the features of the
invention. Unless specifically stated otherwise, reference to such external documents
is not to be construed as an admission that such documents, or such sources of
information, in any jurisdiction, are prior art, or form part of the common general
knowledge in the art.
In the description in this specification reference may be made to subject
matter that is not within the scope of the claims of the current application. That
subject matter should be readily identifiable by a person skilled in the art and may
assist in putting into practice the invention as defined in the claims of this
application.
Claims (15)
1. Use of liposomes composed of non-charged vesicle-forming lipids, optionally including not more than 10 mole percent of negatively charged vesicle-forming lipids and/or not more than 10 mole percent of PEGylated lipids, the liposomes having a selected mean particle diameter in the size range of 40-200 nm and comprising a first corticosteroid in water soluble form for the preparation of a medicament for the treatment of an inflammatory disorder in a human at a dose of at most 5 mg/kg body weight of prednisolone or an equipotent dose of a corticosteroid other than prednisolone, wherein said treatment has a treatment frequency of at most once per two weeks.
2. A kit of parts comprising: a) a pharmaceutical composition comprising liposomes composed of non-charged vesicle-forming lipids, optionally including not more than 10 mole percent of negatively charged vesicle- forming lipids and/or not more than 10 mole percent of PEGylated lipids, the liposomes having a selected mean particle diameter in the size range of 40-200 nm and comprising a first corticosteroid in water soluble form, comprising one or more dosage units, each dosage unit suitable for administration of the liposomes comprising the corticosteroid at a dose of at most 5 mg/kg of prednisolone or an equipotent dose of a corticosteroid other than prednisolone, and b) a pharmaceutical composition comprising a second, free corticosteroid.
3. Use according to claim 1, wherein said treatment is combined with treatment with a second, free corticosteroid.
4. Use according to claim 1, wherein said treatment is combined with treatment with a disease modifying agent selected from the group consisting of methotrexate, hydroxychloroquine, leflunomide, cyclophosphamide, 5-fluorouracil, a 5-ASA agent, 6- mercaptopurine, mycophenolate mofetil and azathioprine.
5. Use according to claim 4, wherein said human receives maintenance therapy with said pharmaceutical composition comprising said disease modifying agent and wherein said human receives temporary treatment with said pharmaceutical composition comprising liposomes following a flare of said inflammatory disorder.
6. Use according to any one of claims 4 or 5, wherein said treatment using said disease modifying agent is part of maintenance therapy for said inflammatory disorder, and wherein said treatment using said liposomes is temporary treatment following a flare of said inflammatory disorder.
7. Use according to any one of claims 1 or 3-6, wherein said inflammatory disorder is a rheumatic disease or a related inflammatory connective tissue disorder, an inflammatory bowel disease, or an inflammatory disease of the kidney.
8. Kit of parts or use according to any one of claims 1-7, wherein said first corticosteroid and/or said second, free corticosteroid is a corticosteroid for systemic administration.
9. Kit of parts or use according to claim 8, wherein said corticosteroid is selected from the group consisting of prednisolone, dexamethasone and methylprednisolone.
10. Kit of parts or use according to any one of claims 1-9, wherein said first corticosteroid and/or said second, free corticosteroid is a corticosteroid for topical application.
11. Kit of parts or use according to claim 10 wherein said corticosteroid is selected from the group consisting of budesonide, flunisolide and fluticasone propionate.
12. Kit of parts or use according to any one of claims 1-6, wherein said dose is: - at most 5 mg/kg body weight of prednisolone, or - at most 4 mg/kg body weight of methylprednisolone or triamcinolone, or - at most 0.8 mg/kg body weight of dexamethasone or betamethasone, or - at most 1.4 mg/kg body weight of fludrocortisone acetate.
13. Kit of parts or use according to any one of claims 1-6, wherein said dose is: - at most 2.5 mg/kg body weight of prednisolone, or - at most 2 mg/kg body weight of methylprednisolone or triamcinolone, or - at most 0.4 mg/kg body weight of dexamethasone or betamethasone, or - at most 0.7 mg/kg body weight of fludrocortisone acetate.
14. A use as claimed in claim 1 substantially as herein described with reference to any example thereof.
15. A kit of parts as claimed in claim 2 substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NLPCT/NL2011/050755 | 2011-11-04 | ||
NLPCT/NL2011/050755 | 2011-11-04 | ||
PCT/NL2012/050766 WO2013066179A1 (en) | 2011-11-04 | 2012-11-02 | Liposomal corticosteroids for treatment of inflammatory disorders in humans |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ625022A NZ625022A (en) | 2016-06-24 |
NZ625022B2 true NZ625022B2 (en) | 2016-09-27 |
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