U.S. patent application number 17/745378 was filed with the patent office on 2022-09-01 for aqueous suspensions of tmc278.
The applicant listed for this patent is Janssen Sciences Ireland Unlimited Company. Invention is credited to Lieven Elvire Colette Baert, Willy Albert Maria Carlo Dries, Marc Karel Jozef Francois, Laurent Bruno Schueller, Peter Jozef Maria Van Remoortere.
Application Number | 20220273653 17/745378 |
Document ID | / |
Family ID | 1000006335279 |
Filed Date | 2022-09-01 |
United States Patent
Application |
20220273653 |
Kind Code |
A1 |
Baert; Lieven Elvire Colette ;
et al. |
September 1, 2022 |
Aqueous Suspensions of TMC278
Abstract
This invention concerns pharmaceutical compositions for
administration via intramuscular or subcutaneous injection,
comprising micro- or nanoparticles of the NNRTI compound TMC278,
suspended in an aqueous pharmaceutically acceptable carrier, and
the use of such pharmaceutical compositions in the treatment and
prophylaxis of HIV infection.
Inventors: |
Baert; Lieven Elvire Colette;
(Brugge 2, BE) ; Dries; Willy Albert Maria Carlo;
(Merksplas, BE) ; Schueller; Laurent Bruno;
(Antwerpen, BE) ; Francois; Marc Karel Jozef;
(Kapellen, BE) ; Van Remoortere; Peter Jozef Maria;
(Kapellen, BE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Janssen Sciences Ireland Unlimited Company |
Co Cork |
|
IE |
|
|
Family ID: |
1000006335279 |
Appl. No.: |
17/745378 |
Filed: |
May 16, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14964297 |
Dec 9, 2015 |
11389447 |
|
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17745378 |
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14493525 |
Sep 23, 2014 |
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14964297 |
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12305276 |
Dec 17, 2008 |
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PCT/EP07/56230 |
Jun 22, 2007 |
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14493525 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 31/505 20130101; A61K 9/146 20130101; A61K 9/0019 20130101;
A61K 9/145 20130101; A61K 31/00 20130101; A61K 9/14 20130101; A61K
47/34 20130101 |
International
Class: |
A61K 31/505 20060101
A61K031/505; A61K 9/00 20060101 A61K009/00; A61K 9/14 20060101
A61K009/14; A61K 31/00 20060101 A61K031/00; A61K 47/10 20060101
A61K047/10; A61K 47/34 20060101 A61K047/34 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 23, 2006 |
EP |
06115398.0 |
Claims
1.-14. (canceled)
15. A method for producing blood plasma levels of
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]-
benzonitrile (TMC278) that are sufficient to treat an HIV infection
in an HIV-infected patient comprising: administering to the
patient, by intramuscular or subcutaneous injection, an aqueous
suspension comprising nanoparticles of
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]-
benzonitrile (TMC278), or a salt, a stereoisomer or a
stereoisomeric mixture thereof, the particles having a poloxamer
adsorbed onto the surfaces thereof; wherein the aqueous suspension
is administered intermittently at a time interval that is once
every two months; and wherein the amount of TMC278, or the salt,
stereoisomer, or stereoisomeric mixture thereof, in the aqueous
suspension is effective in producing a blood plasma level of TMC278
that is sufficient to treat the HIV infection in the patient during
the time interval.
16. The method of claim 15, wherein the amount is calculated on a
basis of about 5 mg/day to about 50 mg/day of TMC278.
17. The method of claim 16, wherein the amount is calculated on a
basis of about 10 mg/day to about 25 mg/day.
18. The method of claim 15, wherein TMC278 is present in base form
or in an acid addition salt form.
19. The method of claim 15, wherein the poloxamer is poloxamer
338.
20. The method of claim 15, wherein the average effective particle
size of the nanoparticles is less than about 1000 nm.
21. The method of claim 15, wherein the average effective particle
size of the nanoparticles is about 50 nm to about 1000 nm.
22. The method of claim 15, wherein the amount of TMC278
corresponds with a monthly dose of a. from about 150 mg to about
1500 mg; b. from about 30 mg to about 300 mg; or c. about 300
mg.
23. The method of claim 15, wherein the aqueous suspension
comprises by weight based on the total volume of the composition:
a. from 3% to 50%, from 10% to 40% or from 10 to 30%, of TMC278 b.
from 0.5% to 10% or from 0.5% to 2% of the poloxamer; c. from 0% to
10%, from 0% to 5%, from 0% to 2%, or from 0% to 1% of one of more
buffering agents; d. from 0% to 10%, or from 0% to 6% of an
isotonizing agent; e. from 0% to 2% preservatives; and f. water for
injection q.s. ad 100%.
24. The method of claim 18, wherein TMC278 is present as the
E-isomer of the base form.
25. The method of claim 18, wherein TMC278 is present as the
E-isomer of the acid addition salt form.
26. The method of claim 23, wherein the buffering agent is tartaric
acid, maleic acid, glycine, sodium lactate, lactic acid, ascorbic
acid, sodium citrates, citric acid, sodium acetate, acetic acid,
sodium bicarbonate, carbonic acid, sodium succinate, succinic acid,
sodium benzoate, benzoic acid, sodium phosphates,
tris(hydroxymethyl)aminomethane, sodium bicarbonate, sodium
carbonate, ammonium hydroxide, benzene sulfonic acid, benzoate
sodium, benzoate acid, diethanolamine, glucono delta lactone,
hydrochloric acid, hydrogen bromide, lysine, methanesulfonic acid,
monoethanolamine, sodium hydroxide, tromethamine, gluconic,
glyceric, gluratic, glutamic, ethylene diamine tetraacetic (EDTA),
triethanolamine, or a mixture of at least two buffering agents.
27. The method of claim 23, wherein the isotonizing agent is
glucose, dextrose, sucrose, fructose, trehalose, lactose, a
polyhydric sugar alcohol, a trihydric or higher sugar alcohol,
glycerin, erythritol, arabitol, xylitol, sorbitol, mannitol, sodium
chloride or sodium sulfate.
28. The method of claim 15, wherein the amount of TMC278 is
calculated on a basis of about 10 mg/day to about 25 mg/day, TMC278
is present as the E-isomer of the base form, and wherein the
poloxamer is poloxamer 338.
29. The method of claim 21, wherein the average effective
nanoparticle size is from about 150 nm to about 220 nm.
30. The method of claim 15, wherein the relative amount by weight
(w/w) of TMC278 to the poloxamer is in the range of 1:2 to about
20:1.
31. The method of claim 30, wherein the relative amount by weight
(w/w) of TMC278 to the poloxamer is about 1:1, about 1:2, about
4:1, about 10:1 or about 20:1.
32. The method of claim 15, wherein the aqueous suspension is
administered by intramuscular injection.
33. The method of claim 21, wherein the average effective
nanoparticle size is from about 50 nm to about 400 nm.
34. The method of claim 21, wherein the average effective
nanoparticle size is from about 50 nm to about 250 nm.
35. The method of claim 21, wherein the average effective
nanoparticle size is about 400 nm.
36. The method of claim 21, wherein the average effective
nanoparticle size is about 200 nm.
Description
FIELD OF THE INVENTION
[0001] This invention concerns pharmaceutical compositions for
administration via intramuscular or subcutaneous injection,
comprising micro- or nanoparticles of the NNRTI compound TMC278,
suspended in an aqueous pharmaceutically acceptable carrier, and
the use of such pharmaceutical compositions in the treatment and
prophylaxis of HIV infection.
BACKGROUND OF THE INVENTION
[0002] The treatment of Human Immunodeficiency Virus (HIV)
infection, known as cause of the acquired immunodeficiency syndrome
(AIDS), remains a major medical challenge. HIV is able to evade
immunological pressure, to adapt to a variety of cell types and
growth conditions and to develop resistance against currently
available drug therapies. The latter include nucleoside reverse
transcriptase inhibitors (NRTIs), non-nucleoside reverse
transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase
inhibitors (NtRTIs), HIV-protease inhibitors (PIs) and the more
recent fusion inhibitors.
[0003] Although effective in suppressing HIV, each of these drugs,
when used alone, is confronted with the emergence of resistant
mutants. This led to the introduction of combination therapy of
several anti-HIV agents usually having a different activity
profile. In particular the introduction of "HAART" (Highly Active
Anti-Retroviral Therapy) resulted in a remarkable improvement in
anti-HIV therapy, leading to a dramatic reduction in HIV-associated
morbity and mortality. Current guidelines for antiretroviral
therapy recommend such triple combination therapy regimen even for
initial treatment. However, none of the currently available drug
therapies is capable of completely eradicating HIV. Even HAART can
face the emergence of resistance, often due to non-adherence and
non-persistence with antiretroviral therapy. In these cases HAART
can be made effective again by replacing one of its components by
one of another class. If applied correctly, treatment with HAART
combinations can suppress the virus for many years, up to decades,
to a level where it no longer can cause the outbreak of AIDS.
[0004] One class of HIV drugs often used in HAART is that of the
NNRTIs, a number of which are currently on the market and several
others are in various stages of development. An NNRTI currently in
development is the compound
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidi-
nyl]-amino]-benzonitrile, also referred to as TMC278. This compound
not only shows pronounced activity against wild type HIV, but also
against many of its mutated variants. The compound TMC278, its
pharmacological activity as well as a number of procedures for its
preparation have been described in WO 03/16306. Various
conventional pharmaceutical dosage forms, including tablets,
capsules, drops, suppositories, oral solutions and injectable
solutions are exemplified therein.
[0005] Because of their pharmacokinetic properties and the need to
keep plasma levels above a minimum level, currently used anti-HIV
drugs require frequent administration of relatively high doses. The
number and/or volume of dosage forms that need to be administered
are commonly referred to as "pill burden". A high pill burden is
undesirable for many reasons, such as the frequency of intake,
often combined with the inconvenience of having to swallow large
dosage forms, as well as the need to store and transport a large
number or volume of pills. A high pill burden increases the risk of
patients not taking their entire dose, thereby failing to comply
with the prescribed dosage regimen. As well as reducing the
effectiveness of the treatment, this also leads to the emergence of
viral resistance. The problems associated with a high pill burden
are prominent in anti-HIV therapy where a patient must take a large
number of different anti-HIV agents.
[0006] Therefore, it would be desirable to provide HIV inhibitory
therapy that reduces pill burden in that it involves the
administration of dosage forms of relatively small size and
additionally does not require frequent dosing. It would be
attractive to provide anti-HIV therapy involving the administration
of dosage forms at long time intervals such as one week or longer,
or even one month or longer.
[0007] HIV can never completely be eradicated so that persons
infected with HIV pose a continuous risk of infecting others. After
initial infection it takes a long time before the outbreak of the
first symptoms of AIDS. People may live for years with the
infection without experiencing any effects of it thereby being
unaware of the risk of further transferring the virus to others.
Prevention of HIV transmission therefore is crucial.
[0008] Prevention currently focuses on avoiding transmission by
sexual contacts, in particular by the use of condoms in populations
at risk of being infected, on careful monitoring of blood samples
for the presence of HIV and on avoiding of contact with blood of
potentially infected subjects.
[0009] Despite these measures there is always an imminent risk of
individuals being in contact with HIV infected persons of becoming
infected. This in particular is the case for those providing
medical care to infected patients or patients at risk of being
infected such as physicians, nurses or dentists. Another group of
individuals at risk are breast-fed infants whose mother is infected
or at risk of becoming infected, especially in developing countries
where alternatives for breast-feeding are less obvious.
[0010] Hence there is a need for further means that provide
prevention against transmission of HIV. There is a particular need
for effective prevention means that are easy to apply. Providing
such prevention means is another object of the present
invention.
[0011] It now has been found that the compound TMC278 can be
formulated into micro- or nanoparticles and that such formulations
can be used as depot formulations, which may find use in the
treatment of HIV infection as well as in the prevention against
transmission of HIV. Nanoparticles are known in the prior art,
having been described, for example, in EP-A-0 499 299. Such
particles have an average particle size in the submicron range and
consist of particles of a crystalline drug substance having a
surface modifier adsorbed on their surface. Nanoparticles have been
used to formulate poorly water-soluble active ingredients.
[0012] The invention furthermore relates to the intermittent
administration of these micro- or nanoparticle formulations at time
intervals of one week or longer that result in plasma levels that
may be sufficient to suppress the growth of HIV. This allows for a
reduced number of administrations thereby being beneficial in terms
of pill burden and drug compliance of the patient. The micro- or
nanoparticle formulations of TMC278 of the invention therefore may
be useful in the long-term treatment of HIV infection.
[0013] The intermittent administration of micro- or nanoparticle
formulations of TMC278 at time intervals of one week or longer
furthermore results in plasma levels that may be sufficient to
provide prevention against transmission of HIV. Also in this
instance, a reduced number of administrations is required, which
again is advantageous in terms of pill burden and drug compliance
of the individual at risk of being infected.
SUMMARY OF THE INVENTION
[0014] The present invention is concerned with a pharmaceutical
composition for administration by intramuscular or subcutaneous
injection, comprising a therapeutically effective amount of TMC278,
a salt, a stereoisomer or a stereoisomeric mixture thereof, in the
form of a suspension of micro- or nanoparticles comprising: [0015]
(a) TMC278, a salt, a stereoisomer or a stereoisomeric mixture
thereof, in micro- or nanoparticle form, having a surface modifier
adsorbed to the surface thereof; and [0016] (b) a pharmaceutically
acceptable aqueous carrier; wherein the TMC278 active ingredient is
suspended.
[0017] The invention further concerns a method of treating a
subject infected with HIV, said method comprising the
administration, by intramuscular or subcutaneous injection, of an
anti-HIV effective amount pharmaceutical composition as specified
above or hereinafter. Or, alternatively, the invention concerns the
use of a pharmaceutical composition as specified above or
hereinafter, for the manufacture of a medicament for treating HIV
infection. In one embodiment, the composition is for the long-term
treatment of HIV infection.
[0018] In another aspect, there is provided a method for the long
term treatment of a subject infected with HIV, said method
comprising the administration of an effective amount of a
pharmaceutical composition as specified above or hereinafter, for
administration by intramuscular or subcutaneous injection; wherein
the composition is administered or is to be administered
intermittently at a time interval that is in the range of one week
to one year, or one week to two years. Or, alternatively, the
invention concerns the use of a pharmaceutical composition as
specified above or hereinafter, for the manufacture of a medicament
for the long term treatment of a subject infected with HIV, for
administration by intramuscular or subcutaneous injection, wherein
the composition is administered or is to be administered
intermittently at a time interval that is in the range of one week
to one year, or one week to two years.
[0019] The invention further concerns a method for the prevention
of HIV infection in a subject at risk of being infected by HIV,
said method comprising administering an amount, effective in
preventing HIV infection, of a pharmaceutical composition as
specified above or as further specified hereinafter, to said
subject. Or alternatively, the invention concerns the use of a
pharmaceutical composition as specified above or as further
specified hereinafter for the manufacture of a medicament for the
prevention of HIV infection in a subject at risk of being infected
by HIV.
[0020] In another aspect the invention relates to a method for the
long term prevention of HIV infection in a subject at risk of being
infected by HIV, said method comprising administering to said
subject an effective amount of a pharmaceutical composition as
specified above or as further specified hereinafter, wherein the
composition is administered or is to be administered intermittently
at a time interval that is in the range of one week to one year, or
one week to two years.
[0021] The present invention furthermore relates to the use of a
pharmaceutical composition as specified above or as further
specified hereinafter, for the manufacture of a medicament for the
long term prevention for the long term prevention of HIV infection
in a subject at risk of being infected by HIV, wherein the
composition is administered or is to be administered intermittently
at a time interval that is in the range of one week to one year or
one week to two years.
[0022] In one embodiment the invention concerns a use or a method
as specified herein, wherein the pharmaceutical composition is
administered or is to be administered at a time interval that is in
the range of one week to one month, or in the range of one month to
three months, or in the range of three months to six months, or in
the range of six months to twelve months, or in the range of 12
months to 24 months.
[0023] In another embodiment the invention concerns a use or a
method as specified herein, wherein the pharmaceutical composition
is administered or is to be administered once every two weeks, or
once every month, or once every three months.
[0024] Further pharmaceutical compositions, methods of treatment or
prevention, as well as uses for the manufacture of medicaments
based on these compositions will be described hereinafter and are
meant to be part of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The compound used in the invention is the compound TMC278
(also referred to as R278474 or rilpivirine) or
4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]-
benzonitrile.
[0026] TMC278 can be used in base form or as a suitable
pharmaceutically acceptable addition salt form, such as an acid
addition salt form. The pharmaceutically acceptable addition salts
are meant to comprise the therapeutically active non-toxic salt
forms. The acid addition salt forms can be obtained by treating the
base form with appropriate acids as inorganic acids, for example,
hydrohalic acids, e.g. hydrochloric, hydrobromic and the like;
sulfuric acid; nitric acid; phosphoric acid and the like; or
organic acids, for example, acetic, propanoic, hydroxyacetic,
2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic,
maleic, fumaric, malic, tartaric,
2-hydroxy-1,2,3-propanetri-carboxylic, methanesulfonic,
ethanesulfonic, benzenesulfonic, 4-methylbenzene-sulfonic,
cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and
the like acids. In one embodiment, the TMC278 active ingredient
used is the base form of TMC278.
[0027] The term "addition salt" also comprises pharmaceutically
acceptable hydrates and solvent addition forms that the compound
TMC278 is able to form. Examples of such forms are e.g. hydrates,
alcoholates and the like.
[0028] TMC278 occurs in stereoisomeric forms, more in particular as
E- and Z-isomeric forms. Both isomers may be used in the present
invention. Whenever reference is made herein to TMC278, the E- or
the Z-form as well as any mixture of both forms are meant to be
included. A preferred form of TMC278 for use in the invention is
the E-isomer, i.e.
(E)-4-[[4[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-a-
mino]-benzonitrile, which may be referred to as E-TMC278. The
Z-isomer of TMC278, i.e.
(Z)-4-[[4[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-a-
mino]-benzonitrile, which may be referred to as Z-TMC278), can also
be used.
[0029] Whenever reference is made herein to the E-form of TMC278
(i.e. E-TMC278), the pure E-isomer or any isomeric mixture of the
E- and the Z-forms wherein the E-form is predominantly present is
meant to be comprised, i.e. an isomeric mixture containing more
than 50% or in particular more than 80% of the E-form, or even more
than 90% of the E-form. Of particular interest is the E-form
substantially free of the Z-form. Substantially free in this
context refers to E-Z-mixtures with no or almost no Z-form, e.g.
isomeric mixtures containing as much as 90%, in particular 95% or
even 98% or 99% of the E-form. Equally, whenever reference is made
herein to the Z-form of TMC278 (i.e. Z-TMC278), the pure Z-isomer
or any isomeric mixture of the Z- and the E-forms wherein the
Z-form is predominantly present is meant to be comprised, i.e. an
isomeric mixture containing more than 50% or in particular more
than 80% of the Z-form, or even more than 90% of the Z-form. The
Z-form substantially free of the E-form can also be used.
Substantially free in this context refers to E-Z-mixtures with no
or almost no E-form, e.g. isomeric mixtures containing as much as
90%, in particular 95% or even 98% or 99% of the Z-form. In one
embodiment, the TMC278 active ingredient used is the E-form of
TMC278, in particular the E-form of TMC278 base.
[0030] Also meant to be included for use in this invention are
salts of the stereoisomeric forms of TMC278, in particular the
salts mentioned above of Z-TMC278 or of E-TMC278.
[0031] Whenever used herein, the term "TMC278" refers to as well
the base form as any pharmaceutically acceptable acid-addition salt
thereof, and also to the stereoisomeric forms of TMC278 as well as
any pharmaceutically acceptable acid-addition salt of said
stereoisomeric forms. In particular, the term "TMC278" refers to
the E-isomer of TMC278 as well as its pharmaceutically acceptable
acid-addition salts. The term "TMC278" may also refer to the base
form of the E-isomer of TMC278.
[0032] It has been found that the physico-chemical properties of
TMC278 allow for the manufacture of micro- or nanoparticle
suspensions that have unique pharmacokinetic properties in that
they can be used for the long-term treatment of HIV infection as
well as in the long-term prevention of HIV infection and to this
purpose only a limited number of drug administrations is required.
This is beneficial in terms of pill-burden as well as patient
compliance with the prescribed dose regimen.
[0033] As used herein the term "treatment of HIV infection" relates
to the treatment of a subject being infected with HIV. The term
"treatment of HIV infection" also relates to the treatment of
diseases associated with HIV infection, for example AIDS, or other
conditions associated with HIV infection including
thrombocytopaenia, Kaposi's sarcoma and infection of the central
nervous system characterized by progressive demyelination,
resulting in dementia and symptoms such as, progressive dysarthria,
ataxia and disorientation, and further conditions where HIV
infection has also been associated with, such as peripheral
neuropathy, progressive generalized lymphadenopathy (PGL), and
AIDS-related complex (ARC).
[0034] The term "prevention of HIV infection" relates to the
prevention or avoidance of a subject becoming infected with HIV.
The source of infection can be various, a material containing HIV,
in particular a body fluid that contains HIV such as blood or
sperm, or another subject who is infected with HIV. Prevention of
HIV infection relates to the prevention of the transmission of the
virus from the material containing HIV or from the HIV infected
individual to an uninfected person, or relates to the prevention of
the virus from entering the body from an uninfected person.
Transmission of the HIV virus can be by any known cause of HIV
transfer such as by sexual transmission or by contact with blood of
an infected subject, e.g. medical staff providing care to infected
subjects. Transfer of HIV can also occur by contact with HIV
infected blood, e.g. when handling blood samples or with blood
transfusion. It can also be by contact with infected cells, e.g.
when carrying out laboratory experiments with HIV infected
cells.
[0035] The terms "treatment of HIV infection", "anti-HIV therapy",
as well as similar terms, refer to a treatment by which the viral
load of HIV (represented as the number of copies of viral RNA in a
specified volume of serum) is reduced. The more effective the
treatment, the lower the viral load. Preferably the viral load
should be reduced to as low levels as possible, e.g. below about
200 copies/ml, in particular below about 100 copies/ml, more in
particular below 50 copies/ml, if possible below the detection
limit of the virus. Reductions of viral load of one, two or even
three orders of magnitude (e.g. a reduction in the order of about
10 to about 10.sup.2, or more, such as about 10.sup.3) are an
indication of the effectiveness of the treatment. Another parameter
to measure effectiveness of anti-HIV treatment is the CD4 count,
which in normal adults ranges from 500 to 1500 cells per .mu.l.
Lowered CD4 counts are an indication of HIV infection and once
below about 200 cells per .mu.l, AIDS may develop. An increase of
CD4 count, e.g. with about 50, 100, 200 or more cells per .mu.l, is
also an indication of the effectiveness of anti-HIV treatment. The
CD4 count in particular should be increased to a level above about
200 cells per .mu.l, or above about 350 cells per .mu.l. Viral load
or CD4 count, or both, can be used to diagnose the degree of HIV
infection.
[0036] The terms "effective treatment of HIV" and similar terms
refer to that treatment that lowers the viral load, or increases
CD4 count, or both, as described above. The terms "effective
prevention of HIV" and similar terms refer to that situation where
there is a decrease in the relative number of newly infected
subjects in a population in contact with a source of HIV infection
such as a material containing HIV, or a HIV infected subject.
Effective prevention can be measured, for example, by measuring in
a mixed population of HIV infected and non-infected individuals, if
there is a decrease of the relative number of newly infected
individuals, when comparing non-infected individuals treated with a
pharmaceutical composition of the invention, and non-treated
non-infected individuals. This decrease can be measured by
statistical analysis of the numbers of infected and non-infected
individuals in a given population over time.
[0037] The terms "therapeutically effective amount", "an amount,
effective in preventing HIV infection", and similar terms, refer to
amounts of the active ingredient TMC278 that result in efficacious
blood plasma levels. With "efficacious blood plasma levels" is
meant those blood plasma levels of the HIV inhibitor TMC278 that
provide effective treatment or effective prevention of HIV
infection.
[0038] The term "subject" in particular relates to a human
being.
[0039] The term "micro- or nanoparticles" refers to particles in
the micrometer or nanometer range. The size of the particles should
be below a maximum size above which administration by subcutaneous
or intramuscular injection becomes impaired or even no longer is
possible. Said maximum size depends for example on the limitations
imposed by the needle diameter or by adverse reactions of the body
to large particles, or both. In one embodiment, the pharmaceutical
compositions of the invention comprise TMC278 in nanoparticle
form.
[0040] The average effective particle size of the micro- or
nanoparticles of the present invention may be below about 50 .mu.m,
or below about 20 .mu.m, or below about 10 .mu.m, or below about
1000 nm, or below about 500 nm, or below about 400 nm, or below
about 300 nm, or below about 200 nm. The lower limit of the average
effective particle size may be low, e.g. as low as about 100 nm or
as low as about 50 nm. In one embodiment, the average effective
particle size is in the range of about 50 nm to about 50 .mu.m, or
about 50 nm to about 20 .mu.m, or about 50 nm to about 10 .mu.m, or
about 50 nm to about 1000 nm, about 50 nm to about 500 nm, or about
50 nm to about 400 nm, or about 50 nm to about 300 nm, or about 50
nm to about 250 nm, or about 100 nm to about 250 nm, or about 150
nm to about 220 nm, or 100 to 200 nm, or about 150 nm to about 200
nm, e.g. about 130 nm, or about 150 nm.
[0041] As used herein, the term average effective particle size has
its conventional meaning as known to the person skilled in the art
and can be measured by art-known particle size measuring techniques
such as, for example, sedimentation field flow fractionation,
photon correlation spectroscopy, laser diffraction or disk
centrifugation. The average effective particle sizes mentioned
herein may be related to volume distributions of the particles. In
that instance, by "an effective average particle size of less than
about 50 .mu.m" it is meant that at least 50% of the volume of the
particles has a particle size of less than the effective average of
50 .mu.m, and the same applies to the other effective particle
sizes mentioned. In a similar manner, the average effective
particle sizes may be related to weight distributions of the
particles but usually this will result in the same or about the
same value for the average effective particle size.
[0042] The pharmaceutical compositions of the present invention
provide release of the active ingredient TMC278 over a prolonged
period of time and therefore they can also be referred to as
sustained or delayed release compositions. After administration,
the compositions of the invention stay in the body and steadily
release TMC278, keeping such levels of this active ingredient in
the patient's system for a prolonged period of time, thereby
providing, during said period, anti-HIV therapy or prevention of
HIV infection. Because of the fact that the pharmaceutical
compositions of the invention stay in the body and steadily release
TMC278, they can be referred to as pharmaceutical compositions
suitable as depot formulations.
[0043] As used herein with the term "prolonged period of time",
there is meant a term (or time period) that may be in the range of
one week up to one year or up to two years, or a term in the range
of one to two weeks, or two to three weeks, or three to four weeks,
or a term in the range of one to two months, or two to three
months, or three to four months, or three to six months, or six
months to 12 months, or 12 months to 24 months, or a term that is
in the range of several days, e.g. 7, 10 or 12 days, or several
weeks, e.g. 2, 3 or 4 weeks, or one month, or several months, e.g.
2, 3, 4, 5 or six months or even longer, e.g. 7, 8, 9 or 12
months.
[0044] The pharmaceutical compositions of this invention may be
applied in the long-term treatment or the long-term prevention of
HIV infection, or with other words they may be used in the
treatment of HIV infection, or in the prevention of HIV infection,
during a prolonged period of time. The compositions of the
invention are effective in anti-HIV therapy or in the prevention of
HIV infection for a prolonged period of time, for example for at
least about one week or longer, or for about 1 month or longer. By
the expression "effective for at least about one week or longer",
one means that the plasma level of the active ingredient, TMC278,
should be above a threshold value. In case of therapeutic
application said threshold value is the lowest plasma level at
which TMC278 provides effective treatment of HIV infection. In case
of application in the prevention of HIV infection said threshold
value is the lowest plasma level at which TMC278 is effective in
preventing transmission of HIV infection.
[0045] With "long term" for example as used in relation to "long
term prevention of HIV infection" or "long term treatment of HIV
infection", or similar terminology, there are meant terms that may
be in the range of one week up to one year or up to two years, or
longer, such as five or 10 years. In particular in the case of
treatment of HIV infection, such terms will be long, in the order
of one to several years. Such terms may also be relatively short,
in particular in the case of prevention. Shorter terms are those of
several days, e.g. 7, 10 or 12 days, or several weeks, e.g. 2, 3 or
4 weeks, or one month, or several months, e.g. 2, 3, 4, 5 or six
months or even longer, e.g. 7, 8, 9 or 12 months. In one embodiment
the methods and uses in accordance with the present invention are
for the prevention of HIV infection during one month, or several
months, e.g. 2, 3, 4, 5 or six months or even longer, e.g. 7, 8, 9
or 12 months.
[0046] The pharmaceutical compositions of the present invention can
be administered at various time intervals. When used in the
prevention of HIV infection, the pharmaceutical compositions of
this invention can be administered only once or a limited number of
times such as twice, three, four, five or six times, or more. This
may be recommendable where prevention is required during a limited
period of time, such as the period during which there is a risk of
infection.
[0047] The pharmaceutical compositions of the present invention can
be administered at the time intervals mentioned above, such as at a
time interval that is in the range of one week to one month, or in
the range of one month to three months, or in the range of three
months to six months, or in the range of six months to twelve
months. In one embodiment, the pharmaceutical composition can be
administered once every two weeks, or once every month, or once
every three months. In another embodiment the time interval is in
the range of one to two weeks, or two to three weeks, or three to
four weeks, or the time interval is in the range of one to two
months, or two to three months, or three to four months, or three
to six months, or six months to 12 months, or 12 months to 24
months. The time interval may be at least one week, but may also be
several weeks, e.g. 2, 3, 4, 5 or 6 weeks, or at time intervals of
one month, or of several months, e.g. 2, 3, 4, 5 or 6 months or
even longer, e.g. 7, 8, 9 or 12 months. In one embodiment, the
pharmaceutical compositions of the present invention are
administered at a time interval of one, two or three months. These
longer periods between each administration of the pharmaceutical
compositions of the invention provide further improvements in terms
of pill burden and compliance. To further improve compliance,
patients can be instructed to take their medication at a certain
day of the week, where the composition is administered on a weekly
schedule, or at a certain day of the month in case of a monthly
schedule.
[0048] The length of the time intervals between each administration
of a composition of the present invention may vary. For example
said time intervals may be selected in function of the blood plasma
levels. The intervals may be shorter where the blood plasma levels
of TMC278 are deemed too low, e.g. when these approach the minimum
blood plasma level specified hereinafter. The intervals may be
longer where the blood plasma levels of TMC278 are deemed too high.
In one embodiment, the compositions of the invention are
administered at equal time intervals. The compositions may be
administered without any interjacent additional administrations, or
with other words, the compositions may be administered at
particular points in time separated from one another by a time
period of varying or equal length, e.g. a time period of at least
one week, or any other time period specified herein, during which
no further TMC278 is administered. Having time intervals of the
same length has the advantage that the administration schedule is
simple, e.g. administration takes place at the same day in the
week, or the same day in the month. Such administration schedule
therefore involves limited "pill burden" thereby contributing
beneficially to the patient's compliance to the prescribed dosing
regimen.
[0049] The concentration (or "C") of TMC278 in the blood plasma of
a subject treated therewith is generally expressed as mass per unit
volume, typically nanograms per milliliter (ng/ml). For
convenience, this concentration may be referred to herein as "blood
plasma drug concentration" or "blood plasma concentration".
[0050] The dose (or amount) of TMC278 administered, depends on the
amount of TMC278 in the pharmaceutical compositions of the
invention, or on the amount of a given composition that is
administered. Where higher blood plasma levels are desired, either
or both of a composition of higher TMC278 concentration, or more of
a given composition, may be administered. This applies vice versa
if lower plasma levels are desired. Also a combination of varying
time intervals and varying dosing may be selected to attain certain
desired blood plasma levels.
[0051] The dose (or amount) of TMC278 administered also depends on
the frequency of the administrations (i.e. the time interval
between each administration). Usually, the dose will be higher
where administrations are less frequent. All these parameters can
be used to direct the blood plasma levels to desired values
[0052] The dosing regimen also depends on whether prevention or
treatment of HIV infection is envisaged. In case of therapy, the
dose of TMC278 administered or the frequency of dosing, or both,
are selected so that the blood plasma concentration of TMC278 is
kept above a minimum blood plasma level. The term "minimum blood
plasma level" (or C.sub.min) in this context refers to the blood
plasma level of TMC278 that provides effective treatment of HIV. In
particular, the blood plasma level of TMC278 is kept at a level
above a minimum blood plasma level of about 10 ng/ml, or above
about 15 ng/ml, or above about 20 ng/ml, or above about 40 ng/ml.
The blood plasma level of TMC278 may be kept above a minimum blood
plasma level that is higher, for example above about 50 ng/ml, or
above about 90 ng/ml, or above about 270 ng/ml, or above about 540
ng/ml In one embodiment, the blood plasma level of TMC278 is kept
above a level of about 13.5 ng/ml, or is kept above a level of
about 20 ng/ml. Or the blood plasma level of TMC278 may be kept
within certain ranges, in particular ranges starting from a minimum
blood plasma level selected from those mentioned above and ending
at a higher blood plasma levels selected from those mentioned above
and selected from 500 ng/ml and 1000 ng/ml (e.g. from 10 to 15, 10
to 20, 10 to 40, etc., or from 15 to 20, or 15 to 40, or 15 to 90,
etc., or 20 to 40, 20 to 90, or 20 to 270, etc., or 40 to 90, 40 to
270, or 40-540, etc., each time from about the indicated value in
ng/ml to about the indicated value in ng/ml). In one embodiment
said range is from about 10 to about 20, from about 20 to about 90,
from 90 to 270, from 270 to 540, from 540 to 1000, each time from
about the indicated value in ng/ml to about the indicated value in
ng/ml.
[0053] The plasma levels of TMC278 should be kept above the
above-mentioned minimum blood plasma levels because at lower levels
the virus may no longer be sufficiently suppressed so that it can
multiply with the additional risk of the emergence of
mutations.
[0054] In the instance of HIV prevention, the term "minimum blood
plasma level" (or C.sub.min) refers to the lowest blood plasma
level of TMC278 that provides effective prevention of HIV
infection. In the case of transmission of HIV from a material
containing HIV or from a subject infected by HIV to a subject not
infected by HIV, this is the lowest blood plasma level that is
effective in inhibiting said transmission.
[0055] In particular, in the instance of HIV prevention, the blood
plasma level of TMC278 can be kept at a level above a minimum blood
plasma level mentioned above in relation to therapy. However in
prevention the blood plasma level of TMC278 can be kept at a lower
level, for example at a level above about 4 ng/ml, or about 5
ng/ml, or about 8 ng/ml. The blood plasma levels of TMC278 should
preferably be kept above these minimum blood plasma levels because
at lower levels the drug may no longer be effective thereby
increasing the risk of transmission of HIV infection. Plasma levels
of TMC278 may be kept at somewhat higher levels to have a safety
margin. Such higher levels start from about 50 ng/ml or more. The
blood plasma level of TMC278 can be kept at a level that is in the
ranges mentioned above in relation to therapy, but where the lower
limits include the blood plasma levels of about 4 ng/ml, or about 5
ng/ml, or about 8 ng/ml.
[0056] An advantage of TMC278 is that it can be used up to
relatively high blood plasma levels without any significant side
effects. The plasma concentrations of TMC278 may reach be
relatively high levels, but as with any drug should not exceed a
maximum plasma level (or C.sub.max), which is the blood plasma
level where TMC278 causes significant side effects. As used herein,
the term "significant side effects" means that the side effects are
present in a relevant patient population to an extend that the side
effects affect the patients' normal functioning. The C.sub.max for
TMC278 can be determined from the extrapolation of test data in
cellular assays or from the evaluation of clinical testing and
preferably should not exceed a value of about 500 ng/ml or 1000
ng/ml. In an embodiment, the amount and the frequency of
administrations of TMC278 to be administered are selected such that
the blood plasma concentrations are kept during a long term at a
level comprised between a maximum plasma level (or C.sub.max as
specified above) and a minimum blood plasma level (or C.sub.min as
specified above).
[0057] In certain instances it may be desirable to keep the plasma
levels of TMC278 at relatively low levels, e.g. as close as
possible to the minimum blood plasma levels specified herein. This
will allow reducing the frequency of the administrations and/or the
quantity of TMC278 administered with each administration. It will
also allow avoiding undesirable side effects, which will contribute
to the acceptance of the dosage forms in most of the targeted
population groups who are healthy people at risk of being infected
and therefore are less inclined to tolerate side effects. The
plasma levels of TMC278 may be kept at relatively low levels in the
instance of prevention. One embodiment concerns uses or methods for
prevention of HIV infection, as specified above or hereinafter,
wherein the minimum blood plasma level of TMC278 is as specified
herein and the maximum blood plasma level is about equal to the
lowest blood plasma level that causes the RT inhibitor to act
therapeutically, also as specified herein.
[0058] In other embodiments, the blood plasma level of TMC278 is
kept at a level below a lower maximum blood plasma level of about
10 ng/ml, more in particular about 15 ng/ml, further in particular
about 20 ng/ml, still more in particular about 40 ng/ml. In a
particular embodiment, the blood plasma level of TMC278 is kept
below a level of about 13.5 ng/ml. In one embodiment, the plasma
level of TMC 278 is kept in an interval of the lower maximum blood
level specified above, and the minimum blood plasma levels
mentioned in relation to prevention. For example the blood plasma
levels of TMC278 are kept below about 10 ng/ml and above a minimum
level of about 4 ng/ml.
[0059] In other instances it may be desirable to keep the plasma
levels of TMC278 at relatively higher levels, for example where
there is a high risk of infection and more frequent and/or higher
doses are not an issue. In these instances the minimum blood plasma
level may be equal to the lowest blood plasma level of TMC278 that
provides effective treatment of HIV, such as the specific levels
mentioned herein.
[0060] In the instance of prevention, the dose to be administered
should be calculated on a basis of about 0.2 mg/day to about 50
mg/day, or 0.5 mg/day to about 50 mg/day, or of about 1 mg/day to
about 10 mg/day, or about 2 mg/day to about 5 mg/day, e.g. about 3
mg/day. This corresponds to a weekly dose of about 1.5 mg to about
350 mg, in particular of about 3.5 mg to about 350 mg, in
particular of about 7 mg to about 70 mg, or about 14 mg to about 35
mg, e.g. about 35 mg, or to a monthly dose of from 6 mg to about
3000 mg, in particular about 15 mg to about 1,500 mg, more in
particular of about 30 mg to about 300 mg, or about 60 mg to about
150 mg, e.g. about 150 mg.
[0061] Doses for other dosing regimens can readily be calculated by
multiplying the daily dose with the number of days between each
administration.
[0062] In the instance of therapy, the dose to be administered
should be somewhat higher and should be calculated on a basis of
about 1 mg/day to about 150 mg/day, or of about 2 mg/day to about
100 mg/day, or of about 5 mg/day to about 50 mg/day, or about 10
mg/day to about 25 mg/day, e.g. about 15 mg/day. The corresponding
weekly or monthly doses can be calculated as set forth above. For
applications in prevention, the doses may be lower although the
same dosing as for therapeutic applications may be used.
[0063] It has been found that, once administered, the blood plasma
levels of TMC278 are more or less stable, i.e. they fluctuate
within limited margins. The blood plasma levels have been found to
approach more or less a steady state mode or to approximate more or
less a zero order release rate during a prolonged period of time.
By "steady state" is meant the condition in which the amount of
drug present in the blood plasma of a subject stays at more or less
the same level over a prolonged period of time. The plasma levels
of TMC278 generally do not show any drops below the minimum plasma
level at which the drug is effective. The term "stays at more or
less the same level" does not exclude that there can be small
fluctuations of the plasma concentrations within an acceptable
range, e.g. fluctuations within a range of about +/-30%, or about
+/-20%, or about +/-10%, or about +/-10%.
[0064] In some instances there may be an initial plasma
concentration peak after administration, after which the plasma
levels achieve a "steady-state", as mentioned hereinafter.
[0065] The compositions of the invention show good local tolerance
and ease of administration. Good local tolerance relates to minimal
irritation and inflammation at the site of injection; ease of
administration refers to the size of needle and length of time
required to administer a dose of a particular drug formulation. In
addition, the compositions of the invention show good stability and
have an acceptable shelf life.
[0066] The micro- or nanoparticles of the present invention have a
surface modifier adsorbed on the surface thereof. The function of
the surface modifier is to act as a wetting agent as well as a
stabilizer of the colloidal suspension.
[0067] In one embodiment, the micro- or nanoparticles in the
compositions of the invention mainly comprise crystalline TMC278 or
a salt thereof and the surface modifier, the combined amount of
which may at least comprise about 50%, or at least about 80%, or at
least about 90%, or at least about 95%, or at least about 99% of
the micro- or nano particles.
[0068] In a further aspect, the present invention is concerned with
a pharmaceutical composition for administration by intramuscular or
subcutaneous injection, comprising a therapeutically effective
amount of TMC278, or a stereoisomer or a stereoisomeric mixture
thereof, in the form of a suspension of particles consisting
essentially of: [0069] (1) TMC278, or a stereoisomer or a
stereoisomeric mixture thereof in micro- or nanoparticle form,
having a surface modifier adsorbed to the surface thereof and
[0070] (2) a pharmaceutically acceptable aqueous carrier; wherein
the active ingredient is suspended.
[0071] Suitable surface modifiers can be selected from known
organic and inorganic pharmaceutical excipients, including various
polymers, low molecular weight oligomers, natural products and
surfactants. Particular surface modifiers include nonionic and
anionic surfactants. Representative examples of surface modifiers
include gelatin, casein, lecithin, salts of negatively charged
phospholipids or the acid form thereof (such as phosphatidyl
glycerol, phosphatidyl inosite, phosphatidyl serine, phosphatic
acid, and their salts such as alkali metal salts, e.g. their sodium
salts, for example egg phosphatidyl glycerol sodium, such as the
product available under the tradename Lipoid.TM. EPG), gum acacia,
stearic acid, benzalkonium chloride, polyoxyethylene alkyl ethers,
e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene
castor oil derivatives; polyoxyethylene stearates, colloidal
silicon dioxide, sodium dodecylsulfate, carboxymethylcellulose
sodium, bile salts such as sodium taurocholate, sodium
desoxytaurocholate, sodium desoxycholate; methylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropyl-methylcellulose, magnesium aluminate silicate,
polyvinyl alcohol (PVA), poloxamers, such as Pluronic.TM. F68, F108
and F127 which are block copolymers of ethylene oxide and propylene
oxide; tyloxapol; Vitamin E-TGPS (.alpha.-tocopheryl polyethylene
glycol succinate, in particular .alpha.-tocopheryl polyethylene
glycol 1000 succinate); poloxamines, such as Tetronic.TM. 908
(T908) which is a tetrafunctional block copolymer derived from
sequential addition of ethylene oxide and propylene oxide to
ethylenediamine; dextran; lecithin; dioctyl ester of sodium
sulfosuccinic acid such as the products sold under the tradename
Aerosol OT.TM. (AOT); sodium lauryl sulfate (Duponol.TM. P); alkyl
aryl polyether sulfonate available under the tradename Triton.TM.
X-200; polyoxyethylene sorbitan fatty acid esters (Tweens.TM. 20,
40, 60 and 80); sorbitan esters of fatty acids (Span.TM. 20, 40, 60
and 80 or Arlacel.TM. 20, 40, 60 and 80); polyethylene glycols
(such as those sold under the tradename Carbowax.TM. 3550 and 934);
sucrose stearate and sucrose distearate mixtures such as the
product available under the tradename Crodesta.TM. F110 or
Crodesta.TM. SL-40; hexyldecyl trimethyl ammonium chloride (CTAC);
polyvinylpyrrolidone (PVP). If desired, two or more surface
modifiers can be used in combination.
[0072] Particular surface modifiers are selected from poloxamers,
.alpha.-tocopheryl polyethylene glycol succinates, polyoxyethylene
sorbitan fatty acid esters, and salts of negatively charged
phospholipids or the acid form thereof. More in particular the
surface modifiers are selected from Pluronic.TM. F108, Vitamin E
TGPS, Tween.TM. 80, and Lipoid.TM. EPG. One or more of these
surface modifiers may be used. Pluronic.TM. F108 corresponds to
poloxamer 338 and is the polyoxyethylene, polyoxypropylene block
copolymer that conforms generally to the formula
HO--[CH.sub.2CH.sub.2O].sub.x--[CH(CH.sub.3)CH.sub.2O].sub.y--[CH.sub.2CH-
.sub.2O].sub.z--H in which the average values of x, y and z are
respectively 128, 54 and 128. Other commercial names of poloxamer
338 are Hodag Nonionic.TM. 1108-F and Synperonic.TM. PE/F108. In
one embodiment, the surface modifier comprises a combination of a
polyoxyethylene sorbitan fatty acid ester and a phosphatidyl
glycerol salt (in particular egg phosphatidyl glycerol sodium).
[0073] The optimal relative amount of TMC278 in relation to the
surface modifier depends on the surface modifier selected, the
specific surface area of the TMC278 suspension which is determined
by the average effective particle size and the TMC278
concentration, the critical micelle concentration of the surface
modifier if it forms micelles, etc. The relative amount (w/w) of
TMC278 to the surface modifier preferably is in the range of 1:2 to
about 20:1, in particular in the range of 1:1 to about 10:1, e.g.
about 4:1.
[0074] The particles of this invention can be prepared by means of
micronization/particle size reduction/nanonization by mechanical
means and by controlled precipitation from a supersaturated
solution, or by using supercritical fluids such as in the GAS
technique ("gas anti-solvent"), or any combination of such
techniques. In one embodiment a method is used comprising the steps
of dispersing TMC278 in a liquid dispersion medium and applying
mechanical means in the presence of grinding media to reduce the
particle size of TMC278 to an average effective particle size of
less than about 50 .mu.m, in particular less than about 1,000 nm.
The particles can be reduced in size in the presence of a surface
modifier.
[0075] A general procedure for preparing the particles of this
invention comprises [0076] (a) obtaining TMC278 in micronized form;
[0077] (b) adding the micronized TMC278 to a liquid medium to form
a premix/predispersion; and [0078] (c) subjecting the premix to
mechanical means in the presence of a grinding medium to reduce the
average effective particle size.
[0079] TMC278 in micronized form is prepared using techniques known
in the art. It is preferred that the average effective particle
size of the TMC278 active agent in the predispersion be less than
about 100 .mu.m as determined by sieve analysis. Where the average
effective particle size of the micronized TMC278 is greater than
about 100 .mu.m, it is preferred that the particles of the TMC278
compound be reduced in size to less than 100 .mu.m.
[0080] The micronized TMC278 can then be added to a liquid medium
in which it is essentially insoluble to form a predispersion. The
concentration of TMC278 in the liquid medium (weight by weight
percentage) can vary widely and depends on the selected surface
modifier and other factors. Suitable concentrations of TMC278 in
compositions vary between about 0.1% to about 60%, or between about
1% to about 60%, or between about 10% to about 50%, or between
about 10% to about 30%, e.g. about 10%, 20% or 30% (each % in this
paragraph relating to w/v).
[0081] The premix can be used directly by subjecting it to
mechanical means to reduce the effective average effective particle
size in the dispersion to less than 2,000 nm. It is preferred that
the premix be used directly when a ball mill is used for attrition.
Alternatively, TMC278 and, optionally, the surface modifier, can be
dispersed in the liquid medium using suitable agitation such as,
for example, a roller mill, until a homogeneous dispersion is
achieved.
[0082] The mechanical means applied to reduce the effective average
effective particle size of TMC278 conveniently can take the form of
a dispersion mill. Suitable dispersion mills include a ball mill,
an attritor/attrition mill, a vibratory mill, a planetary mill,
media mills, such as a sand mill and a bead mill. A media mill is
preferred due to the relatively shorter milling time required to
provide the desired reduction in particle size. The beads
preferably are ZrO.sub.2 beads.
[0083] The grinding media for the particle size reduction step can
be selected from rigid media preferably spherical or particulate in
form having an average size less than 3 mm and, more preferably,
less than 1 mm (as low as 200 .mu.m beads). Such media desirably
can provide the particles of the invention with shorter processing
times and impart less wear to the milling equipment. Examples of
grinding media are ZrO.sub.2 such as 95% ZrO.sub.2 stabilized with
magnesia or stabilized with yttrium, zirconium silicate, glass
grinding media, polymeric beads, stainless steel, titania, alumina
and the like. Preferred grinding media have a density greater than
2.5 g/cm.sup.3 and include 95% ZrO.sub.2 stabilized with magnesia
and polymeric beads.
[0084] The attrition time can vary widely and depends primarily
upon the particular mechanical means and processing conditions
selected. For rolling mills, processing times of up to two days or
longer may be required.
[0085] The particles should be reduced in size at a temperature
that does not significantly degrade the TMC278 compound. Processing
temperatures of less than 30 to 40.degree. C. are ordinarily
preferred. If desired, the processing equipment may be cooled with
conventional cooling equipment. The method is conveniently carried
out under conditions of ambient temperature and at processing
pressures, which are safe and effective for the milling
process.
[0086] The pharmaceutical compositions according to the present
invention contain an aqueous carrier that preferably is
pharmaceutically acceptable. Said aqueous carrier comprises sterile
water optionally in admixture with other pharmaceutically
acceptable ingredients. The latter comprise any ingredients for use
in injectable formulations. These ingredients may be selected from
one or more of a suspending agent, a buffer, a pH adjusting agent,
a preservative, an isotonizing agent, and the like ingredients. In
one embodiment, said ingredients are selected from one or more of a
suspending agent, a buffer, a pH adjusting agent, and optionally, a
preservative and an isotonizing agent. Particular ingredients may
function as two or more of these agents simultaneously, e.g. behave
like a preservative and a buffer, or behave like a buffer and an
isotonizing agent.
[0087] Suitable buffering agents and pH adjusting agents should be
used in amount sufficient to render the dispersion neutral to very
slightly basic (up to pH 8.5), preferably in the pH range of 7 to
7.5. Particular buffers are the salts of week acids. Buffering and
pH adjusting agents that can be added may be selected from tartaric
acid, maleic acid, glycine, sodium lactate/lactic acid, ascorbic
acid, sodium citrates/citric acid, sodium acetate/acetic acid,
sodium bicarbonate/carbonic acid, sodium succinate/succinic acid,
sodium benzoate/benzoic acid, sodium phosphates,
tris(hydroxymethyl)aminomethane, sodium bicarbonate/sodium
carbonate, ammonium hydroxide, benzene sulfonic acid, benzoate
sodium/acid, diethanolamine, glucono delta lactone, hydrochloric
acid, hydrogen bromide, lysine, methanesulfonic acid,
monoethanolamine, sodium hydroxide, tromethamine, gluconic,
glyceric, gluratic, glutamic, ethylene diamine tetraacetic (EDTA),
triethanolamine, including mixtures thereof.
[0088] Preservatives comprise antimicrobials and anti-oxidants
which can be selected from the group consisting of benzoic acid,
benzyl alcohol, butylated hydroxyanisole (BHA), butylated
hydroxytoluene (BHT), chlorbutol, a gallate, a hydroxybenzoate,
EDTA, phenol, chlorocresol, metacresol, benzethonium chloride,
myristyl-.gamma.-piccolinium chloride, phenylmercuric acetate and
thimerosal. Radical scavengers include BHA, BHT, Vitamin E and
ascorbyl palmitate, and mixtures thereof. Oxygen scavengers include
sodium ascorbate, sodium sulfite, L-cysteine, acetylcysteine,
methionine, thioglycerol, acetone sodium bisulfite, isoacorbic
acid, hydroxypropyl cyclodextrin. Chelating agents include sodium
citrate, sodium EDTA and malic acid.
[0089] An isotonizing agent or isotonifier may be present to ensure
isotonicity of the pharmaceutical compositions of the present
invention, and includes sugars such as glucose, dextrose, sucrose,
fructose, trehalose, lactose; polyhydric sugar alcohols, preferably
trihydric or higher sugar alcohols, such as glycerin, erythritol,
arabitol, xylitol, sorbitol and mannitol. Alternatively, sodium
chloride, sodium sulfate, or other appropriate inorganic salts may
be used to render the solutions isotonic. These isotonifiers can be
used alone or in combination. The suspensions conveniently comprise
from 0 to 10% (w/v), in particular 0 to 6% of isotonizing agent. Of
interest are nonionic isotonifiers, e.g. glucose, as electrolytes
may affect colloidal stability.
[0090] A desirable feature for a pharmaceutical composition of the
invention relates to the ease of administration. The viscosity of
the pharmaceutical compositions of the invention should be
sufficiently low to allow administration by injection. In
particular they should be designed so that they can be taken up
easily in a syringe (e.g. from a vial), injected through a fine
needle (e.g. a 20 G 11/2, 21 G 11/2, 22 G 2 or 22 G 11/4 needle) in
not too long a time span. In one embodiment the viscosity of the
compositions of the invention is below about 75 mPas, or below 60
mPas. Aqueous suspensions of such viscosity or lower usually meet
the above-mentioned criteria.
[0091] Ideally, the aqueous suspensions according to the present
invention will comprise as much TMC278 as can be tolerated so as to
keep the injected volume to a minimum, in particular from 3 to 40%
(w/v), or from 3 to 30% (w/v), or from 3 to 20% (w/v), or from 10
to 30% (w/v), of TMC278. In one embodiment the aqueous suspensions
of the invention contain about 10% (w/v) of TMC278, or about 10%
(w/v) of TMC278, or about 30% (w/v) of TMC278.
[0092] In one embodiment, the aqueous suspensions may comprise by
weight, based on the total volume of the composition: [0093] (a)
from 3% to 50% (w/v), or from 10% to 40% (w/v), or from 10% to 30%
(w/v), of TMC278; [0094] (b) from 0.5% to 10%, or from 0.5% to 2%
(w/v) of a wetting agent; [0095] (c) from 0% to 10%, or from 0% to
5%, or from 0% to 2%, or from 0% to 1% of one or more buffering
agents; [0096] (d) from 0% to 10%, or from 0% to 6% (w/v) of a
isotonizing agent [0097] (e) from 0% to 2% (w/v) preservatives; and
[0098] (f) water for injection q.s. ad 100%.
[0099] To the suspensions may optionally be added an amount of acid
or base to bring the pH to a value of about pH 7. Suitable acids or
bases are any of those that are physiologically acceptable, e.g.
HCl, HBr, sulfuric acid, alkali metal hydroxides such as NaOH.
[0100] The administration of TMC278 as in the present invention may
suffice to treat HIV infection although in a number of cases it may
be recommendable to co-administer other HIV inhibitors. The latter
preferably include HIV inhibitors of other classes, in particular
those selected from NRTIs, PIs and fusion inhibitors. In one
embodiment, the other HIV inhibitor that is co-administered is a PI
inhibitor. HIV inhibitors that may be co-administered by preference
are those used in HAART combinations comprising an NNRTI. For
example two further NRTIs or an NRTI and a PI may be
co-administered. Such co-administration may be by oral
administration or parenterally.
[0101] In certain instances, the treatment of HIV infection may be
limited to only the administration of a composition of TMC278 in
accordance with this invention, i.e. as monotherapy without
co-administration of further HIV inhibitors. This option may be
recommended, for example, where the viral load is relatively low,
for example where the viral load (represented as the number of
copies of viral RNA in a specified volume of serum) is below about
200 copies/ml, in particular below about 100 copies/ml, more in
particular below 50 copies/ml, specifically below the detection
limit of the virus. In one embodiment, this type of monotherapy is
applied after initial treatment with a combination of HIV drugs, in
particular with any of the HAART combinations during a certain
period of time until the viral load in blood plasma reaches the
afore mentioned low viral level.
[0102] In a further aspect the present invention relates to the use
of a pharmaceutical composition comprising an anti-virally
effective amount of TMC278 or a pharmaceutically acceptable
acid-addition salt thereof, in accordance with the present
invention, for the manufacture of a medicament for maintenance
therapy of a subject being infected with HIV, wherein the
composition is administered or is to be administered intermittently
at a time interval that is in the range of one week to one year, or
one week to two years.
[0103] Thus in a further aspect, the present invention provides a
method for the long term treatment of a patient being infected with
HIV, said method comprising [0104] (i) the treatment of said
patient with a combination of HIV inhibitors; followed by [0105]
(ii) the intermittent administration of a pharmaceutical
composition comprising an anti-virally effective amount of TMC278
or a pharmaceutically acceptable acid-addition salt thereof, in
accordance with the present invention, wherein the composition is
administered at a time interval of at least one week.
[0106] The present invention also concerns a pharmaceutical
composition as described hereinbefore for use as a medicament in
the treatment or prophylaxis of HIV infection.
[0107] In addition, the present invention concerns the use of a
pharmaceutical composition as described herein for the preparation
of a medicament for the prophylaxis or treatment of HIV
infection.
[0108] The present invention further concerns a method of treating
a subject infected with HIV, said method comprising the
administration of a therapeutically effective amount of a
pharmaceutical composition as described herein.
[0109] As used herein, the word "substantially" does not exclude
"completely" e.g. a composition which is "substantially free" from
Y may be completely free from Y.
[0110] Where necessary, the word "substantially" may be omitted
from the definition of the invention. The term "about" in
connection with a numerical value is meant to have its usual
meaning in the context of the numerical value. Where necessary the
word "about" may be replaced by the numerical value.+-.10%, or
.+-.5%, or .+-.2%, or .+-.1%. All documents cited herein are
incorporated by reference in their entirety.
[0111] The following examples are intended to illustrate the
present invention and should not be construed as limiting the
invention thereto.
Example 1: Preparation of Nanosuspensions
[0112] Glass bottles of 250 ml and ZrO.sub.2 beads, used as the
milling media, were sterilized in an autoclave. Five grams of drug
substance were put into the 250 ml glass bottle as well as a
solution of 1.25 g Pluronic F108 in 60 ml of water for injection.
Three hundred grams of ZrO.sub.2-beads with an average particle
size of 500 .mu.m were added. The bottle was placed on a roller
mill. The suspension was micronized at 100 rpm during 72 hours. At
the end of the milling process the concentrated nanosuspension was
removed with a syringe and filled into vials. The resulting
formulation is Formulation 1 in the following table. Determination
of the concentration was done by HPLC/UV. A dilution was made to a
final concentration of 25 mg/ml of TMC278. The resulting suspension
was shielded from light.
[0113] Using similar procedures, Formulations 2, 3 and 4 were
prepared. These were titrated with sodium hydroxide 1N solution to
a pH of about 7. In formulations 2, 3 and 4 the Lipoid.TM. EPG is
solubilized in the Tween.TM. 80.
TABLE-US-00001 Ingredient Formula 1 Formula 2 Formula 3 Formula 4
TMC278 5 g 300 mg 300 mg 300 mg Pluronic .TM.F108 1.25 g -- -- --
Tween .TM. 80 -- 75 mg 75 mg 75 mg Lipoid .TM. EPG -- 9.375 mg
9.375 mg 9.375 mg Glucose -- 50 mg 50 mg 50 mg NaH.sub.2PO.sub.4. 1
aq -- -- 2 mg 2 mg citric acid. 1 aq -- -- -- 1 mg NaOH 1N -- at pH
6.72 at pH 6.98 at pH 6.99
Example 2: Kinetic Study
[0114] The present study demonstrates that an injectable
formulation of nanonised TMC278 or its HCl-salt results in stable
blood plasma levels during a prolonged period of time. This study
compares the plasma kinetics of TMC278 base and hydrochloric salt
after single intramuscular (IM) or subcutaneous injection of a
nanosuspension (Formula 1 of the previous example) at 5 mg/kg in
male beagle dogs.
[0115] Six healthy male beagle dogs with body weights ranging from
8 to 16 kg at the start of the study, were used. Each dog was
identified by an ear tattoo number. Two dogs were dosed
intramuscularly (IM) in the left and right m. biceps femoris
(treatment group A). Two dogs were dosed IM with TMC278.HCl
(treatment group B). Two dogs were dosed subcutaneously (SC) in the
left and right thoracal region. The injection volume was
2.times.0.1 ml/kg in all treatment groups. A 20 G needle was
used.
[0116] Blood samples of 3 ml were taken from the left jugular vein
from all dogs on day 0 at 0 h (predose), 20 min, 1 h, 3 h, 8 h and
24 h post-dose and further on days 2, 3, 6, 8, 10, 13, 16, 20, 23,
27, 29, 36, 43, 50, 57, 64, 71, 78, 85 and 92 at approximately 8
AM. Blood samples were placed on EDTA, EDTA Vacuette Greiner, Cat.
No. 454086, Greiner Labortechnik N.V.). Within 2 h of blood
sampling, samples were centrifuged at room temperature at about
1900.times. g for 10 minutes to allow plasma separation. Plasma was
immediately transferred into a second tube and stored in the
freezer within 2 hours after the start of centrifugation. Plasma
samples were analysed individually for TMC278 by means of a
validated LC-MS/MS-method.
TABLE-US-00002 TABLE 1 Individual and mean plasma concentrations
and some basic pharmacokinetic parameters of TMC278 in male beagle
dogs after single IM administration of a nanosuspension of TMC278
at 5 mg/kg Treatment group A Compound TMC278 Dose (mg/kg) 5 Adm.
Route IM DogNo Time (h) 17264 18186 Mean 0 (d 0) <1.00 <1.00
<1.00 0.33 121 186 154 1 110 82.6 96.3 3 131 145 138 8 130 136
133 24 (d 1) 150 120 135 48 (d 2) 159 132 146 72 (d 3) 115 99.6 107
144 (d 6) 86.2 91.9 89.1 192 (d 8) 72.4 75.5 74.0 240 (d 10) 56.7
62.5 59.6 312 (d 13) 33.4 38.0 35.7 384 (d 16) 23.9 20.6 22.3 480
(d 20) 20.5 16.6 18.6 648 (d 27) 11.4 9.08 10.2 696 (d 29) 11.3
11.2 11.3 864 (d 36) 7.33 6.44 6.89 1032 (d 43) 5.19 5.18 5.19 1200
(d 50) 3.40 3.25 3.33 1368 (d 57) 3.00 3.00 3.00 1536 (d 64) 2.84
2.44 2.64 1704 (d 71) 2.48 1.84 2.16 1872 (d 78) 1.79 1.45 1.62
2040 (d 85) 1.99 1.61 1.80 2208 (d 92) 1.56 1.25 1.41 Cmax (ng/ml)
159 186 173 Tmax (h) 48 0.33 24 AUC0-312 h (ng h/ml) 27400 26600
27000 AUC0-696 h (ng h/ml) 34800 33000 33900 AUC0-2208 h (ng h/ml)
40500 38200 39400
TABLE-US-00003 TABLE 2 Individual and mean plasma concentrations
and some basic pharmacokinetic parameters of TMC278 in male beagle
dogs after single IM administration of a nanosuspension of
TMC278.HCl at 5 mg (eq.)/kg Treatment group B Compound TMC278.HCl
Dose (mg eq./kg) 5 Adm. Route IM DogNo Time (h) 19072 19080 Mean 0
(d 0) <1.00 <1.00 <1.00 0.33 4.42 4.68 4.55 1 7.80 7.19
7.50 3 14.7 16.3 15.5 8 32.2 27.1 29.7 24 (d 1) 50.1 69.8 60.0 48
(d 2) 85.6 105 95.3 72 (d 3) 47.5 69.5 58.5 144 (d 6) 48.3 62.3
55.3 192 (d 8) 46.8 65.8 56.3 240 (d 10) 55.7 82.2 69.0 312 (d 13)
27.0 45.8 36.4 384 (d 16) 17.0 31.9 24.5 480 (d 20) 13.7 25.5 19.6
648 (d 27) 7.91 14.4 11.2 696 (d 29) 10.2 18.8 14.5 864 (d 36) 6.18
11.4 8.79 1032 (d 43) 6.32 8.18 7.25 1200 (d 50) 4.56 5.68 5.12
1368 (d 57) 4.73 5.08 4.91 1536 (d 64) 4.47 4.43 4.45 1704 (d 71)
3.38 3.90 3.64 1872 (d 78) 3.12 3.20 3.16 2040 (d 85) 3.20 4.00
3.60 2208 (d 92) 2.96 2.81 2.89 Cmax (ng/ml) 85.6 105 95.3 Tmax (h)
48 48 48 AUC0-312 h (ng h/ml) 15000 20900 18000 AUC0-696 h (ng
h/ml) 20300 30500 25400 AUC0-2208 h (ng h/ml) 27400 39900 33600
TABLE-US-00004 TABLE 3 Individual and mean plasma concentrations
and some basic pharmacokinetic parameters of TMC278 in male beagle
dogs after single SC administration of a nanosuspension of TMC278
at 5 mg/kg Treatment group C Compound TMC278 Dose (mg/kg) 5 Adm.
Route SC DogNo Time (h) 19129 19349 Mean 0 (d 0) <1.00 <1.00
<1.00 0.33 <1.00 <1.00 <1.00 1 1.62 1.37 1.50 3 7.96
8.42 8.19 8 27.6 13.8 20.7 24 (d 1) 15.7 28.5 22.1 48 (d 2) 34.8
29.1 32.0 72 (d 3) 26.1 30.6 28.4 144 (d 6) 18.9 32.7 25.8 192 (d
8) 17.7 23.0 20.4 240 (d 10) 24.3 42.0 33.2 312 (d 13) 21.7 38.8
30.3 384 (d 16) 21.7 16.6 19.2 480 (d 20) 29.8 21.2 25.5 648 (d 27)
19.0 11.0 15.0 696 (d 29) 21.0 10.5 15.8 864 (d 36) 12.7 5.49 9.10
1032 (d 43) 5.22 6.03 5.63 1200 (d 50) 6.37 3.40 4.89 1368 (d 57)
4.78 2.52 3.65 1536 (d 64) 6.45 2.05 4.25 1704 (d 71) 3.96 3.57
3.77 1872 (d 78) 3.66 1.91 2.79 2040 (d 85) 8.60 2.82 5.71 2208 (d
92) 3.05 2.49 2.77 Cmax (ng/ml) 34.8 42.0 38.4 Tmax (h) 48 240 144
AUC0-312 h (ng h/ml) 6910 9880 8400 AUC0-696 h (ng h/ml) 15900
16700 16300 AUC0-2208 h (ng h/ml) 26400 22400 24400
* * * * *