U.S. patent application number 15/104683 was filed with the patent office on 2017-03-09 for oral formulations of pyrrolidine derivatives.
The applicant listed for this patent is OBSEVA S.A.. Invention is credited to Andre Chollet, Olivier Pohl.
Application Number | 20170065556 15/104683 |
Document ID | / |
Family ID | 49765403 |
Filed Date | 2017-03-09 |
United States Patent
Application |
20170065556 |
Kind Code |
A1 |
Chollet; Andre ; et
al. |
March 9, 2017 |
ORAL FORMULATIONS OF PYRROLIDINE DERIVATIVES
Abstract
The present invention relates to solid oral formulations
comprising a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof, and
the use of said formulations in the treatment and/or prevention of
preterm labor, premature birth, dysmenorrhea and embryo
implantation failure due to uterine contractions. The present
invention is furthermore related to processes for their
preparation.
Inventors: |
Chollet; Andre;
(Plan-Les-Ouates, CH) ; Pohl; Olivier;
(Plan-Les-Ouates, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OBSEVA S.A. |
Plan-Les-Ouates |
|
CH |
|
|
Family ID: |
49765403 |
Appl. No.: |
15/104683 |
Filed: |
December 15, 2014 |
PCT Filed: |
December 15, 2014 |
PCT NO: |
PCT/EP2014/077767 |
371 Date: |
June 15, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/20 20130101; A61K
9/2054 20130101; A61K 9/2018 20130101; A61K 9/0056 20130101; A61K
45/06 20130101; A61K 9/2031 20130101; A61K 31/401 20130101; A61K
9/2009 20130101; A61K 9/2027 20130101; A61P 15/08 20180101; A61K
9/2013 20130101; A61K 9/0095 20130101; A61K 31/40 20130101; A61K
47/40 20130101 |
International
Class: |
A61K 31/40 20060101
A61K031/40; A61K 45/06 20060101 A61K045/06; A61K 9/20 20060101
A61K009/20 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 17, 2013 |
EP |
13197606.0 |
Claims
1. A dispersible tablet comprising a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and at least one or more
pharmaceutically acceptable excipients.
2. The dispersible tablet according to claim 1, wherein the at
least one or more pharmaceutically acceptable excipients is/are
selected from the group comprising a disintegrant, a wetting agent,
a carrier, a lubricant, a binder, a diluent, a sweetener, and/or a
taste-masking agent.
3. The dispersible tablet according to claim 2, wherein the carrier
is selected from the group comprising calcium silicate, calcium
carbonate, calcium phosphate, tribasic calcium phosphate, lactose,
starch, modified starch, sugars, celluloses, cellulose derivatives,
polymethacrylates, chitin, chitosan and combination thereof.
4. The dispersible tablet according to claim 2, wherein the binder
is selected from the group comprising polyvinylpyrrolidone,
cross-linked PVP, cellulose or cellulose derivatives such as
hydroxypropylmethyl cellulose (HPMC), carboxymethylcellulose
sodium, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, methyl cellulose, carboxyethylcellulose calcium, guar
gum, tragacanth, polyvinylacetates, gelatin, pregelatinised starch,
starch, polyvinylalcohols, alginic acid, sodium alginate, sorbitol,
glucose, magnesium aluminium silicate, dextrin, polyethylene
glycol, polymethacrylates and combination thereof.
5. The dispersible tablet according to claim 2, wherein the wetting
agent is selected from the group comprising poloxamer, sodium
lauryl sulphate, polyoxyethylene sorbitan fatty acid esters,
polyoxyethylene stearate, sorbitan fatty acid esters and
combination thereof.
6. The dispersible tablet according to claim 2, wherein the
disintegrant is selected from the group comprising sodium
croscarmellose, crospovidone, sodium alginate, colloidal
magnesium-aluminum silicate, calcium silicate, sodium starch
glycolate, acrylic acid derivatives, microcrystalline cellulose,
sodium carboxymethyl cellulose, calcium carboxymethyl cellulose,
modified cellulose gum, cross-linked povidone, alginic acid and
alginates, pregelatinised starch, modified corn starch and
combination thereof.
7. The dispersible tablet according to claim 2, wherein the diluent
is selected from the group comprising microcrystalline cellulose,
lactose monohydrate, lactose, compressible sugar, sugar, dextrose,
mannitol, dextrin, maltodextrin, sorbitol, xylitol, sodium
chloride, calcium carbonate, magnesium carbonate, calcium
phosphate, calcium sulphate, magnesium oxide, kaolin, powdered
cellulose, pregelatinized starch, starch, barium sulphate,
magnesium trisilicate, aluminium hydroxide and combination
thereof.
8. The dispersible tablet according to claim 2, wherein the
sweetener is sodium saccharine.
9. The dispersible tablet according to claim 2, wherein the
lubricant is selected from the group comprising glycerol
dibehenate, glycerol tribehenate, magnesium stearate, calcium
stearate, talc, sodium stearyl fumarate, sodium behenate, stearic
acid, cethyl alcohol, polyoxyethylene glycol, leucine, sodium
benzoate, stearates, talc, polyethylene glycol, glyceryl
monostearate, glyceryl palmitostearate, liquid paraffin, poloxamer,
sodium lauryl sulphate, magnesium lauryl sulphate, hydrogenated
castor oil, colloidal silicon dioxide, palmitostearate, stearic
acid, zinc stearate, stearyl alcohol, hydrogenated vegetable oil
and combination thereof.
10. The dispersible tablet according to claim 1, wherein the
concentration of the compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime is comprised between about 1% and 50%
w/w.
11. The dispersible tablet according to claim 1, wherein said
dispersible tablet comprises about 10 mg to 500 mg of the compound
of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime.
12. The dispersible tablet according to claim 1, wherein the
maximum concentration in blood of the compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime is reached at a time between 0.5 to 2
hours after administration.
13. The dispersible tablet according to claim 1, wherein the
concentration in blood of the compound of formula (3Z,5
S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidin-
-3-one-O-methyloxime is at least 40% of Cmax at 0.5 h after
administration.
14. The dispersible tablet according to claim 1, wherein said
dispersible tablet is characterized by a bioavailability of the
compound of formula (3Z,5
S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrr-
olidin-3-one-O-methyloxime comprised between 50-100%, preferably
between 80-100%.
15. The dispersible tablet according to claim 1, wherein said
dispersible tablet is to be administered concomitantly or
separately with at least one compound selected from the group
comprising calcium channel blockers, magnesium sulfate, selective
prostaglandin modulators, beta-2-adrenergic agonists,
beta-3-adrenergic receptor agonists, and/or corticosteroids.
16. The dispersible tablet according to claim 14, wherein
corticosteroids are selected from the group comprising
betamethasone, dexamethasone, and/or salts thereof.
17. The dispersible tablet according to claim 1, wherein said
dispersible tablet is in a unit dose.
18. The dispersible tablet according to claim 1, comprising: 20% by
weight of a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime; 1-20% by weight of calcium silicate;
0.1-20% by weight of PVP30K; 0.01-5% by weight of poloxamer 188;
0.5-20% by weight of sodium croscarmellose; 1-90% by weight of
microcrystalline cellulose 112; 1-90% by weight of lactose
monohydrate; 0.01-0.5% by weight of sodium saccharine; and 0.1-10%
by weight of glycerol dibehenate.
19. The dispersible tablet according to claim 18, consisting of:
20% by weight of a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, 5% by weight of calcium silicate, 1% by
weight of PVP30K, 2% by weight of poloxamer 188, 5% by weight of
sodium croscarmellose, 15% by weight of microcrystalline cellulose
112, 47.8% by weight of lactose monohydrate, 0.2% by weight of
sodium saccharine and 4% by weight of glycerol dibehenate.
20. The dispersible tablet according to claim 1, for use in the
treatment and/or prevention of disorders selected from the group
comprising preterm labor, premature birth, embryo implantation
failure due to uterine contractions, dysmenorrhea, premature
ejaculation, sexual dysfunction, endometriosis, infertility, benign
prostatic hyperplasia, neuro-psychiatric disorders, autism, social
behavior disorders, psycho-social stress, and/or cardiovascular
disorders.
21. A process for the preparation of a dispersible tablet according
to claim 1 characterized in that it comprises a step of wet
granulation.
22. A kit comprising a dispersible tablet according to claim 1, and
information for use.
Description
TECHNICAL FIELD
[0001] The present invention relates to solid oral formulations
comprising a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof, and
the use of said formulations in the treatment and/or prevention of
preterm labor, premature birth, dysmenorrhea and embryo
implantation failure due to uterine contractions. The present
invention is furthermore related to processes for their
preparation.
BACKGROUND OF THE INVENTION
[0002] Oxytocin (OT) is a cyclic nona-peptide that mediates its
physiological actions through activation of the oxytocin receptor
(OT-R), a cell membrane receptor belonging to the class of G
protein-coupled receptors that is similar to arginine vasopressin
receptors. One important action of OT is to cause the contraction
of the uterus of mammals during labor. Repeated, concerted and
regular contraction of the uterus will cause the dilatation of the
cervix, the rupture of foetal membranes and lead to expulsion of
the foetus. Premature labor is when these contractions occur before
the normal term of pregnancy. Preterm increase of uterine activity
is the most common expression of preterm labor.
[0003] Premature labor leads to undesired premature birth, a
serious health problem that remains the major cause of perinatal
mortality and severe morbidity, especially respiratory distress
syndrome, intraventricular haemorrhage, bronchopulmonary dysplasia
and necrotising enterocolitis that are far more common in preterm
than in term infants. Long-term impairments such as cerebral palsy,
visual impairment and hearing loss are also more common in preterm
infants. Nowadays, preterm birth remains the leading cause of
infant mortality and morbidity in industrialized nations, where,
despite the significant improvements in obstetrical medicine, it is
causing high costs for neonatal intensive care of premature babies.
The actual costs are even higher to society when taking into
consideration the healthcare provision of preterm
childbirth-related ailments, such as respiratory distress syndrome,
heart conditions, cerebral palsy, epilepsy, and severe learning
disabilities. The management of preterm labor represents a
significant problem in the field of obstetrics.
[0004] The OT/OT-R system plays a vital role in initiating labor in
mammals, in particular in humans. The density of OT-R increases
markedly in the myometrium before the onset and during labor. Also
it is thought that the local OT peptide hormone concentration
increases markedly before parturition in human. The high
circulating concentrations of progesterone induce uterine
quiescence while the uterus acquires contractile ability. Shortly
before term, plasma progesterone concentrations fall, OT-R
expression in the uterus increases markedly, OT is released and
uterine contractile activity increases. At term, the contractions
rise to a crescendo, resulting in delivery as a result of two
interacting positive feedback loops. The first is a local uterine
loop: within the uterus itself, contractile prostaglandins are
produced and released in response to OT and uterine contractions.
These prostaglandins may play a further role in cervical ripening
and weakening of fetal membranes. The second loop involves the
hypothalamus: in response to uterine contractions and vaginal and
cervical distension, magnocellular oxytocin neurons in the
hypothalamus increase their activity resulting in the release of OT
from their axon terminals in the posterior pituitary. The released
OT acts upon the uterus both to stimulate the further production of
prostaglandins and to contribute further to the contractions of the
uterus.
[0005] Therefore, blocking the effect of OT by antagonizing OT-R
might represent an attractive modality for the treatment of
diseases related to the OT-R activity, in particular preterm labor,
premature birth and dysmenorrhea.
[0006] Tocolytic, i.e. uterus relaxing agents, have been used in
clinical studies for the pharmaceutical treatment of preterm labor.
Most of these agents are used off-label. They have shown very
limited efficacy, if any, in prolonging gestation and without clear
demonstration of improvement of neonate outcome. Current tocolytics
are very often associated with unwanted adverse effects on women,
foetus or neonate. Such tocolytics include beta-2-adrenergic
agonists, prostaglandin synthesis inhibitors, magnesium sulfate,
nitric acid donors and calcium channel blockers. Beta-2-adrenergic
agonists such as ritodrine or terbutaline cause a number of
cardiovascular and metabolic side effects including maternal
tachycardia, palpitations, hypotension, altered thyroid function
and fetal and neonatal hypoglycaemia, tachycardia. Ritodrine is no
longer FDA approved. The calcium channel blocker nifedipine is also
a medicine that is used to try to stop contractions. Some of the
side effects that may occur include facial flushing, headache,
nausea, palpitations, and lightheadedness. The total prostaglandin
synthesis inhibitor (NSAID) indomethacin has been used. It can also
have serious effects on the fetus: constriction of ductus
arteriosus, pulmonary hypertension, decrease in renal function with
oligohydramnios, intraventricular hemorrhage, hyperbilirubinemia,
necrotizing enterocolitis. Maternal side effects include abdominal
discomfort, nausea, vomiting, depression and dizzy spells for the
mother. Another NSAID is sulindac that has a side effect profile
similar to indomethacin. For magnesium sulfate, meta-analyses have
failed to support it as a tocolytic agent. Women reported important
side effects such as flushing, lethargy, headache, muscle weakness,
pulmonary edema and cardiac arrest. A newborn that has been exposed
to magnesium sulfate may show lethargy, hypotonia, respiratory
depression, bone problems, osteopenia and fractures. Recently, the
FDA is advising healthcare professionals against using magnesium
sulfate injection for longer than 5-7 days to stop preterm labor in
women.
[0007] Atosiban, a dual vasopressin V1a receptor and OT-R
antagonist is marketed in EU and used to stop contractions and
delay preterm delivery by a few days. The principal drawback to the
use of peptide antagonists like Atosiban is the problem of low oral
bioavailability resulting from intestinal degradation. Hence, they
must be administered parenterally.
[0008] The development of orally active small molecule antagonists
that are selective for the OT-R is expected to overcome these
problems. Pyrrolidine derivatives being OT-R antagonists are
disclosed in WO 01/72705, WO 02/102799, WO 2002/074741, and WO
2004/005249.
[0009] Thus, in the management of preterm labor and premature
birth, there is a need for an oral formulation which is convenient
to administer, which is suitable for providing a fast onset of
action and which provides a good bioavailability of a compound
being an OT-R antagonist.
SUMMARY OF THE INVENTION
[0010] The present invention provides a dispersible tablet
comprising a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and at least one or more
pharmaceutically acceptable excipients.
[0011] The invention also provides said dispersible tablet, for use
in the treatment and/or prevention of disorders selected from the
group comprising preterm labor, premature birth, embryo
implantation failure due to uterine contractions, dysmenorrhea,
premature ejaculation, sexual dysfunction, endometriosis,
infertility, benign prostatic hyperplasia, neuro-psychiatric
disorders, autism, social behavior disorders, psycho-social stress,
and/or cardiovascular disorders.
[0012] Also provided is a process for the preparation of said
dispersible tablet characterized by a step of wet granulation.
[0013] The invention further provides a kit comprising said
dispersible tablet, and information for use thereof.
BRIEF DESCRIPTION OF THE FIGURES
[0014] FIG. 1: Plasma concentration profiles of solid oral
formulations in the dog. FIG. 1A shows the plasma concentration
(ng/ml) vs. time profile of formulations 1 (10% granules), 2 (5.8%
granules), 3 (dispersible tablets) and 4 (conventional tablets)
over the time period from 0 to 72 h. FIG. 1B shows an enlargement
of FIG. 1A for the period from 0 to 12 h.
[0015] FIG. 2: Individual plasma concentration profiles of
formulation 3 (dispersible tablets) in the dog. Plasma
concentration of the compound of formula (3Z,5S) is measured
(ng/ml) for each dog (n=5) for the time period from 0 to 12 h.
[0016] FIG. 3: Individual plasma concentration profiles of
formulation 4 (conventional tablets) in the dog. Plasma
concentration of the compound of formula (3Z,5S) is measured
(ng/ml) for each dog (n=5) for the time period from 0 to 12 h.
DETAILED DESCRIPTION OF THE INVENTION
[0017] Generally, the present invention relates to a solid oral
formulation comprising a compound of formula
5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3--
one-O-methyloxime, its geometrical isomers, its optically active
forms as enantiomers, diastereoisomers, mixtures of these, its
racemate forms as well as active metabolites thereof, and at least
one or more pharmaceutically acceptable excipients.
[0018] Preferably, the present invention relates to a solid oral
formulation comprising a compound of formula
(3Z/E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyr-
rolidin-3-one-O-methyloxime, and/or an active metabolite thereof,
and at least one or more pharmaceutically acceptable
excipients.
[0019] Even more preferably, the present invention relates to a
solid oral formulation comprising a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof, and
at least one or more pharmaceutically acceptable excipients.
[0020] The compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime also named (3Z,5S) herein is produced by
methods such as those disclosed for example in WO2004/005249 and
WO2005/082848.
[0021] Usually, said compound is synthesized and obtained in
isomeric mixtures
(3Z/E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)car-
bonyl]pyrrolidin-3-one-O-methyloxime comprising
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime and
(3E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime.
[0022] In case the isomer Z is preferred, then the compound of
formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime synthesized and obtained in isomeric
mixtures is purified according to methods disclosed in
PCT/EP2014/066075.
[0023] Thus, the purity of the compound
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime in said isomeric mixtures is at least 85%
to 100%, preferably 85% to 99.9%, more preferably 90% to 99.9%, and
even more preferably 95% to 99.9%.
[0024] Alternatively, the present invention relates to a solid oral
formulation comprising a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof,
provided in substantially pure form, and at least one or more
pharmaceutically acceptable excipients.
[0025] As used herein, the term "substantially pure" refers to a
compound provided in a form which is substantially free of other
compounds. Examples of said "other compounds" include
(3E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime,
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one,
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one oxime,
(3R,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]-3-me-
thoxyamino-pyrrolidine,
(3S,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]-3-me-
thoxyamino-pyrrolidine, (3Z,5
S)-5-(O-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyl-
oxime and (3E,5
S)-5-(O-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3-one-O-methyl-
oxime.
[0026] Most preferably, the compound of formula (3Z,5
S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidin-
-3-one-O-methyloxime, and/or an active metabolite thereof is
substantially free of the compound of formula
(3E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime.
[0027] Even more preferably, the purity of a substantially pure
form compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof, is
at least 55%, at least 60%, at least 65%, at least 70%, at least
75%, at least 80%, at least 85%, at least 90%, at least 95%, at
least 98%, at least 99%, at least 99.2%, at least 99.3%, at least
99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least
99.8%, at least 99.9% or at least 100% and is therefore
substantially free of compound of formula
(3E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime.
[0028] Even more preferably, the purity of the substantially pure
form compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof, is
at least in the range of 85% to 100%, preferably 85% to 99.9%, more
preferably 90% to 99.9%, and even more preferably in the range of
95% to 99.9%.
[0029] As used herein, the term "active metabolite thereof" refers
to a product produced through metabolism in the body, or in vitro,
of a specified compound, i.e. in the present case
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime and which exhibits the same biological
activity as
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]py-
rrolidin-3-one-O-methyloxime.
[0030] Active metabolites of
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime may be identified using routine
techniques known in the art and their activities determined using
tests such as those described herein. Such metabolites may result
for example from the oxidation, glucuronidation or other
conjugation, hydrolysis, reduction and the like, of the
administered Z form. Accordingly, the invention includes active
metabolites of
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, including compounds produced by a
process comprising contacting a compound of this invention with a
mammal for a period of time sufficient to yield a metabolic product
thereof. Such metabolite may also be produced in vitro by
oxidation, reduction, hydrolysis, glucuronidation or other
conjugation transformation of the corresponding
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime. Examples of actives metabolites of
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, include compounds whose structures are
shown below:
##STR00001## ##STR00002##
[0031] A compound which, upon administration to the recipient, is
capable of being converted into a compound of
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof as
described above, is known as a "prodrug". A prodrug may, for
example, be converted within the body, e.g. by hydrolysis in the
blood, into its active form that has medical effects.
Pharmaceutical acceptable prodrugs are described in T. Higuchi and
V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A. C.
S. Symposium Series (1976); "Design of Prodrugs" ed. H. Bundgaard,
Elsevier, 1985; and in Edward B. Roche, ed., Bioreversible Carriers
in Drug Design, American Pharmaceutical Association and Pergamon
Press, 1987, which disclosures are incorporated herein by
reference.
[0032] As used herein, the term "solid oral formulation" refers to
a tablet, a dispersible tablet, a fast dissolving tablet, a quick
dissolving tablet, a fast melt tablet, a mouth-dissolving tablet, a
melt-in mouth tablet, an orodispersible tablet, a lyophilised unit,
a porous tablet, a conventional tablet, a coated tablet, an
uncoated tablet, a gastro-resistant tablet, an effervescent tablet,
a soluble tablet, a chewable tablet, an oral lyophilisate, a
powder, an oral powder, a pellet, a capsule and/or a granule.
Preferably, the solid oral formulation is a tablet, more
preferably, a dispersible tablet.
[0033] As used herein, the term "dispersible tablet" includes a
disintegrating tablet that is swallowed, or intended to be
disintegrated rapidly in water and to be swallowed.
[0034] As used herein, "pharmaceutically acceptable excipients"
includes any carriers, diluents, adjuvants, vehicles, preserving
agents, antioxidant agents, fillers, bulking agent, glidant,
buffering agents, thickening agents, disintegrating agents,
lubricants, binders, wetting agents, sweeteners, flavouring agent,
taste-masking agents, emulsifying agents, suspending agents,
solvents, dispersion media, coatings, antibacterial agents,
anti-oxidants, antifungal agents, isotonic and absorption delaying
agents and the like. The use of such media and agents for
pharmaceutical active substances is well-known in the art. Except
insofar as any conventional media or agent is incompatible with the
active ingredient, its use in the solid oral formulation is
contemplated. Supplementary active ingredients can also be
incorporated into the solid oral formulation as suitable
therapeutic combinations.
[0035] Preferably, the dispersible tablet of the invention
comprises a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime and at least one or more pharmaceutically
acceptable excipients selected from the group comprising a
disintegrant, a wetting agent, a carrier, a lubricant, a binder, a
diluent, a sweetener, and/or a taste-masking agent.
[0036] Thus, the present invention relates to a dispersible tablet
comprising a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and a disintegrant. For example, the
"disintegrant" is selected from one of the group comprising sodium
croscarmellose, crospovidone, sodium alginate, colloidal
magnesium-aluminum silicate, calcium silicate, sodium starch
glycolate, acrylic acid derivatives, microcrystalline cellulose,
sodium carboxymethyl cellulose, calcium carboxymethyl cellulose,
modified cellulose gum, cross-linked povidone, alginic acid and
alginates, pregelatinised starch, modified corn starch and
combination thereof. Preferably, the "disintegrant" is selected
from the group comprising sodium croscarmellose, crospovidone and
combination thereof. More preferably, the "disintegrant" is sodium
croscarmellose.
[0037] The present invention alternatively relates to a dispersible
tablet comprising a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and a wetting agent. For example, the
"wetting agent" is selected from the group comprising poloxamer,
sodium lauryl sulphate, polyoxyethylene sorbitan fatty acid esters,
polyoxyethylene stearate, sorbitan fatty acid esters and
combination thereof. Preferably, the "wetting agent" is selected
from the group comprising poloxamer, sodium lauryl sulfate and
combination thereof. More preferably, the "wetting agent" is
poloxamer 188.
[0038] Furthermore, the present invention relates to a dispersible
tablet comprising a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and a carrier. For example, the
"carrier" is selected from the group comprising calcium silicate,
calcium carbonate, calcium phosphate, tribasic calcium phosphate,
lactose, starch, modified starch, sugars, celluloses, cellulose
derivatives, polymethacrylates, chitin, chitosan and combination
thereof. Preferably, the "carrier" is selected from the group
comprising calcium silicate, calcium carbonate, calcium phosphate
and combination thereof. More preferably, the carrier is calcium
silicate.
[0039] The present invention also relates to a dispersible tablet
comprising a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or a disintegrant, and/or a wetting
agent, and/or a carrier. Preferably, said dispersible tablet
comprises a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or sodium croscarmellose, and/or
poloxamer 188, and/or calcium silicate.
[0040] The present invention also relates to a dispersible tablet
comprising a compound of formula (3Z,5
S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidin-
-3-one-O-methyloxime and at least one or more pharmaceutically
acceptable excipients in an amount effective to provide a tablet
that releases between about 90 to 100% of
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime. A classical Pharmacopeia compliant
dissolution test was performed. As shown in the example, a rapid
dissolution profile of the dispersible tablet of 200 mg is observed
at 15 min wherein the concentration of (3Z,5S) in water is between
90% to 100% of the initial concentration value (Table 30).
[0041] Preferably the one or more pharmaceutical acceptable
excipients includes at least one disintegrant. More preferably, the
disintegrant is selected from the group consisting of sodium
croscarmellose, crospovidone and a combination thereof. More
preferably, the "disintegrant" is sodium croscarmellose.
[0042] For example, the "binder" is selected from the group
comprising polyvinylpyrrolidone, cross-linked PVP, cellulose or
cellulose derivatives such as hydroxypropylmethyl cellulose (HPMC),
carboxymethylcellulose sodium, ethyl cellulose, hydroxyethyl
cellulose, hydroxypropyl cellulose, methyl cellulose,
carboxyethylcellulose, calcium, guar gum, tragacanth,
polyvinylacetates, gelatin, pregelatinised starch, starch,
polyvinylalcohols, alginic acid, sodium alginate, sorbitol,
glucose, magnesium aluminium silicate, dextrin, polyethylene
glycol, polymethacrylates and combination thereof.
[0043] For example, the "diluent" is selected from the group
comprising microcrystalline cellulose, lactose monohydrate,
lactose, compressible sugar, sugar, dextrose, mannitol, dextrin,
maltodextrin, sorbitol, xylitol, sodium chloride, calcium
carbonate, magnesium carbonate, calcium phosphate, calcium
sulphate, magnesium oxide, kaolin, powdered cellulose,
pregelatinized starch, starch, barium sulphate, magnesium
trisilicate, aluminium hydroxide and combination thereof.
[0044] For example, the "sweetener" is sodium saccharine, sucrose,
sucralose, aspartame, sorbitol or combination thereof.
[0045] For example, the "lubricant" is selected from the group
comprising glycerol dibehenate, glycerol tribehenate, magnesium
stearate, calcium stearate, talc, sodium stearyl fumarate, sodium
behenate, stearic acid, cethyl alcohol, polyoxyethylene glycol,
leucine, sodium benzoate, stearates, talc, polyethylene glycol,
glyceryl monostearate, glyceryl palmitostearate, liquid paraffin,
poloxamer, sodium lauryl sulphate, magnesium lauryl sulphate,
hydrogenated castor oil, colloidal silicon dioxide,
palmitostearate, stearic acid, zinc stearate, stearyl alcohol,
hydrogenated vegetable oil and combination thereof.
[0046] The present invention also relates to a solid oral
formulation comprising a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof, and
at least one or more pharmaceutically acceptable excipients,
wherein the concentration of said compound and/or active metabolite
thereof, is comprised between about 1% and 50% w/w.
[0047] Preferably, the concentration of the compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof is
10-40% w/w, 20-30% w/w, about 20% w/w.
[0048] As used herein, the term "about" applies to numeric values
and refers to a range of numbers that one of skill in the art would
consider equivalent to the recited values. For example, "about 20%
w/w" refers to the range 15%-25% w/w.
[0049] The present invention also relates to a solid oral
formulation comprising a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof, and
at least one or more pharmaceutically acceptable excipients,
wherein said formulation comprises about 10 mg to about 500 mg of
the compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbon-
yl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite
thereof.
[0050] Preferably, said formulation comprises about 20-400 mg or
40-200 mg of the compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof.
Preferably, said formulation in the form of a dispersible tablet
comprises about 50 mg or 200 mg of a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime.
[0051] Advantageously, the present invention provides a solid oral
formulation, which is i) convenient to administer, ii) suitable for
providing a fast onset of action and which provides a good
bioavailability of the compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or active metabolite thereof. As
used herein, the term "Tmax" refers to the time to reach the peak
plasma concentration (Cmax) of a drug after administration wherein
the concentration is the amount of the drug in a given volume of
plasma, expressed in ng/ml in the examples.
[0052] As used herein, the term "onset of action" refers to the
time required after administration of a drug to become
effective.
[0053] As shown in the examples, the solid oral formulations of the
present invention, in particular in the form of a dispersible
tablet, have the advantage of being suitable for providing a rapid
onset of action. The maximum concentration in blood of the compound
of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or active metabolite thereof, is
reached at a time Tmax less than 5 h, preferably less than 4 h,
more preferably less than 3 h, less than 2 h, less than 1.5 h, even
more preferably less than 1 h following administration of said
solid oral formulation.
[0054] Also, the maximum concentration in blood of the compound of
formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or active metabolite thereof, is
reached at a time Tmax between 0.5 to 4 hours, 0.5 to 2 hours,
preferably 0.5 to 1.5 hours, more preferably at a time between 0.5
to 1 hour following administration of said solid oral formulation.
Preferably, said solid oral formulation is a dispersible
tablet.
[0055] Noteworthy, at a time of 0.5 hour following administration
of the solid oral formulation, the concentration in blood of the
compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbon-
yl]pyrrolidin-3-one-O-methyloxime, and/or active metabolite
thereof, is at least 25%, at least 35%, at least 40%, at least 45%,
at least 55%, at least 65%, at least 75%, or at least 85% of Cmax.
Preferably, said solid oral formulation is a dispersible
tablet.
[0056] Also, at a time of 0.5 hour following administration of the
solid oral formulation, the concentration in blood of the compound
of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or active metabolite thereof, is
comprised between 35% to 100%, 45% to 100%, 55% to 100% of Cmax,
preferentially 57% to 92% of Cmax indicating that the solid oral
formulation is suitable for providing a rapid onset of action.
Preferably, said solid oral formulation is a dispersible
tablet.
[0057] As shown in the examples, at a time of 0.5 hour following
administration of the dispersible tablet, the concentration in
blood of the compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, is comprised between 59% to 100% of Cmax
in animal (Table 17), preferentially 57% to 92% of Cmax in human
subjects (Table 22).
[0058] Thus, the present invention provides a solid oral
formulation, preferably a dispersible tablet that is suitable for
providing a rapid onset of action, which is crucial for the
management of preterm labor and premature birth.
[0059] In particular, it has been shown that the maximum
concentration of the active substance (3Z,5S) is detected rapidly
at about 4 hours, 2 hours, 1.5 hours, or 1 hour following
administration of the dispersible tablet of the present
invention.
[0060] Furthermore, the solid oral formulation of the present
invention is characterized by a bioavailability of the compound of
formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or active metabolite thereof,
comprised between 50-100%, and/or 50-99%. Preferably, said
bioavailability is comprised between 75-100%, or 75-99%, more
preferably, between 80-100%, or 80-99%.
[0061] As used herein, the term "bioavailability" (F %) refers to
the fraction of an administered dose of a product that reaches the
systemic circulation. By definition, when the product is
administered intravenously, its bioavailability is 100%. When the
product is administered via other routes, its bioavailability
generally decreases.
[0062] As shown in the examples, the bioavailability (F %) of the
solid oral formulations of the present invention, is comprised
between 58% and 90% (Table 16). In particular, the bioavailability
of the solid oral formulation in the form of a dispersible tablet
is comprised between 80% and 100% (Table 18, 102% in table 18 is
indicated as 100% based on the standard deviation).
[0063] In particular, it has been shown that the bioavailability of
the active substance (3Z,5S) is about 89% following administration
of the dispersible tablet of the present invention (Table 16).
[0064] Advantageously, patients administered with the solid oral
formulation of the present invention will benefit from a fast onset
of action and/or a good bioavailability.
[0065] Also, the present invention provides a solid oral
formulation comprising:
20% by weight of a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof;
1-20% by weight of calcium silicate; 0.1-20% by weight of PVP30K;
0.01-5% by weight of poloxamer 188; 0.5-20% by weight of sodium
croscarmellose; 1-90% by weight of microcrystalline cellulose 112;
1-90% by weight of lactose monohydrate; 0.01-0.5% by weight of
sodium saccharine; and 0.1-10% by weight of glycerol
dibehenate.
[0066] Alternatively, the present invention provides a dispersible
tablet comprising 20% by weight of a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and 0.5-20% by weight of a disintegrant.
Preferably said disintegrant is sodium croscarmellose.
[0067] Also alternatively provided is a dispersible tablet
comprising 20% by weight of a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and 1-20% by weight of a carrier.
Preferably, said carrier is calcium silicate.
[0068] Alternatively, it further provides a dispersible tablet
comprising 20% by weight of a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and 0.01-5% by weight of a wetting
agent. Preferably, said wetting agent is poloxamer 188.
[0069] Preferably, said solid oral formulation consists of:
20% by weight of a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof, 5%
by weight of calcium silicate, 1% by weight of PVP30K, 2% by weight
of Poloxamer 188, 5% by weight of Sodium croscarmellose, 15% by
weight of Microcrystalline cellulose 112, 47.8% by weight of
Lactose monohydrate, 0.2% by weight of Sodium saccharine and 4% by
weight of Glycerol dibehenate.
[0070] Whilst the compound
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime and/or the active metabolite thereof may
be used as the sole active ingredient of the solid oral
formulation, it is also possible for the compound to be used in
combination with at least one or more further active compounds.
Such further active compounds may be further compounds according to
the invention, or other active compounds selected from the group
comprising calcium channel blockers, magnesium sulfate, selective
prostaglandin modulators, beta-2-adrenergic agonists,
beta-3-adrenergic receptor agonists, and/or corticosteroids.
[0071] Preferably, corticosteroids are selected from the group
comprising Betamethasone and Dexamethasone, and/or salts thereof.
These corticosteroids are given before birth to accelerate a
preterm fetus' lung development and maturation to prevent
respiratory distress syndrome (RDS) and other related complications
following premature birth.
[0072] Alternatively, the solid oral formulation of the invention
can be administered concomitantly or separately with at least one
compound selected from the group comprising calcium channel
blockers (such as nifedipine), magnesium sulfate, prostaglandin
receptors modulators (such as agonists or antagonists of either EP1
or EP2 or EP3 or EP4 or FP receptors), prostaglandin synthesis
inhibitors (such as indomethacin, nimesulide, sulindac, rofecoxib,
celecoxib), beta-2-adrenergic agonists (such as ritodrine,
terbutaline, salbutamol), beta-3-adrenergic receptor agonists,
nitric acid donors (such as glyceryl trinitrate) and/or
corticosteroids (such as dexamethasone, betamethasone).
[0073] As used herein, the term "concomitantly" refers to the
administration of a solid oral formulation comprising a compound of
formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbon-
yl]pyrrolidin-3-one-O-methyloxime, and/or an active metabolite
thereof, which is then immediately followed by the administration
of at least one compound selected from the group disclosed
supra.
[0074] As used herein, the term "separately" encompasses sequential
or subsequent administration and refers to the administration of a
solid oral formulation of the invention comprising the compound of
formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof,
followed by a time period of discontinuance, which is then followed
by the administration of at least one compound disclosed supra.
[0075] The compound of formula (3Z,5
S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidin-
-3-one-O-methyloxime, and/or an active metabolite thereof, is an
oxytocin receptor antagonist.
[0076] As used herein, the term "oxytocin receptor antagonist"
refers to a compound that functions by inhibiting (partially or
completely) or blocking the oxytocin receptor (OT-R), thereby
preventing activation of the receptor by oxytocin.
[0077] Generally, the compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof, is
a vasopressin V1a receptor antagonist.
[0078] As used herein, the term "vasopressin V1a receptor
antagonist" refers to a compound that functions by inhibiting
(partially or completely) or blocking the vasopressin V1a receptor
(also known as Arginine vasopressin receptor 1A), thereby
preventing activation of the receptor by vasopressin. Vasopressin
V1a receptor is one of the three major receptor types for the
peptide hormone arginine vasopressin, the others being V1b and V2
receptors.
[0079] Hence, the present invention relates to a solid oral
formulation comprising a compound of formula (3Z,5
S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidin-
-3-one-O-methyloxime, and/or an active metabolite thereof, and at
least one or more pharmaceutically acceptable excipients, wherein
said compound is an oxytocin receptor antagonist and/or a
vasopressin V1a receptor antagonist.
[0080] Disorders associated with the oxytocin receptor activity
and/or vasopressin V1a receptor activity are selected from the
non-limiting group comprising preterm labor, premature birth,
embryo implantation failure due to uterine contractions,
dysmenorrhea, premature ejaculation, sexual dysfunction,
endometriosis, infertility, benign prostatic hyperplasia,
neuro-psychiatric disorders, autism, social behavior disorders,
psycho-social stress, and/or cardiovascular disorders.
[0081] The term "preterm labor" referring also to "premature
labor", shall mean expulsion from the uterus of a viable infant
before the normal end of gestation, or more particularly, onset of
labor with effacement and dilation of the cervix before the 37th
week of gestation. It may or may not be associated with vaginal
bleeding or rupture of the membranes.
[0082] The term "dysmenorrhea" refers to a condition characterized
by cyclic pain associated with menses during ovulatory cycles. The
pain is thought to result from uterine contractions and
ischemia.
[0083] The term "sexual dysfunction" refers to any disturbance or
variation in the four phases--excitement phase, plateau phase,
orgasmic phase and resolution phase characterizing the human sexual
response.
[0084] The term "neuro-psychiatric disorders" as used herein refers
to mental disorders attributable to diseases of the nervous system,
e.g. depression, obsessive-compulsive disorder and others.
[0085] The term "social behavior disorders" as used herein refers
to emotional disturbance, inappropriate types of behavior or
feelings, pervasive mood of unhappiness or depression and a range
of perceived difficulties to build or maintain satisfactory
interpersonal relationships
[0086] The term "psycho-social stress" as used herein refers to a
condition resulting from a perceived threat to the social status,
social esteem, self-worth, respect or acceptance within a group,
and that lead to development of a stress response in the body and
physical symptoms.
[0087] Assisted reproduction technologies are methods applied in
humans for the treatment of infertility and in animals for
producing pregnancies. Infertility, which affects about 10% of
human pairs worldwide, may be treated by in vitro fertilization and
embryo transfer (IVF-ET) or in less complicated cases, by
artificial insemination. Generally, a success of an embryo transfer
is dependent on uterine receptivity, an entity that is defined as
an ability of uterus to provide optimal conditions mandating proper
implantation and embryo development. Basic components of uterine
receptivity are uterine contractile activity and the condition of
endometrium.
[0088] Uterine contractions occurring during the embryo transfer
may expel embryos from the uterus towards vagina or oviducts, which
may be a cause of unsuccessful treatment, or in latter case a cause
of extra uterine pregnancy, a serious, potentially life-threatening
complication.
[0089] Hence, the present invention provides a solid oral
formulation, for use in the treatment and/or prevention of
disorders selected from the group comprising preterm labor,
premature birth, dysmenorrhea, premature ejaculation, sexual
dysfunction, endometriosis, embryo implantation failure due to
uterine contractions, infertility, benign prostatic hyperplasia,
neuro-psychiatric disorders, autism, social behaviour disorders,
psycho-social stress, and/or cardiovascular disorders. Preferably,
said solid oral formulation is a dispersible tablet.
[0090] Preferably, the present invention provides a solid oral
formulation for use in the treatment and/or prevention of preterm
labor, premature birth, dysmenorrhea and embryo implantation
failure due to uterine contractions.
[0091] The present invention also provides a process for the
preparation of a solid oral formulation comprising a compound of
formula (3Z,5
S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidin-
-3-one-O-methyloxime, and/or an active metabolite thereof,
characterized by a step of wet granulation.
[0092] In wet granulation, granules are formed by the addition on
powder particles of a liquid such as water, ethanol and
isopropanol, either alone or in combination.
[0093] Preferably, the present invention provides a process for the
preparation of a tablet comprising a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof,
characterized by a step of wet granulation. More preferably, said
tablet is a dispersible tablet.
[0094] Alternatively, the present invention provides a process for
the preparation of a solid oral formulation comprising a compound
of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof, and
at least one or more pharmaceutically acceptable excipients,
characterized by the steps of: (i) mixing the compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof, and
at least one or more pharmaceutically acceptable excipients;
(ii) wet-granulating; (iii) sieving the granules (iv) blending with
a lubricant such as glycerol dibehenate; and (v) compressing the
mixture obtained in step (iv) to form a tablet.
[0095] Preferably, said tablet is a dispersible tablet.
[0096] The tablet cores may vary in shape and be, for example,
round, oval, oblong, cylindrical or any other suitable shape.
[0097] The present invention also provides a kit comprising a solid
oral formulation comprising a compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof, and
at least one or more pharmaceutically acceptable excipients, and
information for use thereof. The information contains instructions
to administer the oral formulation to a subject in need
thereof.
[0098] Generally, in the present invention the subject in need
thereof is preferably a mammal, most preferably a human, more
preferably a woman.
[0099] For practical reason, the solid oral formulation of the
present invention can be packaged in a unit dose. As used herein,
the term "unit dose" refers to a solid oral formulation that is
dispensed in a package ready to administer to the patient. Each
unit dose contains a predetermined quantity of active product
calculated to produce the desired therapeutic effect, in
association with at least one or more suitable pharmaceutical
excipients.
EXAMPLES
Example 1
Purification of
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime
1.1 Synthesis of
(3Z/E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyr-
rolidin-3-one-O-methyloxime
[0100] In the present invention, the compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime was obtained as a crude isomeric mixture
comprising
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime and
(3E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime.
[0101] Synthetic pathways of compounds used in the invention are
for example those described in WO2004005249 and WO2005082848.
[0102] The compound
"(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrr-
olidin-3-one-O-methyloxime" used herein is also defined as
"(4Z,2S)-2-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl-carbonyl)]pyr-
rolidine-4-one-O-methyloxime" depending on the nomenclature
used.
[0103] The compound
(3Z/E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyr-
rolidin-3-one-O-methyloxime can also be prepared following stages 1
to 6 as described below:
Stage 1: Preparation of 4-(2-methylphenyl)benzoic acid
##STR00003##
[0105] A solution of potassium carbonate (0.908 Kg, 6.57 mol, 2.06
wt) in water (2.20 L, 5.0 vol) was charged to a slurry of
4-bromobenzoic acid (0.441 Kg, 2.19 mol, 1.0 wt) in water (4.41 L,
15.0 vol) at 15 to 25.degree. C. The resulting slurry was stirred
at 15 to 25.degree. C. and degassed three times using a
vacuum-nitrogen purge cycle.
Tetrakis(triphenylphosphine)palladium(0) (0.022 Kg, 0.019 mol, 0.05
wt) was charged and the vacuum-nitrogen purge cycle repeated. A
solution of o-tolylboronic acid (0.313 Kg, 2.30 mol, 0.707 wt) in
methanol (3.53 L, 8.0 vol) was degassed three times, using a
vacuum-nitrogen purge cycle, and then charged to the 4-bromobenzoic
acid slurry at 15 to 25.degree. C. The reaction mixture was heated
to and maintained at reflux (71 to 78.degree. C.) until reaction
completion (The reaction is considered complete at 95% conversion),
as determined by `H NMR analysis (d6-DMSO), typically 1.5 to 2.5
hours. The reaction mixture was concentrated to 15 vol under vacuum
at 40 to 45.degree. C. Toluene (4.41 L, 10.0 vol) and
tetrahydrofuran (4.41 L, 10.0 vol) were added to the residue, the
resulting mixture stirred vigorously and acidified to pH 1 with
hydrochloric acid (6M, 2.00 L, 4.5 vol). The contents were stirred
vigorously for 30 to 60 minutes and the layers separated. Toluene
(2.20 L, 5.0 vol) and tetrahydrofuran (2.20 L, 5.0 vol) were added
to the aqueous phase and the mixture stirred for 5 to 10 minutes.
The layers were separated, the combined organic phases filtered and
concentrated to 10.0 vol under vacuum at 35 to 40.degree. C.
Toluene (4.41 L, 10.0 vol) was added to the residue and the
resultant concentrated under vacuum at 35 to 40.degree. C. The
tetrahydrofuran content of the resulting slurry was determined by
`H NMR analysis (d6-DMSO) (Pass level: .ltoreq.1.0% w/w
tetrahydrofuran with respect to toluene). The slurry was cooled to
and aged at 0 to 5.degree. C. for 30 to 60 minutes, the solid
collected by filtration and the filter-cake washed with toluene
(2.20 L, 5.0 val). The solid was dried in a vacuum oven at 35 to
40.degree. C. to give 4-(2-methylphenyl)benzoic acid [0.438 Kg,
94.1% th, 99.3% w/w, 1H NMR (d6-DMSO) concordant with structure] as
a pale yellow solid.
Stage 2: Preparation of 4-(2-methylphenyl)benzoic acid chloride
##STR00004##
[0107] Thionyl chloride (0.300 L, 4.11 mol, 0.685 vol) was added to
a slurry of 4-(2-methylphenyl)benzoic acid (0.435 Kg, 2.05 mol, 1.0
wt) in toluene (4.35 L, 10.0 vol) at 10 to 25.degree. C. and the
mixture heated to and maintained at 75 to 80.degree. C. 3 until
complete by 1H NMR analysis (d6-benzene,), typically 4 to 5 hours.
Reaction completion was accompanied by the formation of a hazy
solution. The resultant was concentrated to 5.0 vol by removal of
toluene under reduced pressure at 35 to 45.degree. C. Toluene (2.18
L, 5.0 vol) was added to the concentrate and the mixture
concentrated to 4.0 vol by removal of toluene under reduced
pressure at 35 to 45.degree. C. The resultant was filtered through
glass microfibre paper and the filter-cake washed with toluene
(0.44 L, 1.0 vol). The toluene solution of
4-(2-methylphenyl)benzoic acid chloride [0.439 Kg, 92.8% th, 100.9%
w/w, 1H NMR (d6-benzene) concordant with structure] was used
directly in Stage 3.
Stage 3: Preparation of
(4R)-4-hydroxy-1-[(2'-methyl-1,1'-biphenyl-4yl)-carbonyl]-L-proline
##STR00005##
[0109] A solution of potassium carbonate (0.526 Kg, 3.81 mol, 1.2
wt) in water (0.57 L, 1.3 vol) was charged to a solution of
4-hydroxy-L-proline (0.274 Kg, 2.09 mol, 0.625 wt) in
tetrahydrofuran (2.20 L, 5.0 vol) and water (0.44 L, 1.0 vol) at 15
to 25.degree. C. followed by a line rinse of water (0.44 L, 1.0
vol). The mixture was cooled to 0 to 5.degree. C. with rapid
stirring and a solution of 4-(2-methylphenyl)benzoic acid chloride
(0.438 Kg, 1.90 mol, 1.0 wt) in toluene (2.19 L, 5.0 vol) charged
at that temperature followed by a line rinse of toluene (0.44 L,
1.0 vol). The reaction mixture was warmed to 15 to 25.degree. C.
over 1 to 2 hours and stirred at this temperature until judged
complete by TLC analysis. Water (2.20 L, 5.0 vol) was charged to
the reaction mixture at 15 to 25.degree. C. and the layers
separated. The aqueous phase was acidified to pH 5 to 6 with aq.
hydrochloric acid (6M, 0.66 L, 1.5 vol) and then to pH1 with aq.
hydrochloric acid (2M, 0.88 L, 2.0 vol) at 15 to 25.degree. C. The
mixture was cooled to and aged at 0 to 5.degree. C. for 30 to 60
minutes, the precipitated solid collected by filtration, the
filter-cake washed with water (2.times.1.75 L, 2.times.4.0 vol) and
toluene (0.88 L, 2.0 vol) and pulled dry on the filter for 12 to 24
hours. The collected solid was dried under vacuum at 40 to
45.degree. C. until the water content by KF was .ltoreq.0.2% w/w to
afford
(4R)-4-hydroxy-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]-L-proline
[0.599 Kg, 97.0% th, 136.8% w/w, .sup.1H NMR (d.sub.6-DMSO)
concordant with structure] as an off-white solid.
Stage 4: Preparation of
1-(2'-methyl-1,1'-biphenyl-4-yl)carbonyl-4-oxo-L-proline
##STR00006##
[0111] Triethylamine (1.80 L, 13.56 mol, 3.0 vol) was charged to a
solution of
(4R)-4-hydroxy-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]-L-proline
(0.598 Kg, 1.84 mol, 1.0 wt) in dimethyl sulfoxide (4.42 L, 7.4
vol) at 15 to 20.degree. C. Pyridine-sulphur trioxide complex
(0.879 Kg, 5.52 mol, 1.47 wt) was charged portion-wise at 15 and
25.degree. C. and the reaction mixture stirred at that temperature
until reaction completion, as determined by TLC analysis (typically
1 to 3 hours). 7 The reaction was quenched with aq. hydrochloric
acid (3M, 4.80 L, 8.0 vol) at 0 to 30.degree. C., tetrahydrofuran
(3.00 L, 5.0 vol) and heptanes (0.60 L, 1.0 vol) charged, the
layers separated and the aqueous phase extracted with
tetrahydrofuran (2.times.3.00 L, 2.times.5.0 vol). The combined
organic phases were washed with aq. hydrochloric acid (1 M,
2.times.1 0.20 L, 2.times.2.0 vol) and saturated sodium chloride
solution (2.times.1.20 L, 2.times.2.0 vol), the aqueous washes
combined and back-extracted with tetrahydrofuran (2.times.0.60 L,
2.times.1.0 vol). The combined organics were dried over magnesium
sulphate (1.794 Kg, 3.0 wt), filtered, the filtercake washed with
tetrahydrofuran (0.60 L, 1.0 vol) and the filtrates concentrated
under vacuum at 40 to 45.degree. C. to give a pale brown foam.
Ethyl acetate (6.00 L, 10.0 vol) was charged to the foam, the
contents stirred for 5 to 10 minutes to reach dissolution and the
solvent removed under vacuum at 40 to 45.degree. C. This was
repeated using ethyl acetate (6.00 L, 5.0 vol) until
tetrahydrofuran was not detected by .sup.1H NMR analysis
(d.sub.6-DMSO). The residue was slurried in ethyl acetate (4.80 L,
8.0 vol), activated carbon (0.084 Kg, 0.14 wt) added followed by a
line rinse of ethyl acetate (3.00 L, 5.0 vol), the resultant heated
to and maintained at 70 to 80.degree. C. for 20 to 30 minutes,
cooled to 40 to 55.degree. C. and filtered through glass microfibre
paper. The filter-cake was washed with ethyl acetate (1.50 L, 2.5
vol) and the combined filtrates and wash concentrated to 2.5 to 3.5
vol under vacuum at 40 to 45.degree. C.
[0112] Crystallisation commenced during the concentration. The
concentrate was transferred to a suitable vessel with a line rinse
of ethyl acetate (0.30 L, 0.5 vol) and heated to 70 to 80.degree.
C. Additional ethyl acetate (0.30 L, 0.5 vol) was added as
necessary to achieve dissolution. Heptanes (1.80 L, 3.0 vol) was
added at 70 to 80.degree. C. and the contents allowed to cool to
between 15 and 25.degree. C. over 1 to 2 hours. The slurry was
further cooled to and aged at 0 to 5.degree. C. for 2 to 3 hours,
filtered and the filtercake washed with ethyl acetate:heptanes
(1:1, 0.60 L, 1.0 vol) at 0 to 5.degree. C. followed by heptanes
(3.0 L, 2.5 vol). The collected solid was dried under vacuum at 40
to 45.degree. C. to give
1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]-4-oxo-L-proline [0.444
Kg, 74.7% th, 74.2% w/w, .sup.1H NMR (d.sub.6-DMSO) concordant with
structure] as an off-white solid.
Stage 5: Preparation of
(4Z/E)-4-methoxyimino-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]-L-prolin-
e
##STR00007##
[0114] Triethylamine (0.40 L, 2.85 mol, 0.92 vol) was added to a
solution of
1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]-4-oxo-L-proline (0.434
Kg, 1.34 mol, 1.0 wt) in dichloromethane (4.40 L, 10.0 vol) at 10
to 25.degree. C. followed by a line rinse of dichloromethane (0.43
L, 1.0 vol). Methoxylamine hydrochloride (0.130 Kg, 1.56 mol, 0.30
wt) was added portionwise at 10 to 25.degree. C. followed by a line
rinse of dichloromethane (0.43 L, 1.0 vol) and the reaction mixture
stirred at 10 to 25.degree. C. until reaction completion, as
determined by TLC analysis (typically 3 to 5 hours, TLC eluent:
dichloromethane:methanol:acetic acid (90:10:1); uv visualization).
The solvent was removed under vacuum at 35 to 40.degree. C., the
resultant dissolved in ethyl acetate (4.40 L, 10.0 vol) and washed
with aq. hydrochloric acid (1 M, 2.times.2.20 L, 2.times.5.0 vol).
The acidic washes were back extracted with ethyl acetate (2.20 L,
5.0 vol), the combined organic phases washed with sat. aq. sodium
chloride solution (3.10 L, 7.0 vol), dried over magnesium sulfate
(0.300 Kg, 0.69 wt), filtered and the filtercake washed with ethyl
acetate (2.20 L, 5.0 vol). The filtrate and washes were combined
and concentrated under vacuum at 35 to 40.degree. C. to afford
4-methoxyimino-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]-L-proline
[0.476 Kg, 100.6% th, 109.6% w/w, .sup.1H NMR (CDCl.sub.3)
concordant with structure) as an off-white solid.
Stage 6: Preparation of (4Z/E,
2S)-methyl-1-[(2'-methyl-1,1'-biphenyl-4-yl)-carbonyl]-4-methoxyimino
pyrrolidine-2-carboxylate
##STR00008##
[0116] Potassium carbonate (0.476 Kg, 3.44 mol, 1.0 wt) was added
to a solution of
4-methoxyimino-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]-L-proline
(0.475 Kg, 1.35 mol, 1.0 wt) in acetone (4.75 L, 10.0 vol) and the
mixture cooled to 0 to 10.degree. C. Dimethyl sulfate (0.128 L,
1.35 mol, 0.27 vol) was added at 0 to 15.degree. C. and the mixture
stirred at 15 to 25.degree. C. until reaction completion, as
determined by TLC analysis, typically 3 to 16 hours. The solvent
was removed under vacuum at 40 to 45.degree. C. and the resultant
partitioned between ethyl acetate (3.80 L, 8.0 vol) and water (3.80
L, 8.0 vol). The layers were separated, the organic phase washed
with sat. aq. sodium chloride solution (2.85 L, 6.0 vol), dried
over sodium sulfate (0.953 Kg, 2.0 wt) and filtered. The
filter-cake was washed with ethyl acetate (0.48 L, 1.0 vol) and the
combined filtrate and wash concentrated under vacuum at 40 to
45.degree. C. Excess ethyl acetate was removed by azeotropic
distillation with tetrahydrofuran (2.times.0.95 L, 2.times.2.0 vol)
under vacuum at 40 to 45.degree. C. to give
(4Z/E,2S)-methyl-1-[(2'-methyl-1,1'-biphenyl-4-yl)-carbonyl]-4-methoxyimi-
no pyrrolidine-2-carboxylate [0.492 Kg, 99.6% th, 103.6% w/w,
.sup.1H NMR (CDCl.sub.3) concordant with structure] as a viscous
brown oil.
Stage 7: Preparation of
(3Z/E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyr-
rolidin-3-one-O-methyloxime
##STR00009##
[0118] Lithium borohydride (0.049 Kg, 2.26 mol, 0.1 wt) was added
portionwise under nitrogen to a stirred solution of (4Z/E,
2S)-methyl-1-[(2'-methyl-1,1'-biphenyl-4-yl)-carbonyl]-4-methoxyimino
pyrrolidine-2-carboxylate (0.492 Kg, 1.34 mol, 1.0 wt) in
tetrahydrofuran (2.31 L, 4.7 vol) and methanol (2.31 L, 4.7 vol) at
0 to 30.degree. C. The mixture was stirred at 15 to 25.degree. C.
to reaction completion, as determined by TLC analysis (Eluent:
ethyl acetate; Visualisation: ninhydrin), typically 2 to 6 hours.
The reaction mixture was quenched with water (0.40 L, 0.8 val) at
15 to 25.degree. C. and stirred at 15 to 25.degree. C. for 16 to 20
hours. The resultant was concentrated under vacuum at 40 to
45.degree. C. and the residue partitioned between water (2.46 L,
5.0 vol) and ethyl acetate (4.92 L, 10.0 vol). The layers were
separated, the organic phase washed sequentially with aq.
hydrochloric acid (1M, 2.46 L, 5.0 vol), sat. aq. sodium hydrogen
carbonate solution (2.46 L, 5.0 vol) and sat. aq. sodium chloride
solution (2.46 L, 5.0 vol). The organic phase was dried over
magnesium sulfate (0.985 Kg, 2.0 wt), filtered and the filter-cake
washed with ethyl acetate (0.50 L, 1.0 vol). The combined filtrate
and wash were concentrated under vacuum to give a crude isomeric
mixture comprising
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime and
(3E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime [0.395 Kg, 86.9% th, 80.3% w/w, 1H NMR
(CDCl.sub.3) concordant with structure; 82.0% area by HPLC,
71.4:28.6 Z/E ratio] as a viscous brown oil. The oil was dissolved
in toluene (0.40 L, 1.0 vol, with respect to weight of product) and
stored until required.
1.2 Dry flash chromatography of crude
(3Z/E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyr-
rolidin-3-one O-methyloxime
[0119] A dry flash chromatography purification of the crude
isomeric mixture obtained following the protocol described above
was attempted using different elution conditions. A crude mixture
of
(3Z/E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyr-
rolidin-3-one O-methyloxime concentrated to dryness was
re-dissolved in 2 volume toluene and loaded onto a pad of SiO.sub.2
(5 wt) prior to elution using 25 volume fractions of eluent.
Fractions 1-5: eluted with pure toluene Fractions 6-10: eluted with
Toluene/MeOH 1% vol/vol Fractions 10 to 15: eluted with
Toluene/MeOH 2% vol/vol
Schematic TLC Profile of the Collected Fractions
##STR00010##
[0121] The Z and E forms are shown by shaded spots. Fractions 8 to
13 were combined and concentrated to dryness. The results show a
recovery of 75%. There was no improvement in the E/Z ratio. A minor
gain of about 4% area in purity of the isomeric mixture (E+Z) was
observed before and after dry-flash chromatography (Table 1).
TABLE-US-00001 TABLE 1 Comparative impurity profile before and
after dry-flash chromatography % area Impurity at E + Z- Impurity
at RRT 1.12 RRT 0.7 isomers RRT 1.08 (Ar--Ar--CH2OH) Before dry 4.6
91.3 <0.5 4.1 flash After dry- 2.5 95.6 <0.5 0.7 flash RRT:
Relative retention time
[0122] The dry-flash chromatography of the crude isomeric mixture
does not allow the purification of
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one O-methyloxime. The E/Z ratio pre and post dry-flash
remain in the range of 30/70 to 40/60.
[0123] Furthermore, such an approach should be considered on the
basis of the scale at which the operation has to be carried out. On
a 20 L scale, this operation would not be a time saving
approach.
1.3 Assessment Toward Crystallization of the Pure Z from the Crude
Isomeric Mixture
[0124] The first part of the assessment toward crystallisation of
the pure
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one O-methyloxime from the crude mixture
(3Z/E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyr-
rolidin-3-one O-methyloxime, has been looking at solubility and
possible crystallisation conditions of the pure
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one O-methyloxime. The results of the
solubility/crystallisation tests carried out on 15 mg scale are
reported in Table 2 below
TABLE-US-00002 TABLE 2 Qualitative solubility data for
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-
1,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime Solvent
Dissolves in: Comment heptanes -- insoluble in 20 vol toluene 2 vol
cold DIPE 40 vol hot THF 4 vol cold tBuOH 6 vol hot MIBK 4 vol hot
IPA 4 vol hot
[0125] The initial solubility screen showed that pure
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one O-methyloxime isomer is soluble in a range of solvents.
On the basis of the above results, crystallisation by addition of
anti-solvent was examined and the results reported in Table 3. The
anti-solvent was added to a warm solution ca 40-50.degree. C. and
allowed to cool to room temperature.
[0126] In particular, the water (anti-solvent) was added to a warm
(40-50.degree. C.) solution of
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)
carbonyl]pyrrolidin-3-one O-methyloxime in IPA until cloudiness was
reached and the mixture was allowed to cool to room
temperature.
TABLE-US-00003 TABLE 3 Crystallisation via addition of anti-solvent
Solvent Antisolvent Comment toluene 20 vol heptanes 39 vol oils out
THF 10 vol heptanes 40 vol oils out tBuOH 10 vol water 20 vol oils
out MIBK 10 vol heptanes 40 vol oils out IPA 20 vol water 160 vol
very fine solid, oils out on standing IPA 8 vol water 18 vol very
fine solid, oils out on standing DMSO 10 vol water 12 vol gel NMP
10 vol water 28 vol oils out MeOH 10 vol water 10 vol oils out DMSO
20 vol water 16 vol oils out acetone 10 vol water 10 vol oils out
DCM 10 vol heptanes 50 vol oils out
[0127] The IPA/water crystallisation conditions were applied to a
crude isomeric mixture. The toluene solution was first concentrated
to dryness prior to dissolution in IPA (8 vol) and addition of
water (18 vol). Unfortunately, this resulted in material de-mixing
as oil.
[0128] In another experiment, the antisolvent was added to a
solution of crude
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl-
]pyrrolidin-3-one O-methyloxime (90.4% area purity, contained 0.5%
w/w toluene and 3.7% w/w THF) at room temperature until cloudiness
was reached and the mixture was left to stand at room temperature
(Table 4).
TABLE-US-00004 TABLE 4 Crystallisation by addition of water at
18-22.degree. C. Solvent Antisolvent Comment MeOH 5 vol water 3 vol
oils out DMSO 5 vol water 3 vol oils out
[0129] At this point of the investigation, no suitable conditions
of crystallisation of the pure
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one O-methyloxime or allowing isolation of solid containing
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one O-methyloxime have been identified.
[0130] Further crystallisation attempts were carried out using
crude isomeric mixture of
(3Z/E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyr-
rolidin-3-one O-methyloxime. In all cases, the volume of solvents
was smaller than what used previously and based only on a single
solvent. The crude material (E/Z ratio 33:67 and purity (E+Z)
79.52% area) used for this crystallisation was concentrated to a
foam (Table 5).
TABLE-US-00005 TABLE 5 crystallisation from single solvent at lower
volume Material Solvent Ageing in freezer Ageing in fridge `Pure Z`
Ethyl Crystallises re- Stays in solution, with Acetate dissolves as
warms and without seeding 1.8 vol after 2 days. Crude Does not
crystallize n/a with or without seeding. `Pure Z` Diethylether On
addition of ether n/a 2.3 vol at 18-22.degree. C. starts to
dissolve then crashes out again. Recovery 70% Used for seeding
Crude Oils Crystallises recovery 41 Re-dissolves as % E/Z ratio
40/60 purity warms 85.4% area. (mother liquors E/Z ratio 20/80
purity 62.1% area). Seeds not used. `Pure Z` TBME Oils Stays in
solution, with 2.3 vol Re-dissolves as and without seeding warms
after 2 days. Crude Oils Stays in solution, with Re-dissolves as
and without seeding warms after 2 days.
[0131] Crystallisation using ethyl acetate followed by aging in a
freezer overnight gave crystallisation using the pure
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one O-methyloxime material, but quickly re-dissolved as the
sample warmed. No crystals were observed using crude material in
ethyl acetate even when seeds were added.
[0132] Crystallisation using diethylether followed by aging in a
fridge gave crystallisation using the crude
(3Z/E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyr-
rolidin-3-one O-methyloxime material. The solid was collected in
41% recovery. Unfortunately, the collected solid had a slighter
poorer E/Z ratio than the input material and a slightly higher
chemical purity.
[0133] TBME as solvent for both pure Z and crude gave oiling after
aging in freezer, and stayed in solution after aging in the fridge
with and without seeds.
[0134] Suitable crystallization conditions of the crude isomeric
mixture allowing improvement of the Z/E ratio and of the purity of
the isomeric mixture (E+Z) have not been found.
1.4 Substantially pure form of
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one O-methyloxime
1.4.1 Small Scale Purification
[0135] The isolation procedure in substantially pure form of
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one O-methyloxime was performed by chromatography using a
Biotage system (Biotage AB, SE-751 03 Uppsala, Sweden) of the crude
isomeric mixture isolated after reduction of the oxime ester (Stage
7 of Example 1).
[0136] Five distinct batches (No. 020, 180, 062, 068, 076) of the
crude isomeric mixture were purified by Biotage chromatography.
Furthermore, different conditions were used regarding batches No.
068 and 076. Purification was performed with a 5% w/w spike of
oxime methyl ester added (No. 068), and with an overloaded Biotage
column (No. 076).
[0137] Each chromatography was run using Biotage 40M cartridges (40
g silica) which had been pre-flushed with toluene. Toluene:MeOH
(99:1 v/v) was then eluted and collected in 100 ml fractions (total
volume 4 L), followed by a flush of toluene:MeOH (96:4 v/v).
[0138] Fractions were analysed by TLC (eluent: ethylacetate) to
determine which fractions could be discarded and which fractions
contained Z isomer. These Z fractions were then analyzed by HPLC.
The pass criteria for a fraction was >96% Z isomer and <1.2%
E isomer.
[0139] Surprisingly, the purification through Biotage
chromatography of various batches was very efficient as the
substantially pure form of
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one O-methyloxime is purified at 99.4% (Batches No. 020,
No. 062, No. 068) and at 99.2% (Batches No. 180, No. 076). In
particular, the Biotage chromatography in presence of oxime ester
removes 5% w/w oxime ester without detriment to recovery or quality
(Batch No. 068) and a 25% overcharge of the Biotage column does not
cause a decrease in yield or quality (batch No. 076).
TABLE-US-00006 TABLE 6 efficiency of the Biotage chromatography
Batch yield of No. Input % E/Z Output % E/Z Z isomer 020 3.0 g Pure
Z-fractions: 33% 85.7% area purity 1.0 g % E/Z: 30.5/69.5 98.8%
area purity % E/Z: 0.6/99.4 180 2.0 g Pure Z-fractions 45% 92.0%
area purity 0.9 g % E/Z: 32.8/67.2 99.6% area purity % E/Z:
0.8/99.2 062 3.0 g Pure Z-fractions 43% 83.5% area purity 1.3 g %
E/Z: 32.7/67.3 99.8% area purity % E/Z: 0.6/99.4 Mixture: 11% 1.2 g
91.0% area purity % E/Z: 69.6/30.4 068 3.0 g spiked with ~5% Pure Z
fractions: 40% ester 1.2 g ~78% area purity 99.8% area purity %
E/Z: 32.7/67.3 % E/Z: 0.6/99.4 Mixture: 14% 0.6 g 98.8% area purity
% E/Z: 27.9/72.1 Pure E fractions: N/A 1.1 g 70.7% area purity %
E/Z: 98.7/1.3 (19.3% ester) 076 3.8 g Pure Z fractions 37% 83.5%
area purity 1.4 g % E/Z: 32.7/67.3 99.8% area purity % E/Z:
0.8/99.2 Mixture: 17% 1.8 g 95.0% area purity % E/Z: 63.6/36.4
1.4.2 Large Scale Purification
[0140] Various batches of crude
(3Z/E,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyr-
rolidin-3-one-O-methyloxime (0.392 kg, 1.16 mol, 1.0 wt) were
charged to a Biotage 150 L SIM unit as an approximate 50% w/w
solution in toluene and purified using 1% methanol in toluene (150
L) followed by 2% methanol in toluene (50 L), fraction size 5.0 L.
The collected fractions were analysed by TLC.sup.15 and HPLC
analyses, as appropriate. The fractions that were deemed to contain
clean
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime (criteria: Z-isomer.gtoreq.96.00% area,
E-isomer.ltoreq.1.20% area) were combined and concentrated under
vacuum at 40 to 45.degree. C. Absolute ethanol (2.times.2 L) was
added to the residue and the solution concentrated under vacuum at
40 to 45.degree. C. until the foamy solid could be manipulated. The
desired product,
(3Z,5S)-1-[(biphenyl-4-yl-carbonyl)-5-hydroxy-methyl]pyrrolidine-3-one-O--
methyloxime (0.089 Kg, 22.7% w/w, .sup.1H NMR (CDCl.sub.3)
concordant with structure, 99.3% area by HPLC, 98, 4:0.9 Z/E ratio
was obtained as an off-white to light brown solid.
TABLE-US-00007 TABLE 7 Summary of purification of different batches
of (3Z,5S)-5-
(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidin-
3-one-O-methyloxime in substantially pure form. Batch Input Output
Yield % Z form % E form No. (kg) (kg) (% w/w) (% area) (% area) 12
0.392 0.089 22.8 98.65 0.85 116 0.392 0.114 29 98.34 0.89 120 0.441
0.081 18.4 97.90 1.81 122 0.380 0.094 24.3 98.52 1.14 124 0.387
0.096 25.3 98.89 0.73 126 0.390 0.132 33.8 98.40 0.95 128 0.526
0.010 2 98.20 0.83 130 0.453 0.086 19 98.46 1.23 132 0.440 0.082
19.3 98.86 0.85 134 0.39 0.144 36.9 98.73 0.96 138 0.273 0.098 35.9
98.92 0.66 140 0.463 0.059 13.1 98.52 1.13 142 0.462 0.084 18.4
99.37 0.48 144 0.442 0.126 29 99.1 0.68 146 0.409 0.135 33.5 99.21
0.46 148 0.460 0.107 23.8 99.13 0.65 150 0.409 0.071 18 98.92 0.66
152 0.392 0.054 14.3 98.82 0.76 156 0.445 0.039 8.8 98.64 0.87 158
0.392 0.06 15.3 98.73 0.63 162 0.435 0.150 34.5 98.94 0.79 164
0.434 0.192 44.2 99.21 0.58 166 0.415 0.074 17.8 98.79 0.73 174
0.518 0.108 20.8 99.11 0.64 176 0.342 0.072 21 98.88 0.77 178 0.415
0.074 17.8 99.07 0.71 180 0.353 0.174 49.3 99.03 0.82 182 0.270
0.178 65.9 99.10 0.53
[0141] Appropriate batches of
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime (2.713 kg, 1.0 wt) isolated from the
Biotage chromatography were combined and dissolved in absolute
ethanol (5.16 L, 2.0 vol) at 15 to 25.degree. C., clarified by
filtration through glass microfibre paper and an absolute ethanol
wash (0.50 L, 0.2 vol) applied to the filter. The combined
filtrates were concentrated portion wise under vacuum at 40 to
45.degree. C. The resultant was transferred to drying trays and
dried under vacuum at 30.degree. C. for 24 hours. The oven
temperature was then increased incrementally from 30 to 40.degree.
C. over 80 hours. The level of residual solvent was determined by
.sup.1H NMR analysis (CDCl.sub.3) and when found to be <1.0% w/w
the solid was passed through a 500 nm aperture sieve. The solid was
returned to the oven and dried at 40 to 42.degree. C. until the
solvent level was .ltoreq.0.40% w/w to afford
(3Z,5S)-1-[(biphenyl-4-yl-carbonyl)-5-hydroxy-methyl]-pyrrolidine-3-one-O-
-methyloxime (2.633 Kg, 97.1% w/w, 1H NMR (CDCl.sub.3) concordant
with structure, 98.65% area by HPLC.
[0142] The combination procedure is summarized below:
Input: 2.713 kg
Output: 2.633 kg
Yield: 97.1% w/w
Example 2
Capsule Oral Formulation
2.1 Bulk Preparation
[0143] Excipients were weighed directly into a beaker, which was
transferred into a thermostatic water bath until all excipients
were molten at 60.degree. C. Then, always under controlled
temperature, small aliquots of
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime were added until all the drug was
dissolved or dispersed, under magnetic stirring, helix mixer or
homogenizer.
2.2 Liquid Filling Capsules
[0144] The semi-solid bulk was maintained at 60.degree. C. during
the liquid filling of the capsule shells. The filling step was
performed at 60.degree. C. (both dosing pump and feeder) with an
automatic lab-scale capsule-filler machine. The machine was set to
the correct dosage by weighing the filled capsules.
Composition of Active Capsules (Table 8):
TABLE-US-00008 [0145] TABLE 8 Component mg/capsule (3Z,5S) 30.0
300.0 Gelucire 50/13TM 33.4 334.0 LabrasolTM 16.6 166.0 Capsule,
gelatine Size 00 Size 00
Composition of Placebo Capsules (Table 9):
TABLE-US-00009 [0146] TABLE 9 Component mg/capsule Gelucire 50/13TM
63.4 634.0 LabrasolTM 16.6 166.0 Capsule, gelatine Size 00 Size
00
Example 3
Granules Oral Formulation
[0147] Granules 10% were Prepared by Hot Melt Granulation (Table
10):
[0148] Hot melt granulation was conducted in a high shear
granulator MiMiPro (Procept) using different set-ups depending on
the batch size. The general method of manufacture is characterized
by the steps of:
i) heat granulator water jacket to melting of waxy binder; ii)
screen powders into the heated bowls and mix gently; iii) add waxy
binder and mix gently; allow wax to soften; iv) granulate for few
minutes; rest the material for few minutes and granulate again if
necessary and v) cool and screen the granules.
[0149] In particular, the jacketed vessel was used at 65.degree. C.
when Gelucire 50/13 was used as binder. Cover temperature was set
at 5.degree. C. lower than the jacketed vessel's. Duration of
phases depend on the desired particle size distribution and on the
batch size.
TABLE-US-00010 TABLE 10 Component Amount w/w (3Z,5S) 10.0%
Saccharose 10.0% Acdisol 5.0% Gelucire 50/13 15.0% Sodium
Saccharine 0.2% Lactose anhydrous 59.8%
[0150] Hot melt granulation is an alternative technique of
granulation: unlike the traditional use of aqueous or organic
solvents as binders, in this process the agglomeration is obtained
through the addition of a molten binder or a solid binder, which
melts during the process and remains as a constituent of the
formulation.
Composition of Granules 5.8% Prepared by Spray-Drying (Table
11):
[0151] The spray-drying process produces porous/hollow particles
and amorphous forms of the sprayed material. This approach is used
when dissolution rate improvement is required. The spray-drying
process consists of four steps: atomisation of feed solution into a
spray camera, spray-air contact involving flow and mixing, drying
of sprayed droplets at elevated temperatures and separation of
dried product from air.
[0152] The granules 5.8% were prepared by spray-drying of (3Z,5S),
in presence of HP-.beta.-CD (hydroxypropyl-.beta.-cyclodextrin) in
hydroethanolic solution. (3Z,5S) is an amorphous material that
forms clumps of particles in water, which reduces the drug
dissolution rate. Therefore, a hydrophilic excipient, spray-dried
together with (3Z,5S) was used to improve the dissolution rate of
the drug by preventing the aggregation in water. HP-.beta.-CD was
selected as hydrophilic excipients.
[0153] HP-.beta.-CD spray dried product was obtained from the
hydroalcoholic solution both using the Mini AirPro or Buchi
equipment. The feeding solution was prepared by mixing an equal
volume of a HP-.beta.-CD (100 g in 200 ml) aqueous solution and an
(3Z,5S) (24 g in 200 ml) ethanolic solution that was left for 24
hours under agitation at room temperature. The spray-drying
conditions in the fluid bed Mini AirPro were: blower speed 1
m.sup.3/min, nozzle pressure 1 bar, liquid speed 3, inlet air
temperature 70.degree. C.
[0154] Spray-dried materials presented very poor flow properties
precluding their use for sachet filling. To obtain an easy handling
powder, dry granulation and ethanolic wet granulation were the
processes applied to the (3Z,5S)-HP-.beta.-CD spray-dried material.
The dissolution rate of (3Z,5S) after spray-drying with
HP-.beta.-CD was almost instantaneous, in 15 minutes almost all
drug was dissolved.
[0155] The granulation process by ethanolic wet granulation was
performed on the (3Z,5S)-HP.beta.CD spray-dried material. It did
not modify the dissolution rate of the drug when compared to the
(3Z,5S)-HP.beta.CD spray-dried material.
[0156] It produced a material that showed almost instantaneous
dissolution of the drug (Table 11).
TABLE-US-00011 TABLE 11 Component Amount w/w (3Z,5S) 5.8%
Saccharose 10.0% Acdisol 3.0% Sodium saccharine 0.2% HP-.beta.-CD
24.2% Poloxamer 188 2.0% Avicel RC 591 10.0% Avicel PH 112 10.0%
Lactose monohydrate 34.8%
Example 4
Conventional Tablet Oral Formulation
[0157] A solution containing (3Z,5S) dissolved in Labrasol:Ethanol
3:1 v/v was prepared by heating at 45.degree. C. and adding
stepwise the required amount of drug. Zeopharm 600 was dried for 2
hours into a vacuum oven at 50.degree. C. The addition of the
solution on Zeopharm 600 bed was carried out into a 1900 ml bowl at
5 ml/min. The granulator was set as follows: impeller at 900 rpm,
chopper at 3500 rpm, and cover temperature at 80.degree. C. To
remove most of the solvent, the material was left overnight at room
temperature, and 3.5 hours in a vacuum oven at 50.degree. C. As the
granule-adsorbate particle size was slightly high, the material was
sieve-milled first through a 1.5 mm sieve and then through a 1 mm
sieve. The production yield, including the milling step, was
89.68%. The granule-adsorbate (87.5%) was then mixed with AcDiSol
(4%), Compritol 888 ATO (3.5%), GL100 (0.2%) and Zeopharm 600
(4.8%) for 20 minutes at 22 r.p.m in the Turbula mixer. The final
blend for tabletting possessed a good (3Z,5S) content uniformity.
The conventional tablets were produced by compression of the
granules using the eccentric tabletting machine EK-0.
[0158] Conventional tablets of the compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof,
were prepared using carriers of calcium silicate (Table 12).
TABLE-US-00012 TABLE 12 Component Amount w/w (3Z,5S) .sup. 35%
Acdisol 4% Calcium silicate (Zeopharm 600) 32.7% Compritol ATO 888
3.5% Labrasol 24.6% Rx GL 100 0.2%
Example 5
Dispersible Tablet Oral Formulation
[0159] A 850 g batch granulate was produced and then compressed
into tablets. A 5000 ml vessel set-up was used for this
preparation. Calcium silicate was vacuum dried prior to use. The
wet granulation was conducted with
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]-
pyrrolidin-3-one-O-methyloxime and all excipients (with the
exception of the lubricant) in a high shear granulator at room
temperature with only the cover of the granulator heated
(65.degree. C.).
[0160] In the granulation process after a gentle pre-mix phase, an
alternation of liquid addition and mixing phases of few minutes
duration was set-up.
[0161] A total amount of 80 ml of ethanol was necessary to obtain
suitable granules. A final milling and/or sieving step was
necessary to obtain a better granule size distribution. The
resulting granules were blended with the lubricant before
compression.
[0162] A single punch eccentric tabletting machine was used.
[0163] The compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, and/or an active metabolite thereof, is
in the form of dispersible tablets containing 50 or 200 mg of
active drug substance (Table 13).
TABLE-US-00013 TABLE 13 Amount Component mg mg % (w/w) Function
(3Z,5S) 50.0 200.00 20.0 Active drug substance Calcium silicate
12.5 50.0 5.0 Carrier PVP 30K 2.5 10.0 1.0 Binder Poloxamer 188 5.0
20.0 2.0 Wetting agent Sodium 12.5 50.0 5.0 Disintegrant
croscarmellose Microcrystalline 37.5 150.0 15.0 Diluent cellulose
112 Lactose monohydrate 119.5 478.0 47.8 Diluent Sodium saccharine
0.5 2.0 0.2 Sweetener Glycerol dibehenate 10.0 40.0 4.0 Lubricant
Total 250.0 1000.0 --
Example 6
Dimensions of the Tablets
[0164] For example, the shape and dimensions of the tablets are the
following:
TABLE-US-00014 TABLE 14 Tablet or dispersible tablet Shape and
dimensions 50 mg Capsule shape; 14 .times. 6 mm or 13 .times. 6 mm
200 mg Capsule shape; 22 .times. 9 mm or 19 .times. 9 mm
Example 7
Pharmacokinetics Studies in the Dog
[0165] A pharmacokinetic study was conducted to measure the plasma
concentration of the compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime following oral administration of said
compound to female Beagle dogs.
[0166] Following the protocol (Table 15), 5 dogs were administered
with an oral formulation composed of liquid filled capsules
("Reference capsule"), 5 dogs were administered with an oral
formulation composed of granules 10% (formulation 1), 5 dogs were
administered with an oral formulation composed of granules 5.8%
(formulation 2), 5 dogs were administrated with a dispersible
tablet (formulation 3), 5 dogs were administered with a
conventional tablet (formulation 4). Also 5 dogs were administered
by the IV route of administration ("Reference IV") a solution of
the compound of formula
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime at 15 mg/kg. Blood sampling was performed
at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 24, 48 and 72 h.
TABLE-US-00015 TABLE 15 Group Reference Reference IV capsule
Formulation 1 Formulation 2 Formulation 3 Formulation 4 Formulation
Solution Liquid Granules Granules Dispersible Conventional of
(3Z,5S) filled 10% 5.8% tablet tablet capsules 200 mg 200 mg Dose
mg/kg 15 mg/kg 300 mg/ 20 20 23.4 (3.4) 23.3 (3.2) dog (200 mg/dog)
(200 mg/dog) Volume of 1 capsule 5 ml/kg 5 ml/kg 50 ml/dog 50
ml/dog administration size 00
7.1 Plasma Concentration Profiles of Solid Oral Formulations in the
Dog
[0167] FIG. 1A shows the plasma concentration vs. time profile of
the different formulations over the time period from 0 to 72 h.
FIG. 1B shows an enlargement of FIG. 1A for the time period from 0
to 12 h. The curve corresponding to formulation 3 (dispersible
tablet) shows that the maximum concentration of the active
substance is detected rapidly at about 0.5-1 hour following its
administration. In comparison, the maximum concentration of the
active substance is detected at about 2-4 hours following
administration of formulation 4 (conventional tablet).
[0168] Individual plasma profile for each dog are presented on FIG.
2 (formulation 3), and FIG. 3 (formulation 4) to show the
inter-animal variability.
7.2 Pharmacokinetic Parameters of Solid Oral Formulations in the
Dog
[0169] In pharmacokinetics, the bioavailability is measured by
calculating the area under the curve (AUC) of the product
concentration vs. time profile. The absolute bioavailability
compares the bioavailability of the product in systemic circulation
following oral administration with the bioavailability of the
product following intravenous administration.
[0170] "D" as used herein refers to the dose that is the amount of
drug administered.
[0171] "Cmax" as used herein refers to the peak plasma
concentration of a drug after administration wherein the
concentration is the amount of drug in a given volume of
plasma.
[0172] "Tmax" as used herein refers to the time to reach Cmax.
[0173] "T.sub.1/2" as used herein refers to the elimination
half-life as the time required for the concentration of the drug to
reach half of its original value.
[0174] "AUC" as used herein refers to the area under the curve that
is the integral of the concentration-time curve (after a single
dose or in steady state).
[0175] "F %" as used herein refers to the bioavailability that is
the systemically available fraction of a drug. The index of
bioavailability after oral administration is calculated by the
following equation using the AUC found after i.v.
administration:
F
%=(AUC.sub.OS/AUC.sub.IV).times.(Dose.sub.IV/Dose.sub.OS).times.100
TABLE-US-00016 TABLE 16 Group Reference Reference IV Capsule 1 2 3
4 Formulation IV Capsule Granules Granules Dispersible Conventional
10% 5.8% tablet tablet Route of IV OS OS OS OS OS administration
Dose 15 34.4 (.+-.4.0) 20 20 25.7 (.+-.2.3) 23.3 (.+-.3.2) (mg/kg)
C (0.25 h) -- 13 (.+-.15) 3590 (.+-.1450) 4523 (.+-.2757) 5108
(.+-.1955) 88 (.+-.54) (ng/ml) Cmax 17071 (.+-.6162) 15243
(.+-.3194) 7488 (.+-.2236) 8722 (.+-.2036) 13966 (.+-.3217) 9245
(.+-.2869) (ng/ml) Tmax (h) -- 4 (4-4) 1 (0.5-2) 0.5 (0.5-0.5) 1
(0.5-1) 2 (2-4) AUC 38684 (.+-.2310) 80139 (.+-.18793) 32775
(.+-.9120) 29893 (.+-.7483) 58952 (.+-.5770) 53563 (.+-.7570) (h *
ng/ml) T.sub.1/2 (h) 9.5 (.+-.4.4) 7.1 (.+-.1.2) 5.9 (.+-.3.9) 4.7
(.+-.0.9) 6.6 (.+-.0.6) 5.0 (.+-.1.7) F (%) -- 90 (.+-.15) 64
(.+-.18) 58 (.+-.15) 89 (.+-.9) 89 (.+-.13) Numbers in brackets
represent the standard deviation.
[0176] Formulations 1 and 2 (granules) showed equivalent responses
and were characterized by a favorable fast compound absorption
(Table 16). Their absolute bioavailability was good (about 60%),
even though lower than the other formulations tested, but
associated with a moderate variability between animals. Dispersible
tablets Formulation 3 showed a rate of absorption comparable to
granules followed by a decay comparable to the Reference Capsule
formulation. A very high compound exposure highlighted by the
absolute bioavailability (higher than after administration of
granules and comparable to the liquid filled capsule reference
formulation) was observed. Conventional tablets Formulation 4 gave
a delayed absorption compared to Formulation 3 with a roughly
similar bioavailability.
[0177] Formulation 3 appears overall the most suitable for the
indication of preterm labor. By comparison with the Reference
Capsule formulation (300 mg/dog, liquid filled capsules), the
results highlight a faster compound absorption (about 37% of the
amount found at Cmax already found at the first sampling time, 0.25
h), Cmax reached at earlier time (median Tmax=1 h), terminal
elimination rate comparable (T.sub.1/2 of about 7 h) and overall
more uniform responses between animals. Formulation 3 exposure was
equivalent to the Reference Capsule formulation and also absolute
bioavailability was equivalent to that of the Reference Capsule
formulation (89% vs. 90%).
7.3 Individual Plasma Concentration Profiles of Formulation 3 in
the Dog
[0178] Route of administration: Oral Administered dose of (3Z,5S):
200 mg/dog Formulation 3: 200 mg dispersible tablet Dose regimen:
Single
TABLE-US-00017 TABLE 17 Sampling time Animal No. (3Z,5S) plasma
concentrations in ng/mL (h) 6F 7F 8F 9F 10F 0 (pre-dose) 1.5 2.3 *
3.4 * 0.25 8122 3965 2937 4994 5522 0.5 14107 9206 6913 16555 9070
1 18285 11934 11575 9137 11479 2 8175 7289 8341 7476 7942 4 5151
5188 6589 5660 4924 6 2508 2807 3434 2849 3027 8 1343 1626 2456
1819 3389 24 70 166 422 355 36 48 5 8.7 12 22 12 72 3.7 2 2.1 2.3
3.4 * = Below the lower limit of quantification (1 ng/mL)
[0179] Remarkably, at 0.5 hour time point following administration
of the dispersible tablet, the concentration in blood of the
compound of formula (3Z,5S) is comprised between 59% to 100% of
Cmax indicating that said formulation is suitable for providing a
rapid onset of action (Table 17).
7.4 Individual Pharmacokinetic Parameters of Formulation 3 in the
Dog
TABLE-US-00018 [0180] TABLE 18 Animal No. PK parameter 6F 7F 8F 9F
10F Cmax (ng/ml) 18285 11934 11575 16555 11479 Tmax (h) 1 1 1 0.5 1
C (0.25 h) (ng/ml) 8122 3965 2937 4994 5522 AUC (h*ng/ml) 56242
52929 67865 61111 56615 T.sub.1/2 (h) 6 5.8 5.7 6.6 7.2 F (%) 85 80
102 92 85
[0181] The maximum concentration in blood of the compound of
formula (3Z,5S) is reached at a time Tmax between 0.5 to 1 hour
following administration of Formulation 3 (dispersible tablet). In
addition, Formulation 3 is characterized by a bioavailability of
the compound of formula (3Z,5S) comprised between 80-100% (Table
18).
7.5 Individual Plasma Concentration Profiles of Formulation 4 in
the Dog
TABLE-US-00019 [0182] TABLE 19 Sampling time Animal No. (3Z,5S)
plasma concentrations in ng/mL (h) 1F 2F 3F 4F 5F 0 (pre-dose) * *
* * * 0.25 152 17 53 116 104 0.5 2217 2379 1680 2926 1945 1 3907
3031 3241 4339 4482 2 7759 5761 6671 9227 13492 4 5171 5646 9983
7085 7848 6 2806 4822 4307 3856 3185 8 1527 4195 3051 2713 2211 24
87 78 53 92 172 48 1.8 3.1 1.9 4.5 4.5 72 * * * 1.2 1.6 * = Below
the lower limit of quantification (1 ng/mL)
[0183] The maximum concentration in blood of the compound of
formula (3Z,5S) is reached at a time Tmax between 2 to 4 hours
following administration of Formulation 4 (conventional
tablet).
[0184] At 0.5 hour time point following administration of
Formulation 4 (conventional tablet), the concentration in blood of
the compound of formula (3Z,5S) is comprised between 14% to 41% of
Cmax (Table 19) a value markedly lower than for formulation 3 which
is characterized by a higher concentration of the compound of
formula (3Z,5S) comprised between 59% to 100% of Cmax (Table
17).
7.6 Individual Pharmacokinetic Parameters of Formulation 2 in the
Dog
TABLE-US-00020 [0185] TABLE 20 Animal No. PK parameter 11F 12F 13F
14F 15F Cmax (ng/ml) 7029 9050 9897 6347 11287 Tmax (h) 0.5 0.5 0.5
0.5 0.5 C (0.25 h) (ng/ml) 3521 1275 4512 4445 8865 AUC (h ng/ml)
21062 34881 39126 23931 30466 T.sub.1/2 (h) 3.3 5.3 4.5 5.1 5.4 F
(%) 41 68 76 46 59
[0186] Formulation 2 (granule 5.8%) is characterized by a
bioavailability of the compound of formula (3Z,5S) comprised
between 41-76% (Table 20) markedly lower than for formulation 3
which is characterized by a very high bioavailability comprised
between 80-100% (Table 18).
[0187] Thus, the dispersible tablet formulation 3 displays
characteristics that are suitable for providing a fast onset of
action and high bioavailability for the treatment of preterm labor.
In contrast conventional tablet (formulation 4) or granules
(formulation 2) do not meet the pharmacokinetic requirements for
treating preterm labor.
Example 8
Pharmacokinetics Studies in Human
Study Protocol
[0188] Twelve healthy Caucasian women aged 54-62 years (mean 58.3
years), with a weight of 51 to 67 kg (mean 60.6 kg.+-.5.1) and a
body mass index ranging between 19.4-25.5 kg/m2 (mean 23.12
kg/m2.+-.2.05) were enrolled. They were administered, on three
separate treatment periods of one week, either two consecutive
(3Z,5S) doses of 600 mg/day (administered to subjects using 3
dispersible tablets of 200 mg in 150 ml of water) or two
intramuscular injections of 12 mg/day betamethasone or both drugs
in combination.
[0189] Betamethasone (Celestene.RTM., Schering-Plough, France) was
administered by intramuscular injection of 12 mg/3 ml into the
gluteus muscle, which is a recommended dose for antenatal
betamethasone in preterm labor for the prevention of respiratory
distress syndrome in neonates.
[0190] One subject (Subject S6) was withdrawn from the study after
the first treatment period, due to high pre-dose blood pressure in
the second treatment period. Therefore, pharmacokinetic parameters
of the treatment with (3Z,5S) dispersible tablets were calculated
for 12 subjects, whereas pharmacokinetic parameters of the
combination treatment were assessed for 11 participants.
[0191] During each treatment period of one week, blood samples were
collected for the analysis of (3Z,5S) and betamethasone at time
points 0 (pre-dose) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8,
10, 12, 16, 20 and 24 hours after first dose on day 1. The plasma
was prepared and stored below -20.degree. C. All samples were
analysed using validated LC-MS/MS methods. For the analysis of
(3Z,5S), the lower limit of quantification was 1.0 ng/ml. For
betamethasone analyses, the lower limit of quantification was 0.5
ng/ml.
[0192] Pharmacokinetic parameters were estimated by
non-compartmental methods using the Phoenix.RTM. WinNonLin.RTM.
version 6.3 (Pharsight). The following pharmacokinetic parameters
were calculated for (3Z,5 S) during each treatment period: measured
maximum concentration (Cmax), time to Cmax (Tmax), and area under
the plasma concentration-time curve (AUC).
8.1 Individual Plasma Concentration Profiles of (3Z,5S) Dispersible
Tablet (Formulation 3) in Human
[0193] Tables 21 to 23 show plasma concentration profiles of
(3Z,5S) and pharmacokinetic parameters concerning (3Z,5S) which was
administered to subjects using 3 dispersible tablets of 200 mg in
150 ml of water.
TABLE-US-00021 TABLE 21 Subject S Plasma concentration of (3Z,5S)
in ng/ml Time S1 S2 S3 S4 S5 S6 S7 S8 S9 S10 S11 S12 0.25 1190 270
335 867 574 234 481 407 1730 1610 409 1990 0.5 3020 1170 1310 3120
2020 860 1550 1510 2630 2640 2510 2690 0.75 3010 1450 1810 2760
2220 1400 2090 1440 2700 2120 2350 3070 1 3100 2410 1810 3160 1830
1560 1440 1450 2670 2180 1940 2900 1.5 3280 3380 1650 4070 1600
1770 1790 1370 2570 3190 2990 3600 2 3170 3150 1520 3820 1550 1940
2440 2100 3050 2980 4100 3630 3 3060 3360 1540 3070 1560 2060 2280
2060 2660 2980 3410 3570 4 2870 2600 2300 2940 1990 3060 2290 2160
2730 2770 3300 3460 6 2400 2200 1910 1910 1580 2000 1800 1670 2280
1780 1960 1980 8 1710 1870 1800 1940 1310 1670 1560 1290 1690 1550
1620 1760 10 1510 1700 1620 1560 1130 1490 1370 973 1570 1430 1490
1490 12 1420 1870 1720 1630 949 1380 1250 794 1510 1400 1650 1410
16 1000 1040 1030 1170 640 981 762 586 928 844 1020 866 20 804 868
718 978 554 812 654 444 698 818 827 699 24 765 680 567 843 385 792
501 327 555 560 759 612
TABLE-US-00022 TABLE 22 Subject S % of Cmax Time S1 S2 S3 S4 S5 S6
S7 S8 S9 S10 S11 S12 0.25 36% 8% 15% 21% 26% 8% 20% 19% 57% 50% 10%
55% 0.5 92% 35% 57% 77% 91% 28% 64% 70% 86% 83% 61% 74% 0.75 92%
43% 79% 68% 100% 46% 86% 67% 89% 66% 57% 85% 1 95% 71% 79% 78% 82%
51% 59% 67% 88% 68% 47% 80% 1.5 100% 100% 72% 100% 72% 58% 73% 63%
84% 100% 73% 99% 2 97% 93% 66% 94% 70% 63% 100% 97% 100% 93% 100%
100% 3 93% 99% 67% 75% 70% 67% 93% 95% 87% 93% 83% 98% 4 88% 77%
100% 72% 90% 100% 94% 100% 90% 87% 80% 95% 6 73% 65% 83% 47% 71%
65% 74% 77% 75% 56% 48% 55% 8 52% 55% 78% 48% 59% 55% 64% 60% 55%
49% 40% 48% 10 46% 50% 70% 38% 51% 49% 56% 45% 51% 45% 36% 41% 12
43% 55% 75% 40% 43% 45% 51% 37% 50% 44% 40% 39% 16 30% 31% 45% 29%
29% 32% 31% 27% 30% 26% 25% 24% 20 25% 26% 31% 24% 25% 27% 27% 21%
23% 26% 20% 19% 24 23% 20% 25% 21% 17% 26% 21% 15% 18% 18% 19%
17%
[0194] Following administration of the dispersible tablet of the
invention, the maximum concentration Cmax in blood of the compound
of formula (3Z,5S) is reached at a time Tmax between 0.5 to 4
hours. In particular, Tmax is in the range of 0.5 to 2 hours for 9
subjects, and in the range of 0.5 to 1.5 hours for 5 subjects.
[0195] Of note, at 0.5 hour time point, the concentration in blood
of the compound of formula (3Z,5S) is comprised between 55% to 95%
of Cmax for 10 subjects, preferentially between 57% to 92% of Cmax,
indicating that the solid oral formulation is rapidly absorbed and
suitable for providing a rapid onset of pharmacological action. For
subjects S2 and S6, the plasma concentration of (3Z,5S) was below
55% at 0.5 h, respectively 35% and 28% of Cmax. However, it was
respectively 71% and 51% of Cmax at 1 h following administration of
the dispersible tablet which concentration is suitable for the
management of preterm labor.
8.2 Individual Pharmacokinetic Parameters of (3Z,5S) Dispersible
Tablet (Formulation 3) in Human
TABLE-US-00023 [0196] TABLE 23 Subject S S1 S2 S3 S4 S5 S6 Cmax
ng/ml 3280 3380 2300 4070 2220 3060 Tmax hour 1.5 1.5 4 1.5 0.75 4
AUC 38557 39042 32421 41209 24814 33388 ng h/ml Subject S S7 S8 S9
S10 S11 S12 Cmax ng/ml 2440 2160 3050 3190 4100 3630 Tmax hour 2 4
2 1.5 2 2 AUC 29867 24085 36317 34853 38944 38467 ng h/ml
8.3 Plasma Concentration Profiles in Human for a Combination of
(3Z,5S) and Betamethasone
[0197] Tables 24 to 26 show plasma concentration profiles of
(3Z,5S) and pharmacokinetic parameters concerning (3Z,5S)
administered in combination with Betamethasone.
TABLE-US-00024 TABLE 24 Plasma concentration of (3Z,5S) Subject S
Plasma concentration of (3Z,5S) in ng/ml Time S1 S2 S3 S4 S5 S7 S8
S9 S10 S11 S12 0.25 41.8 597 322 486 264 536 359 396 1150 934 934
0.5 210 3240 978 1890 1250 2510 1100 2420 2590 2040 1980 0.75 407
5290 1130 2210 1780 2910 1610 2570 2490 2060 3010 1 593 5320 1100
2290 1580 2600 1730 2250 2350 1930 3020 1.5 1050 4940 1350 3550
2010 2620 1860 2300 3130 1920 3430 2 1050 4750 2180 4230 2080 3290
2400 2270 3520 4170 3550 3 1480 4480 3500 3620 2280 3540 2520 2340
3150 4440 3780 4 2040 4130 3500 3880 2350 3430 2540 2310 3340 4020
3550 6 1440 2510 1710 2290 2050 2710 1600 2910 2350 2690 2670 8
1470 1950 1530 2180 1680 2180 1250 2280 1820 2300 1970 10 1570 2090
1250 2120 1270 1960 981 2120 1620 1840 1750 12 1300 1870 1430 1930
1040 1750 1000 1970 1430 1630 2130 16 521 1140 1000 1330 693 935
550 959 869 951 1010 20 512 1100 943 1240 481 831 471 825 746 786
877 24 418 828 712 1020 353 569 383 605 533 650 657
TABLE-US-00025 TABLE 25 % of Cmax Subject S % of Cmax Time S1 S2 S3
S4 S5 S7 S8 S9 S10 S11 S12 0.25 2% 11% 9% 11% 11% 15% 14% 14% 33%
21% 25% 0.5 10% 61% 28% 45% 53% 71% 43% 83% 74% 46% 52% 0.75 20%
99% 32% 52% 76% 82% 63% 88% 71% 46% 80% 1 29% 100% 31% 54% 67% 73%
68% 77% 67% 43% 80% 1.5 51% 93% 39% 84% 86% 74% 73% 79% 89% 43% 91%
2 51% 89% 62% 100% 89% 93% 94% 78% 100% 94% 94% 3 73% 84% 100% 86%
97% 100% 99% 80% 89% 100% 100% 4 100% 78% 100% 92% 100% 97% 100%
79% 95% 91% 94% 6 71% 47% 49% 54% 87% 77% 63% 100% 67% 61% 71% 8
72% 37% 44% 52% 71% 62% 49% 78% 52% 52% 52% 10 77% 39% 36% 50% 54%
55% 39% 73% 46% 41% 46% 12 64% 35% 41% 46% 44% 49% 39% 68% 41% 37%
56% 16 26% 21% 29% 31% 29% 26% 22% 33% 25% 21% 27% 20 25% 21% 27%
29% 20% 23% 19% 28% 21% 18% 23% 24 20% 16% 20% 24% 15% 16% 15% 21%
15% 15% 17%
[0198] Following administration of the combination (3Z,5S)
dispersible tablet and betamethasone, the maximum concentration
Cmax in blood of the compound of formula (3Z,5S) is reached at a
time Tmax between 1 to 6 hours. In particular, Tmax is in the range
of 2 to 4 hours for 9 subjects, and in the range of 2 to 3 hours
for 6 subjects.
[0199] At 0.5 hour time point, the concentration in blood of the
compound of formula (3Z,5S) is comprised between 43% to 83% of Cmax
for 10 subjects indicating that the solid oral formulation
administered in combination with betamethasone is rapidly absorbed
and suitable for providing a rapid onset of pharmacological action.
For subjects S1 and S3, the plasma concentration of (3Z,5S) was
below 43% at 0.5 h, respectively 10% and 28% of Cmax. However, it
was respectively 51% and 62% of Cmax at 2 h following
administration of the dispersible tablet.
8.4 Pharmacokinetic Parameters in Human for a Combination of
(3Z,5S) Formulation 3 and Betamethasone
TABLE-US-00026 [0200] TABLE 26 Subject S S1 S2 S3 S4 S5 S7 S8 S9
S10 S11 S12 Cmax 2040 5320 3500 4230 2350 3540 2540 2910 3520 4440
3780 ng/ml Tmax 4 1 3 2 4.03 3 4 6 2 3 3 hour AUC 24060 50306 34518
47627 28322 42044 25974 39688 38208 43314 44082 ng h/ml
Example 9
The Manufacturing Process of Dispersible Tablets
[0201] The manufacturing process of the dispersible tablets of the
present invention comprises the following steps:
(i) Preparing a mixture consisting of 20% of
(3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrro-
lidin-3-one-O-methyloxime, 5% of calcium silicate, 1% of PVP 30K,
2% of Poloxamer 188, 5% of sodium croscarmellose, 15% of
Microcrystalline cellulose 112, 47.8% of lactose monohydrate, 0.2%
sodium saccharine, in weight based on the total weight of the
tablet; (ii) Wet granulating in presence of ethanol and vacuum
drying; (iii) Sieving the granules; (iv) Blending the granules with
4% of glycerol dibehenate in weight based on the total weight of
the tablet;
(v) Tabletting.
[0202] The wet granulation is preferably conducted in a high shear
granulator at room temperature with a minimal amount of ethanol
equivalent to at least 7.4% (in weight based on the total weight of
the tablet). The vacuum drying is performed at room temperature
[0203] A sieving step is applied on the resulting granules. Sieved
glycerol dibehenate is blended with the granules. The final blend
is compressed with an eccentric or rotary tablet press and adapted
punches for the targeted dispersible tablet strength.
Example 10
Stability Study of Dispersible Tablet (Formulation 3)
[0204] The determination of the (3Z,5S) content after dissolution
of dispersible tablets is performed by HPLC using the following
parameters:
Apparatus: USPII paddle apparatus Dissolution medium: 0.5% Sodium
Lauryl Sulfate in water Dissolution medium volume: 900 ml
Dissolution medium temperature: 37.degree. C.+/-0.5.degree. C.
Rotation speed: 50 rpm Sampling time: 15, 30, 45, 60 and 120 min
Sampling volume: 3 ml Separative technique: PALL Acrodisc PSF
GxF/Glass 1.0 .mu.m
[0205] The paddle assembly is arranged so that the bottom of the
paddle was 2.5 cm.+-.0.2 cm from the inside bottom of the flask.
The appropriate volume of dissolution medium is poured into each
one of the six dissolution vessels. The medium is equilibrated at
37.0 C.+-.0.5 C. A (3Z,5S) dispersible tablet is inserted into each
vessel. The paddles rotation was controlled at 50 rpm. At the
designated time-points, 3 ml of medium is taken from a zone midway
between the surface of the dissolution medium and the top of the
blade of the paddle. Then, the sample is filtered through a PALL
Acrodisc PSF GxF/Glass 1.0 .mu.m directly into an HPLC vial for
analysis.
[0206] Stability data are available at 1, 2 and 6 months storage
time for (3Z,5S) dispersible tablets packaged in Alu/Alu blister
packs. Parameters such as tablet appearance, (3Z,5S) content in %
compared to the initial content value, disintegration time and
dissolution were assessed (Tables 28 and 29).
[0207] The initial concentration value of (3Z,5S) measured by HPLC
with a dispersible tablet is 90.0-110.0%.
TABLE-US-00027 TABLE 28 Dispersible tablet of 50 mg (3Z,5S) Storage
Water Content Time Tablet content (% initial Disintegr. % Dissolved
Storage condition (months) appearance (% w/w) value) Time (sec)
after 60 min Initial 0 White capsule 4.5 102.9 42 101 shaped
5.degree. C. 1 White capsule 4.7 102.4 19 100 shaped 2 White
capsule 4.6 102.2 17 100 shaped 6 White capsule 4.8 103.3 26 99
shaped 25.degree. C./60% RH 1 White capsule 4.6 102.2 16 97 shaped
2 White capsule 4.6 103.8 22 97 shaped 6 Off-white 4.7 105.7 28 99
capsule shaped 40.degree. C./75% RH 1 White capsule np np np np
shaped 2 Off-white 4.5 99.9 50 95 capsule shaped 6 Yellowish 4.6
102.1 113 94 capsule shaped* np = not performed
TABLE-US-00028 TABLE 29 Dispersible tablet of 200 mg (3Z,5S)
Storage Water Content Time Tablet content (% initial Disintegr. %
Dissolved Storage condition (months) appearance (% w/w) value) Time
(sec) after 60 min Initial 0 White capsule 4.5 98.1 102 93 shaped
5.degree. C. 1 White capsule 4.0 97.7 26 99 shaped 2 White capsule
4.3 97.7 26 96 shaped 6 White capsule 4.1 99.7 28 99 shaped
25.degree. C./60% RH 1 White capsule 4.0 98.0 26 96 shaped 2 White
capsule 4.2 98.9 28 100 shaped 6 Off-white 4.1 99.5 40 98 capsule
shaped 40.degree. C./75% RH 1 White capsule np np np np shaped 2
Off-white 4.2 96.6 107 98 capsule shaped 6 Yellowish 4.1 98.3 170
96 capsule shaped* np = not performed
[0208] A rapid disintegration of the tablet is observed following
dissolution in the range of 20 to 40 sec at 25.degree. C./60%
RH.
[0209] The disintegration property of the dispersible tablet is
likely due to its disintegrant component, for example, Sodium
croscarmellose that promotes the breakup or disintegration of the
tablet when placed in an aqueous environment and supports a fast
dissolution profile. In addition, the wetting agent, for example,
Poloxamer 188, facilitates the water uptake during the
disintegration and assists the drug dissolution. Furthermore, the
carrier agent selected with a large surface area, for example
Calcium silicate, was also identified as a potential benefit for
the disintegration of the tablet.
TABLE-US-00029 TABLE 30 Dissolution profile of 200 mg dispersible
tablet and content of (3Z,5S) at 15, 30, 45, 60, and 120 min. 15
min 30 min 45 min 60 min 120 min Storage Time (3Z,5S) (3Z,5S)
(3Z,5S) (3Z,5S) (3Z,5S) Condition (Months) Content % Content %
Content % Content % Content % Initial 0 89 94 96 97 99 5.degree.
C./AmbH 1 91 95 96 97 99 3 92 95 97 97 99 6 95 98 98 100 101
25.degree. C./60% RH 1 93 95 96 97 98 3 94 97 98 98 100 6 97 99 100
100 102 40.degree. C./75% RH 1 96 98 99 99 100 3 95 97 97 98 99 6
95 97 98 98 99
[0210] A rapid dissolution profile of the tablet is observed for
the different storage conditions. In particular, at 25.degree.
C./60% RH, the content of (3Z,5S) measured at 15 min is between 90
to 100% of the initial value.
* * * * *