U.S. patent application number 10/267690 was filed with the patent office on 2003-07-10 for stabilized aqueous suspensions for parenteral use.
This patent application is currently assigned to PHARMACIA & UP JOHN S.p.A.. Invention is credited to Colombo, Giuseppe, Fox, Lloyd E., Martini, Alessandro.
Application Number | 20030130245 10/267690 |
Document ID | / |
Family ID | 24283530 |
Filed Date | 2003-07-10 |
United States Patent
Application |
20030130245 |
Kind Code |
A1 |
Colombo, Giuseppe ; et
al. |
July 10, 2003 |
Stabilized aqueous suspensions for parenteral use
Abstract
A pharmaceutical aqueous suspension formulation for parenteral
administration having substantially stabilized pH, comprising a
biologically active compound and a pH controlling effective
concentration of L-Methionine. Preferably, the biologically active
compound is a steroidal compound, for instance exemestane,
medroxyprogesterone acetate and estradiol cypionate or a
combination of medroxyprogesterone acetate and estradiol
cypionate.
Inventors: |
Colombo, Giuseppe; (Milan,
IT) ; Martini, Alessandro; (Milan, IT) ; Fox,
Lloyd E.; (Richland, MI) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
PHARMACIA & UP JOHN
S.p.A.
Via Robert Koch, 1.2
Milan
MI
20152
PHARMACIA & UP JOHN COMPANY
301 Henrietta Street
Kalamazoo
49001
|
Family ID: |
24283530 |
Appl. No.: |
10/267690 |
Filed: |
October 10, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10267690 |
Oct 10, 2002 |
|
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09571395 |
May 15, 2000 |
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6495534 |
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Current U.S.
Class: |
514/171 ;
514/178; 514/562 |
Current CPC
Class: |
A61P 35/04 20180101;
A61P 5/34 20180101; A61K 9/0019 20130101; A61K 9/10 20130101; A61P
43/00 20180101; A61P 15/18 20180101; A61P 5/32 20180101; A61K 47/20
20130101 |
Class at
Publication: |
514/171 ;
514/178; 514/562 |
International
Class: |
A61K 031/56; A61K
031/57; A61K 031/198 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 25, 2001 |
WO |
PCT/EP01/04643 |
Claims
1. A pharmaceutical aqueous suspension formulation for parenteral
administration having substantially stabilized pH comprising a
biologically active compound and a pH controlling effective
concentration of L-Methionine.
2. A pharmaceutical formulation according to claim 1, wherein the
pH controlling effective concentration of L-Methionine is from
about 0.005% w/v or w/w to about 5% w/v or w/w.
3. A pharmaceutical aqueous suspension formulation for parenteral
administration having substantially stabilized pH, comprising a
biologically active compound, a buffering agent and L-Methionine in
concentrations effective to produce a pH controlling superadditive
effect.
4. A pharmaceutical composition according to claim 3, wherein the
buffering agent is a phosphoric acid salt in a concentration lower
than 0.4% w/v or w/w.
5. A pharmaceutical composition according to claim 4, wherein the
concentration of the phosphoric acid salts is lower than 0.2% w/v
or w/w.
6. A pharmaceutical composition according to any preceding claims,
wherein the pH range of the formulation is from about pH 3.0 to
about pH 8.0.
7. A pharmaceutical composition according to claim 6, wherein the
biologically actiye compound is a steroidal compound.
8. A pharmaceutical composition according to claim 7, wherein the
biologically active steroidal compound is selected from exemestane,
medroxyprogesterone acetate and estradiol cypionate or a mixture of
medroxyprogesterone acetate and estradiol cypionate.
9. Use of L-Methionine, in the preparation of a pharmaceutical
aqueous suspension formulation having substantially stabilized pH,
for parenteral administration of a biologically active compound,
characterized in that a pH controlling effective concentration of
L-Methionine is added thereto.
10. Use of L-Methionine and a buffering agent in concentrations
effective to produce a pH controllling superadditive effect, in the
preparation of a pharmaceutically aqueous suspension formulation
having substantially stabilized pH, for parenteral administration
of a biologically active compound.
Description
SUMMARY OF THE INVENTION
[0001] The present invention is in the field of galenic
preparations. It concerns in particular a pharmaceutical aqueous
suspension of a biologically active compound, e.g. a steroidal
compound, having stabilized pH, particularly suitable for
parenteral administration. The inventors of the present invention
have found that the pH of a pharmaceutical aqueous suspension of a
biologically active compound can be controlled by adding a pH
controlling effective concentration of L-Methionine thereto.
[0002] Moreover, when a pH controlling effective concentration of
L-Methionine is used, it strengthens the buffering capacity of low
concentrations of conventional buffering agents with a
super-additive (synergistic) effect. In this way the use of
conventional buffering agents can be eliminated or limited, thus
improving the re-suspendability and controlled flocculation of the
pharmaceutical preparation.
BACKGROUND OF THE INVENTION
[0003] A pharmaceutical suspension is a coarse dispersion in which
insoluble solid particles are dispersed in a liquid medium.
[0004] Suspensions contribute to pharmacy and medicine by supplying
insoluble and often distasteful substances in a form that is
pleasant to the taste, by providing a suitable form for the
application of dermatological materials to the skin and sometimes
to the mucous membranes, and for the parenteral administration of
insoluble drugs. Therefore pharmaceutical suspensions may be
classified into three groups: orally administered mixtures,
externally applied lotions and injectable preparations.
[0005] An acceptable suspension possesses certain desirable
qualities, including the followings:
[0006] i) the suspended material should not settle rapidly;
[0007] ii) the particles that do settle to the bottom of the
container must not form a hard cake but should be readily
re-dispersed into a uniform mixture when the container is
shaken;
[0008] iii) the suspension must not be too viscous to pour freely
from the orifice of the bottle or to flow through a syringe
needle.
[0009] It is important that the characteristics of the dispersed
phase are chosen with care so to as to produce a suspension having
optimum physical, chemical and pharmacological properties. Particle
size distribution, specific surface area, inhibition of crystal
growth, and changes in the polymorphic form are of special
significance and the formulator must ensure that these and other
properties do not change sufficiently during storage to adversely
affect the performance of the suspensions with aging.
[0010] In the field of injectable preparations, aqueous suspensions
for parenteral administration have already been described in
scientific and patent literature and have been known for a long
time. Parenteral suspensions are often prepared with the so called
"controlled flocculation" approach, i.e. by the application of
known principles of formulation chemistry to produce vehicles which
permits drug flocs to form and settle, but which they are easily
re-suspended with slight agitation and remain uniformly dispersed
or suspended during the period required for therapeutic
administration. Specifically, it is well known that one of the main
difficulty in formulating parenteral aqueous suspensions of
steroids is the overcome of their hydrophobicity, that
significantly reduce the wettability, suspendability or
re-suspendibility of the active in aqueous media. Both wetting and
suspending agents are needed in order to gain the proper
formulation of the active compound such as the concomitant use of
preservatives. This is described, for example, by Nash and
coworkers in the U.S. Pat. No. 3,457,348 where non-ionic
surfactants (such as polysorbates) and suspending agents (like
polyethylene glycols) are the basic excipients to gain the proper
stability of the formulation.
[0011] Sometimes, even in the presence of the proper suspending and
wetting agents, the suspension is not stable for a long time, but
it is necessary to form it just before the administration (while it
is stored as lyophilized formulation). This is described, for
example, in the case described by Geller and coworkers in the U.S.
Pat. No. 5,002,940 and greatly impacts on the cost of the
manufacturing process, since an additional freeze-drying process is
mandatory.
[0012] Even if an improved physical stability of steroidal drug
suspensions in water can be gained, as above mentioned, by the use
of polyethylene glycols and non-ionic surfactants, some chemical
stability issues, such as a relevant pH reduction, are likely to be
faced during development.
[0013] In fact, for instance, both polyethylene glycols and
polysorbates, when in solution, may undergo degradation, leading to
the formation of acid species such as formic and acetic acid.
[0014] An example of this pH reduction effect is given in Table
1.
1TABLE 1 pH of a typical vehicle for parenteral aqueous suspensions
formulations Storage condition PH Time zero 6.46 10 days at
65.degree. C. 3.43 15 days at 65.degree. C. 3.16 1 month at
65.degree. C. 3.32 3 months at 40.degree. C. 3.24 6 months at
40.degree. C. 3.15 6 months at 25.degree. C. 4.93 Vehicle
composition (batch 13169/12-1A): Methylparaben 0.2%, propylparaben
0.02%, sodium chloride 0.9%, PEG 4000 3%, polysorbate 80 0.3%,
sodium hydroxide q.s. to pH 6.5, WFI q.s to 100 ml.
[0015] This pH reduction occurs both at accelerated testing
conditions and at room temperature. Considering that after only 6
months at room temperature a relevant decrease of approximately 1.5
pH unit is experimented, very low pH values (close or below 3) are
anticipated after long-term storage (1-2 years). This fact
necessarily causes the reduced shelf life of parenteral suspension,
being the progressive acidification of the formulation linked to
the impossibility to administer the formulation, e.g. by
intramuscular or subcutaneous injection, without generating
significant pain on patients (it is advisable that the pH value is
maintained above 3 for administering a painless formulation).
[0016] This pH variation during storage can be minimized by
appropriately buffering the formulation. The most obvious approach,
in order to maintain the pH within specific and predetermined
limits, is the use of buffering agents, such as inorganic acid
salts, in appropriate concentrations in order not only to exert but
also to maintain their buffering capacity. An example of buffering
agents commonly used in parenteral formulations and of their usual
concentrations can be found in Pharmaceutical Dosage Form:
Parenteral Medications, Volume 1, 2.sup.nd Edition, Chapter 5, p.
194, De Luca and Boylan, "Formulation of Small Volume Parenterals",
Table 5: Commonly used additives in Parenteral Products.
[0017] The use of inorganic acid salts as buffering agents offers
to the formulator both advantages and disadvantages. In fact, if a
careful control of pH of formulations could be gained, on the
contrary, when suspension formulations are concerned, ionic species
tend to destabilize the formulations with detrimental effects on
the re-suspendability and on the controlled flocculation of the
formulation. This means that the use of inorganic acid salt based
buffering systems into the formulations has to be minimized.
[0018] In fact, when talking about parenteral suspension, according
to Nash (Parenteral Suspensions, Bulletin of Parenteral Drug
Association, March-April 1972, Vol. 26, No. 2), ". . .
indiscriminate use of salts and buffers is normally avoided,
provided chemical stability is not a problem since changes in
electrolyte concentration often have a profound effect on the
absorbed surface charge of suspension particles".
[0019] An example of the relevant pH decrease occurring in a
medroxyprogesterone acetate parenteral aqueous suspension is showed
in Table 2. This accelerated stability study shows that the pH of
an unbuffered formulation significantly decrease from an initial pH
value of approx. 6.5 to pH values of 3 or lower than 3. It also
demonstrates that , when a usual concentration (approx. 1%) of
phosphate buffer is added to control the pH, a detrimental effect
on the suspension re-suspendability and syringeability is
experimented. In fact an increased time of manual wrist shaking is
needed to re-suspend the buffered suspension after 1 month at
55.degree. C. vs. the unbuffered one. Besides, after 2 month at
55.degree. C. the buffered suspension cannot be re-suspended at all
by manual wrist shaking and, as a consequence, cannot be
administered. On the other hand, when a lower and unusual
concentration (approx. 0.1%) of phosphate buffer is used, no
relevant effect on suspension re-suspendability is experimented
but, at the same time, no substantial pH control is obtained.
2TABLE 2 pH, re-suspendability and syringeability study of
"buffered" vs. "as is" 20% Medroxy ProgesteroneAcetate parenteral
aqueous suspension formulations 13451/01-1 B: + Phosphate buffer A:
as is .about. 0.1% C: Phosphate buffer .about. 1% Batch pH Syring.
PH Resusp. Syring. PH Resusp. Syring. Time zero 6.35 R MT 6.71 R MT
6.30 R MT (T = 7 s) (T = 8 s) (T = 10 s) 1 month at 55.degree. C.
3.12 R MT 3.67 R MT 5.94 R MT (T = 18 s) (T = 29 s) (T = 40 s) 2
months 2.92 R MT 3.28 R MT 5.93 NR NP at 55.degree. C. (T = 33 s)
(T = 24 s) 3 months 2.83 R MT 3.15 R MT 5.81 NR NP at 55.degree. C.
(T = 31 s) (T = 32 s) Phosphate Buffers (M = molar) Concentration
.about. 0.1% Concentration .about. 1% Monobasic Sodium Phosphate.1
H2O (MW 137.99) mg 69.4/100 ml mg 694/100 ml (0.005 M) (0.05 M)
Dibasic Sodium Phosphate.12 H20 (MW 358.14) mg 58.8/100 ml mg
588/100 ml (0.0016 M) (0.016 M) Suspension composition (batch
13451/01-1): Medroxyprogesterone acetate 20%,
MyristylGammaPicoliniumChloride 0.2%, sodium sulphate 1.1%, PEG
3350 2.03%, sodium hydroxide q.s. to pH 6.5 , WFI q.s to 100 ml.
Resuspendability R = RESUSPENDABLE by manual wrist shaking. In
brackets: T = time of manual wrist shaking requested in order to
obtain a homogeneous suspension (s = seconds). NR = NOT
RESUSPENDABLE Syringeability MT = meets test NP = not performed as
product cannot be resuspended and therefore cannot be homogeneously
withdrawed and syringed
DESCRIPTION OF THE INVENTION
[0020] The inventors of the present invention have surprisingly
found out that suitable concentrations of L-Methionine are able
both to control the pH of a pharmaceutical aqueous suspension of a
biologically active compound, in particular a steroidal compound,
by minimizing its pH decrease and to strengthen the pH controlling
capacity of lower and unusual concentrations of conventional
buffering agents, with a super-additive (synergistic) effect.
[0021] In fact the gist of the present invention is based on the
finding that an oxygen scavenger such as L-Methionine not only
shows antioxidant properties per se, like known anti-oxidant
thiol-derivatives, but surprisingly itself takes part in pH
controlling activity.
[0022] A first object of the present invention is thus to provide
the use of L-Methionine as pH controlling agent in a pharmaceutical
aqueous suspension formulation having substantially stabilized pH,
for parenteral administration of a biologically active
compound.
[0023] A further object of the present invention is to provide a
pharmaceutical aqueous suspension formulation for parenteral
administration having substantially stabilized pH comprising a
biologically active compound and a pH controlling effective
concentration of L-Methionine.
[0024] Object of the invention is also the use of L-Methionine, in
a pH controlling effective concentration, in the preparation of a
pharmaceutical aqueous suspension formulation having substantially
stabilized pH, for parenteral administration of a biologically
active compound.
[0025] A further object is a method for preparing a pharmaceutical
aqueous suspension formulation for parenteral administration of a
biologically active compound having substantially stabilized pH,
characterized in that a pH controlling effective concentration of
L-Methionine is added thereto.
[0026] The inventors have also found that L-Methionine, besides
exercising a pH controlling activity per se, also strengthens the
pH controlling capacity of a conventional buffer with a
(super-additive) synergistic effect.
[0027] A super-additive (synergistic) effect is a pH controlling
effect that is greater than the one which is expected to be
obtainable by summing up the experimentally verified pH controlling
effects of the single agents.
[0028] This means that low unusual concentrations of conventional
buffering agents can be included into the formulations, without any
risk of loosing in buffering capacity and, at the same time, to
deteriorate the physico-technological quality of parenteral
suspensions. A further advantage is given by the fact that as no
relevant concentrations of buffers are needed, the formulation has
low or no buffering capacity per se and therefore, once
administered, the pH of the formulation will be easily adjusted to
the physiological value by the buffering capacity of body
fluids.
[0029] As stated above, the reduction in the quantity of
conventional buffering agents, such as inorganic acid salts,
improves the physical stability of the formulation, since ionic
species tend to destabilize the formulations with detrimental
effects on the re-suspendibility and on the controlled flocculation
of the formulation.
[0030] A further object of the invention is therefore to provide a
pharmaceutical aqueous suspension formulation for parenteral
administration having substantially stabilized pH comprising a
biologically active compound, a buffering agent and L-Methionine in
concentrations effective to produce a pH controlling super-additive
effect.
[0031] The present invention also provides the combined use of
L-Methionine and a conventional buffering agent in concentrations
effective to produce a pH controlling super-additive effect, in the
preparation of a pharmaceutical aqueous suspension formulation
having substantially stabilized pH, for parenteral administration
of a biologically active compound.
[0032] The term "a buffering agent" is herein meant to comprise
(unless otherwise specified) both a single buffering agent and a
mixture of two or more thereof.
[0033] The term "substantially pH stabilized" means that the pH of
the formulation remains within acceptable limits for parenteral
administration over the time, according to well known practice in
the art. It also means that the pH of the formulation containing
L-Methionine, or the combination of L-Methionine and a buffering
agent in concentrations effective to provide a pH controlling
super-additive effect, is maintained over the time closer to the
initial value than the pH of the "as is" formulation (i.e. the
formulation without L-Methionine or the combination of L-Methionine
and a buffering agent).
[0034] The pH range for the suspension formulation of the invention
is from about pH 3.0 to about pH 8.0, preferably pH 3.0 to pH 7.5,
and most preferably pH 4.0 to pH 7.0.
[0035] A pH controlling effective concentration of L-Methionine,
when used as a single pH controlling agent, may vary from about
0.005% w/v to about 5% w/v, preferably from about 0.01% w/v to
about 1.0% w/v.
[0036] The pH controlling effective concentration of L-Methionine,
when used as a combined pH controlling agent, may be substantially
the same as above. p Thanks to the pH controlling properties of
L-Methionine and the superadditive pH controlling effect, which is
obtainable by using L-Methionine in combination with a conventional
buffering agent, the concentration of the latter can be reduced by
about 50% to about 95%. Namely the concentration of the buffering
agent can thus range from about 5% to about 50% of the usual
buffering concentration thereof, preferably from about 5% to about
25%.
[0037] The usual concentrations of conventional buffering agents
employed in parenteral formulations can be found in: Pharmaceutical
Dosage Form: Parenteral Medications, Volume 1, 2.sup.nd Edition,
Chapter 5, p. 194, De Luca and Boylan, "Formulation of Small Volume
Parenterals", Table 5: Commonly used additives in Parenteral
Products.
[0038] According to said literature, the usual buffering
concentration for phosphoric acid salts range from about 0.8% to
about 2.0% w/v or w/w. On the contrary, thanks to the newly found
super-additive effect, the concentration of phosphoric acid salts
according to the formulation of the invention are lower than 0.4%
w/w or w/v, preferably lower than 0.2% w/w or w/v.
[0039] Re-suspendibility and controlled flocculation of the
pharmaceutical aqueous suspension are thus improved.
[0040] The pharmaceutical aqueous suspension, according to the
invention, may in addition also include one or more surfactants,
suspending agents and/or thickening agents.
[0041] Suitable surfactants are for instance phospholipids (e.g.
lecithin), cationic surfactants (e.g. myristylgammapicolinium
chloride), anionic surfactants and non-ionic surfactants (e.g.
polysorbate 80).
[0042] Suitable suspending and/or density adjusting agents are for
instance polyvinylpyrrolidone compounds and polyethylene glycols.
Preferred examples of polyethylene glycols are those having a
molecular weight from about 300 to about 6000, e.g. polyethylene
glycol 3350 and polyethylene glycol 4000. Preferred
polyvinylpyrrolidone (PVP) compounds according to the invention are
those having a molecular weight from about 7000 to about 54000, for
instance PVP K12, K17, K25 and K30, in particular K12 and K17, PVP
K17 being the most preferred. According to a preferred embodiment
of the invention, the pharmaceutical aqueous suspension formulation
of the invention in addition contain a suitable amount of a PVP
compound, in particular K12 or K17, especially K17.
[0043] Suitable thickening or viscosity agents are for instance
well known cellulose derivatives (e.g. methylcellulose,
carboxymethylcellulose, hydroxyethylcellulose and
hydroxypropylmethylcellulose), gelatin and acacia, in particular
methylcellulose.
[0044] In addition, the formulations of the present invention may
also include metal chelating agents, antioxidants or
thiol-containing compounds and preservatives.
[0045] Suitable metal chelating agents are for instance
ethylenediamine-tetracetic acid salts (e.g. edetate disodium).
[0046] Suitable antioxidants are for instance ascorbic acid
derivatives (e.g. ascorbic acid, erythorbic acid, sodium
ascorbate), thiol derivatives (e.g. thioglycerol, cysteine,
acetylcysteine, cystine, dithioerythreitol, dithiothreitol,
gluthathione), tocopherols, butylated hydroxyanisole, butylated
hydroxytoluene, sulfurous acid salts (e.g. sodium sulfate, sodium
bisulfite, acetone sodium bisulfite, sodium metabisulfite, sodium
sulfite, sodium formaldehyde sulfoxylate, sodium thiosulfate) and
nordihydroguaiareticacid. Suitable preservatives are for instance
phenol, chlorobutanol, benzylalcohol, methyl paraben, propyl
paraben, benzalkonium chloride and cetylpyridinium chloride.
[0047] In addition, the formulations of the present invention may
also include tonicity-adjusting agents. Suitable tonicity adjusting
agents are for instance sodium chloride, sodium sulfate, dextrose,
mannitol and glycerol.
[0048] The formulations of the present invention may also have a
nitrogen blanket overlay on the head-space of the vial.
Additionally, the formulations of the present invention may include
purging the formulation buffer with helium, argon, or nitrogen.
[0049] When the formulation of the invention, besides L-Methionine,
contains also buffering agents, useful buffers include e.g. those
derived from acetic, aconitic, citric, glutaric, lactic, malic,
succinic, phosphate and carbonic acids, as known in the art.
Typically employed is an alkali or alkaline earth salt of one of
the aforementioned acids. Phosphate and citrate buffers, such as
phosphoric acid or a pharmaceutically acceptable salt thereof, or
citric acid or a pharmaceutically acceptable salt thereof, are
preferred. Sodium phosphate or sodium citrate is the preferred
buffering agents, with sodium phosphate being most preferred.
[0050] The pharmaceutical aqueous suspension according to the
invention is e.g. for intramuscular, subcutaneous and intradermal
administration, preferably for intramuscular and subcutaneous
administration.
[0051] A biological active compound according to the invention is
any compound that after administration to a mammal, including
humans, provides a therapeutic effect. Preferably it is a steroidal
biologically active compound.
[0052] A steroidal biologically active compound according to the
invention is the steroidal compound itself or, when appropriate, a
pharmaceutically acceptable salt thereof as known in the art, e.g.
medroxyprogesterone acetate, exemestane, estradiol cypionate,
methylprednisolone acetate, oxabolone cypionate, clostebol acetate,
testosterone cypionate; preferably medroxyprogesterone acetate,
estradiol cypionate and exemestane, or a combination of two or more
thereof according to the art.
[0053] Concentrations of medroxyprogesterone acetate in the
formulation can range from about 1% w/v to about 40% w/v,
preferably from about 3% w/v to about 30% w/v.
[0054] Concentrations of estradiol cypionate in the formulation can
range from about 0.1% w/v to about 5% w/v, preferably from about
0.25% w/v to about 2.5% w/v.
[0055] When a combination of estradiol cypionate and
medroxyprogesterone acetate is the active ingredient of the
pharmaceutical preparation of the invention, the amounts of such
compounds present in the pharmaceutical preparation are
substantially as here above.
[0056] Concentrations of exemestane in the formulation can range
from about 1% w/v to about 25% w/v, preferably from about 5% w/v to
about 20% w/v.
[0057] The steroidal biologically active compound is preferably in
milled or micronized form according to the common practice.
[0058] The pH controlling activity of L-Methionine either alone or
in combination with a conventional buffer is shown for instance by
the following examples.
EXAMPLE 1
[0059] pH stabilization of a parenteral aqueous suspension of
Exemestane (CAS: 6-Methylenandrosta-1,4-diene-3,17-dione; other
name: Androsta-1,4-diene-3,17-dione-6-methylene) by means of
L-Methionine.
[0060] Exemestane is an irreversible aromatase inhibitor,
structurally related to the natural steroid androstenedione and it
is a molecule prone to oxidation. When performing an experimental
study, by adding different antioxidants to a 10% Exemestane
parenteral aqueous suspension we have surprisingly found out that
L-Methionine can stabilize the pH of the suspension. In fact, the
experimental data provided in Table 3 clearly demonstrate that in
the suspension formulation containing L-Methionine the pH reduction
is minimized in comparison with the "as is" and that by adding
L-Methionine, the pH of the suspension is stabilized at values
above pH 4.5 even after 2 months storage at 55.degree. C.
[0061] What is outmost surprising is that among the added
antioxidants, only Methionine is effective in substantially
controlling/stabilizing the pH of the suspension (after 2 months
storage at 55.degree. C. the pH decrease of the formulations
containing ascorbic acid, and sodium metabisulfite is in fact
comparable or worse than the one experimented in the "as is"
formulation).
[0062] Therefore a simple antioxidant effect cannot explain the
result obtained and the presence of a specific stabilizer, such as
L-Methionine, is needed in order to prevent a dramatic pH decrease
and stabilize the parenteral aqueous suspension.
[0063] The present invention, however, is not intended to be
limited to any particular theory of the exact mechanism of this
substantial pH stabilization but relates to the fact that a
substantial pH stabilization is obtained, to the unconventional way
through which this substantial pH stabilization is obtained and to
its possible advantages.
[0064] It is an advantage of the present invention that the pH of
these stabilized parenteral aqueous suspensions does not
dramatically decrease during storage but, on the contrary, is
maintained closer to the initial value (i.e. closer to neutrality)
and therefore these stabilized suspensions can be safely
administered without generating significant pain on patients.
3TABLE 3 pH study of a 10% Exemestane parenteral aqueous suspension
formulation containing different antioxidants. B: + D: + Ascorbic
Sodium E: + A: as is Acid Metabisulfite L-Methionine Time zero 6.02
6.40 6.47 6.00 1 month at 4.28 4.20 2.30 4.86 55.degree. C. 2
months at 4.03 4.18 2.50 4.74 55.degree. C. Suspension composition
(batch 13833/11): Exemestane 10%, methylparaben 0.18%,
propylparaben 0.02%, sodium chloride 0.9%, PEG 4000 3.0%,
polysorbate 80 0.2%, sodium hydroxide q.s. to pH 6.0-6.5, WFI q.s
to 100 ml.
EXAMPLE 2
[0065] pH and technological quality (re-suspendability,
syringeability) stabilization of a medroxyprogesterone acetate
parenteral aqueous suspension by means of L-Methionine used alone
or in combination with low and unconventional concentrations of
phosphate buffer.
[0066] As previously shown in Table 2, the use of a conventional
buffering agent, such as Phosphate buffer, in usual effective
concentrations (approx. 1%) in order to stabilize the pH of a
medroxyprogesterone acetate aqueous suspension has a detrimental
effect on the suspension technological quality, i.e.
resuspendability and syringeability.
[0067] In this example, outlined in Table 4 (Tables 4a and 4b), it
is evident that the pH of the same type of suspension can be
controlled/stabilized by using L-Methionine alone or by a
combination of L-Methionine with a lower and unusual concentration
of phosphate buffer (approx. 0.1%). In fact, when L-Methionine is
used alone, as in the case of batch 13451/47-I, a substantially
stabilized pH is obtained.
[0068] Besides, when L-Methionine is used in combination with a low
unusual concentration of Phosphate buffer (approx. 0.1%) a
synergistic effect is obtained.
[0069] In fact, as clearly shown in the case of batch 13451/47-C,
when an unusually low concentration of phosphate buffer (approx.
0.1%) is used, no significant pH stabilization is obtained vs. the
"as is" forrnulation.
[0070] On the contrary, when the same low unusual concentration of
phosphate buffer (approx. 0.1%) is used in combination with
L-Methionine, as in the case of batch 13451/84-D, a surprising
super-additive effect is obtained in controlling/stabilizing the pH
of the formulation.
[0071] Besides, when L-Methionine is used alone or in combination
with a low unusual amount of phosphate buffer, no negative effect
is produced on the suspension's technological quality, thus
allowing the achievement of a pH stabilized medroxyprogesterone
acetate suspension with good re-suspendability and syringeability
properties that are maintained during storage.
[0072] On the contrary, when a usual effective concentration of
phosphate buffer (approx. 1%) is used in order to stabilize the pH,
as in the case of batch 13451/47-G, a detrimental effect on the
physical stability of the formulation is obtained.
[0073] It is an advantage of this invention that the pH of
parenteral aqueous suspensions can be substantially stabilized
without using effective usual concentrations of conventional
buffering agents, i.e. typically inorganic or organic acid salts,
thus avoiding some substantial drawbacks, such as the profound
effects caused by ionic species, and especially by polyvalent ions,
on the nature and the stability of flocculated suspensions, with
detrimental effects on suspension re-suspendability and
syringeability.
4TABLE 4 pH, resuspendability and syringeability study of a 20%
Medroxyprogesterone Acetate (MPA) parenteral aqueous suspension
formulated with different amounts of L-Methionine and Phosphate
buffers. 13451/47-C 13451/47-G 13451/47-1 13451/47-A Phosphate
.about. 0.1% Phosphate .about. 1% L-Methionine TABLE 4a as is
(0.0066 M) (0.066 M) 0.5% pH Time zero 6.07 6.35 6.33 6.11
65.degree. C. : 10 days 2.85 3.03 * 5.29 65.degree. C. : 15 days
2.82 2.97 * 5.13 65.degree. C. : 1 month 2.88 3.06 5.13* 4.76
13451/84-1 L-Methionine 0.1% 13451/84-B 13451/84-C + 13451/47-A
L-Methionine L-Methionine Phosphate .about. 0.1% TABLE 4b as is
0.1% 0.25% (0.0066 M) pH Time zero 6.10 6.04 5.94 6.31 65.degree.
C. : 10 days 3.00 4.49 5.28 5.92 65.degree. C. : 15 days 2.89 4.30
4.88 6.25 65.degree. C. : 1 month 3.01 3.83 4.55 6.20
Resuspendability 65.degree. C. : 1 month resuspendable
resuspendable resuspendable Resuspendable (15 s) (13 s) (15 s) (14
s) Syringeability 65.degree. C. : 1 month meets test meets test
meets test Meets test Phosphate Buffers (M = molar) approx. 0.1%
approx. 1% Monobasic Sodium Phosphate mg 69.4/100 ml mg 694/100 ml
.1 H2O (MW 137.99) (0.005 M) (0.05 M) Dibasic Sodium Phosphate mg
58.8/100 ml mg 588/100 ml .12 H20 (MW 358.14) (0.0016 M) (0.016 M)
Suspension composition: MedroxyprogesteroneAcetate 20%,
MyristylGammaPicoliniumChloride 0.1% (batch 13451/84) or 0.2%
(batch 13451/47), sodium sulphate 1.1%, PEG 3350 2.03%, sodium
hydroxide q.s. to pH 6.5, WFI q.s to 100 ml. *not resuspendable by
manual wrist shaking. pH measured after mixing the suspension with
a spatula Resuspendability: In brackets the time of manual wrist
shaking requested in order to obtain a homogeneous suspension (s =
seconds).
EXAMPLE 3
[0074] pH stabilization of a medroxyprogesterone acetate and
estradiol cypionate parenteral aqueous suspension by means of
L-Methionine used alone or in combination with unconventional low
amounts of phosphate buffer.
[0075] Estradiol cypionate and medroxyprogesterone acetate is an
estro-progestinic combination that is used in contraception. Both
estradiol cypionate and medroxyprogesterone acetate are quite
stable molecules and no relevant degradation is reported when the
two actives are formulated as a parenteral aqueous suspension. In
fact, no particular stabilizers are requested to chemically
stabilize the two active ingredients molecules, being the only
issue to be solved is their hydrophobicity and therefore the need
to use suitable wetting/suspending agents in order to obtain a
re-suspendable and syringeable suspension. In the experimental
trial reported in Table 5, a 1% estradiol cypionate and 5%
medroxyprogesterone acetate parenteral aqueous suspension,
containing suitable wetting/suspending agents has been formulated
with different amounts of L-Methionine and with a combination of
L-Methionine and a low and unusual concentration (approx. 0.1%) of
Phosphate buffer. From the data obtained, not only L-Methionine
"per se" is capable to prevent the relevant pH decrease occourring
to the "as is" formulation and to maintain the pH of the
formulation well above 4.5 even after 1 month storage at 65.degree.
C., but, most surprisingly, when used in combination with an lower
and unconventional amount of phosphate buffer (approx. 0.1% or
0.0066M), the pH is stabilized to values close to the time zero
value. Besides, the stabilizing effect is similar to the one
obtained by buffering the formulation with a usual effective
concentration (approx. 1% or 0.066M) of phosphate buffer.
[0076] It is an advantage of this invention that the pH of certain
parenteral aqueous suspensions can be stabilized without buffering
the formulation with a conventional buffering agents (i.e.
inorganic/organic acid salts) or without usual effective
concentrations of a conventional buffering agent.
[0077] As said before, the pH stabilized parenteral aqueous
suspensions obtained by means of this invention do not contain
conventional buffering agents or usual effective concentrations of
buffering agents. As a consequence, a further advantage of this
invention is that the so obtained parenteral aqueous suspensions do
not have buffering capacity or significant buffering capacity per
se, and therefore, when injected, the pH of the product can be more
easily adjusted to the physiological value by the buffering
capacity of the tissue fluids.
5TABLE 5 pH study of a 1% Estradiol Cypionate (ECP) and a 5%
Medroxyprogesterone Acetate (MPA) parenteral aqueous suspension
formulated with different amount of L-Methionine and Phosphate
buffers. 13510/01-F L-Methionine 13510/01-E 0.1% + 13510/01-B
13510/01-C 13510/01-D Phosphate Phosphate 13510/01-A L-Methionine
L-Methionine L-Methionine .about.1% .about. 0.1% Batch as is 0.5%
0.25% 0.1% (0.066 M) (0.0066 M) pH Time zero 6.31 6.37 6.40 6.45
6.32 6.41 65.degree. C.: 10 days 4.49 5.71 5.62 5.54 6.26 6.21
65.degree. C.: 15 days 4.29 5.69 5.46 5.40 6.33 6.25 65.degree. C.:
1 month 3.91 4.73 4.67 4.62 6.29 5.98 Phosphate Buffers (M = molar)
Approx. 0.1% approx. 1% Monobasic Sodium Phosphate . 1 H2O (MW
137.99) mg 69.4/100 ml mg 694/100 ml (0.005 M) (0.05 M) Dibasic
Sodium Phosphate . 12 H20 (MW 358.14) mg 58.8/100 ml mg 588/100 ml
(0.0016 M) (0.016 M) Suspension composition: MPA 5%, ECP 1%,
methylparaben 0.18%, propylparaben 0.02%, sodium chloride 0.856%,
PEG 3350 2.856%, polysorbate 80 0.19%, sodium hydroxide q.s. to pH
6.0-6.5, WFI q.s to 100 ml.
[0078] The following are examples of pharmaceutical compositions
according to the invention and are not intended to limit the scope
of the invention itself.
EXAMPLE A
[0079] Stabilized Parenteral Aqueous suspension of Medroxy
Progesterone Acetate.
6 The formulation is as follows (% w/v): Medroxyprogesterone
Acetate (micronized) 20% Myristyl Gamma Picolinium Chloride 0.085%
Sodium Sulphate 1.1% Polyethylene Glycol 3350 2.03%
Polyvinylpyrrolidone K17 0.25% Monobasic Sodium Phosphate hydrate
0.0694% Dibasic Sodium Phosphate dodecahydrate 0.0588% L-Methionine
0.150% Sodium Hydroxide or Hydrochloric Acid q.s. to pH 6.0-7.0
Water for Injections q.s. to 100 ml
[0080] The excipients are dissolved in Water for Injections. The
obtained vehicle is sterilized by steam sterilization or sterilant
filtration. Sterile micronized medroxyprogesterone acetate is added
to the vehicle, the obtained suspension is passed through a
suitable homogenizer in aseptic condition and the pH is adjusted.
The homogeneous suspension is then aseptically distributed in
single-use containers.
[0081] The obtained product has desirable properties for parenteral
use, keeps well and has a substantially stabilized pH.
EXAMPLE B
[0082] Stabilized Parenteral Aqueous Suspension of Medroxy
Progesterone Acetate.
[0083] The formulation is as follows (% w/v):
7 Medroxyprogesterone Acetate 14% Methylparaben 0.18% Propylparaben
0.02% Sodium Chloride 0.8% Polyethylene Glycol 3350 2.875%
Polysorbate 80 0.3% Polyvinylpyrrolidone K17 0.5% L-Methionine
0.15% Monobasic Sodium Phosphate hydrate 0.0694% Dibasic Sodium
Phosphate dodecahydrate 0.0588% Sodium Hydroxide or Hydrochloric
Acid q.s. to pH 6.0-7.0 Water for Injections q.s. to 100 ml
[0084] The manufacturing method includes preparation of a sterile
vehicle, aseptic compounding of sterile micronized
medroxyprogesterone Acetate into the vehicle and aseptic
distribution of the obtained sterile homogenous suspension into
single dose container.
[0085] The product has a substantially stabilized pH, good
resuspendability and can be administered with a syringe-needle
suitable for subcutaneous and intramuscular use.
EXAMPLE C
[0086] Stabilized Parenteral Aqueous Suspension of a combination of
Medroxyprogesterone Acetate and Estradyol Cypionate.
8 The formulation is as follows (% w/v): Medroxyprogesterone
Acetate (micronized) 5% Estradiol cypionate (micronized) 1
Methylparaben 0.180% Propylparaben 0.020% Sodium Chloride 0.800%
Polyethylene Glycol 3350 2.856% Polysorbate 80 0.190%
Polyvinylpyrrolidone K17 0.250% L-Methionine 0.150% Monobasic
Sodium Phosphate hydrate 0.0694% Dibasic Sodium Phosphate
dodecahydrate 0.0588% Sodium Hydroxide or Hydrochloric Acid q.s. to
pH 6.0-7.0 Water for Injections q.s. to 100 ml
[0087] The parabens are dissolved in Water for Injections
previously heated at approximately 70-90.degree. C. The parabens
solution is cooled down to room temperature, the remaining
excipients are added and dissolved and the pH is adjusted to the
desired range.
[0088] Micronized medroxyprogesterone acetate and estradiol
cypionate are slurried into the vehicle and the obtained dispersion
is homogenized until a fine, syringeable suspension is
obtained.
[0089] In order to obtain a sterile suspension suitable for
parenteral administration sterile active drugs and vehicle are used
and the obtained suspension aseptically distributed into single
dose containers.
[0090] The obtained product can be easily resuspended and can
easily flow though a syringe needle, has a substantially stabilized
pH and is suitable for intradermal, subcutaneous and intramuscular
administration.
EXAMPLE D
[0091] Stabilized Parenteral Aqueous Suspension of Exemestane.
9 The formulation is as follows (% w/v): Exemestane (micronized)
10% Methylparaben 0.18% Propylparaben 0.02% Sodium Chloride 0.83%
Polyethylene Glycol 4000 3.0% Polysorbate 80 0.2% Methylcellulose
0.15% Lecithin 0.5% L-Methionine 0.1% Edetate disodium 0.05%
Monobasic Sodium Phosphate hydrate 0.0694% Dibasic Sodium Phosphate
dodecahydrate 0.0588% Sodium Hydroxide or Hydrochloric Acid q.s. to
pH 6.0-7.0 Water for Injections q.s. to 100 ml
[0092] Lecithin and methylcellulose are dispersed in approximately
20% of Water for Injections and the obtained dispersion autoclaved.
The other excipients are dissolved in the remaining 80% of Water
for Injections and the obtained solution sterilized by sterilant
filtration. The two preparations are compounded in aseptic
environment, the pH is adjusted and sterile exemestane is
added.
[0093] The obtained suspension is passed though a suitable
homogenizer until a fine, syringeable suspension is obtained and
then aseptically distributed.
[0094] The product has desirable properties for parenteral use,
keeps well and has a substantially stabilized pH.
* * * * *