Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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4-16314/=
Parenteral suspensions
The present invention relates to a dry formulation, in particular a
dry formulation obtainable by lyophilisation, which can be used for
the preparation of an aqueous stable suspension for the parenteral
administration of a diclofenac salt, to the use of said formulation
for the preparation of a stable aqueous suspension containing said
diclofenac salt, and to the use of this suspension in a therapeutic
method of treating the human body.
Various medicaments of different structure are available for the
treatment of inflammatory diseases, e.g. rheumatism. As the course
inflammations ta~e is often chronic, it is usually necessary to
carry out the treatment with antiinflammatory drugs over a prolonged
period of time without interruptlon. In particular, many non-
steroidal antiinflammatory drugs ~NAIDS), when administered orally,
can cause disorders in the entire gastrointestinal tract, especially
gastric ulcers.
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The sodium salt of diclofenac, available under the registered
~trademark Voltaren~ (Ciba-Geigy), belongs to the group of non-
;~steroidal antiinflammatory drugs of the first importance.
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To enhance drug safety, there is a need to provide novel parenteral
; dosage forms for diclofenac and the salts thereof which, compared
with the parenteral in~ection solutions of the known prior art
disclosed e.g. in German Offenlegungsschrift 2 914 788 and European
patent application 185 374, have the advantage of a very rapid onset
o~ action with loDg-1asting therapeutic effects.
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Suspensions of dlclofenac or diclofenac sodium for parenteral, in
particular intramuscular, administration are disclosed in US patent
specification 4 614 741. Fatty oils such as sesame oil, olive oil
and the like, are used as suspending media for these suspensions.
Quite generally, the use of fatty oils as sd~uvants for parenteral
dosage forms is inexpedient, as they increase the viscosity of the
dosage form, thereby causing pain when it is administered (q.v.
R. ~oigt, Lehrbuch der Pharmazeutischen Technologie, Verlag Chemie,
p. 383~ 19.5.1.2.1). Consequently, there is also a need for suspen-
sions containing a diclofenac salt, in particular diclofenac sodium,
for substantially pain-free intramuscular administration.
The above objects of the invention are achieved by means of the
present invention, which relates to a dry formulation containing a
diclofenac salt in micronised form without deleterious at~uvants.
This dry formulation, after being suspended in an aqueous liquld
vehicle, is converted into a dosage form for parenteral admini-
stration.
Accordingly, tha present invention relates to a dry formulation, in
particular a dry formulation obtainable by lyophilisation, which can
be used for the preparation of a stable aqueous suspension for the
parenteral administration of a diclofenac salt. The dry formulation
contains a pharmaceutically acceptable and micronised salt of
diclofenac and optional pharmaceutically acceptable adjuvants.
A pharmaceutically acceptable salt of diclofenac, o-(2,6-dichloro-
anilino)phenylacetic acid, is in particular an alkali metal salt,
e.g. the sodium or potassium salt, or a salt with an amine, e.g. a
;~ ~ mono~, di- or trialkylamine containing 1 to 4 carbon atoms in the
alkyl moiety or moieties, e.g. diethylamine or triethylamine,
hydroxyalkylamine containing 2 to 4 carbon atoms in the alkyl
moiety, e.g. ethanolamine, hydroxyalkylalkylamine containing 2 to 4
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and 1 to 4 carbon atoms respectively in each of the alkyl moieties,
e.g. dimethylethanolamine, or a quaternary ammonium salt, e.g. the
tetramethylammonium salt or choline salt of diclofenac.
Particularly preferred salts of diclofenac are the sodium and
potassium salts (q.v. Merck Index, Tenth ~dition, No. 3066).
The dry formulation of this invention contains the diclofenac salt,
in particular the sodium or potassium salt of diclofenac, in micron-
ised form.
The micronised diclofenac salt has a preferred average partlcle size
smaller than 50 ~m, preferably sma]ler than 20 ~m. Particles of this
size are obtained by conventional comminution methods, e.g. grinding
in an air jet mill, ball mill or vibrator mill. Micronisation is
preferably effected by per se known methods using an ultrasonics
disintegrator, e.g. of the Branson Sonifier type as described e.g.
in J. Pharm. Sci. 53 (9), 1040-1045 (1965), or by stirring a
- suspension with a high-speed agitator, for example with a stirrer of
the Homorex type (supplied by Brogli & Co., Basel). In these
preferred methods, micronisation is effected at ca.
500 to 10,000 rpm by dissolving -the appropriate salt of diclofenac
ln an organic solvent, e.g. methanol, ethanol or propylene glycol,
and precipitating it in microcrystalline form at ca. 0-5C in water
or an aqueous salt solution, e.g. 2 % sodium chloride solution which
may additionally contain a protective colloid such as gelatin or a
cellulose ether, e.g. methyl cellulose or hydroxypropyl methyl
cellulose, in low concentration (0.1-1 %), and filtering the
resultant stirred suspension. The filter cake is dried at low
temperature, e.g. ca. 0-5C, under vacuum (e.g. below 50 mbar,
;~ preferably at 0.5 mbar). The subsequent drying can be effected at
ca. 50-90C-~
Pharmaceutically acceptable adjuvants which the dry formulation may
contain are e.g. ionic isotonic components such as sodium chloride,
or nonionic components, especially builders, such as sorbltol,
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mannitol or glucose. Preferably the dry formulation contains these
adjuvants, e.g. sodium chloride or mannitol, in the prescrlbed
amounts which are necessary for establishing the isotonic conditions
of the suspension.
Further adjuvants present in low concentration are e.g. emulsifiers
which may be used as wetting agents, e.g. phospholipids, e.g.
phosphatidyl choline (lecithin), phosphatidyl ethanolamine
(cephalin), phosphatidyl serine, phosphatidyl linositol or mixtures
of these lipids.
Preferred phospholipids are, for example, soybean or egg lecithin,
or soybean or egg cephalin in pharmaceutical purity, or mixtures of
phospholipids of different phosphatidyl choline content approved for
pharmaceutical use, e.g. mixtures of l~cithins which are commercial-
ly available under the registered trademarks Epikuron~ 145, 170
or 200 (Lucas Meyer, Hamburg) or Lipoid~ 45, 80 or 100 (Lipoid KG,
Mannheim).
The cited phospholipids may be present in the solid formulation in
weight ratios of active drug to phospholipid of 1:0~1 to 1:1,
preferably from 1:0.1 to 1:1.
Further suitable adjuvants in the dry formulation are wetting agents
useful for liquid pharmaceutical formulations or true surfactants,
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~ ~ ~ in particular nonionic surfactants of the fatty acid polyhydroxy
; alcohol ester type such as sorbitan monolaurate, monooleate,
monostearate or monopalmitate, sorbitan tristearate or trioleate,
adducts of polyoxethylene and fatty acid polyhydroxy alcohol esters
such as polyo~yethylene sorbitan monolaurate, monooleate, mono-
stearate, monopalmitate, tristearate or trioleate, polyethylene
glycol fatty acid esters such as polyoxyethyl stearate, poly-
ethylene glycol 400 stearate, polyethylene glycol 2000 stearate, in
particular ethylene oxide/propylene oxide block polymers of the
~ ~ Pluronlcs~ type (Wyandotte) or Synperonic~ (ICI).
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These surfactants may be present in the dry formulation in weight
ratios of active drug to surfactant of 1:1.0 x 10 4 to 1:0.1,
preferably of 1:0.03 to 1:0.1.
The dry formulation of this invention is prepared by suspending the
amount of diclofenac salt intended for parenteral administration, in
micronised form, in a suspending medium that contains the optional
pharmaceutically acceptable adjuvants, and removing the solvent.
If the dry formulation contains water-soluble components or ad-
~uvants, such as sodium chloride, mannitol or glucose, which Are
necessary e.g. for establishing isotonic conditions, then an aqueous
suspending medium is preferred. After dissolving the ad~uvants in
water purified for injection, the aqueous solution is preferably
filtered and sterilised or filtered under sterile condltions. To
this sterilised solution is then added the micronised diclofenac
salt. The preparation of the dry formulation can be effected by
known methods of lyophilisation, e.g. normally by filling a speciflc
amount of the prepared suspension into suitable containers such as
ampoules, e.g. vials, and thereafter freezing the filled vials at
ca. -40 to -50C, preferably at -45C, and then carrying out
lyophilisation under a pressure of ca. 0.05 to 0.6 mbar by slowly
warming to a final temperature of ca. 25-55C.
If the dry formulation contains an adjuvant or component which is
poorly soluble in water, e.g. a phospholipid 3uch as lecithin, then
said adjuvant is dissolved e.g. in a purified organic solvent such
as tert-butanol, methanol, ethanol or methylene chloride, and the
micronlsed salt ls suspended in this solution. After stripping off
- the organic solvent, the dry formulation coated with the adjuvant,
such as a phospholipid, is filled in powder form into suitable
containers, e.g. vials.
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Surprisingly, by means of the process of this invention it is
posslble to prepare dry formulations, especially lyophilised
formulations, and ~uspenslons that can be reconstituted therefrom
and which are stable and suitable for in~ection.
The use of the dry formulations obtainable by the process of this
invention for the preparation of injection suspensions is also an
ob~ect of this invention. These in~ection suspensions can be
administered as injection formulations parenterally, preferably
intramuscularly.
The dry formulatiDn of this invention is reconstituted, prior to
administration, as a suspension in the prescribed amount of liquid,
especially sterilised (pyrogen-free) water for injection.
A homogeneous suspension of the previously micronised drug is formed
once more by shaking. Instead of a dry formulation containing the
diclofenac salt and the water-soluble ad~uvants such as sodium
chloride or mannitol, it is also possible to suspend a dry formula-
tion containing only the diclofenac salt (without adjuvants) in the
prescribed amount of liquid containing the cited water-soluble
adjuvants.
The particle size of the micronised drug remains unchanged during
the preparation of the suspension. Thus no noticeable crystal
growth, e.g. resulting from hydrate formation, is observed in the
suspension to be administered. The suspension of the drug also has
the advantage that it does not adhere to the wall of the a~poule and
can be readily and completely withdrawn from the ampoule with the
syringe. A particularly preferred embodiment of the invention
comprises preparing injection suspensions that contain the customary
doses of 50~ 75 or lob mg of diclofenac sodium, having a total
volume of 1.0 to 3.0 ml, preferably of 2.0-].0 ml, especially a
volume of 1.0 ml.
These suspensio~s can be used a~ ready for use formulations.
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The present invention relates in particular to dry formulations and
to the use thereof for the preparation of an aqueous suspension for
the intramuscular administration of diclofenac sodium. The dry
Eormulation and the suspension preferably contain micronised
diclofenac sodium having an average particle size smaller than 20 ~m
and optional adjuvants such as sodium chloride, mannitol, sorbitol
as well as lipids such as lecithin or wetting agents of the
SYNPERONIC~ or PLURONIC~ type.
The suspensions of this invention can be used for parenteral
~intramuscular) formulations for the treatment of painful condi-
tions, inflammations and/or rheumatic diseases in warm-blooded
animals (human and animals). Daily doses of ca. 25 to 200 mg of
active drug can be administered, while the individual dosage form
contains the customary amounts of drug of e.g. 25, 50, 75, 100 or
150 mg.
The following Examples illustrate the invention, but imply no
restriction to what is described therein.
Example 1:
a) Preparation of the lyophilised drug formulation
Composition of each ampoule:
diclofenac sodium 75 mg
NaCl 18 mg
Preparation of 10 ampoules:
180 mg of sodium chloride ~puriss.) are dissolved in 10 ml of
distilled water and the solution is filtered through a membrane
filter (pore size: 0.2 ~m) and sterilised, e.g. in an autoclave at
ca. 120C. The sterilised sodium chloride solution is coolad to 5C.
To the cooled solution are added 750 mg of micronised diclofenac
sodium (puriss.) having an average particle size smaller than 20 ~m
and the resultant suspension is deagglomerated, e.g. in a piston
homogeniser or ultrasonics disintegrator. The crystalline suspension
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i9 fillet at 5C into 10 sterilised vials of 1.0 ml volume. The
vials are fro~e~ at -45C, lyophilised in a free~e dryin~ apparatus
and then sealed.
b) Preparation of the active drug suspension for parenteral
administration (reconstitution)
To the contents of a vial containing 75 mg of lyophilised diclofenac
sodium (preparation as described in a) above) are added, at room
temperature, 2.0 ml of sterilised water for injection and the
lyophilised drug i9 suspended by shaking. The suspension is with~
drawn from the vial with a sterilised syringe and can be ad-
ministered intramuscularly.
~xample 2:
a) Following the procedure of Example la), it is posslble to prepare
lyophilised drug formulations contalning 75 mg of diclofenac sodlum
and 100 mg of mannitol and 9 mg of NaCl.
Alternatively, these lyophilised Eormulations may also additlonally
contain 0.01 to 10 mg of Synperonic~.
b~ Following the procedure of Example lb), it is possible to
suspend, at room temperature, lyophilised drug formulations con-
taining 75 mg of diclofenac sodium in 2.0 ml of sterilised water for
injection which contains 0.9 % of NaCl, or lyophilised drug formula-
tions containing 75 mg of diclofenac sodium and 100 mg of mannitol,
or 75 mg of diclofenac sodium, S0 mg of mannitol and 9 mg of NaCl in
2.0 ml of sterilised water for injection. Alternatively, these
lyophilised drug formulations can also be suspended with the
addition of 0.01 to 10 mg of Synperonic~. The isotonic suspensions
so obtalned can be withdrawn by a sterilised syringe and adminis-
tered intramuscularly.
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Example 3:
a) Preparation of the dry formulation (powder)
Composltion of each ampoule:
diclofenac 75 mg
lecithin (Epikuron~ 145, 170 or 200) 2-20 mg
Preparation of 10 ampoules:
The lecithin is dissolved in 10 ml of methylene chloride and the
solution is filtered through a membrane (pore size: 0.2 ~m). To the
filtered solution are added 750 mg of micronised diclofenac sodium
having an average particle size smaller than 20 ~m, and the sus-
pension so obtained is deagglomerated (q.v. Example la). The solvent
is then removed under vacuum. The diclofenac sodium powder coated
with lecithln ls filled into vials such that each contains 75 mg of
diclofenac sodium.
'o) Preparation of the actlve drug suspenslon for parenteral
administration
Following the procedure of Example la), the contents of a Ylal
containing 75 mg of diclofenac sodium ln the form of the lecithin-
coated powder are suspended at room temperature in 2.0 ml of
sterilised water for injection which contains 0.9 % of NaCl or in
2.0 ml of sterilised water which contains an isotonic mixture of
~aCl and mannltol.
Example 4:
a) Preparation of the lyophilised dru~ formulation
Composition of each ampoule:
:
diclofenac sodium 75 mg
NaCl 5.4 mg
mannitol 20 mg
PLURONIC 0.07 ng
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Preparation of 10 ampoules:
54.0 mg of sodium chloride (puriss.), 200 mg mannitol and 0.7 mg
PLURONIC are dlssolved in 7.0 ml of distilled water and the solution
is filtered through a membrane filter (pore size: 0.2 ~m) and
sterilised, e.g. in an autoclave at ca. 120C. The sterilised
suspending agent is cooled to 5C. To the cooled solution are added
750 mg of micronised diclofenac sodium (puriss.) having an average
particle size smaller than 20 ~Im and the resultant suspension is
deagglomerated, e.g. in a piston homogeniser or ultrasonics disinte-
grator. The crystalline suspension is filled at 5~C into 10 sterili-
sed vials of a volume suitable for 0.8 g substance. Ths vials are
frozen at -45C, lyophilised in a freeze drying apparatus and then
sealed.
b) Preparation of the active drug suspension for parenteral
administration (reconstitution)
To the contents of a vial containing 75 mg of lyophilised diclofenac
sodium (preparation as described in a) above) are added, at room
temperature, 1.0 ml of sterilised water for injection and the
lyophilised drug is suspended by shaking. The suspension is with-
drawn from the vial with a sterilised syringe and can be ad-
~inistered iDtrsmuscu1sr1y.
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