Note: Descriptions are shown in the official language in which they were submitted.
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SIJSTAINED RELEASE SUF~NTANIL COMPOSITIONS
The present invention concerns sustained release sufentanil compositions for
5 intramuscular ~lmini~tration, the preparation of said compositions and the use of said
compositions for inhibiting pain, in particular post-operative pain, in ~nimP~l.c,
particularly in companion ~nim~
Sufentanil is the generic name of N-[4-(methoxymethyl)-1-[2-(2-thienyl~ethyl]-4-10 piperidinyl]-N-phenylpropanamide and can be represented by the formula
¢~CH2--C~2--N~<CH2-O-CH3 (1).
S N-C-CH2-CH3
~3~
This compound, its acid addition salt forms, preparation and pharmacological
properties are known from US-3,998,834. Sufentanil is a potent, short-acting opioid
analgesic; 7 to 10 times as potent as fentanyl and 500 to 700 times as potent asmorphine. Sufentanil is known to provide cardiovascular stability and attenuation of
stress reactions with minim~l side-effects and without compromising recovery. Inhumans, it has been used, intravenously, as an adjunct to nitrous oxide/oxygen in
20 general surgery and at higher doses (2 8 ~Lg/kg) as a sole anaesthetic in cardiac and
neurosurgery .
It is not uncommon that human patients and also ~nim~ls suffer pain following a
surgical procedure. Sufentanil's use for the control of such acute pain in human25 patients and in animals by conventional or intramuscular or intravenous administration
has been limited because of its short duration of action. In human patients, this
problem can be overcome by a continuous infusion or by regular injections at fixed
intervals of about 2 to 4 hours. However, drawbacks of continuous infusion are for
example the need of an infusion device, the need for continuous supervision and the
30 high cost. Most certainly, continuous infusion is impractical, and in many instances not
fit, for use in veterinary medicine. Also, the use of intramuscular injections of short-
acting opioids at fixed intervals has it handicaps. A common failure of pain relief
therapy occurs through the persistent use of shortacting medications on an "as needed"
basis. A major disadvantage of this patient-controlled analgesia is that the indication
35 for analgesic therapy (pain) occurs before the drug can be administered. It may then
.
.L
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take time and higher doses of opioids to relieve the pain and usually leads to a cycle of
undermedication and pain, alternating with periods of overmedication and drug
toxicity. Thus, while intramuscular injection of shortacting opioids is a simplc and
inexpensive technique, it falls short in achieving an efficacious control of acute pain.
Moreover, patient-controlled analgesia is innpossible in veterinary medicine. '?Administration of analgesics by the owner or by a veterinarian will seldom be
programmed "just-in-time". Other drawbacks of current pain relief therapies include
concerns about respiratory depression and drug dependency associated with opioidanalgesics.
The ideal therapeutic regimen for acute pain relief would be to achieve rapidly
therapeutic plasma levels and to maintain these for extended periods (if required)
without undue side-effects such as respiratory depression.
15 W0-92/02256, published on February 20~ 1992, discloses a pharmaceutical
composition comprising sufentanil citrate and 2-hydroxypropyl-,B-cyclodextrin useful
for neuraxial ~lmini.~tration. UK patent application GB-2,287,404, published on
September 20, 1995, encompasses compositions for the prevention or treatment of pain
or inflammatory diseases which comprise a substance P receptor antagonist and an anti-
20 infl~nm~tory or analgesic agent, such as, e.g. sufentanil. WO-95/31182, pub}ished on
November 23, 1995, discloses formulations, useful for aerosol delivery with a metered
dose inhaler, comprising a base form of a narcotic drug such as, e.g. sufentanil, and a
propellant. Optionally lubricants such as saturated vegetable oils, e.g. fractionated
coconut oils, may be present to lubricate valvcs in said metered dose inhaler.
The present invention now provides specific pharmaceutical compositions suitable for
intramuscular ~tlrnini~tration, comprising a medium-chain triglyceride as a carrier and
as an active ingredient an effective analgesic amount of sufentanil. Said compositions
are particularly useful in veterinary medicine and give a constant sustained release of
sufentanil over a period ranging from 12 to 48 hours, in particular 2~ hours~ and retain
all advantageous properties of the known short-acting sufentanil compositions.
Therapeutic plasma levels can be achieved rapidly and maintained for the above
periods.
The term "medium-chain triglyceride" as used hereinabove defines triglycerides of
saturated fatty acids, in particular of octanoic (caprylic) and dccanoic (capric) acid.
Said triglycerides correspond to the requirements laid down in the European
Pharmacopoeia EP93 (Triglycerida saturata media~. the British Pharmacopoeia BP88
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(Fractionated coconut oil) and the DAB 9 (Mittelkettige Triglyceride). Synonyms for
medium-chain triglyceride are, for example, fractionated coconut oil, thin vegetable oil,
7 mittelkettige Triglyceride, triglycerida mediocatenalia and are meant to be comprised
under the term '~medium-chain triglyceride" as used herein. A particular example of
said triglycerides is Miglyol 812~', a substantially colourless, odourless, tasteless,
neutral and stable, oil-like liquid with low viscosity. Comparable medium-chain
triglycerides are Estasan GT8-40 35/78~, Myritol 3 l 8~ and the like.
The term "sufentanil" as used in the specification and the claims herein comprises
sufentanil in the free base form and in particular the salts thereof which are soluble in
medium-chain triglycerides, especially salts of sufentanil with C8 22carboxylic acids,
including saturated and unsaturated C8 22carboxylic acids.
Said C8 22carboxylic acids are meant to comprise those carboxylic acids having from 8
to 22 carbon atoms such as, for example octanoic (caprylic), nonanoic (pelargonic),
decanoic (capric), undecanoic, lauric, tridecanoic, tetradecanoic (myristic),
pentadecanoic, hexadecanoic (palmitic), heptadecanoic, octadecanoic (stearic),
nonadecanoic, eicosanoic, heneicosanoic and docosanoic acid. Examples of
unsaturated C8 22carboxylic acids include oleic, linoleic, linolenic acid and the like.
Particular salt forming carboxylic acids are Cg 22carboxylic acids, preferably myristic,
palmitic, stearic and eicosanoic acid, more preferably stearic acid.
Most preferred are compositions wherein sufentanil and stearic acid are formulated in
stoechiometric amounts, i.e. sufentanil in its ( l: l) stearic acid salt form.
In the compositions according to the present invention the concentration of sufentanil in
free base form ranges from O. l mg/ml to l mg/ml, in particular from 0.3 mg/ml to 0.
mg/ml. Preferably, the concentration of sufentanil in free base form is 0.5 mg/ml.
3û
If desired, other active ingredients may be incorporated in the present compositions,
such as, for example, antimicrobials, antioxidizing agents or a combination thereof, e.g.
methyl parahydroxy benzoate, ethyl parahydroxybenzoate, salicylic acid, benzoic acid,
benzyl alcohol, butylhydroxytoluol, butylhydroxyanisole, propylgallate, ascorbyl-
palmitate, oc-tocopherol and the like. The individual concentration of said other active
ingredients in the present compositions is small, in general less than 2% (w/w).
Preferred compositions contain an appropriate amount of an antimicrobial, more in
particular. b~nzyl alcohol, and/or an appropriate amount of an antioxidizing agent such
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as, for example, butylhydroxytoluol, butylhydroxyanisole, propylgallate, ascorbyl-
palmitate, oc-tocopherol or a combination thereof.
Preferably, BHT (also known as butylated hydroxytoluene, butylhydroxytoluol or
2,6-di-tert-butyl-4-methylphenol) is used as an antioxidizing agent in an amountbetween 0. l and l mg/ml, in particular 0.25 mg/ml.
For preparing the compositions of the present invention, the active ingredient sufentanil
in its free base forrn or in its salt forrn as defined hereinabove, is intimately mixed with
a medium-chain triglyceride. Compositions comprising a salt of sufentanil with acarboxylic acid as defined hereinabove may also be prepared by intimately mixing said
carboxylic acid in the medium-chain triglyceride at a temperature ranging between
room temperature and 60~C, preferably between 40~C and 50~~, prior to intimatelymixing the active ingredient sufentanil in its free base form. Where appropriate, one or
more other active ingrcdients as defined hereinabove may be added to the admixture.
The thus obtained solutions are then brought to the final volume by the addition of
medium-chain triglyceride as required. l he addition of the required amount of the
medium-chain triglyceride may also be performed at an earlier time during thc
preparation procedure. The resulting oil solution of sufentanil may be sterilized by
filtration and filled in sterile ampoules. If desired, the resulting oil solution may be
filled in said sterile ampoules under an inert atmosphere such as~ for example. oxygen-
free nitrogen. Optionally, said ampoules may be made of amber colored glass.
An interesting preparation procedure comprises the following steps
(a) intimately mixing a carboxylic acid with a medium-chain triglyceride;
(b) intimately mixing sufentanil in free base form with a solution of a carboxylic acid
in a medium-chain triglyccride;
(c) intimately mixing one or more acti~ e ingredients with a solution of a carboxylic
acid and sufentanil in free base form in a mcdium-chain triglyceride;
(d) filtering a solution of a carboxylic acid and sufentanil in free base form and one or
more other active ingredients in a medium-chain triglyceride under sterile
conditions;
(e~ filling a filtered solution of a carboxylic acid and sufentani] in frec base form and
one or more other active ingredients in a medium-chain triglyceride in ster;le
ampoules.
The present compositions may be formulated in dosage unit forms Ol in multi-dosecontainers. It is especially advantageous to formulate the present composition.s in multi-
.
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dose containers. A multi-dose container as used herein refers to a physically discrete
container containing between l and lO ml, more preferably between 2 ml and 5 ml, of
one of the present compositions, and from which multiple unitary dosages may be
taken. A multi-dose container may have the advantage that a physician or a
-~ 5 veterinarian can select on the basis of the diagnosis of the subject to be treated the
appropriate amount, and if desired, that the multi-dose container may be stored and
used afterwards to treat the same or a different subject.
The present invention further relates to the pharmaceutical compositions as defined
hereinabove for use as an analgesic. In particular, the present invention relates to the
use of the present pharmaceutical compositions for preparing a medicament to treat
animals suffering from acute pain, more in particular post-operative pain.
Pain as used herein relates to post-operative pain following surgery, including dental
surgery; cancer pain; pain occurring while a veterinary surgeon performs an
intervention which does not require general anesthesia such as, for example, in case a
veterinary surgeon treats an ear infection; post-traumatic pain and the like instances of
acute pain.
Thus, the present invention provides a method of inhibiting pain, particularly acute
pain, more in particular post-operative pain, in an animal, in particular companion
animals, comprising ~mini.~tering intramuscularly to said animal a therapeutically
effective amount of a composition as defined hereinabove.
The intramuscular injection of the present compositions may be ~lministered just prior
to surgery or at the end of surgery, preferably during the carly postoperative period.
Said injection can conveniently be given in, for example, the musculus gluteus with, for
example, the use of an appropriate intramuscular needle with long bevel.
30 Companion ~nim~l.s as used herein are meant to include all ~nim~l.c that are not used for
the produclion of food. ~xamples of companion animals are dogs, cats and the like.
In order to achieve rapidly therapeutic plasma levels and to maintain thesc for extended
periods (if required) without undue side-effects such as respiratory depression, and,
35 depending on the species, it is contemplated that an effective amount of sufentanil
would range from 25 ~g/24 h to 25 mg/24 h, preferably from lO0 ,ug/24 h to lO mg/24
h of the active ingredient sufentanil in free base form, in order to obtain effective
analgesia with therapeutic plasma levels in the range of from 0.3 ng/ml to 3 ng/ml, in
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particular from 0.85 ng/ml to 1.5 ng/ml. Taking into account the body weight of the
subject to be treated, said required therapeutic plasma levels, and hcnce, the desired
clinical effects can be obtained by ~-lministering intramuscularly a dose ranging
between 25 ~g/kg body weight to 75 ~g/kg body weight, preferably a dose ranging
5 between 35 ~g/kg body weight to 70 ~g/kg body weight, more preferably a dose of
50, Lg/kg body weight of the active ingredient sufentanil in base form. Using a
composition comprising 0.5 mg/ml of sufentanil in free base forrn, e.g., an animal
weighing about 50 kg should receive about 5 ml of the composition, animals weighing
about 5 kg should receive 0.5 ml of the composition. Obviously these doses may be
10 lowered or increased, depending on the severity of the pain, the individual response of
the animal and the re~uired duration of effective analgesia. Further, if deemed
necessary, the present composition may be ~flmini~tered repeatedly at appropriate
intervals, e.g. at 12 hour or longer intervals, preferably at 24 hours intervals.
15 Pharmacokinetic studies as presented in the experimental part B hereinafter show that
therapeutic plasma concentrations may be obtained soon after injection of a 0.5 mg/ml
solution at a dose ranging between 35 ,ug/kg body weight and 70 ~g/kg body weight,
and are maintained for up to 48 hours after injection.
20 The following examples are intended to illustrate the present invention and not to limit
the scope thereof.
Experimental part
A. Preparation of the com~ositions
25 Formula F. l: Injectable solution - 0.5 m~/ml
Miglyol 812(~ (500 grams) was stirred at 46~C and stearic acid ~ } .85 grams) was added.
Stirring was continued for 30 minutes. While stirring~ the solution was diluted witl
Miglyol 812~) (4140 grams). The resulting solution was allowed to cool to room
temperature, and sufentanil in its free base form (2.5 grams) was added. Stirring was
30 continued for 16 minutes. Benzyl alcohol (75 grams) was added while stirring at room
temperature. The resulting solution conlaining 0.5 mg/ml of the active ingredient
sufentanil was filtered under sterile conditions and filled in sterile ampoules.
Hence, the F. l formulation has the following composition:
35 Sufentanil 0.5 m~
Stearic acid 0.37 mg
Benzyl alcohol lS m~
Miglyol 81~'~' 928 m~
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In a simil~r way, the following compositions were prepared:
Formula ~.2: In~ectable solution - 0.4 m~/ml
Sufentanil 0.4 mg
Stearic acid ().2g4 mg
Miglyol 812~ 928 mg
Formula F.3: Injectable solution - 0.2 m~/ml
Sufentanil 0.2 mg
Stearic acid 0.147 mg
Miglyol 812~ 928 mg
Formula F.4: Injectable solution - 0.5 m~:/ml
Sufentanil 0.5 mg
Stearic acid 0.37 mg
Benzyl alcohol 15 mg
BHT 0.25 mg
Miglyol 812~) 928 mg
B. Pharmacokinetic studies: Plasma kinetics of sufentanil in bea~le do~s after sin~le
20 intramuscular ~tlrnini.~tration of a sustained release formulation of sufentanil.
Dosing Three groups of seven male beagle dogs, weighing between 11 and 20 kg,were used in the experiment. A first group received a single intramuscular
dose of 35 mg/kg body weight by injection of a 0.5 mglml sufentanil
solution in Miglyol 812~) (Formula F. l as described in the experimental part
A) in the thigh muscle. A second group received under the same conditions
a single intramuscular dose of 50,ug/kg body weight, and a third group
received under the same conditions a single intramuscular dose of 70 ,ug/kg
body weight. Owing to the precision of the dosing syringe (0.1 ml),
administered doses differed less than I % from the intended dose.
Sa)7lpling Blood samples (5 ml on heparin 15-18 IU/ml blood) were taken from a
jugular vein from the sufentanil treated dogs. Sampling was performed
before (0 hours) and at 15, 30, 45, 60 and 90 minutes and at 2, 3, 4, 6, 8, 12,
24, 48 and 72 hours after dose administration. The blood samples were
centrifuged at 3000 rpm for 10 minutes to allow plasma separation.
~ 35 AnalYsis Plasma samples were analyzed for sufentanil using a l?IA mcthod as
described in Woestenborghs et al., Anesthesiology 1994, 80, 666-670.
Mean plasma concentrations ~in ng/ml) per dose level and per sampling
time werc calculated and al-e listed in Table l.
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Table I
Post-dosing time (hours) plasma conccntration per dosage level (ng/ml)
35,ug/kg SO,ug/kg 70,ug/kg
O S 0.050 ~ 0.050 < 0.050
0.25 0.194 0.532 0.331
0.5 0.342 0.727 0.498
0.75 0.388 0.771 0.600
0.478 0.808 0.734
1.5 0.484 0.782 0.839
2 0.575 0.906 1.04
3 0.712 1.05 1.3
4 0.793 1.12 1.67
6 0.929 1.16 2.17
8 0.893 1.13 1.91
12 0.843 1.10 1.61
24 0.440 0.718 0.849
48 0.142 0.205 0.360
72 < 0.050 < 0.050 0.095
