DESCRIPTION
FIELD OF THE INVENTiON
The present invention is related to a sterile pharmaceutical formulation for the
management of moderate to severe pain. The present invention describes the
formulation containing Tramadol ready-to-use infusion.
PRIOR ART TO THE INVENTION
Tramadol is a centrally-acting synthetic an analgesic of the aminocyclohexanol
group with opioid-like effects. It is not derived from natural sources, nor is it
chemically related to opiates. Although pre-~linical testing has. not completely
explained the mode· of action, at least two complementary mechanisms appear
applicable: binding to IJ'"Opioid receptors and inhibition of re-uptake of nor-
· adrenaline and serotonin. The opioid-like activity of tramadol derives from low
affinity binding of the parent compound to IJ'"Opioid receptors and higher affinity
. binding of the principal active metabolite,_O-desmethyltramadol,: denoted M1, to
1-1-opioid receptors. In animal models, M1 is up to 6 times more potent than
tramadol in producing analgesia and 200 times more potent in 1-1-opioid binding.
The contribution to human analgesia of tramadol relative to M1 is unknown.
Both animal and human studies have shown that antinociception induced by
tramadol is only partially c:mtagoriised by the . opiate antagonist naloxone. In
addition, tramadol has been shown to inhibit re-uptake of noradrena line and
serotonin in vitro, as have some other opioid analgesics. These latter
mechanisms may contribute independently· to the overall analgesic profile of
tramadol. The analgesic effect is dose-dependent, but the relations hip between
serum concentrations and analgesic effect varies considerably between
individuals. In one study, the median serum concentration of tramadol required
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for effective post-operative analgesia was 300 ng/ml, with individual values
ranging from 20 to 990 ng/ml. Ap~rt from analgesia, tramadol. may produce
other symptoms similar to that of opioids including: dizziness, somnolence,
nausea, constipation, sweating and pruritus. However, tramadol causes
significantly less respiratory depression than morphine. In contrast to morphine,
tramadol has not been shown to cause histamine release. At therapeutic doses,
tramadol has no clinically significant effect on heart rate, left ventricular function
or cardiac index. Orthostatic changes in blood pressure have been observed.
Forty one patients undergoing open heart surgery were randomly assigned into
two groups; Fentanyl group (21 patients) and Tramadol group (20 patients).
Both groups received the same anaesthetic technique. Infusion of both drugs :,
started directly after the end of cardiopulmonary bypass and continued for 48·
·:hours after surgery. Fentanyl was given at a dose of 0.5-11Jg.kg-1'.h-1 by
continuous infusion for 48 hours, whil.e Tram. adol was infused at a dose of 0.1- ·
0.2 mg.kg1.h-. In addition, both. groups received 1 gm rectal paracetamol.every
six hours. Patients were assessed for the analgesic efficacy by 11-point verbal
rating scale (VRS), sedatiqn by Ramsay sedation scale and patients'
satisfaction with analgesia using a 1 00-point verbal rating scale, with 1 = highly
dissatisfied to 100 = highly satisfied [1.] at the following time points; 6h, 12h,
.24h, 36h and 48h after surgery. Both groups were matched as regard age, sex,·
bypass and ischemic times as well as to the type of .surgery and duration of
mechanical ventilation and hospital stay. No significant differer:Jces were
observed between groups as regard the analgesic efficacy, sedation scale and
satisfaction with the type of analgesia. However, 11 patients in tramadol group
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by Fisher's exact test). Also, 13 patients requested boluses of tramadol as
rescue analgesia 25-50 mg in tramadol group, while 8-patients required 25-50
tJg fentanyl in fentanyl group, p=0.121 by Fisher's exact test. (Shabaan Ali et.al)
Visual analogue scale of ·pain was measured both immediately after and 15
. minutes after the procedure. Stress hormones (ACTH, cortisol), blood pressure,
. and heart frequency were evaluated before~ during, and 15 minutes after the
procedure. In the tramadol· group, the visual analogue scale of ·pain wa~
significantly lower than in the placebo group 'both immediately after the
procedure and 15 minutes later. Basal levels of ACTH and cortisol did not differ
between the groups. In both groups, the ACTH levels remained unchanged
during the study,. and the cortisol levels were higher 15 minutes after the
procedure than before the procedure. Procedure time, heart. frequency, blood .·
pressure, and. adverse effects did· not differ between the groups. In parous
· ·women without uterine malformations, a treatment with tramadol before
hysteroscopy a~d ·endometrial biopsy appears to be capable of reducing the !; ·
pain and discomfort that are· associated with this procedure. (Fertil Steril 2007;
87:147-51. ©2007 by American Society for Reproductive Medicine.)
. The effects of long-term opioid intake on the development of tolerance, physical
dependence and psychological addiction are reduced with tramadol use. In an
experimental setting, it was demonstrated that even experienced opioid users
could not recognise tramadol in lower doses as an opioid, whereas in higher
doses they could recognise it, but did not "like" it, presumably due to its tricycliclike
properties. Hence, the incidence of abuse of tramadol is low in all post- .
marketing surveys; the FDA reports a rate of abuse in the range of 1 in 100,000
patient exposures. Furthermore, tramadol is not registered as _a controlled drug.
in any cou_nt~ .. ~o~eve~ this ~qe~ o_ot mean that its use in "at-risk" patients
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should be encouraged. Rare cases of withdrawal reactions after abrupt
discontinuation of tramadol have also been reported. (Abuse potential and
pharmacological comparison of tramadol and morphine. Drug & Alcohol Dep~ndence 1991.;
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27:7-~ 7, Prescription Pharmaceuticals and Biotechnology 1998; 60:4-5. Revisions of
Contemporary Pharmacotherapy 1995; 6:513-531.)
In the entire prior art, the infusion of tramadol was freshly prepared and the
exact dose of the tramadol was not" determined. Thus, there is a need· to
provide a sterile, stable, ready-to-use infusion which can be conveniently
administered to the patient.
. OBJECT OF THE INVENTION
The object of the present invention is to provide a formulation for the
'
management of Moderate to severe pain'.
Another object of the present invention ·is to manage the pain without seriqus
adverse effects.
Another object of the invention· is to provide a formulation not having
dependence .. ·
It is the further object of the present invention to provide safe and effectiv~
alternative in injectable analgesic in Moderate to severe pain.
Further object of the invention is to provide analgesic to the patients which are
unable to take the pain killer with mouth.
Another object of the invention is to provide a sterile, ready-to-use, stable
infusion.
It is the object of the invention to provide ·a formulation which has a faster onset
of analgesic action.
DETAILED DESCRITION OF THE INVENTION .
Tramadol is a centrally acting synthetic analgesic of the aminocyclohexanol
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group with opioid-like effects. Its mode of action is not completely understood
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but it appears to act by modifying transmission of pain impulses via inhibition of
noradrenaline and serotonin re-uptake and also by weakly binding to mu-opioid
. receptors.
In Australia it is marketed under the trade name Tramal and is available as
capsules (50mg), sustained release tablets (100mg, 150mg, 200mg) and
ampoules (1 00mg/2ml) for relief of moderate to severe pain.
On the basis or published evidence, tramadol app.ears to haVe reasonable dose
related efficacy in comparison with other opioid analgesics, with a relative lack
of respiratory depression, major organ toxicity or abuse potential.
Because of its side-effect profile in comparison with other analgesics, tramadol
· may have a role in patients who are intolerant of conventional opioid and other ;
non-opioid an9lgesics, those who have pre-existing cardiopulmonary disease,
such as the elderly or obese;. and those in whom c.odeine use is inappropriate.
In the acute and post operative settings, it may have a place in multi-modal
analgesia, where opioid and non~opioid drugs are given in combination to
achieve analgesia, with a reduction in the incidence and severity of side effects.
Similarly, in ch.ronic pain conditions, tramadol may be considered (as a single
agent or in combination) where non-opioid analgesics have proven ineffective
or where multimodal therapy might be advantageous in or.d. er to limit sideeffects
(eg where a reduction in NSAID dosage is desirable). The reduced
constipating effect of tramadol compared with other opioids may be useful in
· patients with chronic cancer pain, although nausea may be a dose-limiting side-
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effect and sustained-release .morphine is more effective in severe cancer pain.
Because of its extended duration of effect, the sustained release formulation
may provide convenience in ambulatory patients with chronic pain. However,
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studies of Jong-term use have not yet been reported and the potential for
serious drug-drug interactions with tramadol should not be under-estimated.
As a single agent, tramadol's place in therapy is likely to be limited by both cost
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and tolerability (particularly nausea). In the majority of patients it offers few
advantages at considerable additional cost. However, it may be a useful
alternative to other analgesics in selected patients with moderate to severe
pain. (A Position Statement of the NSW Therapeutic Assessment Group Inc.)
It is ~xtensively metabolised .. Only about 15-19% appears unchanged in the
urine. The production ·of the only active metabolite, · M1 (mono-odesmethyltramadol)
is dependent on the CYP2D6 isoenzyme of the cytochrome
. . . .
P-450 enzyme system and hepatic impairment res-ults in decreased metabolism .·:
of both the parent compound and the active metabolite. The clinical significance
.of this is unclear. However, patients who metabolise drugs poorly via CYP2D6
··may obtain ·reduced benefit from framadol due to reduced formation of M1 .' ·
M 1 binds to the mu recepte>r with greater affinity than tram·adol itself. The drug
reaches its peak serum concentration 1-3 hours after an oral dose (45 minutes
after an intramuscular injection).
The half life is in the order of 5-7 hours in young adults but may be two to three
times longer in patients with cirrh~sis and substantial hepatic impairment. ·
The half life of M1 is also about 6-8 hours. Excretion is impaired in patients with
renal or hepatic impairment. (Critical_ Assessment for NSW Therapeutic Assessment
Group Inc.)
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The formulation of the present invention is prepared in an aseptic environment
and is being stabilized with the help of suitable buffers,
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The buffers are required to maintain the pH of the formulation and should be
. compatible with the formulation.
The strength of Tramadol is 1 mg/ml to 25 rilg/ml in infusion dosage form.
The. dosage form is in ready-to:-use infusion so as to maintain sterility. till the
formulation is being administered to patient.
The buffering. agents used in the formulation are preferably the combination of
Sodium Citrate and Citric acid monohydrate.
The tonicity agent used to maintain the toniGity 'of the formulation is preferably
Sodium chloride.
The administration of the formulation through intravenous route will preferably
be in 10 minutes to 2 hours, more preferably 30 minutes to 60 minutes. ;
The infusion can be formula~ed, but not limited to, in the following manner:
STEP 01- Take 2200 liters Water for injections in compounding vesseL Purge
filtered nitrogen gas till end of the complete manuf~cturing process. . .
· STEP 02- Add and dissolve sodium chloride in Step-01', stir to 20 minutes·~md
ensure the clarity of the solution.
STEP 03- Add and dissolve sodium· citrate in Step-02. Stir to 20 minutes and
ensure the clarity of the solution·.
STEP 04"' Add and dissolve citric acid monohydrate in Step 03. Stir to 20
minutes and ensure the clarity of the solution.
STEP 05- Add and dissolve Tramadol t)ydrochloride in Step 04. Stir to 20
minut~s and ensure the clarity of the solution.
STEP 06- Chec~ the initial pH of the bulk solution of Step-05, pH limit 3.5 to 5.5.
STEP 07- Make up the volume of Step 06 to 2500 liters by adding sufficient
quantity of water for injections. Stir the solution. to .1 0 minutes.
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The above final formulation will lead to a concentration of tramadol 1 OOmg/1 00
ml and concentration of Sodium chloride will be 0.9% w/v .

CLAIMS
We claim:
1) A pharmaceutical formulation comprising Tramadol, along with other
excipients, in ready to· use infusion dosage form.
2) The infusion as claimed in claim 1 contains tramadol in the range of 50
mg/1 00 ml to 150 mg/1 00 mL
3) The other excipients as claimed in claim may include either sodium
citrate, or sodium chloride, or citric acid monohydrate or the combination
of above.
4) The formulation claimed in claim 1 may be used for the management of
moderate to severe pain.