Title of Invention

"AN ANALGESIC PREPARATION CONTAINING MORPHINE AND NIMODIPINE AND A PROCESS FOR PREPARATION THEREOF "

Abstract This invention relates to an analgesic preparation, containing morphine and nimopidine dissolved in the solution containing polyethylene glycol, physiological saline and absolute ethyl alcohol present in the ratio of 2:2:1 respectively. The invention further provides for a process for preparation of analgesic preparation containing morphine and nimopidine wherein nimopidine is dissolved in a solution of polyethylene glycol, physiological saline and absolute ethyl alcohol.
Full Text FIELD OF INVENTION
This invention relates to an analgesic preparation containing morphine and nimodipine.
BACKGROUND OF INVENTION
Intracisternal administration of calcium ion was first observed to antagonize morphine induced analgesia. Later, it was reported that both calcium content and uptake of calcium by synaptosomes are decreased after acute administration of opioids. This could be correlated with the fact that one of the direct opioid-induced neuronal responses is an inhibition of voltage-gated calcium channels (VGCCs) leading to decreased neurotransmitter release.
However, the use of morphine decreases the nerve impubes binding on to specific µ receptors, which are on the sensory nerves, µ receptors are present only on the posterior side, and thus morphine builds only to the receptors and hampers the pain sensation from pursuing on to the brain. It has been reported that
As described herein above, a high concentration of morphine does have side effects, such as respiratory depression & urinary retention and hypotension.
It is known that calcium channels are present both on the posterior and as well as the anterior. However, in case doses of nimodipine has the
disadvantage that it binds both to the sensory and motor nerves. Motor nerves activate the muscle and gets paralyzed in the presence of encases doses of nimodipine. It has been reported by L.Jacobsen et.al in Anesth Analg 1988 November. Respiratory depression after 2.5 mg was more profound than after 1 mg, and produced apnea necessitating large-dose naloxone therapy. Pruritus was unique to intrathecal morphine administration, but nausea, vomiting and urinary retention were common in all the groups. It was included in such a population that no ideal dose of intrathecal morphine exists because, minor adverse affects are evident. Doses between 0.3 and 1 mg, however, should provide good analgesia free from the major complication, respiratory depression. It has also been reported by S.M et.al in Anesth Analog 2004 that intraoperative extubation and intense postoperative analgesia after OPCAB can be achieved with large doses of ITM supplementing general anthesia. A delayed respiratory depression rate of 5.7% suggest that patients receiving large doses of ITM require overnight respiratory monitoring.
OBJECTS OP THE INVENTION
An object of this invention is to propose a novel analgesic composition having an increased analgesic response.
Another object of this invention is to propose a novel analgesic composition having an increased analgesic response which is no longer attended with the disadvantage as associated with the known arc.
Still another of this invention is to propose a novel analgesic composition having an increased analgesic response and is effective.
Yet another of this invention is to propose a novel analgesic composition having an increased response which does not have any side effects
DESCRIPTION OF INVENTION
According to this invention there is provided an analgesic composition comprising morphine and nimodipine dissolved in a solution containing polyethylene glycol and wherein the ratio of morphine to nimodipine is 1:1 to 1:5.
In the present invention nimodipine was administered along with morphine through intrathecal injections. The analgesic response of the combination was compared with that of morphine and nimodipine individually.
Thus, reference is made to the accompanying drawings, and wherein Fig. 1 shows the percentage response with respect to time. Graph S shows the response with respect to saline. Graph C shows the response with respect to nimodipine and graph A shows the response with respect to morphine. Graph B shows the response with respect to the composition of the present invention. Graph B clearly reflects that a better percentage response is achieved with the composition of the present invention.
Fig 2 of the accompanying drawings shows the tailflick response or latterly with respect to time. Graphs S and A to C have the same representation hereinabove.

Fig 3 of the accompanying drawings illustrates the analgesic response or tailflick threshold with respect to time in mice. Graph B once again clearly reflects that the best response is received with the composition of the present invention and wherein intrathecal morphine and nimodipine are injected into the mice. Graph A is intrathecal morphine. Graph C is subcutaneous morphine and intra-peritoneal nimodipine and graph A is only subcutaneous morphine.
Fig. 4 of the accompanying drawings illustrates the enhanced analgesic response or the tail flick threshold using a concentration of morphine and nimodipine at a ratio of 1:2 for graph B and a ratio of 1:1 for graph B.
The present invention will be understood from the following example
Example
Adult male Wistar rats (n=27) weighing 200-250 gm were used for the experiment. They were housed in well ventilated cages and provided with water and food as libitum.
The animals were divided into four groups: Group I (G I, n=8) received 5ug morphine, Group II (n=9) received 5µg morphine and nimodipine, GUI (n=9) received 5µg of nimodipine and G IV (n=5) received normal saline. However, the animals were tested in small groups of 2 to 3 animals at one time. Additional animals (n=ll) were used for standardization of the doses of morphine and nimodipine. All the drugs were given intrathecally in a total volume of 10 µl.
Intrathecal morphine was given at various does (0.2, 0.5, 1, 2, 5, 7.5 and 15 ug) initially. With 5 µg morphine, the analgesic response was reaching the

cutoff time of 10 s and a consistent response was obtained. Similarity, no response was observed with 1 µg nimodipine. However, response was obtained with 5 µg nimodipine. Thus, these does were selected for the study.
Nimodipine was dissolved in a solution of polyethylene glycol, Physiological saline (0.9% weight/volume sodium chloride solution in distilled water) and absolute ethyl alcohol, which together henceforth known as vehicle, in 2:2:1 ratio under dim light as it is light sensitive. Morphine and nimodipine as a composition was administered.
The vehicle containing nimodipine is initially mixed in a vortex for 5 min. later, it is exposed to ultrasonication using a probe ultrasonicator (130 Watt) for 5 min. The ultrasonicator generates high intensity vibrations which breaks down the nimodipine particles into extremely small sizes and causes it to dissolve into the vehicle. The entire procedure needs to e done in a sterile environment and in dim light condition as nimodipine is light sensitive (decomposes under light).
The assessment of sensitivity to noxious thermal stimuli was done by the tail flick test. The animal was placed in a restrainer and the terminal part of the tail was exposed to heart sours (UGO basile). The time of flicking of the tail was taken as the response time. It was measured every 15 min after administration of the drugs till it reached baseline. All the selected animals had baseline latency between 2-4 s. The cutoff time was 10 s to prevent damage to the tail. The response time was calculated as percent maximum possible effect (% MPE) = (Post drug latency baseline latency)/ (Cutoff time-baseline latency) X 100.

The rats were observed for side effects like motor incoordination, pruritus, respiratory distress and general behavioral signs of calcium channel blockade.
Administration of morphine (G 1; 5 µg) alone produced an increase in the tail flick response which reached cutoff level at 30 min and persisted till 1 h (Fig. 1). Thereafter it decreased gradually to reach baseline at 4:15h. In contrast, co-administration of morphine and nimodipine (G II; 5 µg of each) produced a sharp response which reached cutoff level at 15 min. It remained at the level till 45 min before declining but again reached cutoff level at 1:15 h. It declined very slowly with intermittent temporary increases at 2:30 h, 3:15 h and at 4:45 h to reach just above baseline at 7:00 h. The response time of G II was significantly above that of G I at 3:30, 4:00 to 5:30, 6:30 to 6:45 h.
When MPE values were compared, the differences between G I and G II were similar except that the difference was not significant at 6:30 h (Fig. 2).
In G III, the tail flick response had reached cutoff limit of 10 s at 15 min and thereafter decreased to reach close to baseline at 2 h, however, the values were significantly raised above basal values only between 15-45 min (Fig 3).










WE CLAIM
1. An analgesic preparation, containing morphine and nimopidine dissolved in the solution containing polyethylene glycol, physiological saline and absolute ethyl alcohol present in the ratio of 2:2:1 respectively.
2. An analgesic preparation, as claimed in Claim 1, wherein morphine and nimopidine is present in the ratio between 1:1 to 1:5.
3. An analgesic preparation as claimed in Claim 1, wherein physiological saline is obtained by dissolving, 0.9% weight/volume, sodium chloride in distilled water.
4. A process for preparation of analgesic preparation containing morphine and nimopidine wherein nimopidine is dissolved in a solution of polyethylene glycol, physiological saline and absolute ethyl alcohol.
5. A process for preparation of analgesic preparation, as claimed in claim 4, wherein nimopidine is first mixed in a solution of polyethylene glycol, physiological saline and absolute ethyl alcohol for 4-7 minutes and then exposed to ultrasonification using an ultrasonic probe (130 watt) for 5-8 minutes preferable 5 minutes.
6. A process for preparation of analgesic preparation, as claimed in
claim 5, wherein both mixing and ultrasonification is done in a
sterile environment and under dim light.
7. An analgesic preparation morphine and nimopidine and a process of preparation thereof substantially as herein described.

Documents:

1535-DEL-2004-Abstract-(11-04-2011).pdf

1535-del-2004-Abstract-(29-10-2010).pdf

1535-del-2004-abstract.pdf

1535-DEL-2004-Claims-(11-04-2011).pdf

1535-del-2004-Claims-(29-10-2010).pdf

1535-del-2004-claims.pdf

1535-del-2004-Correspodence Others-(22-07-2011).pdf

1535-del-2004-Correspondence Others-(24-05-2011).pdf

1535-DEL-2004-Correspondence-Others-(11-04-2011).pdf

1535-DEL-2004-Correspondence-Others-(18-03-2011).pdf

1535-del-2004-Correspondence-Others-(29-10-2010).pdf

1535-del-2004-correspondence-others.pdf

1535-del-2004-correspondence-po.pdf

1535-DEL-2004-Description (Complete)-(11-04-2011).pdf

1535-DEL-2004-Description (Complete)-(18-03-2011).pdf

1535-del-2004-Description (Complete)-(29-10-2010).pdf

1535-del-2004-description (complete).pdf

1535-del-2004-drawings.pdf

1535-DEL-2004-Form-1-(11-04-2011).pdf

1535-del-2004-form-1.pdf

1535-del-2004-form-19.pdf

1535-DEL-2004-Form-2-(11-04-2011).pdf

1535-del-2004-form-2.pdf

1535-del-2004-Form-3-(29-10-2010).pdf

1535-del-2004-gpa.pdf


Patent Number 248796
Indian Patent Application Number 1535/DEL/2004
PG Journal Number 34/2011
Publication Date 26-Aug-2011
Grant Date 25-Aug-2011
Date of Filing 18-Aug-2004
Name of Patentee ALL INDIA INSTITUTE OF MEDICAL SCIENCE
Applicant Address ANSARI NAGAR, NEW DELHI-110 029, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 HIMANSHU GUPTA ANSARI NAGAR, NEW DELHI-110 029, INDIA.
2 SUBRATA BASU RAY ANSARI NAGAR, NEW DELHI-110 029, INDIA.
3 SHASHI WADHWA ANSARI NAGAR, NEW DELHI-110 029, INDIA.
4 DILIP VERMA ANSARI NAGAR, NEW DELHI-110 029, INDIA.
PCT International Classification Number A61K 31/485
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA