FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
T. TITLE OF THE INVENTION:
"A NOVEL LIQUID RECTAL SPRAY DOSAGE FORM CONTAINING DICLOFENAC AND ITS PHARMACEUTIC ALLY ACTIVE SALTS"
2. APPLICANT:
(a) NAME: Lincoln Pharmaceuticals Limited
(b) NATIONALITY: Indian Company incorporated under the Companies
Act, 1956
(c) ADDRESS: Lincoln House, Science City Road, Sola,
Ahmedabad-380 060, Gujarat, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed:

TECHNICAL FIELD OF THE INVENTION;
The present invention relates to a novel liquid rectal spray dosage form comprising therapeutically effective amount of Diclofenac or its pharmaceutically active salts, in unique blend of solvents and co-solvents, for the treatment of pre- and post-operative pain, gynecological surgery and musculoskeletal disorders such as muscular pain, pain associated with arthritis, acute pain in renal colic and mild body ache.
BACKGROUND OF THE INVENTION:
Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) used to treat the inflammation and pain of musculoskeletal complaints, arthritis, osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis and juvenile forms of arthritis. It is also used to treat mild to moderate post-operative or post-traumatic pain, particularly when inflammation is also present, and is also effective against menstrual pain.
It is supplied in the form of its sodium or potassium salt in UK, India, US and China, while in some other countries only as its potassium salt. Diclofenac is available as a generic drug in a number of formulations. Over the counter (OTC) use is approved in some countries for minor aches and pains and fever associated with common infections.
Chemically, Diclofenac is 2-[2-[(2,6-dichlorophenyl)amino]phenyl]acetic acid having structural formula as follows:

Indian Patent No. 221180 (974/BOM/l 999) discloses the compositions and their method of preparation for topical applications. The composition includes a non-ionic surfactant as one of the excipients which comprises of transcutol, cremophor, tween and capryl

caprylic triglycerides. The composition further includes a chelating agent of a polyamine carboxylic acid, such as ethylenediamine tetraacetic acid (EDTA). Propylene glycol and benzyl alcohol have also been used. However, neither this patent discloses any specific example on liquid formulation nor it suggested any route of administration of the liquid (water insoluble) formulation.
US Patent No. 4711906 discloses aqueous, stable, relatively concentrated solutions of diclofenac, which contain a mixture of propylene glycol and polyethylene glycol in defined quantitative proportions. The solutions preferably contain a local anesthetic such as lidocaine and a reducing agent as stabilizer.
Japanese Patent Publication No. JP10077227 discloses a sustained release suppository of diclofenac sodium capable of manifesting an anti-inflammatory and analgesic effect for a long period by setting the concentration in blood to a specific condition.
Chinese Patent Publication No. CN1830430 discloses slow-release suppository of diclofenac sodium applied via rectum that contains proportionally diclofenac sodium, matrix and carbomer.
US Patent No. 6488954 discloses a liquid suppository composition comprising of diclofenac sodium, poloxamer and at least one polymer selected from the group consisting of polyethylene oxide and polyvinylpyrrolidone.
Rectal administration provides rapid absorption of the drug and may be an easy alternative to the intravenous route, having the advantage of being relatively painless. In this form, usually a drug is mixed with a waxy substance that dissolves or liquefies after it is inserted into the rectum. Because the rectum's wall is thin and its blood supply rich, the drug is readily absorbed.
In the prior art of the article titled, "Drug Delivery: Rectal Route'' by J. Howard Rytting and Joseph A. Fix, DOI: 10.1081/E-EPT-100001708, Watanabe et al. have reported improved rectal absorption with reduced mucosal irritation utilizing rectal gels comprising water-soluble dietary fibers, xanthan gum and locust bean gum.

Article titled, "Alternative Routes of Drug Administration-Advantages and Disadvantages (Subject Review)'' by American Academy of Pediatrics, published in Vol. 100 No.l, July 1997, pp. 143-152, discloses medications that may be administered by the rectal mucosal route for systemic effects. The major limiting factor is, however, the need to incorporate controlling agents designed to regulate drug release which would significantly increase the total size of the dosage form. Since adult rectal dosage forms are acceptable up to 2.5 g, the total drug load which can be formulated in a rectal controlled-release formulation can be 2-3 times that possible in an oral formulation.
Further, the rate of rectal transmucosal absorption is known to be affected by the
following factors:
Formulation (time to liquefaction of suppositories)
Volume of liquid
Concentration of drug
Length of rectal catheter (site of drug delivery)
Presence of stool in the rectal vault
pH of the rectal contents
Rectal retention of drug(s) administered
Differences in venous drainage within the rectosigmoid region
Anatomical differences in hemorrhoidal venous drainage of the rectum may substantially influence the systemic drug level achieved. Drugs administered high in the rectum (drained by the superior rectal veins) are usually carried directly to the liver and thus, are subject to metabolism. Drugs administered low in the rectum are delivered systemically by the inferior and middle rectal veins before passing through the liver.
None of the prior arts however discloses the administration of the active ingredient in liquid rectal spray dosage form.
In view of the above limitations involved in the drug uptake via rectal route, there still remains a need to develop an efficient drug delivery dosage form to be effectively administered to the subject. Accordingly, the present inventors have come up with a novel

drug deliver}' dosage form comprising of therapeutically effective amount of Diclofenac or its pharmaceutically active salts, in association with a unique blend of solvents and co-solvents, for the treatment of pre- and post-operative pain, gynecological surgery and musculoskeletal disorders such as muscular pain, pain associated with arthritis, acute pain in renal colic and mild body ache. Further, this new route of administration offers advantages over the conventional methods in that the administration is easy, relatively painless, minimizes the contact of the delivery system to the subject thus avoiding any further complication due to infections.
Therefore, the object of the present invention is to develop an effective drug delivery dosage form that ensures uniform dose dispensing via the rectal route.
The other object of the present invention is to develop the drug delivery system in a convenient spray form that releases the drug in the form of fine droplets in the rectal orifice thus providing better patient compliance.
SUMMARY OF THE INVENTION:
In accordance with the above, the present invention provides a liquid rectal spray comprising therapeutically effective amount of Diclofenac or its pharmaceutically active salts, for the treatment of pre- and post-operative pain, gynecological surgery and musculoskeletal disorders such as muscular pain, pain associated with arthritis, acute pain in renal colic and mild body ache.
In a preferred aspect, the present invention provides a liquid rectal spray comprising therapeutically effective amount of Diclofenac or its pharmaceutically active salts, in unique blend of solvents and co-solvents which gives a systemic effect of Diclofenac via rectal route, for the treatment of pre- and post-operative pain, gynecological surgery and musculoskeletal disorders such as muscular pain, pain associated with arthritis, acute pain in renal colic and mild body ache.
In an aspect, the composition of the present invention affords a better patient compliance, when compared to intramuscular injections and complicated application of rectal

suppositories or tablets, as the present formulation is in solution form that can be effectively administered by spraying method.
DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The human rectum represents a body cavity in which drugs can be easily introduced and retained and from which absorption is well possible. There are important therapeutic reasons why it is sometimes preferable to give a drug rectally rather than orally, e.g. in cases of nausea and vomiting. The rectal route offers the same possibilities as the oral route, but the influence of the formulation seems to be very critical.
The present invention thus provides a unique delivery system that ensures uniform dose dispensing via the rectal route. Accordingly, in an embodiment, the present invention provides liquid rectal spray formulation comprising therapeutically effective amount of Diclofenac or its pharmaceutically active salts, in association with a unique blend of solvents and co-solvents which gives a systemic effect of Diclofenac for the treatment of pre- and post-operative pain, gynecological surgery and musculoskeletal disorders such as muscular pain, pain associated with arthritis, acute pain in renal colic and mild body ache. Accordingly, the total volume of Diclofenac rectal spray is 100 mg/0.4 ml.
Diclofenac is well absorbed via rectal route as compare to oral and transdermal route. Rectal cavity contains high vascularity for drug absorption. The present dosage form delivers micron size droplets to the large surface area of rectal cavity for excellent drug absorption.
In a preferred embodiment, the present invention provides a spray dispenser comprising therapeutically effective amount of Diclofenac or its pharmaceutically active salts in association with a unique blend of solvents and co-solvents. The composition is filled in a

container assembly which is specifically designed to give drug dispensing in to the rectal orifice in unit dosage form.
In an embodiment, the present invention is in a liquid rectal spray form that does not crystallize at very low temperature during storage and is dispensed in mist form that covers large area of rectal cavity and which requires very small amount of dispensed volume, thus increasing the bioavailability.
Accordingly, the current formulation comprises of organic and inorganic salts of Diclofenac as the active ingredient in association with a blend of solvents and co-solvents along with suitable pharmaceutically acceptable excipients. The organic salts can be selected from diethyl amine, t-butylamine, Dimethylethanolamine etc. The inorganic salts are selected from sodium or potassium. Diclofenac or its pharmaceutically acceptable salts is present in an amount of 50 mg to 100 mg/spray or 12.5% to 25.0% w/v.
Suitable solvents and co-solvents are selected from group of poly ethylene glycol 400, poly ethylene glycol 4000, poly ethylene glycol 6000, propylene glycol, glycofurol, ethyl alcohol, solutol, labrasol, capmul, captex, ethyl alcohol etc. The said solvents and co-solvents are present in an amount of 10% to 80% w/w.
The ratio of Diclofenac and solvents/co-solvents is 1: 0.4: 0.6: 0.4.
Suitable pharmaceutically acceptable excipients are selected from group of preservatives, anti-oxidants, chelating agents, osmotic agents, permeation enhancers, mucoadhesive polymers, surfactants, buffering agents and the like.
Suitable preservatives are selected from sodium methyl paraben, sodium propyl paraben, methyl paraben, benzyl alcohol, propyl paraben in an amount of 0.1 to 0.5 % w/v.
Suitable anti-oxidants are selected from sodium sulphite, butylated hydroxytoluene, butylated hydroxyanisol, Vitamin C in an amount of 0.05 to 0.2 % w/v.
Suitable chelating agent is used as Disodium edetate in an amount of 0.05 to 0.2 % w/v.

Suitable osmotic agents are selected from mannitol, sodium chloride in an amount of 0.5 to 5 % \v/v.
Suitable permeation enhancers are selected from isopropyl myristate, transcutol in an amount of 0.5 to 5 % w/v.
Suitable mucoadhesive polymers are selected from group of polyvinyl pyrollidone K 30, hydroxy propyl methyl cellulose, hydroxy ethyl cellulose, hydroxy propyl cellulose. The said mucoadhesive polymers are present in an amount of 1% to 10% w/v.
Suitable surfactants are selected from group of Cremophor EL, Cresmer RH 40, Tween 80, Span 80. Tween 20, Tween 60, Span 60, Span 40 are present in an amount of 5% to 20%
w/v.
Suitable buffering agents are selected from group of tris buffer, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium citrate are present in an amount of
0.5% to l%w/v.
In another embodiment, the novel mode of delivery of Diclofenac via rectal route in combination with unique blend of solvents and co-solvents, has better patient compliance than intramuscular injections and complicated application of rectal suppositories or tablets.
The two actuation of Diclofenac rectal spray were administered at the time of pain. Not more than two actuations should be administered in a single day.
In a further embodiment, the present invention provides a method of treating muscular pain, pain associated with arthritis, acute pain in renal colic and mild body ache, which comprises administering ;an effective amount' of the spray composition to the subject affected by pre- and post-operative pain, gynecological surgery and musculoskeletal disorders such as muscular pain, pain associated with arthritis, acute pain in renal colic

and mild body ache. The subject mentioned herein is human. 'An effective amount' of the spray composition is 100 mg of Diclofenac sodium.
In another embodiment, the invention provides use of the 'spray composition of the invention comprising Diclofenac or its pharmaceutically active salts' intended to reduce symptoms associated with pre- and post-operative pain, gynecological surgery and musculoskeletal disorders such as muscular pain, pain associated with arthritis, acute pain in renal colic and mild body ache.
CLINICAL STUDY:
Clinical trial is conducted to study improved efficacy of rectal spray comprising Diclofenac of the present invention (described in example 1), on human subjects suffering from pre- and post-operative pain, gynecological surgery and musculoskeletal disorders such as muscular pain, pain associated with arthritis, acute pain in renal colic and mild
body ache.
The aforesaid trial has been performed according to ICH - GCP guidelines and schedule Y. Total 3 0 patients were screened and 9 patients were enrolled and all the nine patients completed the study successfully. Patients were informed about the spray, dose and the way of administration at the time of enrollment. There was no serious or adverse event occurred throughout the trial. Patients Case Report Forms (CRF) was filled during and after completion of the dosage regimen of three alternative days for each patient respectively. The data was collected, compared and analyzed from the Case Report Form (CRF).
Patients received Diclofenac 100mg/0.4ml rectal spray (2 sprays) once daily at the time of pain. Efficacy was evaluated by suppression of pain. All patients have completed the study successfully, except one which was considered as treatment failure. No adverse event occurred during the study.

The study shows that Diclofenac rectal spray is highly effective in patients suffering from pre- and post-operative pain, gynecological surgery and musculoskeletal disorders such as muscular pain, pain associated with arthritis, acute pain in renal colic and mild body ache.
The following example, which includes preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Examples: Example: 1

SR.NO. INGREDIENTS LABEL CALIM (mg/0.4ml)
1. Diclofenac Sodium 100
2. Cresmer RH 40 72
3. Propylene Glycol 40
4. Glycofurol 60
5. P.V.P K 30 4
6. Ethyl alcohol 40
7. Tris buffer 0.6
8. Purified water Q.S
Total volume 0.4 ml
Manufacturing Procedure:
Step 1: Weighing accurately Propylene Glycol, Cresmer RH 40 and Glycofurol in
manufacturing vessels and stiring well for 10-15 min;
Step 2: weighing accurate Diclofenac Sodium and dissolving in to step 1 with application
of heat up to 70°C; after getting clear solution, allowing the solution to cool up to
37±2°C;
Step 3: dissolving separately PVP K 30 in Ethyl Alcohol and transferring it in to step 1;

Step 4: dissolving separately Tris buffer in purified water and transferring it in to step 1,
check the final pH it should be 8.5. (Limit 8.0 to 9.0);
Step 5: making up the final volume with purified water.
In all the above steps, checking the clarity of the solution to maintained clear solution.
The addition and mixing is done in closed vessel.
Example 2:

SR.NO. INGREDIENTS LABEL CALIM (mg/0.4ml)
L Diclofenac diethyl amine 116
2. Tween SO 50
3. Poly ethylene glycol 400 115
4. Benzyl alcohol 4
5. Disodium Edetate 1
6. Propylene Glycol 30
7. Tris buffer 0.6
8. Purified water Q.S
Total volume 0.4 ml
Manufacturing Procedure:
Step 1: Weighing accurately Propylene Glycol, Poly ethylene glycol 400 and Tween 80
in manufacturing vessels and stiring well for 10-15 min;
Step 2: weighing accurate Diclofenac diethyl amine and dissolving in to step 1 with
application of heat up to 70°C; after getting clear solution, allowing the solution to cool
up to 37±2°C;
Step 3: adding benzyl alcohol in to step 1;
Step 4: dissolving disodium edetate in purified water and adding to manufacturing vessel;
Step 5: dissolving separately Tris buffer in purified water and adding it in to step I, check
the final pH it should be 8.5. (Limit 8.0 to 9.0);
Step 6: making up the final volume with purified water.

In all the above steps, checking the clarity of the solution to maintained clear solution. The addition and mixing is done in closed vessel.
Example: 3

SR.NO. INGREDIENTS LABEL CALIM (mg/0.4ml)
1. Diclofenac potassium 110
2. Cresmer RH 40 56
3. Poly ethylene glycol 400 115
4. Ethyl alcohol 3
5. Hydroxyl ethyl cellulose 2
6. Propylene Glycol 30
7. Tris buffer 0.6
8. Purified water Q.S
Total volume 0.4 ml
Manufacturing Procedure:
Step 1: Weighing accurately Propylene Glycol, Poly ethylene glycol 400 and Cresmcr
RH 40 in manufacturing vessels and stiring well for 10-15 min;
Step 2: weighing accurate Diclofenac potassium and dissolving it in to step 1 with
application of heat up to 70°C; after getting clear solution, allowing the solution to cool
upto37±2°C;
Step 3: dissolving separately hydroxy! ethyl cellulose in ethyl alcohol and transferring it
in to step 1;
Step 4: dissolving separately Tris buffer in purified water and adding in to step 1, check
the final pH it should be 8.5. (Limit 8.0 to 9.0);
Step 5: making up the final volume with purified water.
In all the above steps, checking the clarity of the solution to maintained clear solution.
The addition and mixing is done in closed vessel.

Example 4:
Clinical trial to study improved efficacy of Diclofenac sodium rectal spray (as described
in Example 1)
Investigational Product: Diclofenac sodium
Dose: Diclofenac sodium 100 mg/0.4ml
No. of Patients: 9
Mode of administration: Rectal
Duration of treatment: 1 day
Result:
Table 1: Percentage of patients showing reduction in pain score after treatment with Diclofenac Rectal Spray

Total Patients Patients available after 6 hr No Pain Mild Pain
9 9 88.88% U.12%

Assessment of the acceptability of the rectal route as a mode of drug
administration was based on the following criteria:
Patient's apprehension regarding the route of drug administration
Patient's cooperation during per-rectal insertion of drug
Complaints during or after drug administration
The acceptability was assessed as Excellent, Good, Fair and Poor (Table 2)
From the acceptability scale (Table 2) presents the acceptability to the route of
administration, as good in most cases.
Apprehensive Co-operation Complaints
Excellent - - -
Good + + -
Fair + + -
Poor + - -
Table 2: Acceptability Scale
Side effects were few (Table 3) and none of the patient experienced severe side effects so as to exclude from the study.

Table 3: Side effects

Side effects Diclofenac sodium rectal spray patients group (n=9)
Local pain (during pre-rectal drug insertion) 0
Local burning sensation (after drug insertion) 0
Increased bowel movement 0
Acid-peptic disorders 0
Post-operative nausea and vomiting 1
Conclusion:
Hence, Diclofenac sodium 100 mg/0.4 ml rectal spray preparation has below mentioned certain advantages as compared to other analgesic preparations in the market:-
• Because of container having metered dosing spray nozzle, it can deliver accurate dose of drug in mist form to cover large surface area of rectum so as to achieve optimum systemic concentration of Diclofenac through direct absorption from rectum surface in short period of time. While other dosage form like Diclofenac suppository may not allow absorption until this level.
• Patients show suppression of pain score within an hour in most of cases which ensures fast recovery from pain.
• Product is non-sticky as compared to gel. Therefore patients feel easy to administer and are more comfortable after application. In this product, drug gets absorbed without leaving sticky inert particles behind.

We claim,
1. A liquid rectal spray composition comprising Diclofenac in an amount of 12.5% to 25.0% w/v, in a unique blend of solvent/co-so I vent in an amount of 10% to 80% w/v along with pharmaceutically acceptable excipients, for the treatment of pre- and post-operative pain, gynecological surgery and musculoskeletal disorders such as muscular pain, pain associated with arthritis, acute pain in renal colic and mild body ache.
2. The liquid rectal spray composition according to claim 1, wherein solvent/co-solvent are selected from group of poly ethylene glycol, propylene glycol, glycofurol, ethyl alcohol, cremophore ELP, solutol, transcutol, labrasol, capmul, captex, ethyl alcohol, benzyl alcohol or combination thereof.
3. The liquid rectal spray composition according to claim 1, wherein pharmaceutically acceptable excipients is selected from preservatives, antioxidants, chelating agents, osmotic agents, permeation enhancers, mucoadhesive polymers, surfactants and buffering agents.
4. The method of treating pre- and post-operative pain, gynecological surgery and musculoskeletal disorders such as muscular pain, pain associated with arthritis, acute pain in renal colic and mild body ache, which method comprises administering 'an effective amount' of the spray composition according to claim 1 to the subject.
5. The method according to claim 4, wherein said subject is human.
6. Use of the spray composition according to claim 1, for the treatment of pre- and post-operative pain, gynecological surgery and musculoskeletal disorders such as muscular pain, pain associated with arthritis, acute pain in renal colic and mild body ache.
7. A liquid rectal spray dispenser to deliver the composition of claim 1.