FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1.TITLE OF THE INVENTION:
"A NOVEL LIQUID ORAL SPRAY DOSAGE FORM COMPRISING THIOCOLCHICOSIDE AND ANTI-INFLAMMATORY AGENT"
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 INVENTION:
The present invention relates to a liquid oral spray dosage form comprising Thicolchicoside and at least one anti-inflammatory agent useful for pain management in arthritis, rheumatoid arthritis, acute nonspecific low back pain, osteoporosis and osteoarthritis.
BACKGROUND OF THE INVENTION:
Colchicine is a toxic natural product and secondary metabolite, originally extracted from plants of the genus Colchicum (Autumn crocus, Colchicum antumnale, also known as the "Meadow saffron"). Originally used to treat rheumatic complaints and especially gout, it was also prescribed for its cathartic and emetic effects. Its present medicinal use is mainly in the treatment of gout; as well, it is being investigated for its potential use as an anti-cancer drug. It can also be used as initial treatment for pericarditis and preventing recurrences of the condition. In neurons, axoplasmic transport is disrupted by colchicine.
A colchicine derivative 3-demethyl-thiocolchicine giucoside, also commonly known as Thiocolchicoside; is a muscle relaxant agent with anti-inflammatory and analgesic actions. It is used topically for the treatment of muscular spasms and for rheumatologic. orthopedic, and traumatologic disorders. Thiocoichicoside's activity is ascribed to its ability to interact with the strychnine-sensitive glycine receptors and therefore being endowed with glycino-mimetic activity, it is used in the rheumatologic-orthopedic field for its myorelaxant properties.
Chemically, Thiocolchicoside is N-[3-(β-D-glucopyranosyIoxy)-l,2-dimethoxy-10-(methylthio)-9-oxo-5,6,7,9-tetrahydrobenzo[a] heptalen-7-yl]acetamide having structural formula as follows:


Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs are drugs with analgesic, antipyretic (fever-reducing) and, in higher doses, with anti-inflammatory effects (reducing inflammation). The term "non-steroidal" is used to distinguish these drugs from steroids, which have a similar eicosanoid-depressing, anti-inflammatory action. As analgesics, NSAIDs are unusual in that they are non-narcotic.
NSAIDs have therapeutic properties such as anti-inflammatories, analgesics, anti-pyretics, and anti-thrombotics that are used to treat a variety of clinical conditions manifesting such symptoms as pain, inflammation, fever, and to treat and prevent atherosclerosis.
NSAIDs within a group will tend to have similar characteristics and tolerability. There is little difference in clinical efficacy among the NSAIDs when used at equivalent doses. Rather, differences among compounds tend to be with regards to dosing regimens, route of administration, and tolerability profile.
US7456223 relates to composition comprising a muscle relaxant (cyclobenzaprine) and nonsteroidal anti-inflammatory drug (ketoprofen), for treating tooth grinding and tooth clenching,
US20080279933 relates to a novel pharmaceutical composition comprising flurbiprofen in combination with an alpha.-2 adrenergic receptor agonist or a gamma-aminobutiric acid receptor agonist with anti-inflammatory, analgesic and myorelaxant activity for the treatment of painful muscle spasms associated with static and functional disorders of vertebra.

US20090175938 relates to a novel controlled release (CR) flurbiprofen and muscle relaxant combinations for oral administration with anti-inflammatory, analgesic. myorelaxant activity and methods of its manufacture. The pharmaceutical composition of the present invention is administered orally in tablet, multilayer tablet, multicoated tablet and capsule form.
EP2085076 discloses a modified release pharmaceutical composition in capsules with coated Microsphere, combining two active ingredients, namely a Muscle Relaxant (Tizanidine) and a Non-Steroidal Anti-Inflammatory Drug (Meloxicam) for the treatment of spasticity, disorders related to skeletal muscle and/or muscular ailments and moderate to severe pain in general.
US6235314 disclosed is a local skeletal muscle relaxant and a non-steroidal anti-inflammatory drug in a topical composition for topical application to a patient for relief of pain. More particularly and in its preferred form, the invention involves a combination of diazepam and diclofenac in a composition for topical application to the skin of a patient as a colorless transparent gel.
In view of the above state of art, the present inventors have come up with a composition in a liquid oral spray dosage form comprising thiocolchicoside along with at least one anti-inflammatory agent like ketorolac Tromethamine, Dexketoprofen and its pharmaceutically acceptable salts, Ketoprofen, Flurbiprofen etc. at their effective doses. to provide relatively better effect than other dosage forms like tablets or capsules and messy application of gel and creams. Further, the novel mode of delivery is useful for pain management in arthritis, rheumatoid arthritis, osteoporosis and osteoarthritis, which provides better patient compliance as compare to painful intramuscular injections, as it is in solution form.
SUMMARY OF THE INVENTION:
In accordance with the above, the present invention provides a liquid oral spray dosage form comprising therapeutically effective amount of thiocolchicoside in combination with at least one anti-inflammatory agent selected from Ketorolac tromethamine,

Dexketoprofen and its pharmaceutically acceptable salts, Ketoprofen, Flurbiprofen etc. at their effective doses, especially for pain management in arthritis, rheumatoid arthritis, acute nonspecific low back pain, osteoporosis and osteoarthritis.
The composition of the present invention afford a better patient compliance, better bioavailability, when compared to painful intramuscular injections, capsules or tablets and messy application of gel and creams, as the present formulation is in solution form that can administered by spraying method.
DESCRIPTION OF DRAWINGS:
Figure 1: Spray Dispenser to deliver the composition of the present invention.
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.
In an embodiment, the present invention provides a liquid oral spray dosage comprising therapeutically effective amount of Thiocolchicoside along with at least one anti-inflammatory agent selected from Ketorolac tromethamine, Dexketoprofen and its pharmaceutically acceptable salts, Ketoprofen, Flurbiprofen etc; useful for pain management in arthritis, rheumatoid arthritis, acute nonspecific low back pain, osteoporosis and osteoarthritis.
Thiocolchicoside or its pharmaceutically acceptable salts of the current invention is present in an amount of 2 mg to 12 mg/spray preferably 4 mg to 8 mg/spray.
Suitable anti-inflammatory agent is selected from the group of Ketorolac tromethamine, Dexketoprofen and its pharmaceutically acceptable salts, Ketoprofen, Flurbiprofen etc or combinations thereof.

The said anti-inflammatory agent is present in an amount of their pharmacologically active amount of 10 mg to 30 mg/spray.
The oral spray of the present invention is having a palatable taste even though there is large concentration of active pharmaceutical ingredients in the composition. Further, it gives relatively uniform dose dispensing than other oral liquid formulation.
The composition of the present invention has better patient compliance than tablets or capsule or painful intramuscular injection and messy application of gel and creams, as the current formulation is dispensed in mist form that covers large area of oral cavity and very small amount of dispensed volume will be ingested, so there will be minimum chances of hepatic metabolism.
In another embodiment, the present invention provides a liquid oral spray dosage comprising therapeutically effective amount of thiocolchicoside along with at least one anti-inflammatory agent selected from Ketorolac tromethamine, Dexketoprofen, Ketoprofen, Flurbiprofen etc in unique blend of solvents and other pharmaceutically acceptable excipients useful for pain management in arthritis, rheumatoid arthritis, acute nonspecific low back pain, osteoporosis and osteoarthritis.
Suitable solvents are selected from Ethanol, Propylene Glycol, Sorbitol 70% solution. Polyethylene glycol derivatives, in an amount of 10% to 80%.
Other pharmaceutically acceptable excipients are selected from flavoring agent such as Ess. Orange supreme, Ess. Pineapple, supreme Flavor mixed fruit, Flavor Raspberry, menthol and sweeteners are selected from Neotame, Acesulfame, Aspartame, Sucralose, Sodium saccharin and Sucrose etc.
Preservatives are selected from Sodium Benzoate, sodium methyl Paraben, sodium propyl Paraben, propyl Paraben, methyl paraben in an amount of 0.1 % to 0.5%.
In yet another embodiment, the invention provides a spray dispenser comprising therapeutically effective amount of Thiocolchicoside along with at least one antiinflammatory agent selected from Ketorolac tromethamine, Dexketoprofen and its pharmaceutically acceptable salts, Ketoprofen, Flurbiprofen etc. The composition is filled

in a convenient container that can give the formulation in form of fine droplets. Hence, it is easy to deliver even to the pediatrics. The formulation is palatable eventhough the drug concentration is relatively large.
The composition is administered via container having metered dosing spray nozzle to deliver accurate dose of drug. Preferred spray dispenser to deliver the composition of the present invention are disclosed in Figure 1. Specifications of pump actuators are as follows:

Pump type VP7
Material HDPE
Colour white
From bottom to gasket 71 mm
Metered dosing 100 mcl
The invention provides a composition which is in a liquid oral spray dosage form comprising therapeutically effective amount of Thiocolchicoside along with one or more anti-inflammatory agent(s) selected from Ketorolac tromethamine, Dexketoprofen and its pharmaceutically acceptable salts, Ketoprofen, Flurbiprofen etc., wherein the said composition does not crystallize at very low temperature during storage.
In the most preferred embodiment the present invention provides a liquid oral spray dosage comprising therapeutically effective amount of thiocolchicoside in combination with Dexketoprofen and its pharmaceutically acceptable salts in unique blend of solvent alongwith other pharmaceutically acceptable salts, useful for pain management in arthritis, rheumatoid arthritis, acute nonspecific low back pain, osteoporosis and osteoarthritis.
In a further embodiment, the present invention provides a method of reducing the symptoms associated with arthritis, rheumatoid arthritis, acute nonspecific low back pain, osteoporosis and osteoarthritis, which comprises administering 'an effective amount' of the 'Thiocolchicoside with at least one anti-inflammatory agent to the subject suffering affected by arthritis, rheumatoid arthritis, acute nonspecific low back pain, osteoporosis and osteoarthritis. The subject mentioned herein is human.

The invention further discloses use of the 'spray composition of the invention comprising Thiocolchicoside with at least one anti-inflammatory agent' intended to reduce symptoms associated with arthritis, rheumatoid arthritis, acute nonspecific low back pain, osteoporosis and osteoarthritis.
Clinical Trial was conducted to study improved efficacy of oral spray comprising Thiocolchicoside with Dexketoprofen of present invention (described in example 3) on human subjects with acute non-specific low back pain.
The aforesaid trial has been performed according to ICH - GCP guidelines and schedule Y. Total 17 patients were screened and 10 patients were enrolled into study out of which eight patients completed the study. 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 me 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). The study was conducted under the super vision of Dr. Tejas Gandhi.
Patient has received Thiocolchicoside 8 mg/0.4 mL with Dexketoprofen 25 mg (per 2 sprays) Oral Spray twice daily for three consecutive days. Efficacy was evaluated by noting Visual Analogue Score (VAS) for pain on average within last 24 hours, stiffness assessment; and disability assessment through Ronald Morris questionnaire before treatment and after treatment. Global Perceived Effect (GPE) showing extent of improvement was noted to assess the recovery of patients after treatment. Eight patients have completed the study successfully, two patients were dropped out from the study and one patient was under screening failure. No adverse event occurred during the study.
After the completion of three days treatment, it was concluded that oral spray of Thiocolchicoside with Dexketoprofen is highly effective and safe in patients suffering from acute nonspecific low back pain.

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. It will be appreciated by any person skilled in this art that the present invention includes following examples and further can be modified and altered within the technical scope of the present invention.
EXAMPLES: Example 1:

SR.NO INGREDIENTS LABEL CALIM
(mg/spray)
1 Thiocolchicoside 8
2 Flurbiprofen sodium 50
3 Propylene Glycol 30
4 Sorbitol 70% solution 5
5 Sucralose 1
6 Neotame 0.5
7 Menthol 0.1
8 Flavor mixed fruit 0.25
9 Sodium benzoate 0.10
10 Purified water Q.S.
MANUFACTURING PROCEDURE:
1) Dissolving Thiocolchicoside and Flurbiprofen Sodium in small quantity of water in a beaker:
2) adding propylene glycol to the solution of step 1:
3) adding 70% sorbitol in the solution of step 2;
4) dissolving Sucralose, Neotame and sodium benzoate in small amount of water and adding the same to solution of Step 1;
5) dissolving menthol in flavor mixed fruit and adding the same to solution of step-1 and
6) making the volume to quantity sufficient with purified water.

Example 2:

SR.NO INGREDIENTS LABEL CALIM
(mg/spray)
1 Thiocolchicoside 8
2 Ketorolec Tromethamine 50
3 Propylene Glycol 25
4 Sorbitol 70% solution 5
5 Sucralose 1
6 Neotame 0.5
7 Menthol 0.1
8 Flavor mixed fruit 0.25
9 Sodium benzoate 0.10
10 Purified water Q.S.
MANUFACTURING PROCEDURE:
1) Dissolving Thiocolchicoside and Ketorolec Tromethamine in small quantity of water in a beaker;
2) adding propylene glycol to solution of step 1;
3) adding sorbitol 70% to the solution of step 2;
4) dissolving Sucralose, Neotame and sodium benzoate in small amount of water and adding the same to solution of step I;
5) dissolving menthol in flavor mixed fruit and adding in step-1 and
6) making the volume to quantity sufficient with purified water.
Example 3:

SR.NO INGREDIENTS LABEL CALIM
(mg/spray)
1 Thiocolchicoside 4
2 Dexketoprofen 12.5
3 trometamol ethanol 75
4 Sorbitol 70% solution 30

5 Sucralose 2
6 Menthol 0.5
7 Ess. Orange supreme 2.0
8 Purified water Q.S.
MANUFACTURING PROCEDURE:
1) Dissolving Thiocolchicoside and Dexketoprofen and trometamol in small quantity of water in a beaker;
2) adding propylene glycol to solution of step 1;
3) adding sorbitol 70% to the solution of step 2;
4) dissolving Sucralose, Neotame and sodium benzoate in small amount of water and adding the same to solution of step 1;
5) dissolving menthol in flavor mixed fruit and adding in step-1 and
6) making the volume to quantity sufficient with purified water.
Example 4:
Clinical Trial to study improved efficacy of Thiocolchicoside with Dexketoprofen oral
spray (as described in Example 3)
Investigational Product: Thiocolchicoside with Dexketoprofen oral spray
Dose: Thiocolchicoside (8 mg/0.4 mL) with Dexketoprofen oral spray (25 mg) (2 spray)
two times a day for three days
No. of Patients: 8
Mode of administration: Orally
Duration of treatment: 3 days
Results:

Parameters Much improvement Moderate improvement Slight to no improvement
Average pain (During last 24 hours) 50% 50%
Pain on movement 50% 12.5% 37.5%
Stiffness of low
back 12.5% 25% 62.5%

Disability 87.5% - 12.5%
GPE 37.5% 62.5% -
Conclusions:
Thiocolchicoside with Dexketoprofen is highly effective and safe in patients with acute nonspecific low back pain. As the application of the composition was through metered dosing spray nozzle, the composition was delivered in accurate dose of drug. The formulation was more patient compatible due to easy mode of delivery. The composition has goodtime action profile, acceptability and also high success ratio in treating acute non-specific low back pain.

We claim,
1. A liquid oral spray composition comprising:
a) Thiocolchicoside in an amount of 2 mg to 12 mg/spray;
b) at least one anti-inflammatory agent in an amount of 10 mg to 30 mg/spray;
c) solvents in an amount of 10% to 80%; alongwith pharmaceutically acceptable excipients.

2. The spray composition according to claim 1. wherein anti-inflammatory agent is selected from Ketorolac tromethamine, Dexketoprofen, Ketoprofen. Flurbiprofen.
3. The spray composition according to claim 1, wherein solvents are selected from Ethanol, Propylene Glycol, Sorbitol 70% solution, Polyethylene glycol derivatives.
4. The spray composition according to claim 1. wherein pharmaceutically acceptable excipients are selected from flavoring agent, sweetener, preservatives
5. The spray composition according to claim 1 and 4, wherein preservatives are selected from sodium Benzoate, sodium methyl paraben, sodium propyl paraben, propyl paraben. methyl paraben.
6. Method of treating arthritis, rheumatoid arthritis, acute nonspecific low back pain, osteoporosis and osteoarthritis, which method comprises administering 'an effective amount' of the spray composition according to claim 1 to the subject suffering from arthritis, rheumatoid arthritis, acute nonspecific low back pain, osteoporosis and osteoarthritis.
7. The method according to claim 5, wherein said subject is human.
8. A metered dosing spray dispenser to deliver the composition of claim 1.