FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"LIQUID PHARMACEUTICAL COMPOSITION OF THIOCOLCHICOSIDE"
2. APPLICANT
(a) NAME: Lyka Labs Limited.
(b) NATIONALITY: Indian Company incorporated under the
Indian Companies Act, 1956
(c) ADDRESS: 101, Shivshakti Industrial Estate, Andheri-Kurla Road,
Andheri (East), Mumbai - 400059, Maharashtra, India.

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention:

TECHNICAL FIELD OF INVENTION:
The present invention relates to a liquid pharmaceutical composition for the treatment of myorelaxant and the process thereof. More particularly, the present invention relates to liquid pharmaceutical composition comprising therapeutically effective amount of thiocolchicoside along with pharmaceutically acceptable excipients in the form of syrup, for the treatment of muscular spasms and for rheumatologic, orthopedic, and traumatologic disorders
BACKGROUND OF THE INVENTION:
Colchicine is a natural product and secondary metabolite, originally extracted from plants of the genus Colchicum (Autumn crocus, Colchicum autumnale, 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-demethyI-thiocolchicine glucoside, 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.
"Interaction of thiocolchicoside with [3H] strychnine binding sites in rat spinal cord and brainstem" by Cimino M et.al; published in Eur J Pharmacol, 1996 Dec 27; vol 318(1) pp 201-4; discloses that thiocolchicoside displaced the binding of [3H] strychnine with an affinity similar to that of unlabeled glycine, and showed a Hill coefficient and proportionality parameter (P) /ess than unity. The activity of thiocolchicoside towards [3H] strychnine binding sites was confirmed in autoradiographic studies. The results suggest that thiocolchicoside behaves as an
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allosteric compound acting on the strychnine-sensitive glycine receptor in rat brainstem and spinal cord, which provides a possible mechanism for the myorelaxant activity of this colchicoside derivative, making it the first clinically useful drug acting on this I receptor.
WO2007129162 discloses formulation for transdermal use comprising an emulgel, a derivative of colchicines such as thiocolchicoside and a substantially lipophilic compound having pharmacological activity.
300/KOL/2008 having corresponding PCT publication No: WO200709772 discloses pharmaceutical composition comprising thiocolchicoside analogues in admixture with acceptable carriers and/or excipients having myorelaxant and anti-inflammatory activity.
W09836751 discloses a solid pharmaceutical composition for administration via the buccal mucosa, characterized in that it enables either immediate release or prolonged release in time of thiocolchicoside in the absorption site.
119/DEL/2007 discloses biologically active compound (s) like thiocolchicoside in such quality, when suitably formulated and administered through sub lingual or buccal cavity, releases the active compound (s) directly in to blood resulting in rapid absorption, first pass effect, faster onset/minimizing adverse effects such as G.I. disturbances.
W09939717 discloses a pharmaceutical composition for nasal administration of thiocolchicoside in the form of powder.
In light of the above there is still a need in the art to provide a novel and rational pharmaceutical composition in the form of oral non solid medicament such as liquids for the treatment of myorelaxant. Therefore, the present inventors have come up with a liquid pharmaceutical composition comprising therapeutically effective amount of Thiocolchicoside along with pharmaceutical^ acceptable excipients in the form of syrup for the treatment of myorelaxant.
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OBJECT OF THE INVENTION:
The main object of the present invention is to provide a storage-stable liquid formulation of Thiocolchicoside along with pharmaceutically acceptable excipients in the form of syrup for the treatment of myorelaxant.
SUMMARY OF THE INVENTION:
The present invention provides a liquid pharmaceutical composition comprising therapeutically effective amount of Thiocolchicoside for the treatment of myorelaxant and the process thereof.
In one embodiment, the present invention provides a liquid pharmaceutical composition comprising therapeutically effective amount of Thiocolchicoside along with pharmaceutically acceptable excipients in the form of syrup, for the treatment of muscular spasms and for rheumatologic, orthopedic, and traumatologic disorders.
In accordance to the present invention, the said syrup formulation is in two forms viz. sugar free syrup and sugar syrup.
In another embodiment, the present invention provides a process for manufacturing of Thicolchicoside sugar free syrup formulation, summarized as below:
1. Weighing Thiocolchicoside and dissolving it in small qty of Purified Water;
2. Weighing Glycerine in a container; adding to it Sorbitol solution and Propylene Glycol under stirring;
3. Dissolving in small qty of Purified Water the Sodium Methyl paraben, Sodium Propyl Paraben, Disodium EDTA and Saccharine Sodium by heating;
4. Adding solution of STEP 3 to STEP 2;
5. Adding the drug solution of STEP I to bulk of STEP 4 under stirring;
6. Dissolving Quinoline yellow in minimum amount of Purified Water and adding to the bulk of STEP 5 under stirring; and
7. Adding pineapple sweet flavour to the bulk of STEP 6 under stirring.
8. Filtering the solution of STEP 7 and making up the volume.
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In yet another embodiment, the present invention provides a process for manufacturing of Thicolchicoside sugar syrup formulation, summarized as below:
1. Taking small qty of Purified Water and heating it to boil, then adding and dissolving Disodium EDTA, and then adding and dissolving sugar;
2. Cooling syrup of STEP 1 to 40 C to 45 C and straining the cool syrup through 100-mesh s. s. sieve;
3. Weighing Thiocolchicoside and dissolving in minimum qty of Purified Water and adding it to STEP 3;
4. Dissolving Sodium Methyl Paraben and Sodium Propyl Paraben in minimum qty of Purified water and adding it to the STEP 3;
5. Dissolving Colour Sunset yellow in minimum amount of Purified Water and adding to bulk of STEP 4 under stirring;
6. Adding Mango flavour in propylene glycol and then adding to it bulk of STEP 5 under stirring; and
7. Filtering the solution of STEP 7 and making up the volume.
DETAILED DESCRIPTION OF THE INVENTION:
In accordance with the above aspects, 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.
As described herein the term "syrup" in case of current invention also includes those liquid formulations having a sweet taste, provided wholly or partly by artificial sweeteners, such as saccharin, sorbitol, aspartame, sodium cyclamate etc; used to avoid dental and medical problems which may be aggravated by higher caloric sweeteners.
Syrup formulations are commonly used as vehicle for delivery of pharmacological agents. Traditional syrups are concentrated solutions of sugar (generally sucrose) in purified water, such as Syrup, NF prepared by adding sucrose in sufficient purified water. As is well appreciated in the art, syrups frequently are flavored, such as with fruit
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or mint flavors, usually for purposes of masking an unpleasant taste caused by the presence of a dissolved or suspended pharmacologically active substance.
Syrups frequently must contain antimicrobial components to ensure safe storage without the proliferation of pathogenic molds, yeasts, bacteria and the like; a typical antimicrobial deemed suitable for use in foods and other ingestible substances is sodium benzoate. In addition, those syrups which do not contain sugar, or which contain a mixture of sugar and another sweetener, may contain thickening agents such as a Hydroxypropyl Methylcellulose etc to provide a viscous mouth-feel similar to that of traditional syrup.
In accordance to the above objectives the present invention provides a liquid pharmaceutical composition comprising therapeutically effective amount of Thiocolchicoside along with pharmaceutically acceptable excipients in the form of syrup, for the treatment of muscular spasms and for rheumatologic, orthopedic, and traumatologic disorders and process for preparation thereof.
According to the preferred embodiment, the present invention discloses a liquid pharmaceutical composition comprising therapeutically effective amount of Thiocolchicoside along with pharmaceutically acceptable excipients selected from sugar alcohol, co-solvents, sweetener, flavours, colours, preservatives in the form of sugar free or sugar syrup and the process for preparation thereof.
Suitable Sweetener can be selected from Sodium saccharine, Sugar Pharma grade and others known in the art, preferably Sodium saccharine in the range of 0-0.5% w/v and Sugar Pharma grade in the range 0 to 50 % w/v.
Co-solvents can be selected from Glycerine, propylene Glycol and those accepted in the art alone or in combination thereof, preferably Glycerine in the range of 0-15% w/v and propylene Glycol in the range of 1 to 5% w/v alone or combination of both.
Suitable Colours can be selected from Quinoline Yellow, Sunset Yellow FCF etc in the range of 0.001 to 0.1% w/v.
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Suitable Flavours can be selected from Pineapple sweet flavour, mango, orange and the like in the range of 0.5-1.0% w/v.
Suitable Preservatives can be selected from those pharmaceuticlly accepted in the art preferably sodium methyl paraben in the range of 0 to 0.1% w/v and sodium propyl paraben in the range of 0 to 0.01% w/v.
Chellating agent such as Disodium EDTA is used in an amount of 0.05% w/v.
Antioxidant such as Butylated Hydroxy Anisole is used in the range of 0 to 0.01% w/v.
Sugar alcohol such as Sorbitol 70% solution in the range of 0 to 70% w/v
According to another embodiment, Thiocolchicoside sugar free syrup in 4 mg/ 5ml concentration fs prepared according to following process:
1. Weighing Thiocolchicoside and dissolving it in small qty of of Purified Water;
2. Weighing Glycerine in a container; adding to it Sorbitol Solution and Propylene Glycol under stirring;
3. Dissolving in small qty of Purified Water the Sodium Methyl paraben, Sodium Propyl Paraben, Disodium EDTA and Saccharine Sodium by heating;
4. Adding solution of STEP 3 to STEP 2;
5. Adding the drug solution of STEP I to bulk of STEP 4 under stirring;
6. Dissolving Quinoline yellow in minimum amount of Purified Water and adding to the bulk of STEP 5 under stirring; and
7. Adding pineapple sweet flavour to the bulk of STEP 6 under stirring.
8. Filtering the solution of STEP 7 and making up the volume.
According to yet another embodiment, Thiocolchicoside sugar syrup in 4 mg/ 5ml concentration is prepared according to following process:
1. Taking small qty of Purified Water and heating it to boil, then adding and dissolving Disodium EDTA, and then adding and dissolving sugar;
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2. Cooling syrup of STEP 1 to 40 C to 45 C and straining the cool syrup through 100-mesh s. s. sieve;
3. Weighing Thiocolchicoside and dissolving in minimum qty of Purified Water and adding it to STEP 3;
4. Dissolving Sodium Methyl Paraben and Sodium Propyl Paraben in minimum qty of Purified I water and adding it to the STEP 3;
5. Dissolving Colour Sunset Yellow in minimum amount of Purified Water and adding to bulk of STEP 4 under stirring;
6. Adding Mango flavour in propylene glycol and then adding to it bulk of STEP 5 under stirring; and
7. Filtering the solution of STEP 7 and making up the volume.
The following examples, which include 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:
Composition: (For Sugar free syrup)
Thiocolchicoside 4 mg/5 ml
Flavoured Base q.s.
Colour: Quinoline Yellow
The typical ingredients for Batch of 1 liter are

Ingredients Concentration Qty/ liter
Thiocolchicoside 4 mg/5ml 0.8 gm
Glycerine I5%w/v J50gm
Propylene Glycol 1.5%w/v 15gm
Sorbitol 70% solution 67.5%w/v 675 gm
Disodium EDTA 0.05%w/v 0.5 gm
Sodium saccharine 0.3%w/v 3.0 gm
Pineapple sweet flavour 0.75%v/v 7.5 ml
Sodium Methyl paraben 0.072%w/v 0.72 gm
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The process for manufacturing of Thiocolchicoside sugar free syrup is as follows:
STEP 1:
Weigh Thiocolchicoside and dissolve in 100ml of Purified Water.
STEP 2:
Weigh Glycerine in a container; to it add Sorbitol solution and Propylene Glycol under
stirring.
STEP 3:
In 40 ml Purified Water, dissolve Sodium Methyl paraben, Sodium Propyl Paraben,
Disodium EDTA and Saccharine Sodium by heating.
STEP 4:
Add solution of STEP 3 to STEP 2
STEP 5:
Add the drug solution of STEP 1 to bulk of STEP 4 under stirring
STEP 6:
Dissolve Quinoline Yellow in minimum amount of Purified Water and add to bulk of
STEP 5 under stirring
STEP 7:
Add pineapple sweet flavour to the bulk of STEP 6 under stirring
STEP 8:
Filter the solution of STEP 7 and make up the volume to I It
EXAMPLE 2:
Composition: (with sugar)
Thiocolchicoside 4 mg / 5 ml
Flavour Syrupy Base q.s.
Colour: Sunset yellow
The typical ingredients for Batch of 1 liter are
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The process for manufacturing of Thiocolchicoside syrup with sugar is as follows.
STEP 1:
Take 250 ml Purified Water and heat it to boil. Add and dissolve Disodium EDTA.
Add and dissolve sugar.
STEP 2:
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Cool syrup of STEP 1 to 40 Cto 45 C and strain the cool syrup through 100-mesh s. s. sieve.
STEP 3:
Weigh Thiocolchicoside and dissolve in 100ml of Purified Water. Add it to STEP 3
STEP 4;
Dissolve Sodium Methyl paraben and Sodim Propyl Paraben in 50ml water. Add it to the STEP 3
STEP 5:
Dissolve colour Sunset yellow in minimum amount of Purified Water and add to bulk of STEP 4 under stirring
STEP 6:
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Add mango flavour in propylene glycol and add to it bulk of STEP 5 under stirring
STEP 7:
Filter the solution of STEP 7 and make up the volume.
Dated this the 03rd day of June, 2009
Dr. P. Aruna Sree Agent for the Applicant
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