FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION (See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"NEW COMPOSITIONS CONTAINING SKELETAL MUSCLE
RELAXANTS"
2. APPLICANT:
(a) NAME: THEMIS MEDICARE LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956
(c) ADDRESS: 11/12 Udhyog Nagar, S.V. Road, Goregaon (West), Mumbai
400104, Maharashtra, India.
3.PREAMBLE TO THE DESCRIPTION;
The following specification particularly describes the nature of invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION:
The present invention relates to a novel sustained release formulations containing skeletal muscle relaxant drugs and methods of its preparation. More particularly, the present invention relates to pharmaceutical sustained release compositions of Thiocolchicoside and Cyclobenzaprine either alone or in combination thereof along with one or more pharmaceutically acceptable excipients for the treatment of rheumatologic, orthopedic, and traumatologic disorders affecting mammals.
BACKGROUND OF THE INVENTION:
Present invention discloses the pharmaceutical sustained release formulations containing centrally acting muscle relaxant drugs Thiocolchicoside and Cyclobenzaprine alone or in combination with each other or in combination with other suitable muscle relaxant drugs.
Thiocolchicoside and Cyclobenzaprine are centrally acting muscle relaxant drugs. Centrally acting muscle relaxants block interneuronal pathways in the spinal cord and in the midbrain reticular activating system.
Muscle relaxant medicaments reduce the muscle tone spasm and used for treating muscle spasm and contractures. Muscle spasm is one of the main factors responsible for chronic pain and number of pathologies of the locomotor apparatus. Muscle contracture also occurs in the inflammatory-rheumathic and degenerative orthopedic pathologies; when affecting an articulation, it causes, in addition to pain, a stiffening which limits the mutual mobility of the joint extremities and therefore the functionality of the part involved. Due to these reasons Thiocolchicoside and Cyclobenzaprine seem to be drugs of great interest as they are having muscle relaxant and antispastic effects. Moreover Thiocolchicoside has anti inflammatory as well as analgesic properties.
Chemically, Thiocolchicoside is N-[3-((3-D-glucopyranosyloxy)-l, 2-dimethoxy-10-(methylthio)-9-oxo-5, 6, 7, 9-tetrahydrobenzo[a]heptalen-7-yl] acetamide. Thiocolchicoside is a semi-synthetic sulfur derivative of the naturally occurring compound colchicoside from the seeds of various species of Colchicum autumnale (autumn crocus, meadow saffron, Gloriosa superba) viz 2-Demethoxy-2-glucosidoxythiocolchicine. It has muscle relaxant, anti-

inflammatory, analgesic and anesthetic actions with minima] side effects. Quick onset of action with good level of safety without any sedation are others unique features of this drug.
In-vitro, Thiocolchicoside only binds to GABA-A and strychnine sensitive glycine receptors. Thiocolchicoside acting as a GABA-A receptor antagonist, its myorelaxant effects could be exerted at the supraspinal level, via complex regulatory mechanisms. (Reference: http://www. aeonformulations. in/inc.html)
Thiocolchicoside acts both in contractures of central origin and in those of reflex type, rheumatic and traumatic. Spastic sequelae of hemiparesis, Parkinson's disease and Iatrogenic Parkinsonian symptoms, particularly the neurodyslectic syndrome, acute and chronic lumbar and sciatic pain, cervico-brachial neuralgia, persistent torticollis, post-traumatic and postoperative pain.
Cyclobenzaprine is chemically 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)- N,N-dimethyl-l-propanamine. It is Centrally-acting skeletal muscle relaxant pharmacologically related to tricyclic antidepressants; it reduces tonic somatic motor activity influencing both alpha and gamma motor neurons. It is used to manage muscle spasms associated with acute musculoskeletal disorders, such as low back strain, muscle tenderness or movement restriction due to musculoskeletal conditions. It is also used as supportive therapy in patients with tetanus or fibromyalgia.
Cyclobenzaprine relieves muscle spasms through a central action, possibly at the level of the brain stem, with no direct action on the neuromuscular junction or the muscle involved. It reduces pain and tenderness and improves mobility.
The rationale behind preparing a sustained release dosage form is to modify the drug release and to impart benefit of reducing dosage regimen which helps to increase the patient compliance by reducing the influence of adverse effects which are caused by the multiple dosing of the drug. The prime objective of the modifying the drug release is to maintain the drug concentration at a constant level in the blood for predetermined time and achieve better patient compliance. Treatment with muscle relaxants, analgesic, anti-inflammatory agents get

benefited by the sustained release technique as it helps to manage the pain or inflammation for over a period of time and achieves better patient compliance.
Muscle relaxant Thiocolchicoside have been evaluated for the treatment of pain. Following are the prior arts related to Thiocolchicoside.
EP1052995B1 concerns a pharmaceutical composition for nasal administration of Thiocolchicoside, with immediate or sustained release. This prior art does not hint about sustained release tablets dosage form and moreover it doesn't state about duration of the prolonged drug release from such nasal formulations.
WO2007/016676A1 relates to methods of treating spasticity in patient having a neurological disease comprising administering to a patient in need of such treatment a tizanidine formulation providing a tizanidine blood concentration of at least about 900 pg/ml for about five hours. This prior art provides the drug release only upto five hours.
US6080739 relates to colchicine and thiocolchicine derivatives having antiblastic activity which can be obtained by functionalization of the C-7 to ketone or functionalization of the amino group. This prior art does disclose preparation of sustained release formulation.
US20090175938 discloses bilayer tablet formulations providing immediate or sustained release of Thiocolhicoside and controlled release of analgesic drug flurbiprofen in form of bilayer tablets. This prior art lacks certain drawbacks interms of complicated technology, uneconomical and time consuming. Moreover it doesn't specify the particular time duration over which the drug would release from the formulation.
WO2007/009772A1 discloses synthesis of 3-demethoxy -3- aminothiocolchicine glycosyl derivatives having myorelaxant and antiinflammatory activity. This prior art does not hint about preparation of sustained release formulations of colchicine derviatives or Thiocolchicoside.
Following are the nearest prior arts wherein Cyclobenzaprine is used for various sustained release formulations.

US483495 discloses a controlled release formulation which is formulated by complexing the quaternary ammonium salt or organic base drug with an anionic salt and distributed into a hydrophilic polymer. This prior art involves critical processes like complexing drug with surfactant.
US2009/0017127 discloses the technology for the preparation of sustained release beads, pellets, granules which can be incorporated into capsules to achieve the sustained release of active substance. The beads are formulated by coating the active substance with functional polymer on drug granules. The drug granules are formulated by spraying Cyclobenzaprine over the inert base granules. The major drawback of this prior art is that it uses the expensive coating process which has complicated and time consuming steps.
US2009/0148532A1 is an extension of US2009/0017127 which discloses extended release pharmaceutical composition comprising Cyclobenzaprine, in which Cyclobenzaprine is coated over inert beads to form instant release granules which are then seal coated with extended release coating material to formulate extended release granules. This prior art has similar drawbacks as explained above such as complicated coating steps which are expensive.
US2004/0018327 Al is for delayed release dosage form which contains two cores out of which the inner core is a active ingredient with a disintegrant and the other core is comprising of one water insoluble film forming polymer and one water insoluble lipid which helps in modifying the drug release. The main drawback of this prior art is that the process is complicated and involves critical steps.
US2004/0197407 Al is for the dosage form with modified geometry in which modification of geometry of core layers to alter the mixing of layers in additions to modifying the composition of core layers to alter the viscosity during operation. This prior art is having limited application due to complicated processes.
US 7387793 discloses the formulation of modified release multi-particulate pharmaceutical dosage form, more preferably, capsule type containing skeletal muscle relaxants i.e. Cyclobenzaprine hydrochloride to sustain the drug release.

However, said patent does not disclose the drug release pattern above 12 hrs. Also, there is no disclosure of drug to polymer ratio for retarding the drug release. It further discusses the multi-particulate type of complex system for processing the capsule formulation. The above formulation is thus complex and economically non-viable.
WO/2010/120253 discloses pharmaceutical formulation of muscle relaxant with other NSAID's. However, there is no elaboration about stating drug release pattern after 24 hrs to achieve the desired therapeutically drug release.
US 7790199discloses pharmaceutical dosage forms for the ER beads and specifically in the form of capsules. However, there are no examples of tablets for the Cyclobenzaprine in the said patent. Further, said patent does not disclose drug to excipients ratio in the composition. It also does not teach the sustained release form graphically or textually to understand the sustained release pattern.
Among the prior arts discussed above, none of the prior art provides simple, cost effective and industrially feasible method for the preparation of sustained release dosage form which can provide the drug release over the period of 24 hours thereby increasing patient compliance and minimizing side effects. Hence, the inventors were motivated to investigate the sustained release formulations of muscle relaxants like Thiocolchicoside and Cyclobenzaprine and its salts thereof along with other actives in the form of tablets or any other galanicals dosage forms to elevate the pains related to muscle spasm. This therefore remains the object of the invention.
SUMMARY OF THE INVENTION:
The present invention, in accordance to the objective, relates to pharmaceutical compositions in the form of sustained release tablet formulations of Thiocolchicoside and Cyclobenzaprine and its salts either alone or in combination thereof along with one or more pharmaceutically acceptable excipients, for treatment of muscle spasm, rheumatologic, orthopedic, and traumatologic disorders and others. The present inventions also disclose the process for the preparation of the same.

In an aspect, the present invention relates to pharmaceutical formulations of Thiocolchicoside and Cyclobenzaprine and its salts either alone or in combination thereof along with one or more pharmaceutically acceptable excipients. The formulations are meant for once a day administration which provides prolonged drug release over 24 hours period of time and possesses anti-inflammatory, analgesic, and muscle relaxant activity for the treatment of muscle spasm, rheumatologic, orthopedic, traumatologic disorders and others.
In another aspect of the present invention, there is provided a pharmaceutical formulation comprising of combination of thiocolchicoside and Cyclobenzaprine either alone or in combination with other actives selected from muscle relaxants or analgesic drugs in therapeutically allowable doses along with suitable pharmaceutical excipients. particularly, diluents, binders, lubricants and rate controlling polymers.
DETAILED DESCRIPTION OF THE FIGURES
Fig. 1: Comparative dissolution profiles of conventional Cyclobenzaprine marketed formulation and Sustained Release Cyclobenzaprine hydrochloride Tablets.
Fig. 2: Comparative dissolution profiles of conventional IR Thiocolchicoside marketed formulation and Sustained Release Thiocolchicoside Tablets.
Fig. 3: Comparative dissolution profiles of Thiocolchicoside SR + Cyclobenzaprine SR Formulations vs conventional IR marketed formulations.
Fig. 4: Comparative dissolution profiles of Thiocolchicoside 8mg SR vs Thiocolchicoside 8mg SR + Lornoxicam 8mg SR combination Formulation.
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 present invention relates to a sustained release pharmaceutical composition of Thiocolchicoside and Cyclobenzaprine and its salts either alone or in combination thereof along with one or more pharmaceutically acceptable excipients for the treatment muscle spasm, rheumatologic. orthopedic, traumatologic disorders etc and to the process for making such a composition.
In an embodiment, the invention relates to a sustained release pharmaceutical composition of Thiocolchicoside and Cyclobenzaprine and its salts either alone or in combination thereof along with other actives selected from muscle relaxants or analgesic drugs in therapeutically allowable doses and process for making such a composition. The compositions are preferably provided as a sustained release matrix tablets.
In a preferred embodiment the present invention discloses sustained -release pharmaceutical dosage forms that are formulated to release active ingredient gradually over a 24-hour period. These formulations potentially provide greater efficacy in the treatment of chronic illness through more consistent delivery of the medication; reduced side effects; greater convenience; and higher levels of patient compliance due to a simplified dosage schedule, compared with those of immediate-release drug formulations.
Successful fabrication of sustained release products is usually difficult and involves consideration of physicochemical properties of a drug, pharmacokinetic behavior of drug, route of administration and disease state to be treated.
In an embodiment, the present invention provides a method for making a sustained release compositions of Thiocolchicoside and Cyclobenzaprine or its salts either alone or in combination along with other mucoskeletal relaxant agents or analgesic agent and their pharmaceutically acceptable salts, the method comprising intimately blending Thiocolchicoside and Cyclobenzaprine, with a suitable pharmaceutically accpetable excipients by the method of dry or wet granulation. Such fabricated invention is meant for administration to mammals via suitable route.

In yet another embodiment the present invention provides sustained release formulations of Thiocolchicoside and Cyclobenzaprine either alone or in combination thereof along with one or more pharmaceutic ally acceptable excipients in a simple and cost effective manner without need for expensive special coatings or structures.
In another embodiment the present invention provides modified release formulations of Thiocolchicoside and Cyclobenzaprine or its salts either alone or in combination thereof along with one or more pharmaceutically acceptable excipients in the form of matrix tablets using a direct compression or wet granulation process.
In another preferred embodiment, thiocolchicoside is used in the strength of 2-16mg. preferably in the dosage of 8mg/16mg and Cyclobenzaprine in the strength of 5-30mg preferably in the dosage of 15mg/30mg as single drug SR formulations and process to prepare thereof.
In yet another preferred embodiment, thiocolchicoside is used in the strength of 2-16mg preferably in the dosage of 8mg/16mg and Cyclobenzaprine in the strength of 5-30mg preferably in the dosage of 15mg/30mg as bilayer SR formulations and process to prepare thereof.
In another embodiment, the sustained release formulation comprises Thiocolchicoside and its salt thereof in the range of 5 to 15 % w/w and Cyclobenzaprine or its salt thereof in the range of 10 to 20 % w/w alone or in combination with either oxicams in the range 5 to 10 % w/w or azepines in the range 2 to 5 % w/w of total composition.
In another embodiment the process of preparing the sustained release matrix composition of Thiocolchicoside and/or Cyclobenzaprine either alone or in combination along with one or more pharmaceutically acceptable excipients comprises dispensing of ingredients, mixing, granulation, sieving through mesh, drying, sifting, lubrication and finally compression. Optionally tablets can be coated by using aqueous or non aqueous coating materials and optionally using suitable approved colors.

One embodiment of the present invention contains sustained release matrix tablet formulations comprising therapeutically effective amount of Thiocolchicoside or Cyclobenzaprine or its salts thereof or other actives selected from muscle relaxant or analgesic agent in therapeutically allowable dose which is incorporated into around 10-70 % of a high viscocity polymer with suitable filler and lubricants and compressed into tablet using direct compression or wet granulation method. Optionally suitable antioxidant like butylated hydroxy anisole, butylated hydroxy toluene, sodium ascorbate, ascorbyl palmitate. Preservatives like methyl and propyl paraben gallates. sodium sulphites may also be added.
Another embodiment of the present invention contains sustained release matrix tablet formulations comprising therapeutically effective amount of Thiocolchicoside or Cyclobenzaprine or its salts thereof either alone or in combination along with other actives selected from muscle relaxant or analgesic agent in which drug: rate controlling polymer ratios are about 1:2 to 1:6 to provide sustain drug release wherein each or either drug is released over a period of 24 hours .
Another embodiment of the present invention contains pharmaceutical composition comprsing therapeutically effective amount of Thiocolchicoside or Cyclobenzaprine or its salts thereof either alone or in combination along with actives selected from muscle relaxant or analgesic agent in which drug: excipient ratios are about 1:4 to about 1:18 which are fabricated into sustained release matrix tablets to provide prolonged drug release over the period of 24 hours.
One more embodiment of the present invention provides extended release solid pharmaceutical compositions containing Thiocolchicoside and Cyclobenzaprine either alone or in combination along with other mucoskeletal and analgesic drugs. These drugs are formulated into an extended release composition prepared by incorporating the drug substance into rate controlling hydrophilic polymers and the said polymers having a viscosity in the range of about 10-120,000 cps to provide the drug release up to 24 hours.
Thiocolchicoside or Cyclobenzaprine or its salts can also be combined with other muscle relaxant drugs such as carisoprodol, chlorzoxazone, metaxolone, methocarbamol. orphenadrine, diazepam, baclofen, tizanidine, gabapentin, botulin toxin, tetradotoxin and

dantrolene or combinations of the any of the foregoing to prepare sustained release compositions mentioned in the present invention in suitable form for administration into mammals via suitable routes.
Thiocolclchicoside or Cyclobenzaprine or its salts can also be combined with other muscle relaxant drugs such as curare alkaloids and their derivatives to prepare sustained release compositions mentioned in the present invention in suitable form for administration into mammals via suitable routes. Examples of such muscle relaxant from this category include but are not limited to pancuronium, cisatracurium, rocuronium, vacuronium, doxacurium, cisatracurium, atracurium, mivacurium, rapacuronium, tubocuranine. pipecuronium and salts of these drugs and combinations of any of the foregoing.
In one embodiment of the present invention, HPMC having high viscocity (about 10-120,000 cps) along with microcrystalline cellulose have been used.
One embodiment of the present invention is a sustained release formulation of centrally acting muscle relaxant drugs, Thiocolchicoside, Cyclobenzaprine or salts thereof for the treatment of muscular spasm resulting from various mucoskeletal disorders, various injuries and strains with a drug release profile up to 24 hours. These dosage forms provide the drug release over a period of 24 hours, during which 20 to 80%, preferably between 25 to 75% of the active ingredient i.e. Thiocolchicoside and or Cyclobenzaprine or pharmaceutically acceptable salt thereof, is dissolved between 2 to 8 hours; and that of about 90% of active ingredient is dissolved between 8 and 24 hours.
The novel pharmaceutical composition in this present invention may also be prepared in the form of a tablets, multilayer tablets and multicoated tablets, floating tablets, sustained release granules, beads or particles, floating beads, granules or particles which may be filled in capsules.
Further, the novel pharmaceutical composition of the present invention may be administered orally, topically and systemically.

Thiocolchicoside or Cyclobenzaprine or its salts thereof or serratiopeptidase or lornoxicam and/or combinations thereof may also be formulated in the form of single layer matrix tablets or bilayer tablets or multilayer tablets. Such bilayer or multilayer tablets may contain all the layer having sustained drug release profile or may contain one layer with sustained release drug profile and another layer having immediate release drug profile.
Present invention can also be formulated in the form of sustained release or controlled release composition containing Thiocolchicoside or Cyclobenzaprine or its salts thereof or other actives selected from muscle relaxants, analgesics and combinations thereof with therapeutically beneficial compounds to relieve the pain.
Thiocolchicoside or Cyclobenzaprine or its salts thereof or other muscle relaxants or pain relieving agents and combinations thereof may also be formulated in the form of immediate release or extended release compositions such as microspheres, nanosupensions, depot preparations, microcapsules, nanocapsules, magnetic microspheres, liposomes or ethosomes, solid lipid nanoparticles, cochleates, extended release pellets or beads or granules for administration via parenteral route or any other suitable route into mammals. Such sustained relaease release granules can also be filled in spansules or capsules or sachets and may be administered as sustained release liquid formulations after dispersing in water either as a single dose or multiple dosages. Such compositions can be formulated using release retarding polymers as mentioned in the present invention hereunder including natural and biodegradable polymers such as polylactideglycolides and its derivatives, chitosan and polyethylene oxides.
These sustained release formulations are often referred in the art, as "matrix formulations" where by the drug is incorporated into a hydrated polymer matrix system and is released vis diffusion or erosion mechanism or possibly by both of them.
The sustained release composition of the present invention is prepared by the techniques of homogenization, emulsification comprising o/w, w/o or multiple emulsion (s), hot-melt fusion, lyophilization and/or precipitation.

Suitable release retarding excipients include release-retarding polymers, which may be swellable or form gel in contact with physiological fluid such as the GI tract contents. Polymers whose dissolution is pH dependant may be used either alone or with a plasticizer.
Release retarding polymers which may or may not be swellable include, inter alia, cellulose
derivatives, cross- linked sodium carboxymethyl cellulose, cross-linked
hydroxypropylcellulose, hydroxyethylcellulose. high-molecular weight
hydroxypropylmethylcellulose, carboxymethylamide, potassium methacrylatedivinylbenzene co-polymer, polymethylmethacrylate, cross-linked polyvinylpyrrolidone, hydroxyethyl cellulose high- molecular weight polyvinyl alcohols, polyethyleneoxides etc.
Release retarding gellable polymers includes methylcellulose, carboxymethylcellulose, low-molecular weight hydroxypropylmethylcellulose, hydroxyethyl cellulose, low-molecular weight polyvinyl alcohols, polyoxyethyleneglycols, non-cross linked polyvinylpyrrolidone. acrylic acid derivatives, xanthan gum, isapgol husk, chitosan other such polymers which will release the drug in sustained manner.
Release retarding polymers simultaneously possessing swelling and gelling properties include acrylic acid derivative such as carbopol, medium-viscosity hydroxypropylmethylcellulose and medium-viscosity polyvinyl alcohols.
Examples of matrix forming polymers, which may be used, include various commercially available cellulose derivatives in different grades which differ in their viscosity, molecular weight and extent of cross linking. Some of the examples of such polymers are Methocel K4M, Methocel E50, Methocel K15M, Methocel K100M and Methocel K100LV.
Other release-retarding polymers which may be incorporated include hydrocolloids such as natural or synthetic gums, cellulose derivatives other than those listed above, carbohydrate-based substances such as gum acacia, gum karaya, gum tragacanth, locust bean gum, guar gum, gums derived from Tamarindus indica, . agar, pectin, carageenin, soluble and insoluble alginates, carboxypolymethylene, casein, zein, and the like, and proteinaceous substances such as gelatin.

Apart from the ingredients decribed above, tablet may also contain channeling agents which are used to modify the dissolution of the dosage form. Suitable pharmaceutically acceptable water soluble salts such as sodium chloride, potassium chloride, boric acid, sodium borate, and sugars such as sucrose, lactose can be used as channeling agents in the tablet. poly(ethylene glycol), poly(ethylene-co-propylene glycol), and poly(vinylpyrrolidone) can also be used as channeling agent. Apart form these, hydrophilic natural and modified polysaccharides such as dextran, arabinogalactan may be used. Synthetic polymers such as homo and copolymers of acrylic acid and vinyl alcohol can also be utilised as channeling agents.
The sustained release formulation may also include diluents/compression aids such as lactose, microcrystalline cellulose, dicalcium phosphate, sucrose, mannitol, xylitol, starches, and lubricants such as magnesium stearate. sodium stearyl fumarate and stearic acid. The sustained release formulation may further comprise binders such as povidone (polyvinylpyrrolidone); flow aids such as silicon dioxide or talc.
A preferred release-retarding polymer is one of the available grades of hydroxypropylmethyl cellulose or hydroxyethyl cellulose. Hydroxypropyl methylcellulose (HPMC) is a cellulose derivative belonging to group of cellulose ethers, having etherified anhydrous glucose rings. Various types of HPMC are available depending on viscocity used to retard the rate of release to higher extent and lower extent respectively. Hydroxypropyl methylcellulose (HPMC) is commercially available in various grades, under so many trade names, including Methocel® (dow chemicals), HPM (British Celanese Ltd., U.K.), and Metalose® SH of Shin-Etsu Ltd., Japan. The grades mentioned under the particular trade names indicates represents the differences in methoxy and hydropropoxy content as well as molecular weight of HPMC. Our present invention makes use of HPMC K100 M. it is having high viscocity properties.
Methacrylate co-polymers may also be used to retard the drug release formulations. Wide variety of co polymers of methacrylic acid, poly methacrylates and poly methyl methacrylates are available commercially such as Eudragit® RLPO, Eudragit® RS 30, Eudragit® RL 100, Eudragit® RL 30 D, Eudragit® RSPO etc. Methacrylic acid copolymers like Eudragit® 100

and Eudragit® S 100 may be used to give pH dependant sustained release either alone or with a plasticizer.
Other release retarding polymers which may be used include methyl cellulose, carboxymethylcellulose, low-molecular weight hydroxypropylmethylcellulose, hydroxyethyl cellulose, low-molecular weight polyvinyl alcohols, polyoxyethyleneglycols. non-cross linked polyvinylpyrrolidone, acrylic acid derivatives, xanthan gum, isapgol husk, chitosan, hydroxyethyl cellulose high- molecular weight polyvinyl alcohols, polyethyleneoxides carbopol, medium-viscosity hydroxypropylmethylcellulose and medium-viscosity polyvinyl alcohols include hydrocolloids such as natural or synthetic gums, cellulose derivatives other than those listed above, carbohydrate-based substances such as gum acacia, gum karaya, gum tragacanth, locust bean gum, guar gum, gums derived from Tamarindus indica, agar, pectin, carageenin, soluble and insoluble alginates, carboxypolymethylene, casein, zein, and the like, and proteinaceous substances such as gelatin.
The other excipient used in our invention is Microcrystalline cellulose. MCC was used as a filler in the present invention. Microcrystalline Cellulose (MCC) as the most useful filler/ binder for direct compression. MCC also has some disintegrant and anti-adherent properties. MCC has grown in popularity due to its excellent compactibility at low pressures and high-dilution potential.
Apart from Microcrystalline cellulose, the sustained release formulation may also include diluents/compression aids such as lactose, dicalcium phosphate, sucrose, mannitol, xylitol, starches, and lubricants such as magnesium stearate, sodium stearyl fumarate and stearic acid. The sustained release formulation may further comprise binders such as povidone (polyvinylpyrrolidone); flow aids such as silicon dioxide or talc.
Channeling agent in the form of Sodium chloride may be added in one of the embodiments of the present invention. A channelling agent may be employed to increase the porosity of the film coating in order to increase the amount of the fluids that penetrate the tablet core and increase the rate of hydration. Generally, channelling agents may be any salts, surfactants, or short-chain water soluble polymers in a water channel forming effective amount i.e. 1 to 5% by

weight, based on the total weight of the core and all coating components. The channeling agents include any pharmaceutically acceptable water soluble salt, surfactant, or short chain water soluble polymer such as sodium chloride, potassium chloride, sucrose, polysorbate-80, hydroxypropyl cellulose, hydroxyethyl cellulose and the like.
Magnesium stearate is an excipient, which is used as a lubricant, to prevent the tablet mass from sticking to the equipment during the compresion process thereby allowing tablet to eject easily from the die Qavity. Optimum amounyt of magnesium stearate is desired because excess amount of magnesium stearate leads to retardation of release rate due to hydrophobic nature of magnesium stearate iitself.
Colloidal silicon dioxide is used in one of the embodiement of the present invention. Collodial silicon dioxide also being known as aerosil or Carbosil is most widely used glidant. It reduces the interparticles friction thereby results in improved flow properties of powder blend. Talc was also used as antiadhesive in one of the embodiment of the present invention.
Colouring agents may be added optionally at the appropriate stage of manufacturing process in suitable amount. Coloring agents may be chosen from the class of pharmaceutically acceptable colorants meeting required specifications such as GRAS approved colors.
The ingredients with low density can be incorporated into the formulation to formulate floating type sustained release delivery system of stated drugs. Sustained release tablets of Thiocolchicoside and Cyclobenzaprine and its salts thereof can also be formulated in combination with other Antiarthritics/Antirheumatics dnogs either in suitable dose or as fixed dose or as bilayer tablets formulation. Examples of such drugs include Auranofin. Aurothioglucose, aurothioglicande, Azathioprine, Chloroquine, Gold sodium thiosulfate, Hydroxchloroquine, Methotrexate, penicillamine, leflunomide, hyaluronan, Biological response modifiers including etanercept, infliximab, adalimumab, anakinra . Rituximab, Abatacept, Cortcosteroids such as Betamethasone, Cortisone acetate, Dexamethasone, hydrocortisone, methylprednisolone, and prednisone.

Sustained release tablets of Thiocolchicoside and Cyclobenzaprine can also be formulated in combination with other drugs used to treat the syndromes of Inflammatory bowel disease (IBD) either in suitable dose or as fixed dose or as bilayer tablets formulation. Examples of such drugs include sulphasalazine, 5- ASA (5-amino salicylic acid), augmentin, 6-mercaptopurine, azathioprine, methotrexate, cyclosporin, infiximab, ciprofloxacin, metronidazole and corticosteroids such as budesonide, prednisolone, and hydrocortisone.
The same formulation can be formulated either in combination or as fixed dose formulation with the drugs selected from the therapeutic category like analgesic, antipyretic or NSAID's in suitable dose either as fixed dose or in combination or as bi-layer tablets. Non limiting examples of such categories of drugs of analgesic, antipyretic include from class aniline and p-Aminophenol analogues, salicylic acid analogues, quinoline derivatives, pyrazolones and pyrazolidones, N- arylanthranitic acid, drugs from the category NSAID's includes heteroarylacetic acid analogues, arylacetic acid analogues, arylpropionic acid analogues, naphthalene acetic acid analogues, gold compounds, uricosuric agents, salicylic acid analogues, pyrazolones and pyrazolidones, lipo-oxygenase-2 inhibitors like licofelone, COX-2 inhibitors like celecoxib, etoricoxib, lumiracoxib and other classes of drugs. Also in combination with carisoprodol, chlorzoxazone, metaxalone, methocarbamol, orphenadrine, dantrolene, Eperisone, Tolperisone, actarit and other drugs which are spasmolytic and which may be centrally or peripherally acting spasmolytics.
Further the analgesic anti-inflammatory drugs which may belong or may not belong to the above mentioned classes may also be combined with Thiocolchicoside and Cyclobenzaprine for potential benefits in Arthritis or inflammatory bowel disease and others. Non limiting examples of such drugs include aspirin, aceclofenac, acemetacin, aspirin, paracetamol. alminoprofen, amfenac, ampiroxicam, balsalazide, bendazac, bermoprofen, alpha-bisabolol, bromfenac, bromosaligenin, bucloxic acid, butibufen, carprofen, cinmetacin, clidanac, clopirac, diclofenac, diacereine, diflusinal, ditazol, enfenamic acid, etodolac, etofenamate, felbinac, fenbufen, fenclozic acid, fendosal, fenoprofen, fentiazac, fepradinol, flufenamic acid, flunixin, flunoxaprofen, flurbiprofen, glucametacin, glycol salicylate, ibuprofen, ibuproxam, indomethacin, indoprofen, isofezolac. isoxepac, isoxicam, ketoprofen, ketorolac, lornoxicam, loxoprofen, mechlofenamic acid, mefenamic acid, meloxicam, mesalamine, metiazinic acid,

mofezolac, naproxen, niflumic acid, olsalazine, oxaceprol, oxaprozin, oxifenbutazone. parsalmide, pemedolac, perisoxal, phenyl acetylsalicilate, pirazolac, piroxicam, pirprofen, pranoprofen, protizinic acid, salacetamide, salicylamido-O-acetic acid, saliciylsulforic acid. salsalate, sulindac, suprofen, suxibuzone, tenidap, tenoxicam, thiaprofenic acid, thiaramide, tinoridine, tolfenamic acid, tolmetin, tropesin. xenbucin. ximoprofen, zaltoprofen, zomepirac. tomoxiprol, acetaminosalol, aminochlorthenoxazin, 2-amino-4-picoline, anileridine, benoxaprofen, 5-bromosaliciylic acid acetate, bucetin, butorfanol, capsaicin, cincofenol. ciramadol, clometacine, clonixin, dezocine, dimefeptanol, dipyrocetyl, eptazocine, etoxazen, eugenol, floctafenine, fosfosal, glafenine,hydroxypetidine, ibufenac, p-lactophenetide, levorfanol, meptazinol. metazocine, metopon, pentazocine, fenazocine, fenocoll, fenoperidine, fenilbutazone, phenylsalicylate, phenilramidol, salicin, salicylamide, tiorphan, tramadol. The analgesic drugs may also include the derivatives of thebaine and morphine which may be combined with Thiocolchicoside for preparing the sustained release doasge form.
Thiocolcoside and Cyclobenzaprine and its salts may also be combined with such other drugs to formulate bilayer tablet dosage form. Such combination when appropriately mixed with the suitable excipients for the dermal preparation may be used as a sustained release matrix for relieving the spasm and pain. The same sustained release matrix may be used for the formulation of oral liquids using suitable excipients and the same matrix may be also filled in the capsules. Additionally spray formulation of the above drugs can be used in the aerosol forms. The same can be prepared appropriately by covering with a suitable dispersing matrix.
The dissolution profile of one of the embodiment of the formulation is presented in Figures 1-4. The composition is compared with conventional IR formulation available in the market.
The present invention is beneficial from the economic point of view because better drug release profile was achieved when HPMC K100M and Microcrystalline Cellulose were used in such a low concentration to formulate sustained release tablets of Thiocolchicoside and Cyclobenzaprine.
This invention is economically beneficial interms of cost and manpower requirement as it involves simple process with minimum number of steps.

The below preferred embodiments are given to illustrate the scope of the present invention which are not exhaustive and not limiting. A person skilled in the art of pharmaceutics can formulate the similar or modified form for such kind of preparation.
Example 1
Accurately weighed amount of Thiocolchicoside (5.33%) was mixed with lactose (75%) and hydroxypropyl methyl cellulose K15 M (10.66%). This mixture was binded using polyvinylpyrolidone (7%) solution. The wet mass was seived to prepare granules which were dried, milled and lubricated with aerosil (2%). Granules were compressed into tablets. The tablets were evaluated for drug content and release profile. The tablets were optionally coated further with coating solution containing suitable film forming agent and colour.
Example 2
Thiocolchicoside was taken in 5.33% amount and added to lactose (69.66%) and hydroxypropyl methyl cellulose K100M (16%) which were mixed together and were binded using polyvinylpyrolidone (7%) solution. The wet mass was seived to prepare granules which were sieved and lubricated with aerosil (2%). Lubricated granules were compressed to formulate tablets. The tablets were evaluated for drug content and release profile. The tablets were optionally coated further with suitable film forming agent and FDA approved colour.
Example 3
The higher concentration of hydrxypropyl methyl cellulose was also used to produce the sustained release tablets. Thiocolchicoside was taken in 5.33% amount and to it lactose (69.66%) and hydroxypropyl methyl cellulose K100M (16%) were added and mixed together. This blend was binded using polyvinylpyrolidone (7%) solution. The wet mass was sieved to prepare granules which were dried and milled. Further granules were processed for lubrication with aerosil (2%) followed by compression to formulate tablets. The tablets were evaluated for drug content and release profile. Further tablets were optionally coated with coating soluition containing suitable film forming agent and colorants.

Example 4
Thiocolchicoside (5.33%) was accurately weighed and mixed with 67 % amount of microcrystalline cellulose. This was mixed with 21.33 % of HPMC K100 M. This blend was granulated with 2.66% PVP K 30 solution in non aqueous solvent like isopropyl alcohol. The granules were dried followed by lubrication with 2% aerosil and 1.33% talc. This mixture was finally compressed into tablets.
Example 5
Thiocolchicoside (5.33%), hydroxypropyl methyl cellulose K100M (21.33%) and microcrystalline cellulose (71.33%), were accurately weighed and blended well. Aerosil (2%) was added to this blend and mixed together. The mixture was then sieved and compressed into tablets using direct compression technique. The tablets were then evaluated for drug content and release profile.
Example 6
Thiocolchicoside was taken in 5.33% amount and mixed with lactose (71.66%) and hydroxypropyl methyl cellulose K100M (21.33 %). Further granules were processed for lubrication with aerosil (2%) followed by direct compression to formulate tablets. The tablets were evaluated for drug content and release profile. Further tablets were optionally coated with coating soluition containing suitable film forming agent and colorants.
Example 7
Thiocolchicoside (10.66 %) was accurately weighed and mixed with 40 % amount of microcrystalline cellulose. This was mixed with 42.66 % of HPMC K100 M. This blend was granulated with 2.66% PVP K 30 solution in non aqueous solvent like isopropyl alcohol. The granules were dried followed by lubrication with 2.66 % aerosil and 1.33% talc. This mixture was finally compressed into tablets.
Example 8

Example 8
Tablets were prepared by direct compression using hydroxypropyl methyl cellulose in higher concentration of about 42.66% which was mixed with accurately weighed Thiocolchicoside drug (10.66%). Other ingredients like microcrystalline cellulose (44.66%) and aerosil (2%) were added to drug mixture. The mixture was then sieved through sieve and compressed to get tablets under optimum hardness by direct compression tecnique. The tablets were then evaluated for drug content and release profile.
Example 9
Cyclobenzaprine hydrochloride was weighed accurately (20%) and mixed with HPMC K100M (20%). To this mixture microcrystalline cellulose (56%) was added and blended carerfully. Finally the blend was lubricated with magnesium stearate (2%) and aerosil (2%). The mixture was processed for direct compression to prepare the tablets using suitable punch at optimum hardness. The tablets were evaluated for parameters like assay content and drug release profile to meet the predetermined specifications. The tablets were optionally coated further with coating material containing suitable film forming agent and colorant.
Example 10
The once a day formulation of Cyclobenzaprine was formulated using slighlty higher amount of release retarding polymer than the previous formula. The drug Cyclobenzaprine or suitable salt thereof was weighed accurately (20%) and mixed with release retarding polymer HPMC Kl00 (40%) and microcrystalline cellulose (36%). To this mixture, magnesium stearate (2%) and aerosil (2%) were added and mixed uniformly. The powder mixture was then compressed into tablets with desirable hardness by direct compression technique. The tablets were evaluated for parameters like assay content and drug release profile to meet the predetermined specifications.

Example 11
The concentration of release retarding polymer hydroxy propyl methyl cellulose was further increased upto 60% using Cyclobenzaprine hydrochloride in 20% amount. The other ingredients used were diluent like microcrystalline cellulose (16%), lubricant like magnesium stearate and glidant like aerosil in 2% concentration. All ingredients were mixed together and passed through screen. The mixture was then subjected to punching at suitable pressure to impart the desirable hardness to tablets. The tablets were evaluated for parameters like assay content and drug release profile to meet the predetermined specifications.
Example 12
The concentration of release retarding polymer hydroxy propyl methyl cellulose (HPMC) was still further increased upto 70%. Cyclobenzaprine hydrochloride (20%) was mixed with HPMC and microcrystalline cellulose (8%). The blend was lubricated with magnesium stearate (1%) aerosil (1%). This mixture was then subjected to direct compression to prepare tablets which were further evaluated for parameters like assay content and drug release profile to meet the predetermined specifications. The tablets were optionally coated with coating material containing suitable film forming agent and colour.
Example 13
Cyclobenzaprine hydrochloride sustained release tablets were also prepared using wet granulation. Cyclobenzaprine (20%) was accurately weighed and mixed with 11.33% amount of microcrystalline cellulose. This was mixed with 60% of HPMC K100 M. This blend was granulated with 2.66% PVP K 30 solution in non aqueous solvent like isopropyl alcohol. The granules were dried followed by lubrication with 2% aerosil, 2% Magnesium stearate and 2% talc. This mixture was finally compressed into tablets which can be coated optionally.
Example 14
Cyclobenzaprine (10%) was accurately weighed and mixed with 21..33 % amount of microcrystalline cellulose. This was mixed with 60 % of HPMC K100 M. This blend was

granulated with 2.66% PVP K30 solution in non aqueous solvent like isopropyl alcohol. The granules were dried followed by lubrication with 2 % aerosil, 2% Magnesium stearate and 2 % talc. This mixture was finally compressed into tablets which can be coated optionally.
Example 15
Part (I) accurately weighed amount of Thiocolchicoside (5.33 %) was mixed with lactose (20.25%) and hydroxypropyl methyl cellulose K15 M (10.91%) respectively. This mixture was binded using polyvinylpyrolidone (3%) solution. The wet mass was sieved to prepare granules which were dried, milled and lubricated with aerosil (1%).
Part (II) accurately weighed amount of Cyclobenzaprine (10%) was mixed with lactose (23.68%) and hydroxypropyl methyl cellulose K15 M (20.83%) respectively. This mixture was binded using polyvinylpyrolidone (4%) solution. The wet mass was sieved to prepare granules which were dried, milled and lubricated with aerosil (1%).
Granules prepared in Part (I) and Part (II) were compressed to form bilayer tablets. The tablets were evaluated for drug content and release profile. The tablets were optionally coated further with coating solution containing suitable film forming agent and colour.
Example 16
Bilayer tablets of multiple strengths i.e 10.66% of Thioclochicoside and 20% drug were proportionally mixed with other excipients in the same ratio, compressed in to bilayer tablets and were evaluated for drug content and release profile. The tablets were optionally coated further with coating solution containing suitable film forming agent and colour.
Example 17
Thiocolchicoside (5.33%) and Lornoxicam (5.33%) was accurately weighed and mixed with 37.66 % amount of microcrystalline cellulose. This was mixed with 43 % of HPMC K100 M. This blend was granulated with 5 % PVP K 30 solution in non aqueous solvent like isopropyl alcohol. The granules were dried followed by lubrication with 2% aerosil and 1.33% talc. This mixture was finally compressed into tablets and can be coated optionally.

Example 18
Thiocolchicoside and Lornoxicam were taken in 50:50 ratio. These drugs were accurately weighed and mixed with 40 % amount of HPMC K 100M. 13.53 % of HPMC K15 M and 28.66 % of Microcrystalline cellulose. This blend was granulated with 5% PVP K 30 solution in non aqueous solvent like isopropyl alcohol. The granules were dried followed by lubrication with 1.66% aerosil, 0.66 % magnesium stearate and 0.66 % talc. This mixture was finally compressed into tablets and can be coated optionally.
Example 19
The formulation of example 18 also formulated as a bilayer tablet in which Thiocolchicoside is formulated as sustained release layer on which Lornoxicam is punched as a immidiate release layer to form a tablet. The tablets further optionally coated with suitable colouring material. The tablets were further evaluated for release pattern & assay content.
Example 20
Cyclobenzaprine hydrochloride (10%) and diazepam (2.6 %) were accurately weighed and mixed with 28.66% amount of microcrystalline cellulose. This was mixed with 50.66 % of HPMC K100 M. This blend was granulated with 4% PVP K30 solution in non aqueous solvent like isopropyl alcohol. The granules were dried followed by lubrication with 1.3% aerosil, 1.3% Magnesium stearate and 1.33% talc. This mixture was finally compressed into tablets.

We claim,
1. A sustained release pharmaceutical composition useful for the treatment of rheumatologic.
orthopedic, and traumatologic disorders, comprising
a) therapeutically effective amount of Thiocolchicoside or Cyclobenzaprine or its pharmaceutically acceptable salts prepared with either of each as single drug formuation or in combination with each other ,
b) rate controlling polymer(s) having a viscosity in the range of about 10-120,000 cps and present in the range of 10 to 70 % w/w, and
c) pharmaceutically acceptable excipients;
wherein the ratio of drug to polymer is in the range of 1:2 to 1:6, to provide the drug release up to 24 hours period.
2. The sustained release composition according to claim 1, wherein rate controlling polymer is having viscosity grade in the range of 15 to 65 % w/w.
3. The sustained release composition according to claim 1, wherein rate controlling polymer is selected from cellulose derivatives, Methacrylate co-polymers, natural or synthetic gums, soluble and insoluble alginates.
4. The sustained release composition according to claim 1, wherein said composition optionally comprises of another active selected from muscle relaxant or analgesic drugs or anti-inflammatory or Antiarthritics/Antirheumatics.
5. The sustained release composition according to claim 5 wherein the actives are selected from Oxicams like Lornoxicam and Azepines like Diazepam or derivatives thereof.
6. The sustained release composition according to claim 6. wherein said formulation comprises Thiocolchicoside and its salt thereof in the range of 5 to 15 % w/w and Cyclobenzaprine or its salt thereof in the range of 10 to 20 % w/w alone or in combination with either Lornoxicam in the range 5 to 10 % w/w or Diazepam in the range 2 to 5 % w/w of total composition.
7. The sustained release composition according to claim 1, wherein said pharmaceutical composition is administered orally, topically or systemically.

8. The sustained release composition according to claim 1, wherein the pharmaceutical composition is prepared in the form of a raw powders or granules dispersed in a suitable aqueous or non-aqueous liquid(s), pellets, beads, micro or nano particles, micro or a solvated powders, sachets, semisolids, an Injectable preparations, a tablets, a capsules or a suitable specific two- or three-dimensional matrix compositions,
9. The sustained release composition according to claim 9 wherein said composition is a single layer or a bilayer tablet.
10. The sustained release composition according to claim 1, wherein said composition is prepared by the techniques of dry granulation, wet granulation and / or direct compression using aqueous / Non aqueous solvent further fabricate into the single layer, bilayer, and multilayer and / or multicoated tablet dosage forms.
11. The sustained release composition according to claim 1. wherein said composition is prepared by the techniques of homogenization, emulsification comprising o/w, w/o or multiple emulsion (s), hot-melt fusion, lyophilization and/or precipitation.
12. The sustained release composition according to claim 1, wherein the pharmaceutical excipients are selected from the group of binders, diluents, lubricant, glidants, buffering agents, coating agents or coloring agent.
13. The sustained release composition according to claim 1, wherein each or either drugs is released 20 to 80%, in 24 hours.