COMPLETE DESCRIPTION
Filed of the Invention
The present invention relates to a novel pharmaceutical formulation comprising ibuprofen and tizanidine with certain bioavailability enhancer. The invention also relates to a pharmaceutical formulation comprising ibuprofen and tizanidine having quicker onset of action by achieving the peak plasma concentration in lesser time when compared to the presently available pharmaceutical formulation.
Prior Art related to the Invention
US2010179103 (A1) discloses a method of increasing the delivery of curcumin by complexing it with cyclodextrins. Cyclodextrins are well known in the food industry and have been used to carry other drugs to increase bioavailability. The new combination of cyclodextrins and curcumin has been tested in pre-clinical inflammation models where it has demonstrated efficacy superior to both the positive control and curcumin.
SG160330 (A1) relates to novel pharmaceutical formulations of Vardenafil, which rapidly dissolve in the mouth and lead to an increase in bioavailability and a plateau-shaped plasma concentration curve and method for production thereof.
CN101601862 (A) provides application of porous starch and derivatives thereof as a medicament carrier. The porous starch and derivatives thereof as the medicament carrier can improve the physical and chemical properties of the medicament such as solution, dissolution and the like, increase the bioavailability of the medicament, control the release speed of the medicament, keep the

stability of the medicament in vivo, and improve the targeting property of the medicament.
US2009123542 (A1) relates to a primary composition in which at least one lipophilic bioactive compound is mixed with a whey protein, present in an amount effective to increase the bioavailability of the lipophilic bioactive compound.
WO2009052491 (A2) discloses a formulation for repeated administration or continued slow release administration, over prolonged periods of time or targeted slow and regulated delivery. The formulations include those formulations that increase the bioavailability of fenoldopam after oral intake, particularly lipid based nanodispersions and pronanodispersions and surfactant rich formulations. This may be accomplished by entrapment in nanoparticles or liposomal formulations or conjugation to a polymer or small molecule via a soft bond.
KR20020071037 (A) discloses a formulation of ibuprofen into a soft gelatin capsule or an injection using a self-micro emulsifying drug delivery system (SMEDDS) is provided. Therefore, the obtained ibuprofen soft gelatin capsule has excellent elution characteristics and the formulation increases bioavailability of a medicament.
WO0115688 (A1) relates Liquid softgel fill formulations containing ibuprofen in free acid form, and softgel capsules comprised of a gelatin sheath enclosing such fill formulations, are prepared by dissolving more than 30 % of ibuprofen in free acid form in polyethylene glycol and at least 10 % by weight of a polyvinylpyrrolidone having an average molecular weight of from about 2,000 to about 54,000. The formulations may also include a surfactant to increase the bioavailability of the ibuprofen.

JP62084018 (A) provides a suppository having high rate of drug release, by adding a specific amount of a fatty acid alkali metal salt to a suppository containing an acidic drug. Constitution: A suppository containing an acidic drug (e.g. glycyrrhezic acid, indomethacin, ibuprofen, etc.) is added with >=0.01wt% and <0.5wt%, preferably 0.01-0.2 wt% fatty acid alkali metal salt. The fatty acid is preferably 10-16C saturated fatty acid and the alkali metal salt is preferably Na salt or K salt. The additive is effective to increase the releasability of the acidic drug in the suppository from the base and improve the absorption and bioavailability of the drug.
WO2007133476 (A2) is directed to a method and a composition for improving the bioavailability of an orally administered drug having poor systemic bioavailability, by competitively inhibiting and retarding the metabolic inactivation of the drug.
WO2009073661 (A2) describes compositions that include a sulfide containing molecule, such a garlic oil, and a coenzyme Q molecule. The sulfide containing molecule solvates the coenzyme Q molecule, thus enhancing the bioavailability of the coenzyme Q molecule in a subject in need thereof, relative to administration of coenzyme Q devoid of the presence of a sulfide containing molecule.
WO2004064757 (A2) discloses new compounds that increase the absorption of pharmaceutical agents across mucous membranes. These absorption enhancers allow higher bioavailability of administered drugs. The enhancers advantageously have low or no cytotoxicity.
US2003211072 (A1) describes the use of polysaccharides, surfactants, and dendrimers as bioavailability enhancers for oral pharmaceutical compositions. These substances exert an inhibitory action of the gastrointestinal pump efflux

proteins, such as the P-glycoprotein and the MDR protein, responsible for poor drug bioavailability and multidrug resistance.
United States Patent 7,387,791 relates to pharmaceutical compositions for administering a biologically active compound to an animal. Particularly provided are pro-liposomal compositions that are advantageously used to deliver biologically active compounds to the gastrointestinal tract after oral administration.
United States Patent 6,017,932 discloses a novel composition for increasing the bioavailability of Non-steroidal Anti-inflammatory Drugs (NSAIDs), particularly those belonging to the category which exhibits its activity by selectively inhibiting cyclooxygenases-ll (COX-II) and/or lipooxygenases, is disclosed. The composition is characterized in having clinically significant increased bioavailability when compared to the known compositions of the drugs.
WO0051643 (A1) discloses method for increasing bioavailability of an orally administered pharmaceutical compound comprises orally coadministering the pharmaceutical compound to a mammal in need of treatment with the compound and a gallic acid ester. Preferred gallic acid esters of the invention include octyl gallate, propyl gallate, lauryl gallate, and methyl gallate. Improved formulations of pharmaceutical compounds include the gallic acid ester to enhance the biovailability of the active ingredient of the pharmaceutical compound.
United States Patent 7,008,640 a pharmaceutical composition for oral use with improved absorption, which comprises drug, aminoalkyl methacrylate copolymer E, and acidic substance and is obtained by bringing said 3 components together and uniformly mixing at least this polymer and this acidic substance, and a method of improving oral absorption by using this pharmaceutical composition.

US2010166856 (A1) relates to a modified release pharmaceutical composition in capsules with coated microspheres, combining two active ingredients with radically different plasma concentration times, namely a muscle relaxant (tizanidine) and a non-steroidal anti-inflammatory drug (meloxicam), and pharmaceutically acceptable excipients or vehicles; as well as a method for producing the composition and the use of said combination for the preparation of a drug having synergic therapeutic effect in the treatment of spasticity, disorders related to the skeletal muscle and/or muscular ailments, and moderate to severe pain in general.
PH23276 (A) discloses compositions having enhanced analgesic and myotonolytic activity comprising tizanidine and ibuprofen. The composition is preferably formulated as a tablet and desirably the weight ratio of tizanidine to ibuprofen is from 1:50 to 1:200, especially 1:100.
Synthesis of Indomethacin Conjugates with D-Glucosamine
Yi Chun ZHANG, Ying Xia LI, Hua Shi GUAN
Key Laboratory of Marine Drugs, Ministry of Education, Marine Drug and Food Institute,
Ocean University of China, Qingdao 266003
Abstract: Two series of indomethacin conjugates with D-glucosamine were prepared with the objectives of reducing ulcerogenic potency, increasing the bioavailability of indomethacin and exerting the coordinative effects on osteoarthritis. The structures of the conjugates were identified by 1H NMR and 13C NMR. The ester conjugates inhibited edema as potent as indomethacin.

Dendrimers as Potential Drug Carriers. Part I. Solubilization of Nonsteroidal Anti-Inflammatory Drugs in the Presence of Polyamidoamine Dendrimers
References and further reading may be available for this article. To view references and further reading you must purchase this article.
Cheng Yiyuna, b, , and Xu Tongwenb
aSchool of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China
bDepartment of Chemistry, Laboratory of Functional Membrane University of Science and Technology of China, Hefei, Anhui 230026, People's Republic of China
Received 2 June 2005; accepted 14 June 2005. Available online 8 September 2005.
Abstract: The aqueous solubility of non-steroidal anti-inflammatory drugs (NSAIDs) Ketoprofen, Ibuprofen, Diflunisal and Naproxen were measured in the presence of the ethylenediamine (EDA) core polyamidoamine (PAMAM) dendrimers at 37 °C. The effect of concentration and generation of the PAMAM dendrimers has been investigated. Results showed that the solubility of NSAIDs in the PAMAM dendrimer solutions was approximately proportional to dendrimer concentration; the solubility of NSAIDs in higher generation PAMAM solutions was in fact higher that those in lower ones; the order of increased solubility of NSAIDs in PAMAM dendrimers at a constant dendrimer concentration and generation was Naproxen > Ketoprofen > Ibuprofen > Diflunisal. Under suitable conditions PAMAM dendrimers can be highly effective used to enhance the solubility of NSAIDs.

The above prior art has following drawbacks-
• Complex technology is required to manufacture the dosage formulations of the prior art.
• The price of the finished product is increased by using more complex and sophisticated technology.
• Some of the prior art contains the lipids to increase the bioavailability, thus not suitable for the patients which are on antihyperlipidemic drugs.
Objectives of the Invention
• The objective of the invention is to provide the NSAID with enhanced bioavailability by using the bio-enhancers in effective amount.
• Yet another objective of the invention is to enhance the bioavailability without using complex technology.
• Another objective of the invention is to provide a NSAID without any gastro-irritant effect.
• Another objective of the invention is to provide the pharmaceutical formulation providing quick onset of action and for a longer period of time.
Detailed Description of the Invention
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, are drugs with analgesic and antipyretic (fever-reducing) effects and which have, in higher doses, anti-inflammatory effects (reducing inflammation). The term "nonsteroidal" is used to distinguish these drugs from steroids, which (among a broad range of other effects) have a similar eicosanoid-depressing, anti-

inflammatory action. As analgesics, NSAIDs are unusual in that they are nonnarcotic.
NSAIDs are sometimes also referred to as nonsteroidal anti-inflammatory agents/analgesics (NSAIAs) or nonsteroidal anti-inflammatory medicines (NSAIMs). The most prominent members of this group of drugs are aspirin, ibuprofen, and naproxen partly because they are available over-the-counter in many areas.
Most NSAIDs act as nonselective inhibitors of the enzyme cyclooxygenase (COX), inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A2). Prostaglandins act (among other things) as messenger molecules in the process of inflammation. This mechanism of action was elucidated by John Vane (1927-2004), who later received a Nobel Prize for his work. Many aspects of the mechanism of action of NSAIDs remain unexplained, for this reason further COX pathways were hypothesized. The COX-3 pathway was believed to fill some of this gap but recent findings make it appear unlikely that it plays any significant role in humans and alternative explanation models are proposed.
NSAIDS have antipyretic activity and can be used to treat fever. Fever is caused by elevated levels of prostaglandin E2, which alters the firing rate of neurons within the hypothalamus, that control thermoregulation. Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of prostanoid biosynthesis (PGE2) within the hypothalamus. PGE2 signals to the hypothalamus to increase the body's thermal set point. Ibuprofen has been shown to be more effective as an antipyretic than acetaminophen. Arachidonic

acid is the precursor substrate for cyclooxygenase leading to the production of prostaglandins F, D & E.
Ibuprofen is a chiral nonsteroidal anti-inflammatory drug (NSAID) of the 2 arylpropionic acid (2-APA) class. A common structural feature of 2-APANSAIDs is a sp3-hybridised tetrahedral chiral carbon atom within the propionic acid side chain moiety with the S-(+)-enantiomer possessing most of the beneficial antiinflammatory activity. Ibuprofen demonstrates marked stereoselectivity in its pharmacokinetics. Substantial unidirectional inversion of the R-(-) to the S-(+) enantiomer occurs and thus, data generated using nonstereospecific assays may not be extrapolated to explain the disposition of the individual enantiomers. The absorption of ibuprofen is rapid and complete when given orally. The area under the plasma concentration-time curve (AUC) of ibuprofen is dose-dependent. Ibuprofen binds extensively, in a concentration-dependent manner, to plasma albumin. At doses greater than 600mg there is an increase in the unbound fraction of the drug, leading to an increased clearance of ibuprofen and a reduced AUC of the total drug. Substantial concentrations of ibuprofen are attained in synovial fluid, which is a proposed site of action for nonsteroidal antiinflammatory drugs. Ibuprofen is eliminated following biotransformation to glucuronide conjugate metabolites that are excreted in urine, with little of the drug being eliminated unchanged. The excretion of conjugates may be tied to renal function and the accumulation of conjugates occurs in end-stage renal disease. Hepatic disease and cystic fibrosis can alter the disposition kinetics of ibuprofen. Ibuprofen is not excreted in substantial concentrations into breast milk.
Tizanidine is an agonist at a2-adrenergic receptor sites and presumably reduces spasticity by increasing presynaptic inhibition of motor neurons. In animal models, tizanidine has no direct effect on skeletal muscle fibers or the neuromuscular junction, and no major effect on monosynaptic spinal reflexes.

The effects of tizanidine are greatest on polysynaptic pathways The overall effect of these actions is thought to reduce facilitation of spinal motor neurons The imidazoline chemical structure of tizanidine is related to that of the antihypertensive drug clonidine and other a2-adrenergic agonists. Pharmacological studies in animals show similarities between the two compounds, but tizanidine was found to have one-tenth to one-fiftieth (1/50) of the potency of clonidine in lowering blood pressure.
Bioenhancers are known to those skilled in the art, and may vary depending on the desired properties. In various embodiments, the bioenhancers used in the claimed invention may include betacyclodextrin, Piperin, hydroxy propyl methyl cellulose and Ginger. The bioenhancers can be used either alone with the drug or a combination of the above can be used.
The Ibuprofen is used in the pharmaceutically accepted form and used in the range 200mg to 1000mg, preferably 400 mg to 800 mg most preferably 400 mg to 600 mg.
Tizanidine is used as Tizanidine hydrochloride or other pharmaceutically accepted salts thereof, in the range 1 mg to 8 mg as the base, preferably 2 mg to 6 mg, most preferably 2 mg to 4 mg.
Piperine is used in the range 10 mg to 25 mg per 200mg active ingredients, preferably 15 mg per 200 mg active ingredients.
Beta-cyclodextrin is used twice to thrice the amount of active drug used in the formulation.
Hydroxy propyl methyl cellulose is used 5 mg to 15 mg per 100 mg active ingredients, more preferably 10 mg per 100 mg active ingredients.

Ginger is used in the range 5 mg to15 mg per 200mg active ingredients, preferably 10 mg per 200 mg active ingredients.
The invention can be formulated, but not limited to, in the following manner-
(Table Removed )
The particles of the present invention may comprise, in addition to the active substances, also excipients such as fillers, binders, disintegrants, glidants and lubricants. Suitable fillers are microcrystalline cellulose, powdered cellulose, lactose, starch, pregelatinized starch, sucrose, glucose, mannitol, sorbitol, calcium phosphate, calcium hydrogen phosphate, aluminium silicate, sodium chloride, potassium chloride, calcium carbonate, calcium sulfate, dextrates, dextrin, maltodextrin, glycerol palmitostearate, hydrogenated vegetable oil, kaolin, magnesium carbonate, magnesium oxide, polymethacrylates, talc and others, preferably microcrystalline cellulose and lactose. Suitable binders are starch, pregelatinized starch, gelatine, sodium carboxymethylcellulose, polyvinylpyrrolidone, alginic acid, sodium alginate, acacia, carbomer, dextrin, ethylcellulose, guar gum, hydrogenated vegetable oil, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, glucose syrup, magnesium aluminium silicate, maltodextrin, polymethacrylates, zein, preferably hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Suitable disintegrants are starch, pregelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, calcium carboxymethylcellulose, methylcellulose,
microcrystalline cellulose, powdered cellulose, potassium polacrilinin, cross-linked polyvinylpyrrolidone, alginic acid, sodium alginate, colloidal silicon dioxide, guar gum, magnesium aluminium silicate and others, preferably sodium starch glycolate, cross-linked sodium carboxymethylcellulose and cross-linked polyvinylpyrrolidone. Suitable glidants are magnesium stearate, calcium stearate, aluminium stearate, stearic acid, palmitic acid, cetanol, stearol, polyethylene glycol of different molecular weights, magnesium trisilicate, calcium phosphate, colloidal silicon dioxide, talc, powdered cellulose, starch and others, preferably colloidal silicon dioxide. Suitable lubricants are steraic acid, calcium, magnesium, zinc or aluminium stearate, siliconized talc, glycerol monostearate, glycerol palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, light mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, talc and others. Preferred lubricants are magnesium and calcium stearate, and stearic acid.
The formed particles of the present invention have good flow and compressible properties.
Formed particles of the invention may optionally be coated with a release controlling coating or with a protective coating. The coating may be prepared from polymer or nonpolymer substances. Suitable polymers that may be used are hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxyethyl cellulose, sodium carboxymethylcellulose, cellulose phthalate acetate, polyvinyl acetate phthalate, hydroxymethyl cellulose phthalate, polyvinyl alcohol, methyl hydroxyethyl cellulose, polymers of acrylic and methacrylic acid, maltodextrin and others. Nonpolymer substances that may be used are carnauba wax, cetyl alcohol, sucrose, glucose, shellac and others. The coating may optionally comprise other coating agents conventionally used in coating such as fillers, e.g. talc, lactose, polysaccharides and others, plasticizers,
e.g. dibutyl sebacate, triethyl citrate, polyethylene glycol, adipic acid, coconut oil, oleic acid and others, colourants, e.g. titanium dioxide, lakes, pigments and others, antioxidants and others.
The object of the present invention are also pharmaceutical compositions comprising the above described formed particles. Coated and/or uncoated particles may be used. They may be filled into sachets or capsules, they may be compressed together with suitable excipients into tablets or they mey be used for reconstitution into suspension. Tablets may be single- or multilayer, dispersible, orodispersible, effervescent, chewing, pastilles. The tablets of the invention are hard and have suitable physical technological properties. By the addition of suitable excipients the release of the active substance from the tablet may be controlled. Excipients to be added to the formed particles for the preparation of the previously stated pharmaceutical compositions may be different fillers, binders, disintegrants, glidants and lubricants.
Suitable fillers may be microcrystalline cellulose, powdered cellulose, lactose, starch, pregelatinized starch, sucrose, glucose, mannitol, sorbitol, calcium phosphate, calcium hydrogen phosphate, aluminium silicate, sodium chloride, potassium chloride, calcium carbonate, calcium sulfate, dextrates, dextrin, maltodextrin, glycerol palmitostearate, hydrogenated vegetable oil, kaolin, magnesium carbonate, magnesium oxide, polymethacrylates, talc and others, preferably microcrystalline cellulose and lactose.
Suitable binders are starch, pregelatinized starch, gelatin, sodium carboxymethylcellulose, polyvinylpyrrolidone, alginic acid, sodium alginate, acacia, carbomer, dextrin, ethylcellulose, guar gum, hydrogenated vegetable oil, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, glucose syrup, magnesium aluminium silicate, maltodextrin,
polymethacrylates, zein, preferably hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.
Suitable disintegrants are starch, pregelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, calcium carboxymethylcellulose, methylcellulose, microcrystalline cellulose, powdered cellulose, potassium polacrilinin, cross-linked polyvinylpyrrolidone, alginic acid, sodium alginate, colloidal silicon dioxide, guar gum, magnesium aluminium silicate and others, preferably sodium starch glycolate, cross-linked sodium carboxymethylcellulose and cross-linked polyvinylpyrrolidone.
Suitable glidants are magnesium stearate, calcium stearate, aluminium stearate, stearic acid, palmitic acid, cetanol, stearol, polyethylene glycols of different molecular weights, magnesium trisilicate, calcium phosphate, colloidal silicon dioxide, talc, powdered cellulose, starch and others, preferably, colloidal silicon dioxide.
Suitable lubricants are stearic acid, calcium, magnesium, zinc or aluminium stearate, siliconized talc, glycerol monostearate, glycerol palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, light mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate and others. Preferred lubricants are calcium or magnesium stearate and stearic acid.
Capsules and tablets may optionally be coated with a coating which may be applied from an aqueous or non-aqueous medium. A coating may control the release or it is only a protective coating. The coating may be prepared from polymer or nonpolymer substances. Suitable polymers that may be used are polyethylene glycol, hydroxyl propyl cellulose, hydroxyl propyl methylcellulose, methylcellulose, ethyl cellulose, hydroxyl ethyl cellulose, sodium carboxy
methylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxymethyl cellulose phthalate, polyvinyl alcohol, methylhydroxyethyl cellulose, polymers of acrylic and methacrylic acid, maltodextrin and others. Nonpolymer substances may be carnauba wax, cetyl alcohol, sucrose, glucose, shellac and others.
The coating may also comprise other conventionally used coating agents such as fillers, e.g. talc, lactose, polysaccharides and others, plasticizers, e.g. dibytil sebacate, trietyl citrate, polyethylene glycol and others; colorants, e.g. titanium dioxide, lakes, pigments and others, antioxidants and others.
The formed particles are suitable for the preparation of multiple unit forms such as capsules or tablets with the primary formed particles wherein a multiple unit form disintegrates to individual primary formed particles from which the active substance is released. The formed particles are also suitable for the preparation of multiple unit forms such as sachets and dozers for multiple unit systems and others. Uncoated and/or coated particles may be used.

-:Claims:-
1) The pharmaceutical formulation comprising ibuprofen and tizanidine along with the various excipients that are used to increase the bioavailability of the active ingredients.
2) The pharmaceutical formulation, as claimed in 1, may be solid oral dosage or liquid oral dosage formulation.
3) As claimed in 2, the solid oral dosage can be tablets or capsule, more preferably tablets, and the liquid dosage can be syrup or suspension preferably syrup.
4) The Ibuprofen, as claimed in 1, is used in the pharmaceutically accepted form and used in the range 200mg to 1000mg, preferably 400 mg to 800 mg most preferably 400 mg to 600 mg.
5) Tizanidine, as claimed in 1, is used as Tizanidine hydrochloride or other pharmaceutically accepted salts thereof, in the range 1mg to 8 mg as the base, preferably 2 mg to 6 mg, most preferably 2 mg to 4 mg.
6) The bio-enhancers, as claimed in 1, can be Piperine, Betacyclodextrin, Hydroxy Propyl Methyl Cellulose or Ginger, either alone or in combination.
7) Piperine, as claimed in 6, is used in the range 10 mg to 25 mg per 200mg active ingredients, preferably 15 mg per 200 mg active ingredients.
8) Beta-cyclodextrin, as claimed in 6, is used twice to thrice the amount of active drug used in the formulation.
9) Hydroxy propyl methyl cellulose, as claimed in 6, is used 5 mg to 15 mg per 100 mg active ingredients, more preferably 10 mg per 100 mg active ingredients.
10) Ginger, as claimed in 6, is used in the range 5 mg to15 mg per 200mg active ingredients, preferably 10 mg per 200 mg active ingredients.