Title of Invention | TRANSNASAL MICROEMULSION OF AN ANTISPASTIC AGENT |
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Abstract | The present invention relates to a microemulsion based pharmaceutical preparation of an antispastic agent, Baclofen to be administered intranasally. The present invention also relates to method of preparing transnasal microemulsion preparation(s) of antispastic agent, Baclofen. The present invention also relates to the use of transnasal microemulsion preparation(s) of antispastic agent, Baclofen in the treatment of spasticity of spinal or cerebral origin. |
Full Text | FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION [See section 10, Rule 13] TRANSNASAL MICROEMULSION OF AN ANTISPASTIC AGENT; RAJESH HARSHADRAY PARIKH AND ANKIT SHAILESHKUMAR SHAH BOTH INDIAN NATIONAL OF DEPT. OF PHARMACEUTICALS AND PHARMACEUTICAL TECHNOLOGY, RAMANBHAI COLLEGE OF PHARMACY, CHAROTAR UNIVERSITY OF SCIENCE & TECHNOLOGY, CHANGA - 388421, DIST ANAND, GUJARAT. THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED. FIELD OF THE INVENTION The present invention relates to a microemulsion based pharmaceutical preparation of an antispastic agent, Baclofen to be administered intranasally. The present invention also relates to method of preparing transnasal microemulsion preparation(s) of antispastic agent, Baclofen. The present invention also relates to the use of transnasal microemulsion preparation(s) of antispastic agent Baclofen in the treatment of spasticity of spinal or cerebral origin. BACKGROUND OF THE INVENTION Spasticity has been defined as an increase in muscle tone due to hyperexcitability of the stretch reflex and is characterized by a velocity-dependent increase in tonic stretch reflexes. Spasticity is found in conditions where the brain and/or spinal cord are damaged or fail to develop normally. Spasticity is associated with some very common neurological disorders like cerebral palsy, multiple sclerosis, amyotrophic lateral sclerosis, stroke, head and spinal cord injuries, traumatic brain injury and neurodegenerative diseases affecting the upper motor neuron, pyramidal and extrapyramidal pathways. Patients with spasticity may have features like muscle weakness; decreased movement control; clonus (a series of involuntary rapid muscle contractions and/or muscle fatigue); exaggerated deep tendon reflexes; and decreased endurance. A variety of treatments are available for the management of spasticity in which Baclofen is currently the most effective and widely used drug for the treatment of spasticity of spinal or cerebral origin. Baclofen (4-amino-3- (chlorophenyl) butyric acid, a derivative of GABA) is an antispastic agent and GABAB agonist. A principal pharmacologic effect of baclofen in mammals is reduction of muscle tone. Recently some international publication revealed the different uses of Baclofen for example in promoting smoking cessation (WO 01/08675); in reducing addiction liability of narcotic agents (US4126684); in the treatment of emesis (US5719185); as an anti-tussive for the treatment of cough (US5006560). At present, baclofen is administered orally or by intrathecal delivery through a surgically implanted programmable pump. Oral baclofen is associated with severe side effects like sedation, hypotension, constipation, memory loss, dizziness, ataxia, increased urinary frequency or urinary retention, vomiting, respiratory depression, allergic reactions etc. Moreover it is to be administered thrice a day as half life of baclofen is very less (1.3 hours). Baclofen can cross blood brain barrier poorly, and metabolized in liver after oraladministration. Only 12% of the baclofen can reach in cerebrospinal fluid from the plasma {Sweetman S, Muscle relaxants in Martindale-the complete drug reference, 2005, 1386-1388). So the dose required to exert therapeutic action is more. On the other side, baclofen is chronically injected in the intrathecal space. It is the way to continuously administer small amount of drug to the spinal cord over months is by using surgically implanted electronic pumps connected to spinal catheters. The cost of implantation and follow up of these pumps average 28,000 US Dollar per patient (Potsma et al, Pharmacoeconomic 1999, 15(4), 385-404). Moreover, the risk of spinal infection or catheter malfunctioning are significant and may lead to interruption of treatment and toxic effects. Every year, this pump has to be refilled and hence the patient compliance is less. Due to all these reasons, a better, safe and cost effective alternative is needed. An alternative route of drug delivery that can selectively target the drug directly to the brain, including vasculature is needed. Previous studies have demonstrated that intranasal administration offers a practical, noninvasive alternative route of administration for drug delivery to brain (Ilium, J Pharm. Sci., 1999, 11, 1-18, Ugwoke et al, J Pharm. Pharmacol., 2001, 53, 3-21). Intranasal administration allows transport of drugs to the brain circumventing BBB, thus providing a unique feature and better option to target the drugs to the brain (Vyas et al, Curr drug del, 2(2), 165-175). So the formulation for the intranasal administration should be designed so as to provide a rapid transport of drug across nasal mucosa and a longer residence time in nasal cavity to overcome the nasal mucocilliary clearance. Microemulsions are thermodynamicaliy stable, isotropic clear dispersions of oil, water and surfactant (and/or co-surfactant) mixtures, which have high stability, low viscosity and transparency (Mehta et al, Pharm, Res., 2008, 25(1), 227-236). Some of the advantages associated with microemulsions as drug delivery systems are improvement of drug solubilization, protection against enzymatic hydrolysis, enhanced absorption due to surfactant induced permeability, increased penetration of hydrophilic, hydrophobic or amphiphilic substances. Microemulsion comprises different structures (water in oil (w/o), oil in water (o/w) and bicontinuous) and these structural changes help in preferential releasing of the drug. Because of presence of hydrophobic and hydrophilic component as part of structure; these systems may serve as vehicles for drugs of different solubilities. Microemulsions by the virtue of lipophilic nature and low globule size are widely explored as a delivery system to enhance the uptake across the nasal mucosa (Misra et al, AAPS Pharm Sci Tech, 2006, 7(1), Article 8). Microemulsions also possess other advantages like it can give almost 100 % drug entrapment capacity, forms spontaneously without high shear equipment or significant heat input, thermodynamically stable system etc. US6720001 provides pharmaceutical oil-in-water emulsions for delivery of polyfunctional active ingredients. The emulsions include an aqueous phase, an emulsifier, and an oil phase, wherein the oil phase includes a structured triglyceride that is substantially free of triglycerides having three C.sub.6 -C.sub.12 fatty acid moieties, or a combination of a long chain triglyceride and a polarity-enhancing polarity modifier. The present invention also provides methods of treating an animal with a polyfunctional active ingredient, using dosage forms of the pharmaceutical emulsions. In this, baclofen drug has not been used and also the formulation uses high concentration of triglycerides, thus making it hydrophobic in nature. The patent describes about emulsion and not the microemulsion. Also the disclosed invention excludes usage of hydrophilic surfactants e.g. polysorbates. WO2010126818 provides intranasal pharmaceutical compositions comprising dantrolene sodium or any pharmaceutically acceptable salts thereof in a variety of pharmaceutical dosage forms, with and without other compounds. The formulation of this invention uses solvent, complexing agents, polymeric carrier and co-solvents along with mucoadhesive polymers. WO2004041287 discloses a composition which includes membrane modulators. The composition can be used in a wide range of therapies for delivering a membrane modulator which play an active function in regulating, controlling or causing a desired therapeutic effect to a target cell. W01999056727 discloses self-emulsifying microemulsion or emulsion pre-concentrate pharmaceutical compositions capable of forming an oil-in-water microemulsion or emulsion upon dilution with an aqueous solution. The pre-concentrate contains a therapeutically effective amount of a poorly water soluble therapeutic agent; a pharmaceutically effective amount of a low HLB oil component; and a surfactant system consisting essentially of at least one surfactant having an HLB of from about 10 to 20 and is substantially free or contains only minor amounts of a hydrophilic solvent system. Microemulsions or emulsions formed by diluting the self-emulsifying pre-concentrate with an aqueous solution are also provided. This formulation is substantially free from hydrophilic system. US6627211 discloses a method of vehicle modulated administration of an anticonvulsive agent to the nasal mucous membranes of humans and animals. The vehicle system is an aqueous pharmaceutical carrier comprising an aliphatic alcohol, a glycol and a biological surfactant such as a bile salt or a lecithin. The pharmaceutical composition provides a means to control and promote the rate and extent of transmucosal permeation and absorption of the medicaments via a single and multiple administration. Nasal administration of the pharmaceutical preparation produces a high plasma concentration of the anticonvulsant nearly as fast as intravenous administration. Such compositions are particularly suitable for a prompt and timely medication of patients in the acute and/or emergency treatment of status epilepticus and other fever-induced seizures. US7700588 discloses compositions of midazolam, a benzodiazapine, in high concentrations of 35-100 mg/ml for the treatment of anxiety, epilepsy and epileptic seizures, invasive surgical procedures and diagnostic procedures and sedation. These compositions are particularly characterized by a solubilizer such as propylene glycol. Preferably, the compositions are aqueous solutions for intranasal administration. In US20050002987, Diazepam is administered intranasally in the form of specific microemulsions having advantageous properties. The microemulsions are comprised of about equal quantities of a fatty acid and water with the remainder being a hydrophilic surfactant, a polar solvent and an alcohol in a weight ratio such that alcohol is present in a greater quantity by weight than either of the other two. Nasal administration of the subject microemulsions produces a high plasma concentration of diazepam nearly as fast as intravenous administration. US20110172211 provides a transnasal anticonvulsive pharmaceutical composition including a poorly soluble anti-convulsant. The anticonvulsive pharmaceutical composition comprising a poorly soluble anticonvulsant as an active component, which is transnasally spray-administered, comprises diethylene glycol monoethyl ether and fatty acid ester, wherein the fatty acid ester is selected from the group consisting of caprylocaproyl polyoxylglyceride, isopropyl palmitate, oleoyi polyoxylglyceride, sorbitan monolaurate 20, methyl laurate, ethyl laurate, and polysorbate 20. Also, the anticonvulsive pharmaceutical composition comprising a poorly soluble anticonvulsant as an active component, which is transnasally spray-administered, comprises diethylene glycol monoethyl ether, fatty acid ester, methylpyrroiidone, water and alcohol. Therefore, the transnasal anticonvulsive pharmaceutical composition may be useful to highly enhance the bioavailability of the poorly soluble anticonvulsant. Also, the transnasal anticonvulsive pharmaceutical composition may be useful to allow the poorly soluble anticonvulsant to show the improved viscosity and/or enhanced solubility in order to effectively deliver the poorly soluble anticonvulsant at a therapeutic dose. IN245846 discloses drugs Loaded Nasoadhesive Microemulsions for Brain Targeted Delivery in Insomnia, its compositons, optimization, and characterization along with in vitro and in vivo performance and possible transnasal transport mechanisms. IN247325 discloses drugs loaded Intranasal Nasoadhesive Microemulsions for Brain Targeted Delivery in migraine, its compositions, optimization, and characterization along with in vitro and in vivo performance and possible transnasal transport mechanisms. Intranasal delivery of modafinil has been recently disclosed in US7989502, which uses lipid microemulsion in the formulation. EMBODIMENTS OF THE INVENTION In an embodiment of the present invention is disclosed intranasal microemulsion of an antispastic agent, Baclofen to be administered intranasally. In another embodiment of the present invention is enclosed intranasal microemulsion of an antispastic agent, Baclofen wherein the proportion of hydrophobic phase compared to hydrophilic phase is very less. In yet another embodiment is disclosed an antispastic agent, Baclofen preparation containing microemulsions for intranasal administration that are stable, clear liquids and are easy and inexpensive to produce. In a further embodiment of the present invention is disclosed the use of microemulsion based pharmaceutical preparation(s) of Baclofen in the treatment of spasticity of spinal or cerebral origin. SUMMARY OF THE INVENTION The present invention relates to intranasal microemulsion of an antispastic agent, Baclofen to be administered intranasally. The intranasal microemulsion of a antispastic agent, Baclofen comprises of: 1) An antispastic agent, Baclofen or its pharmaceutical^ acceptable salts 2) Oil phase 3) Surfactant (s), co-surfactant (s) 4) Aqueous phase BRIEF DESCRIPTION OF DRAWINGS Some of the features of the present invention may be better explained by way of figures enclosed: Fig. 1A: optical microscopic images of goat nasal mucosa treated with 6.4 pH phosphate buffer Fig.lB: optical microscopic images of goat nasal mucosa treated with Isopropyl alcohol Fig.lC: optical microscopic images of goat nasal mucosa treated with Blank microemulsion Fig.lD: microscopic images of goat nasal mucosa treated with Drug loaded microemulsion Fig.2: Ex-vivo drug diffusion study in goat nasal mucosa Fig.3: Comparative Maximum Possible Effect (MPE) of intranasal Baclofen versus oral Baclofen in analgesic activity BEST MODE FOR CARRYING OUT THE INVENTION In accordance with the present there are provided novel microemulsion formulations containing Baclofen. Baclofen is administered intranasally in the form of specific microemulsions having advantageous properties over similar compositions disclosed in the literature. The intranasal micromulsion of a muscle relaxant, Baclofen comprises of: 1) An antispastic agent, Baclofen or its pharmaceutical^ acceptable salts 2) Oil phase 3) Surfactant (s), co-surfactant (s) 4) Aqueous phase An antispastic agent, Baclofen or its pharmaceutically acceptable salts is generally used in the microemulsion in the concentration range of 0.001% to 0.3%. The oil phase of the microemulsion includes a mixture of monoglycedrides and diglycerides. Surfactants are wetting agents that lower the surface tension of a liquid, allowing easier spreading and also lower the interfacial tension between two liquids. Surfactants reduce the surface tension of water by adsorbing at the liquid-gas interface. They also reduce the interfacial tension between oil and water by adsorbing at the liquid-liquid interface. Many surfactants can also assemble in the bulk solution into aggregates; examples of such aggregates are vesicles and micelles. The concentration at which surfactants begin to form micelles is known as the critical micelle concentrates or CMC. When micelles form in water, their tails form a core that can encapsulate an oil droplet, and their (ionic/polar) heads form an outer shell that maintains favorable contact with water. When surfactants assemble in oil, the aggregate is referred to as a reverse micelle. In a reverse micelle, the heads are in the core and the tails maintain favorable contact with oil. Surfactants are also often classified into four primary groups; anionic, cationic, non-ionic and zwitterions (dual charged). Different types of surfactants are studied for finding suitable microemulsion formulation. Examples includes Polysorbate 20, 40, 60 and 80. The surfactant concentration in the present microemulsion preparation is preferably in the range of 20 to 40% w/w, In the present invention, substances, that functions, as solubilizers or co-solvents as well as surfactants are preferred. Such compounds can be referred to as co-surfactants. Polyhydric alcohols may be used as co-surfactant either alone or in combination with one or more of the like. Given as examples of polyhydric alcohols are propylene glycol, polyethylene glycols with molecular weights of 300-4,000 Dalton. Specific examples of such polyethylene glycols include polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, and polyethylene glycol 4,000. The co-surfactant concentration in the present microemulsion preparation is preferably in the range of 10 to 30% w/w. The proportion of surfactant (s) and co-surfactant (s) in the microemulsion may be used in the ratio range of 0.5: 1 to 5: 1, preferably 1: 1 to 3:1. The aqueous phase comprises of water, phosphate buffer and the like. The subject microemulsions are formed by conventional techniques. The desired quantities of oil, surfactant, co-surfactant, & drug were taken in completely dry beaker. The drug was dissolved completely in oil and surfactant-cosurfactant mixture under constant stirring on the magnetic stirrer at 45 ± 5 ° C After cooling the same to ambient temperature, the required quantity of water was added dropwise with stirring till a clear and transparent liquid microemulsion is formed. The microemulsion is subjected to globule size determination by dynamic light scattering technique. The globule size is generally less than 100 nm, but is preferably desired 50 nm and less. The pH of the microemulsion was found to be in the range of 5.0 and 7.0. The present invention is not to be limited in scope by the specific embodiments describe herein by way of examples provided below. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. A, B, C, D, E, F, G, H, I referred herein in each of the examples denote specific formulations. EXAMPLE 1 component A % w/w B C Baclofen 0.3 0.3 0.3 Capmul MCM C-8 2.5 2.5 2.5 Polysorbate 80 23.33 30 36.66 Propylene glycol 11.66 15 18.33 Water q.s q.s q.s EXAMPLE 2 component D % w/w E F Baclofen 0.3 0.3 0.3 Capmul MCM C-8 5 5 5 Polysorbate 80 23.33 30 36.66 Propylene glycol 11.66 15 18.33 Water q.s q.s q.s EXAMPLE 3 component G % w/w H I Baclofen 0.3 0.3 0.3 Capmul MCM C-8 7.5 7.5 7.5 Polysorbate 80 23.33 30 36.66 Propylene glycol 11.66 15 18.33 Water q.s q.s q.s The above microemulsions so prepared were formulated into suitable dosage forms for intranasal administration like nasal spray and nasal drops and the like. EXAMPLE 4 Ex-vivo diffusion study was carried out using Franz diffusion cell in excised goat nasal mucosa using conventional techniques reported in literature and prepared microemulsion was compared with baclofen solution. It was found that after 4 hours, baclofen microemulsion showed higher % drug diffused (77.53%) than baclofen solution (41.87%) (Fig.2). EXAMPLE 5 Pharmacodynamic study was carried out on intranasal baclofen microemulsion (2 mg/kg) by comparing with oral baclofen (10 mg/kg) in swiss albino mice using the conventional techniques described in the literature. The study assessed analgesic and muscle relaxant activity of the two preparations given with different route of administration. The analgesic responses obtained were calculated as the percentage of the maximum possible effect (MPE). The results of the study showed (Fig.3) that MPE for baclofen nasal formulation was 68.3% and that of oral baclofen was 35%. This clearly indicated the superior effectiveness of nasal formulation of Baclofen microemulsion over oraf Baclofen. Significant increase was observed in muscle relaxant activity also after nasal administration compared to oral formulation of Baclofen. The microemulsion of the present invention are advantageous for the treatment of spasticity and other conditions. Although this invention has been described with respect to the therapeutic application of Baclofen as an analgesic, and muscle relaxant it is understood that the subject microemulsions are also applicable to the other recognized therapeutic indications of baclofen. The present invention has the following advantages: 1) Significant increase in the activity of baclofen after intranasal administration compared to oral formulation even at 5 times lower dose indicating rapid and direct transfer of baclofen from nose to brain. 2) Dose reduction may result into reduction in systemic side effects which are common in conventional oral treatment. 3) Patient compliance is expected to increase due to above advantages. 4) The invention can be useful to pediatric patients who don't like to swallow the tablets thrice a day. 5) It can be a cost-effective treatment as cost of surgical implantation of intrathecal pump is very high. 6) Comparatively safe as in intrathecal surgery, as there is a possibifity of catheter malfunctioning and burst release which can produce toxic effects 7) Improved patient compliance with nasal administration because every year the pump has to be refilled hence intrathecal delivery lacks patient compliance. WE CLAIM 1. A microemulsion for transnasal administration of an antispastic agent comprising of: a. Baclofen or its pharmaceutically acceptable salts, wherein the concentration ranges from 0.001% to 0.3%; b. An oil phase; c. Surfactant (s),co-surfactant (s); d. Aqueous phase. 2. A microemulsion in accordance with claim 1 wherein the oil phase includes a mixture of monoglycerides and diglycerides. 3. A microemulsion in accordance with claim 2 wherein the oil is Capmul MCM C-8; wherein the quantity of the oil is preferably in the range from 2.5 % to 7.5 % w/w of the total microemulsion. 4. A microemulsion in accordance with claim 1 wherein the surfactants include but not limited to Polysorbate 20, 40, 60 and 80 or mixtures thereof; wherein the surfactant concentration is preferably in the range of 20 to 40% w/w; co-surfactants are selected from but not restricted to: polyhydric alcohols like propylene glycol, polyethylene glycols like polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600,polyethylene glycol 4,000 and the like; wherein the co-surfactant concentration is preferably in the range of 10 to 30% w/w. 5. A microemulsion in accordance with claim 1 and 4, wherein the ratio of surfactant and co-surfactant are in the ratio range of 0.5: 1 to 5: 1, preferably 1: 1 to 3:1 w/w. 6. A microemulsion in accordance with claim 1 wherein the aqueous phase is water, phosphate buffer and the like. 7. A microemulsion in accordance with any of the preceeding claims wherein the globule size of the microemulsion is below 100 nm, but preferably 50 nm and less. 8. A microemulsion in accordance with claim 1 wherein the microemulsion formulation comprises a nasal spray, nasal drops and the like. 9. A microemulsion in accordance with any of the preceeding claims and exemplified with the encfosed examples herein. |
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Patent Number | 272781 | |||||||||
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Indian Patent Application Number | 146/MUM/2012 | |||||||||
PG Journal Number | 18/2016 | |||||||||
Publication Date | 29-Apr-2016 | |||||||||
Grant Date | 26-Apr-2016 | |||||||||
Date of Filing | 16-Jan-2012 | |||||||||
Name of Patentee | PARIKH RAJESH HARSHADRAY | |||||||||
Applicant Address | DEPT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY, RAMANBHAI PATEL COLLEGE OF PHARMACY, CHAROTAR UNIVERSITY OF SCIENCE & TECHNOLOGY, CHANGA-388421, DIST. ANAND, GUJARAT | |||||||||
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PCT International Classification Number | A61K9/00,A61K31/00 | |||||||||
PCT International Application Number | N/A | |||||||||
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