Title of Invention

A MICROEMULSION BASED INTRANASAL DRUG DELIVERY SYSTEM AND METHOD FOR PREPARATION THEREOF

Abstract

The present invention discloses a microemulsion based intranasal drug delivery system comprising an oil phase; a long chain surfactant component; a short chain cosurfactant component, a combination of long chain thermosensitive polymers, a mucoadhesive agent, an aqueous phase anddrug, wherein the amounts of the long chain polymer surfactant and short drain alcohol as co-surfactant components are selected to provide for spontaneous formation of thermodynamically stable microemulsion droplets of the oil phase having a particle size from 10 nm to 100 nm.

Full Text

FORM-2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (Section 10, rule 13) "A MICROEMULSION BASED INTRANASAL DRUG DELIVERY SYSTEM AND METHOD FOR PREPRATION THEREOF" Dr. Amrita Bajaj Dr. Nandkumar Chodankar Miss. RupaEi Bhanushali All residing at: 30, Lane No. 2, Koregaon Park, Pune 411 001, Maharashtra, India. The following specification particularly describes the invention and the manner in which it is to be performed: - FILED OF INVENTION The invention is related to the preparation of a microemulsion. More particularly field of invention is related to the preparation of microemulsion based intranasal drug delivery system. Even more particularly, the field of invention is related to the thermoreversible mucoadhesive microemulsion based intranasal drug delivery system for the active ingredients. like 5-HT1, 5HT1B/ID agonists like sumatriptan succinate and all its derivatives, ergotamine tartarate, calcium channel blockers, dopamine D2 agonists. BACKGROUND OF INVENTION Microemulsions are clear, stable, isotropic liquid mixtures of oil, water and surfactants, mostly in combination with a cosurfactant. The aqueous phase may contain salts and/or other ingredients, and the "oil" may actually be a complex mixture of different hydrocarbons and olefins. In contrast to ordinary emulsions, rnicroemulsions form upon simple mixing of the components and do not require the high shear conditions generally used in the formation of ordinary emulsions. The two basic types of microemulsions are direct (oil dispersed in water, o/w) and reversed (water dispersed in oil, w/o). Microemulsions have many commercially important uses A fundamental reason for application of these systems is that a microemulsion phase has an ultralow interfacial tension with a separate oil or aqueous phase, which may release or mobilize them from solid phases even in conditions of slow flow or low pressure gradients. Literature survey reveals several patent applications/ patents disclosing drug delivery systems based on microemulsion carriers. PRIOR ART United States Patent No. 5,633,226 describes a biologically compatible water-in-oil microemulsion composition that is provided with a water-in-oil (w/o) microemulsion which readily converts to an oil-in-water (o/w) emulsion by the addition of aqueous fluid to the w/o microemulsion, whereby any water-soluble biologically-active material in the aqueous phase is released for absorption by the body. The w/o microemulsion is particularly useful for storing proteins and the like for long periods of time at room 2 temperature and above until they are ready for use, at which time the addition of aqueous fluid converts the microemulsion to an o/w emulsion and releases the protein. United States Patent No. 5,759,566 is related to pharmaceutical compositions in the form of microemulsions or lipid dispersions for the transmucousal administration of proteins or peptidic substances which are pharmacologically active; they differ from the known liposomic or microemulsified compositions in that they contain in addition a thermosetting agent able to enhance the residence time on the administration site and, consequently, to promote the absorption of the delivered drug. Patent WO2005-004843 relates to novel microemulsions comprising a non-polar lipid, at least one polar solvent, a surfactant, and a polar lipid. A microemulsion of these ingredients provides an environment that substantially encloses airborne particles, and it can be used for entrapping such particles. The inventive microemulsions are especially adapted for the prevention of symptoms in mammals, which are indirectly or directly caused by airborne particles. United States Patent No. 6,159,933 discloses pharmaceutical compositions in the form of an emulsion preconcentrate or microemulsion preconcentrate, which comprise cyclosporin as active ingredient, propylene carbonate as hydrophilic solvent, glycerides as lipophilic solvent, and a surfactant. OBJECT OF THE INVENTION In view of the above prior art and further development in the field of microemulsion it is an object of the invention to design a microemulsion for intranasal drug delivery. Further object of the invention is to design improved microemulsion based system for intranasal drug delivery. Yet further object of the invention is to design thermoreversible mucoadhesive microemulsion based system for intranasal delivery of drugs having higher retention time. 3 Another object of the invention is to design microemulsion based drug delivery system with higher retention time for 5-HT1, 5HT1B/1D agonists like Rizatriptan Benzoate sumatriptan succinate and all its derivatives, ergotamine tartarate, calcium channel blockers and dopamine D2 agonists. SUMMARY OF THE INVENTION The present invention relates to a thermoreversible mucoadhesive microemulsion based intranasal drug delivery system with higher retention time of the drug in the nasal cavity. The objectives of present invention are development of pharmaceutical compositions in the form of microemulsions. They are characterized by the fact that they contain a combination of thermoreversible agents that are able to allow a product viscosity increase with temperature, with further addition of mucoadhesive agent thus allowing a longer mucousal residence time and enhanced drug absorption profile. Due to the thermosetting properties of the vehicles it is possible to make pharmaceutical compositions which have a reduced viscosity at room temperature, helping the distribution of finely absorbed divided product on a larger surface. When the compositions reach the mucous a structural change takes place as a function of the body temperature, i.e., the viscosity of the product increases, and this with mucoadhesive agent is able to provide a large residence of the system in the absorption zone. The use of formulations that are liquid at room temperature but which increase their viscosity with temperature giving semi-solid products when warmed to body temperature is already known. There are, in fact, some patents that describe the use of a particular polymer (Pluronic) to reach that goal. The desired sol-gel transition temperature of the solution can be modified by changes in polymer concentration or in chemical characteristics of the solution. This is surprisingly found that the same goal can be obtained also in systems more and more complex, like microemulsions. Normally, in this type of formulation it is difficult to balance the 4 composition. In fact, microemulsions are a very complex system with the coexistence of at least three different phases: a disperse phase, an interface layer of surfactants and/or cosurfactants surrounding the disperse phase, and a continuous phase that contains the previous ones. The addition of relevant amount of copolymer in order to obtain the sol-gel system transition, normally changes dramatically the precise ratio between the four main components of the microemulsion system, that are water, surfactants, cosurfactants and oil. Only a formulation with a new balance point allows thermosetting microemulsions. In a typical embodiment, the invention uses as thermosetting vehicle, a polyoxyethylene-polyoxypropylene copolymer, preferably the one known with the trade name of Pluronic F 127™ or Lutrol F 127™. These characteristics, which are favourable even when present in conventional solutions, are particularly important and effective when used in complex and modern vehicles such as the microemulsion systems. The microemulsionated system when well proportioned in combination with its constituents, polyoxyethylene-polyoxypropylene copolymer produces an "apparent solution" able to increase the viscosity when in contact with mucosae. Some structural changes are produced in the polymer on application to the human body due to temperature difference. These thermal changes cause gelation of the formulation, which further with mucoadhesive agent will promote the bioadhesion of the system. Thus, present invention is for pharmaceutical compositions useful for transmucousal administration, in particular intranasal, of hydrophilic molecules, pharmacologically active against migraine. Examples of similar substances include 5HT1B/1D agonists like Rizatriptan benzoate, Sumatriptan succinate and all its derivatives, ergotamine tartarate, calcium channel blockers and dopamine D2 agonists. DETAILED DESCRIPATION OF THE INVENTION Microemulsions are clear, stable, isotropic liquid mixtures of oil, water and surfactants, mostly in combination with a cosurfactant. The aqueous phase may contain salts and/or other ingredients, and the "oil" may actually be a complex mixture of different 5 hydrocarbons and olefins. In contrast to ordinary emulsions, microemulsions form upon simple mixing of the components and do not require the high shear conditions generally used in the formation of ordinary emulsions. The two basic types of microemulsions are direct (oil dispersed in water, o/w) and reversed (water dispersed in oil, w/o) Preparation of blank microemuls ion In order to find out appropriate components in the formation of microemulsions, safe and compatible surfactants combined with co-surfactants were tried out. 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 fay 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. Example includes Polysorbate 80 (commercially also known as Tween 80) a nonionic surfactant and emulsifier derived from polyoxylated sorbitan and oleic acid. Polysorbate 80 is a viscous, water-soluble yellow liquid. The hydrophilic groups in this compound are polyethers also known as polyoxyethylene groups, which are polymers of ethylene oxide. In the nomenclature of Polysorbate, the numeral designation following Polysorbate refers to the lipophilic group, in this case the oleic acid. Cremophor RH 40 (Polyoxyl 40 Hydrogenated Castor Oil) is a solubilizer for fat-soluble vitamins, essential oils and other hydrophobic pharmaceuticals. Particular features are 6 that it has very little odour and in aqueous solutions is almost tasteless. The use of Cremophor RH 40 grades in cosmetic preparations is also established. In common with other surfactants, Cremophor RH 40 may alter the rate of absorption of active substances. Other surfactants studied include: • Plurol Olequie (Decaglyceryl monooleate) • Labrasol (Caprylocaproyl Macrogolglycerides) In the present invention, substances, that function, as solubilizers or cosolvents as well as surfactants are preferred. Such compounds can be referred to as cosurfactants. Monohydric or polyhydric alcohols may be used as cosurfactant either alone or in combination with one or more of the like. Given as examples of monohydric alcohols are benzyl alcohol, ethyl alcohol, and the like; and as examples of polyhydric alcohols are propylene glycol, glycerin, 1,3-butylene 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. Other cosurfactants studied are, • Propylene Glycol • Ethanol • Plurol olequie (Decaglyceryl monooleate) • Transcutol 2-(2-Ethoxyethoxy) ethanol Various natural and mineral oils have been tried for the present invention. Oils or their ester derivatives that are studied for the present invention are listed below, Ethyl oleate is the ester formed by the condensation of the fatty acid oleic acid and ethanol it is a colorless to light yellow liquid. Ethyl oleate is used as a solvent for pharmaceutical drug preparations involving lipophilic substances such as steroids. Isopropyl myristate is used in cosmetic and topical medicinal preparations where good absorption through the skin is desired. 7 Other commercial oils used are • Labrafac(TM) (Medium Chain Triglycerides) • Labrafil(TM) (Oleoyl Macrogolglycerides-Polyoxylglycerides) • Maisine (Glyceryl Monolinoleate) Method for preparation; • Surfactant was blended with cosurfactant in fixed ratios (1:1,2:1 and 3:1), • Aliquots of surfactant and cosurfactant mix (Smix) were then mixed with oil at room temperature (25° Q) • For each phase diagram, the ratio of oil to the Smix was varied as 9:1, 8:2, 7:3, 6:4,5:5,4:6,3:7,2:8, 1:9 (w/w). • Water was added drop wise to each oil-Smix mixture under vigorous stirring. • After equilibrium, the samples were visually checked and determined, as being clear microemulsions, or emulsions, or gels. The pseudo-ternary phase diagrams of oil, surfactant and water were constructed using water titration method to obtain the components and their concentration ranges that can result in large existence area of microemulsion. All the combinations of surfactants: co-surfactants in varying ratios were tried out along with different oils to get a thermodynamically stable microemulsion for intranasal delivery. Table 1 summarizes various S/Cos and oil combinations used to prepare microemulsions. Table 1 Various S/Cos and oil combinations used to prepare microemulsions Batches S:Cos Smix Oil Al Tween 80 : PG 1:1 Ethyl oleate A2 " 2:1 Labrafac A3 " 2:1 Labrafil B4 Labrasol : Ethanol 2:1 Ethyl oleate B5 " 3:1 " B6 " 4:1 Li B7 " 3:1.5 li B8 " 3:0.5 tt B9 " 1:1 Labrafac B10 " 3:0.5 Li C11 Labrasol: Plurol Olequie 1:1 Labrafac C12 " 2:1 " 8 C13 " 3 1 a C14 " 1 1.5 Li. C15 u 2 1.5 u C16 " 2 0.5 it. C17 St 2 1 Labrafil C18 it 2 1 Maisine C19 £C 2 1 IPM D20 Labrasol : PG 2 1 Ethyl oleate E21 Cremophor RH 40 :PG 1 1 IPM E22 ii. 3 1 4i F23 Tween 80: Plurol Olequie 2 1 Labrafil F24 " 2 1 IPM G25 Tween 80 : Transcutol 2 1 Labrafil G26 it 2 1 IPM G27 ct 2 1 Labrafac G28 G29 £( T 1 Maisine H30 CremophorRH40: Transcutol 2 1 IPM H31 a 1:1 Labrafil H32 tc 2:1 " H33 Cremophor RH 40: Transcutol 3:1 Labrafil Amongst all the formulations, Batch H33 showed large microemulsion area in the pseudo-ternary phase diagram as shown in Figure 1. Figure 1: Psedo-ternary phase diagram of Formulation Batch H33 9 The.optimized formulation was selected based on following parameters: 1) pH - Intranasal formulations pH should be 4.5-6.5 to minimize irritation of the nasal mucosa. ■ 2) Clarity - The formulations should be clear and transparent. 3) Viscosity - Viscosity of the formulation should be low enough to be easily sprayable from nasal spray devices 4) Stability - Microemulsion should not separate when subjected to agitation. Formula of Optimized Batch obtained by applying 23 factorial design is as follows: Water -40% ~63.49%w/w Oil - 3% ~4.76%w/w S/Cos -20%~ 31.74%w/w Evaluation of Optimized Microemulsion Formulation: The optimized Microemulsion formulation was evaluated for 1) Stability by Centnfugation: Microemulsions were centrifuged at 6000rpm for 10 minutes. After centnfugation the Microemulsion did not separate in to two phases thus confirming the stability of optimized Microemulsion. 2) Clarity: 10 Microemulsions were clear and transparent solutions. The transmittance was 99.9%. 3) Particle size: The particle size of the Microemulsion droplets was found in the range of 1.5-70nm with a mean particle size of 18nm, 4) pH: The pH of the blank Microemulsions was determined using pH meter and was found to be in the range of 6.0-6.3. CHARACTERIZATION OF THE DEVELOPED MICROEMULSION FORMULATION: The developed microemulsion was characterized using self diffusion NMR and Small Angle Neutron Scattering Techniques as shown in Figure 2 & 3, Figure 2: Self Diffusion Coefficients for each component Figure 3: SANS Data for determining the in microemulsion sample and in pure form Shape and droplet Size of the Microemulsion formulations The self-diffusion coefficients measured for water, Labrafil, Cremophor and Transcutol in the microemulsion systems were compared with the self-diffusion coefficients measured for the pure components. By comparing the self-diffusion coefFicient of component in a sample with that of the single component, the microemulsion type can be 11 identified. If the microemulsion is of droplet-type, the self-diffusion coefficient of the internal pseudo phase is determined by the diffusion of the droplet and will therefore be slower than that of the pure components. In addition, the diffusion of the surfactant or surfactant mixture is also slow because of the formation of a monolayer around the droplet. The self-diffusion coefficients of water and Labrafil in all samples were very low (10-9~-10~!1 m2/s range) as shown in Figure 1; therefore bicontinuous microemulsions were not likely to have formed. From SANS data in Figure 2, it can be concluded that the shape of the micelles formed in the microemulsion was ellipsoidal in nature and the size of the microemulsion droplet increased as the concentration of the water was increased confirming o/w type of microemulsion system. DEVELOPMENT OF THERMOREVERSIBLE MICROEMULSION FOR INTRANASAL DELIVERY: To develop thermoreversible microemulsions, poloxamers (polyoxyethylene- polyoxypropylene copolymers) were added to the optimized microemulsion so that when these microemulsions come in contact with the body temperature they form a gel, which has sufficient mucoadhesive properties. Two poloxamers viz. Poloxamer 108 (Lutrol F127) and Poloxamer 188 (Lutrol F68) were tried out in varying ratios. Viscosity of each batch prepared was measured at room temperature and body temperature using Brookfield Viscometer. Thermoreversible Microemulsions were formulated using Poloxamers 108 and 188 as the thermoreversible polymers in varying ratios. Different batches were developed using various ratios of Poloxamer 108/188. The viscosity of each batch is reported in Figure 4. Figure 4: Effect of Temperature on Viscosity with Poloxamer 108/188%w/v. 12 It can be seen from the histogram in figure 4 that it 3%/2% w/v concentration the viscosity of the formulation at room temperature and body temperature was same. i.e. 400cps. As the concentration of poloxamer 108 was increased to 4%/2%w/v, viscosity increased at room temperature and decreased at body temperature. When the concentration of poloxamer 108 was increased to 5%/2% w/v the difference in viscosity at room temperature and body temperature increased to 450 cps. But the viscosity of the formulation at room temperature was high i.e. 1090 cps. When Poloxamer 108/188 was used in the ratio of 6%/4%w/v there was drastic increase in the viscosity of the formulation from 1340cps to 2320cps. But the viscosity of the formulation at room temperature was also very high affecting sprayability of the formulation. As the concentration of poloxamer 188 in the ratio was increased from 4%/3%w/v - 4%/6%w/v, the difference in the viscosity of the formulation at room temperature and body temperature increased from lOOcps for 4%/3%w/v to 1130cps for 4%/6%w/v. Also, for ratio of 4%/6%w/v of Poloxamer 108/188 the viscosity of the formulation at room temperature was sufficiently low i.e. 730cps. Hence 4%/6% w/v of Poloxamer 108/188 was chosen to give an optimized thermoreversible microemulsion system. Development of a microemulsion based intranasal drug delivery system having higher retention time, 13 The term mucoadhesion is defined as interfacial force interactions between synthetic or natural polymeric materials serving as a dosage form and a mucus layer that covers a mucosal tissue. In the last two decades mucoadhesive polymers have received considerable attention as platforms for controlled delivery due to their ability to prolong the residence time of dosage forms as well as to enhance drug bioavailability Some of the polymeric structural characteristics necessary for mucoadhesion can be summarized as follows: 1. Strong hydrogen bonding groups, e.g., carboxyl, hydroxyl, amino- and sulfate groups 2. Strong anionic or cationic charges 3. High molecular weight 4. Chain flexibility 5. Surface energy properties favoring spreading onto mucus. An attempt was made to develop a mucoadhesive microemulsion for intranasal delivery. To further increase the retention time of the drug in the nasal cavity, various mucoadhesive polymers like Sodium Alginate, Sodium CMC, Carbopol 97IP, Carbopol 980, Pemulen TR2 and Noveon AA-1 were tried out to sustain/control the release of drug for 4hrs following nasal administration. In vitro diffusion studies on developed formulations were performed using Keshary-Chien Apparatus. K-C Apparatus consists of two compartments viz. donor compartment and receiver compartment. The receiver compartment consists of the diffusion medium. The two compartments are separated by diffusion membrane. Cellulose nitrate 0.45u. was used as the diffusion membrane. In order to study the effect of the mucoadhesion agents on the sustained release of drug, several experiments are conducted with different mucoadhesion agents. Drugs studied for the above experimentation were selected from group of drugs, which are active against migraine. The drugs include from the class of 5HTIB/ID agonists like Rizatriptan Benzoate, Sumatriptan Succinate and other pharmaceuitically active derivatives or salts, ergotamine tartarate, calcium channel blockers and dopamine D2 agonists. 14 The principles, preferred embodiments and modes of operation of the present invention have been described in the foregoing specification. However, the invention which is intended to be protected is not to be construed as limited to the particular embodiments or examples disclosed. Further, the embodiments and examples described herein are to be regarded as illustrative rather than restrictive. Variations and changes may be made by others, and equivalents employed, without departing from the spirit of the present invention. Accordingly, it is expressly intended that all such variations, changes and equivalents, which fall within the spirit and scope of the present invention, as defined in the claims be embraced thereby. Following are the examples incorporated herein to illustrate the working of the invention and it is not limiting to the illustrations. Example No 1, Intranasal formulations of Rizatriptan Benzoate using Sodium Alginate as the Mucoadhesive Polymer Sodium Alginate is sodium salt of alginic acid. It is a natural polymer. Various formulations were prepared using different concentrations of Sodium Alginate as given in Table 2. Table 2: Formulations of Thermoreversible Microemulsion Containing Sodium Alginate as Mucoadhesive Polymer: Sr.No Ingredients SA1 SA2 SA3 1. Rizatriptan Benzoate 10 mg l0mg l0mg 2. Water 63.49%w/w 63.49%w/w 63.49%w/w 3. Labrafil 4.76%w/w 4.76%w/w 4.76%w/w 4. Cremophor RH 40/ Transcutol 31.74%w/w 31.74%w/w 31.74%w/w 5. Lutrol 4%w/v 4%w/v 4%w/v 15 F127 6. Lutrol F68 6%w/v 6%w/v 6%w/v 7. Sodium Alginate 0.05%w/w 0.2%w/v 0.3%w/v Formulations were prepared using three different concentrations of sodium alginate. The formulation was stirred on a magnetic stirrer for complete swelling of the polymer. The Invitro diffusion profile of the developed formulation is presented in Table 3 & Figure 5. Table 3: Invitro drug release from Thermoreversible Microemulsion Containing Sodium Alginate as Mucoadhesive Polymer: Time (Minutes) Percent Drug Release Batch SA1 0.05%w/v SA Batch SA2 0.2%w/v SA Batch SA3 0.3%w/v SA 30 55.045 63.94 62.08 60 81.03 88.23 87.134 90 99.33 100 97.33 120 100 ~ 98.88 180 — — 100 240 ~ — — The Invitro diffusion studies on the developed formulation were performed using Keshary-Chien Apparatus. Diffusion Medium- Phosphate Buffer pH6.4 Volume of the diffusion medium - 18ml (mimics the volume of the nasal cavity) Temperature of the diffusion medium- 37°C (body temperature). 16 Figure 5: Invitro drug release from Thermoreversible Microemulsion Containing Sodium Alginate as Mucoadhesive Polymer: ^— — - — — ~— -x Invitro release of Rizatriptan Benzoate using Sodium Alginate 0 50 100 150 200 250 300 Time (Minutes) i As the concentration of the Sodium alginate was increased the permeability of the drug also increased, diffusing the drug within 2 hours. Sodium alginate swells in alkaline medium, but as the pH of the formulations was 5.5-6.0; the polymer did not swell completely thus showing negligible polymer effect. As sustained release effect upto 4hours was desired, this polymer was omitted from the microemulsion formulation. Example No 2, Intranasal formulations of Rizatriptan Benzoate using Sodium Carboxymethyl Cellulose as the Mucoadhesive Polymer, Sodium CMC is a Sodium salt of polycarboxymethyl ether of cellulose. Various formulations were prepared using different concentrations of Sodium CMC as given in Table 4. Table 4: Formulation of Thermoreversible Microemulsions Containing Sodium CMC as Mucoadhesive Polymer S.No. Ingredients SC1 SC2 1. Rizatriptan Benzoate 10 mg l0mg 17 2. Water 63.49%w/w 63.49%w/w 3. Labrafil 4.76%w/w 4.76%w/w 4. Cremophor RH 40/ Transcutol 31.74%w/w 31.74%w/w 5. Lutrol F127 4%w/v 4%w/v 6. Lutrol F68 6%w/v 6%w/v 7. Sodium CMC 0.1%w/v 0.2%w/v Formulation batches were prepared using two different concentrations of Sodium CMC. The formulation was stirred on a magnetic stirrer for complete swelling of the polymer. . The Invitro diffusion profiles of the developed formulations are presented in Table 5 &. Figure 6. Table 5: Invitro drug release from Thermoreversible Microemulsion Containing Sodium CMC as a Mucoadhesive Polymer; Time (Minutes) Percent Drug Re ease Batch SC1 0.1%w/vSC Batch SC2 0.2%w/vSC 30 52.83 53.976 60 64.39 80.65 90 98.16 94.64 120 100 100 180 „ ~ 240 - - Figure 6: Invitro drug release from Thermoreversible Micro emulsions Containing Sodium CMC as Mucoadhesive Polymer; 18 Invitro release of Rizatriptan Benzoate using Sodium CMC 120 100 150 Time (Minutes) 200 0.1%S-CMC ■0.2%S-CMC 250 300 As the concentration of the Sodium CMC was increased the permeability of the drug also increased, diffusing the drug within 2 hours. Sodium CMC swells in alkaline medium, but as the pH of the formulations were 5.5-6.0; the polymer did not swell completely thus showing negligible polymer effect. Also S odium CMC gave a turbid solution. Hence, other polymers were tried out. Example No 3, Intranasal formulations of Rizatriptan Benzoate using Pemulen TR2 as the Mucoadhesive Polymer, Pemulen TR-2 (prop-2-enoic acid) polymer contains the higher level of hydrophobic groups and can emulsify the highest levels of oil (up to 60%-80% by weight) within a pH range of 4-5. It is highly effective at levels below 0.4%, providing a low-viscosity emulsion particularly suitable for application via spray mechanism. Pemulen containing emulsions can be considered as Ellis plastic fluids. An Ellis plastic fluid has a yield stress and exhibits shear-thinning properties. So when enough shear is 19 applied, the viscosity of the emulsion decreases and allows it to become a pumpable liquid which provides fine spray for quick and easy application. Various formulations were prepared using different concentrations of Pemulen TR2 as given in Table 6. Table 6: Formulations of Thermoreversible Microemulsion Containing Pemulen TR2 as a Mucoadhesive Polymer: s. N Ingredients P1 P2 P3 P4 P5 1. Rizatriptan Benzoate ' 10 mg l0mg l0mg l0mg l0mg 2. Water 63.49%w/w 63.49%w/w 63.49%w/w 63.49%w/w 63.49%w/w 3. Labrafil 4.76%w/w 4.76%w/w 4.76%w/w 4.76%w/w 4.76%w/w 4. Cremophor RH 40/ Transcutol 31.74%w/w 31.74%w/w 31.74%w/w 31.74%w/w 31.74%w/w 5. Lutrol F127 4%w/v 4%w/v 4%w/v 4%w/v. 4%w/v 6. Lutrol F68 6%w/v 6%w/v 6%w/v 6%w/v 6%w/v 7. Pemulen TR2 0.1%w/v 0.3%w/v 0.05%w/v 0.03%w/v 0.07%w/v Formulation batches were prepared using different concentrations of Pemulen TR2. The formulation was stirred on a magnetic stirrer for complete swelling of the polymer. The Invitro diffusion profiles of the developed formulations are presented in Table 7 & Figure 7. Table 7: Invitro drug release from Thermoreversible Microemulsion Containing Pemulen TR2 as a Mucoadhesive Polymer: Time (Minutes) Percent Drug Release Batch P1 Batch P2 Batch P3 Batch P4 Batch P5 20 0.1%w/v P-TR2 0.3%w/v PTR2 0.05%w/v PTR2 0.03%w/v PTR2 0.07%w/v PTR2 30 44.32 33.54 44.06 45.68 45.33 60 61.87 52.49 66.43 63.24 64.03 90 71.52 66.11 76.44 80.73 68.41 120 79.09 72.60 80,15 87.90 74.03 180 81.54 73.69 83.92 98.52 82.60 240 84.80 76.49 89 100 87.8 Figure 7: Invitro drug release from Thermoreversible Microemulsion Containing Pemulen TR2 as a Mucoadhesive Polymer: From the graph, it can be concluded that as the concentration of the polymer decreases, the permeability of the drug increases. Hence at 0.03%w/v concentration, Batch P4 was formulated which gave a sustained release effect for 4hours. Example No 4, Intranasal formulations of Rizatriptan Benzoate using Carbopol 971P, Carbopol 980, Noveon AA Polycarbophil as the Mucoadhesive Polymer 21 Carbopol 971 P, Carbopol 980 and Noveon AA-1 are crosslinked acrylic acid-based polymers. The products are crosslinked to different levels with a polyalkenyl polyether. Various formulations were prepared using different concentrations of Carbopol 971P, Carbopol 980 and Noveon AA as given in Table 8. Table 8; Formulations of Thermo reversible Microemulsion Containing Carbopol 971P, Carbopol 980 and Noveon AA Polycarbophil as the Mucoadhesive Polymer Sr.No. Ingredients C1 C2 C3 N3 1. Rizatriptan Benzoate 10 mg l0mg 10 mg l0mg 2. Water 63.49%w/w 63.49%w/w 63.49%w/w 63,49%w/w 3. Labrafil 4.76%w/w 4.76%w/w 4.76%w/w 4.76%w/w 4. Cremophor RH 40/ Transcutol 31.74%w/w 31.74%wAv 31.74%w/w 31.74%w/w 5. Lutrol F127 4%w/v 4%w/v 4%w/v 4%w/v 6. Lutrol F68 6%w/v 6%w/v 6%w/v 6%w/v 7. C971P 0.05%w/v 0.03%w/v — 8. C980 — — 0.05%w/v — 9. NAA-1 — — — 0.05%w/v Formulation batches were prepared using different concentrations of Carbopol 971P, Carbopol 980 and Noveon AA-l polymers. The formulations were stirred on a magnetic stirrer and the pH of the solution was adjusted to 6.0 so that complete swelling of the polymer occurs. The Invitro diffusion studies on the developed formulations were performed using Keshary-Chien Apparatus. The Invitro diffusion profile of the developed formulations are presented in Table9 & Figure 8 Table 9: Invitro drug release from Thermoreversible Microemulsion Containing Carbopol 971P, Carbopol 980 and Noveon AA Polycarbophil as Mucoadhesive Polymer: 22 Time (Minutes) Percent Drug Release Batch C1 0.05 %w/v C971P Batch C2 0.03%w/v C971P Batch C3 0.05%w/v C980 Batch N3 0.05%w/v NAA-1 30 44.218 49.55 37.71 56.378 60 57.02 73.45 59.37 71.83 90 64.35 81.87 68.69 91.141 120 79.64 91.323 76.41 98.02 180 87.69 100 79.96 100 240 89.62 — 85.07 — 300 99.98 — 98.76 — Figure 8: Invitro drug release of Thermo reversible Microemulsion Containing Carbopol 971P, Noveon AA Polycarbophil and Carbopol 980 as the Mucoadhesive Polymer: Invitro release of Rizatriptan Benzoate Using C971P, C980 and NAA-1 as Mucoadhesive polymers -»~0.05%w/vC97-lP ■— 0.03%w/vC971P *— 0.05%w/v C980 *«—-0.05%w/v NAA-1 120 0 50 100 150 200 250 300 Time (Minutes) Formulation C1 containing C971P gave a controlled release of 89% for 4 hrs releasing the drug at a constant rate. Formulation C2 released the entire drug in 3 hrs. Formulation C3 containing C980 gave a controlled release of 85% in 4 hrs. The drug release from Formulation C3 was found to increase linearly with time. Formulation N3 released the entire drug in 3 hrs. 23 Hence, formulations containing C971P, P-TR2 and C980 were found to give controlled release effect. C971P has been reported to be irritating to the nasal mucosa. So this polymer was not studied further. IRRITATION STUDIES OF DEVELOPED INTRANASAL FORMULATIONS: Formulations containing PTR2 and C980 were evaluated for irritation studies using sheep nasal mucosa. The results are presented in Figure 9. There was no significant change in histopathology after application of Blank and drug loaded microemulsion formulation. Figure 9: HistopathoiQgical evaluation of developed formulations for mucosal irritancy studies. formulation Thermoreversible microemulsion formulation-containing C980 as mucoadhesive agent was safe and non-irritating to the nasal mucosa. Evaluation of Optimized Microemulsion Formulations of Rizatriptan Benzoate: 24 The optimized microemulsion was evaluated for parameters as presented in Table 10. Table 10: Evaluation of Optimized Microemulsion Formulations of Rizatriptan Benzoate TESTS MICROEMULSION THERMOREVERSIBLE MICROEMULSION Clarity Clear with 99% transmittance Clear pH 7.0-7.2 6.0-6.3 Viscosity (cps) at RT 150 700 Stability by centrifugation Stable and did not separate. Stable Particle size (nm) 1.5-70 20-120 Drug content 99.9% 98.6% Evaluation of Stability as per ICH Guidelines: The developed thermoreversible mucoadhesive intranasal formulation was evaluated for stability as per 1CH Guidelines at 25°C/60%RH, 300C/65%RH and 40°C/75%RH respectively as shown in Table 11. Table 11: Evaluation of Stability of the developed formulation by ICH guidelines Sr.No. Tests 25°C/60%RH 30°C/65%RH 40°C/75%RH 1st Month 1. Appearance Transparent Transparent Transparent 2. PH 5.7 5.5 5.2 3. Particle Size (nm) 28 30 25 4. Drug Content 99.9% 99.25% 99.3% 2nd Month 1. Appearance Transparent Transparent Transparent 2. pH 5.7 5.5 5.2 3. Particle Size (nm) 26 28 28 4. Drug Content 99.57% 99.19% 99.284% 3rd Month 1. Appearance Transparent Transparent Transparent 2. pH 5.7 5.5 5.2 25 3. Particle Size (run) 30 32 33 4. Drug Content 99.29% 99.04% 99.0% From the above table we can conclude that the developed fonnulation was stable for a period of three months as per ICH guidelines. Evaluation of Mucoadhesive strength of the developed intranasal formulations using sheep nasal mucosa: The developed thermoreversible mucoadhesive intranasal formulations were evaluated for mucoadhesive strength by modified analytical balance technique using sheep nasal mucosa. The results are presented in Figure 10 Figure 10: Mucoadhesive strength of nasal formulations containing different mucoadhesive polymers on sheep nasal mucosa. 18000 16000 - 14000 - 12000 - 10000 - 8000 - 6000 - 4000 2000 0 Plain M.E F127/F68 M.E C980 TR ME Mucoadhesion PTR2 TR ME C971P TR ME As can be seen from the figure 10 mucoadhesive effect of C980 containing intranasal formulation was higher as compared to the other formulations. Evaluation of Brain targeting potential of the Developed Thermoreversible Mucoadhesive Intranasal Formulations of Rizatriptan Benzoate. 26 The brain targeting efficiency of the developed intranasal formulation was evaluated using Sprague-dawley rats. The microemulsion was administered in the nasal cavity of rats using polyethylene tubing attached to a syringe. Rat skull was excised and brain tissues were collected at 15, 30, 60, 120, 180 and 240 minutes time intervals. The amount of drug in the homogenized brain tissue was detected and analysed using developed and validated reverse phase HPLC method. The rizatriptan concentrations obtained in brain tissue from the developed intranasal formulations were compared with those obtained after Intravenous administration. The drug concentrations in brain after intranasal delivery and I.V administration are shown in the figure 11. Figure 11: Brain Targeting of Rizatriptan Benzoate using Intranasal and Intravenous formulations. Rizatriptan Benzoate Concentrations in Brain (ng/gm) following .intravenous and intranasal administration. From the above figure it can be observed that the brain targeting potential of Thermoreversible Mucoadhesive Intranasal formulations is much higher as compared to Intravenous administration of the drug. CONCLUSION: Thus, the developed microemulsion formulation is safe and has the potential for nose to brain targeting via intranasal delivery. 27 We claim 1. A microemulsion based intranasal drug delivery system comprising: (a) an oil phase; (b) a long chain surfactant component; and (c) a short chain cosurfactant component; and (d) a combination of long chain thermosensitive polymers (e) mucbadhesive agent; (f) an aqueous phase, (g)drug wherein the amounts of the long chain polymer surfactant and short chain alcohol as co-surfactant components are selected to provide for spontaneous formation of thermodynamically stable microemulsion droplets of the oil phase having a particle size from 10 nm to 100 nm. 2. A microemulsion based intranasal drug delivery system according to claim 1 wherein oil phase is ethyl oleate, Isopropyl myristate Maisine, Labrafil (TM) Labrafac (™) 3. A microemulsion based intranasal drug delivery system according to claim 1 wherein a long chain polymer surfactant component is Polysorbate 80, Cremophor RH 40, Labrosol ™ 4. A microemulsion based intranasal drug delivery system according to claim 1 wherein in a short chain cosurfactant component is polyhydric alcohol like propylene glycerol, plurol olequie ™, trascutol ™, or monohydric alcohol like ethanol, benzyl alcohol. 28 5. A microemulsion based intranasal drug delivery system according to claim 1 wherein thermosensitive polymers are polyoxyethylene-polyoxypropylene copolymers like Poloxamer 108, Poloxamer 188. 6. A microemulsion based intranasal drug delivery system according to claim 1 wherein mucoadhesive agent is Sodium Alginate, Sodium CMC, Carbopol 971P, Pemulen TR2 and Noveon AA-1. 7. A microemulsion based intranasal drug delivery system according to claim 1 wherein drug is. from class of 5HT1B/1D agonists like Rizatriptan Benzoate, Sumatriptan Succinate and other pharmaceuitically active derivatives or salts, ergotamine tartarate, calcium channel blockers and dopamine D2 agonists. 8. A microemulsion for intranasal drug delivery system comprising of a surfactant, cosurfactant in the ratio of 1:1-3:1 to form ( Smix) which is further mixed with the oil phase 9:1-1:9 w/w and made up to equilibrium by adding aqueous phase with constant stirring. 9. A microemulsion according to claim 8 wherein pH is 4.5-6.5. 10. A microemulsion according to claim 8 wherein transparency is 99.9%. 11. A microemulsion according to claim 8 wherein particle size is 1.5-70nm. 12. A microemulsion according to claim 8 wherein aqueous phase is upto 40-65%. 13. A microemulsion according to claim 8 wherein oil phase is 3.0-5.0%. 14. A microemulsion according to claim 8 wherein surfactant-cosurfactant mix (S mix) is 20-33%. 15. A method for preparation of microemulsion according to claim 8 wherein the surfactant is polysorbate 80, cremophor RH 40, Labrosol 29 16. A method for preparation of microemulsion according to claim 8 wherein co-surfactant is short chain cosurfactant component polyhydric alcohol like propylene glycerol, plurol olequie ™, trascutol ™, or monohydric alcohol like ethanol and benzyl alcohol. 17. A method for preparation of microemulsion according to claim 8 wherein oil phase is Ethyl oleate, Isopropyl myristate, Maisine, Labrafil(TM) or Labrafac (™). 18. A method for preparation of microemulsion based intranasal drug delivery system comprises of following steps, a. preparation of surfactant-cosurfactant mix (Smix) in the ratio of 1:1 -3:1 b. Mixing Smix with oil phase 9:1-1:9 w/w. c. Equilibration by shaking with aqueous phase until clear transparent microemulsion is obtained. d. Addition of polyoxyethylene-polyoxypropylene copolymer polymers in combination. e. Addition of mucoadhesive agent for higher retention time. f. Addition of drug substance to the microemulsion or optionally preparation of drug solution in aqueous phase, 19. A microemulsion according to claim 18 wherein pH is 4.5-6.5. 20. A microemulsion according to claim 18 wherein transparency is 99.9%. 21. A microemulsion according to claim 18 wherein particle size is 18-70nm. 22. A microemulsion according to claim 18 wherein aqueous phase is 40-65%. 23. A microemulsion according to claim 18 wherein oil phase is 3.0-5.0%. 30 24. A microemulsion according to claim 18 wherein surfactant-cosurfactant mix (S mix) is 20-33%. 25. A microemulsion according to claim 18 where combination of polyoxyethylene-polyoxypropylene copolymer is 3-6%. 26. A microemulsion according to claim 18 where mucoadhesive agent is 0.03-0.07%. 27. A method for preparation of microemulsion based intranasal drug delivery system according to claim 18 wherein surfactant is Polysorbate 80, Cremophor RH 40, Labrosol ™ 28. A method for preparation of microemulsion based intranasal drug delivery system according to claim 18 wherein co-surfactant is short chain cosurfactant component polyhydric alcohol like propylene glycerol, plurol olequie ™, trascutol ™, or monohydric alcohol like ethanol, benzyl alcohol. 29. A method for preparation of microemulsion based intranasal drug delivery system according to claim 18 wherein oil phase is Ethyl oleate, Isopropyl myristate, Maisine, Labrafil{TM)' Labrafac {TM). 30. A method for preparation of microemulsion based intranasal drug delivery system according to claim 18 wherein thermosensitive polymers are from the group of polyoxyethylene-polyoxypropylene copolymers like poloxamers 108, poloxamers 188. 31. A method for preparation of microemulsion based intranasal drug delivery system according to claim 18 wherein mucoadhesive agent is Sodium Alginate, Sodium CMC, poly(acrylic acid) derivatives like Carbopol 971P, Carbopol 980, Pemulen TR2 and Noveon AA-1. 31 32. A method for preparation of microemuision based intranasal drug delivery system according to claim 18 where drug is from class of 5HTH5B/ID agonists like Rizatriptan Benzoate, Sumatriptan Succinate and other pharmaceutical^ active derivatives or salts, ergotamine tartarate, calcium channel blockers aricll dopamine D2 agonists. 33. A method for preparation of microemuision based intranasal drug delivery system according to claim 18 that has a potential for nose to twain targeting via intranasal delivery of drugs from class of 5HTIB/ID agonists like Rizatriptan Benzoate, Sumatriptan Succinate and other pharmaceutically .active derivatives or salts, ergotamine tartarate, calcium channel blockers and dopamine D2 agonists. Dated this 19* July, 2008 Dr. Amrita Bajaj

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1770-MUM-2008-ABSTRACT(COMPLETE)-(22-8-2008).pdf

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