WO2025238624A1 - The novel rizatriptan nasal spray compositions - Google Patents

Abstract

The present invention provides the following aspects, subject matters, and preferred embodiments, which respectively taken alone or in combination, contribute to fulfill the object of the present invention. The invention provides stable nasal compositions including Rizatriptan or its pharmaceutically acceptable salts thereof. More specifically, the invention provides the low dose stable compositions of Rizatriptan or its pharmaceutically acceptable salts thereof. As per the important aspect of the invention, the inventors have provided the stable compositions containing one or more permeation enhancers, solvent(s) and/or co-solvent(s) or a combination thereof and other pharmaceutically acceptable excipients that provide the enhanced bioavailability of the drug. According to another aspect of the current invention, the stable nasal compositions of Rizatriptan or its pharmaceutically acceptable salts thereof containing relative quantities of permeation enhancers and solvent(s) and/or co-solvent(s) or a combination thereof are provided.

Description

THE NOVEL RIZATRIPTAN NASAL SPRAY COMPOSITIONS

TECHNICAL FIELD

The present invention relates to the stable compositions for treating serious conditions like migraine and reducing the recurrence of migraine episodes. More specifically, the invention relates to the treatment of migraine using nasal compositions of Rizatriptan or its pharmaceutically acceptable salts thereof that have a quicker onset of action as compared to the oral dosage forms.

BACKGROUND OF THE INVENTION

Migraine is a complex condition including the episodic patterns of disabling headache that are usually severe in nature and disruptive in day-to-day life. Migraine headaches, if untreated, may last from 4 hours to 3 days. The warning symptoms of migraine are commonly known as “aura” and the migraine attacks may or may not precede with aura. The common warning signs of migraine are throbbing pain in head during the movement, visual disturbances, nausea, vomiting, photophobia, phonophobia, irritation due to smell, etc. A migraine with an aura is commonly known as a “classic migraine” and a migraine without aura is referred to as a “common migraine”. The exact chain of neurological events occurring during migraine attacks is still unclear, however, it is believed that the headache is caused by the activation of nerve fibers within the wall of brain blood vessels traveling inside the meninges (three layers of membranes protecting the brain and spinal cord).

The acute symptomatic migraine treatment includes the use of analgesics and common NSAIDs. However, triptans remain the most widely used class of drugs in the treatment of migraine, especially when the headache is severe. Sumatriptan, eletriptan, naratriptan, zolmitriptan, rizatriptan, frovatriptan, and almotriptan are most known triptans. Oral compositions often face challenges such as hepatic first pass metabolism which is the root cause for the lesser availability of drugs during absorption. Moreover, the onset of action is usually delayed in the case of oral dosage forms. However, on the other hand, the nasal dosage form offers the advantages of rapid onset of action, lower degradation of the drug, and higher absorption rates due to the high vascularization and greater permeability.

Rizatriptan is so far approved in the USA as the oral tablet (MAXALT®), the orally disintegrating tablet (MAXALT-MLT®), and the oral film (RIZAFILM®). MAXALT® and MAXALT-MLT® are each approved in the strengths of 5 MG base and 10 MG base. The oral film is approved in the strength of 10 MG base. The most commonly approved dosage form across other countries like Europe, Australia, Canada, etc., is undoubtedly the oral dosage form for Rizatriptan.

Nevertheless, to achieve faster pain relief and to avoid the recurrence of the condition, there is an unmet need for a dosage form that overcomes these challenges. Rizatriptan, having a faster onset of action as compared to the other triptans, poses a suitable candidate for nasal administration.

The nasal administration often faces challenges with mucociliary clearance as the droplets of spray that reach the posterior portion of the nasal cavity are removed by mucociliary clearance. Hence, there is also a need to provide stable compositions of Rizatriptan or its pharmaceutically acceptable salts thereof for nasal administration with enhanced drug absorption.

Maggio (US8440631B2, referred to herein as US’631) discloses the non-toxic enhancing surfactants to stabilize and increase the bioavailability of therapeutic agents. The disclosed compositions specifically include alkyl glycoside or saccharide alkyl ester as drug enhancing agents. US’631 provides the therapeutic agent composition that provides migraine pain relief using the methods of administration such as via the oral, ocular, nasal, nasolacrimal, inhalation, or pulmonary, oral cavity (sublingual or Buccal cell) or cerebral spinal fluid (CSF) delivery route. The therapeutic agents include triptan analogs such as sumatriptan, rizatriptan, naratriptan, zolmitriptan, el etriptan, almotriptan, frovatriptan. US ’631 also provides the composition including tetradecyl-beta-D-maltoside as an alkyl glycoside along with Sumatriptan.

Vaishya Ravi et.al. (US20190224171A1, referred to herein as US’ 171) discloses the liquid Rizatriptan compositions along with the solvents selected from the group consisting of water, ethanol, propylene glycol, polyethylene glycol 400, and a combination thereof. US’ 171 provides various compositions along with their stability studies, characterization studies, and pharmacokinetic studies.

Russo Vincenzo et. al. (EP3863626A1, referred to herein as EP’626) discloses the oral liquid compositions of triptans. EP’626 particularly states that oral administration despite being the most common route of administration, seems challenging for triptans, especially because of their bitter taste and easy oxidation.

Raghuvanshi et.al. (US20170119738A1, referred to herein as US’738) provides the parenteral compositions of Rizatriptan. US’738 mentions the need for alternative dosage forms for Rizatriptan than the commercially available oral dosage forms as the patients who are dependent on Rizatriptan have potentially limited options to choose for the continuous treatment, especially when the patients are advised against the switching of the triptan treatment.

The inventors have thus provided alternative methods, compositions, and devices for the treatment of migraine. The current invention provides the stable pharmaceutical compositions of Rizatriptan or its pharmaceutically acceptable salts that are suitable for nasal administration. Moreover, the present invention also provides the dosage forms that require the low dose of Rizatriptan or its pharmaceutically acceptable salts, thereby preventing the risks of adverse reactions that are associated with increased doses. Also, the nasal spray compositions provided by the current invention enhance the patient compatibility by avoiding issues related to the trouble to some patient populations arising from swallowing of the drugs as well as the issues related to the palatability. SUMMARY OF THE INVENTION

The present invention provides the following aspects, subject matters, and preferred embodiments, which respectively taken alone or in combination, contribute to fulfill the object of the present invention.

The invention provides stable nasal compositions including Rizatriptan or its pharmaceutically acceptable salts thereof. More specifically, the invention provides the low dose stable compositions of Rizatriptan or its pharmaceutically acceptable salts thereof. As per the important aspect of the invention, the inventors have provided the stable compositions containing one or more permeation enhancers, solvent(s) and/or co-solvent(s) or a combination thereof and other pharmaceutically acceptable excipients that provide the enhanced bioavailability of the drug. According to another aspect of the current invention, the stable nasal compositions of Rizatriptan or its pharmaceutically acceptable salts thereof containing relative quantities of permeation enhancers and solvent(s) and/or co-solvent(s) or a combination thereof are provided.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in detail in connection with certain preferred and optional aspects, so that various aspects thereof may be more fully understood and appreciated.

Rizatriptan, represented by the formula of “Compound I”, is chemically a benzoate salt of N,N-dimethyl-5-(lH-l,2,4-triazol-l-ylmethyl)-lH-indole-3- ethanamine. Without limitations, Rizatriptan can be used as a free base or in the salt forms such as hydrochloride, hydrochloride dihydrate, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p toluenesulfonate and pamoate (i.e., l,l'methylene-bis-(2-hydroxy-3-naphthoate)). Most preferably the Rizatriptan benzoate is used.

Compound I

Rizatriptan is a selective 5 -hydroxytryptamine IB/ ID (5-HT1B/1D) receptor agonist and binds to the receptor with high affinity. Being a member of tryptamine class, it plays roles such as serotonergic agonist, vasoconstrictor agent and an antiinflammatory drug.

The involvement of Rizatriptan in the mechanism of treatment of migraine headache pertains to binding to 5-HT1B/1D receptors that are located on the intracranial blood vessels and sensory nerves of the trigeminal system. It exhibits agonistic effect at 5-HT1B/1D receptors on extracerebral intracranial blood vessels thereby constricting the vessels that are dilated during an attack. Moreover, the reduction in trigeminal pain transmission and decrease in inflammation is due to the suppression of neuropeptide release.

Rizatriptan is a BCS Class III drug with strong hydrophilicity and limited permeability. The mean absolute bioavailability of the Maxalt/Maxalt MLT is about 45% and mean peak plasma concentrations (Cmax) are reached in approximately 1- 1.5 hours (Tmax). The current nasal compositions of the invention have pharmacokinetic parameters in such a way that the Cmax is in the range of 50% to 125% of the Cmax produced by the same amount of Rizatriptan administered in the dosage forms of Maxalt/Maxalt MLT. In a similar manner, the relative steady state AUC of the nasal compositions of the current invention is in the range of 80% to 125% of the relative steady state AUC produced by the same amount of Rizatriptan administered in the dosage forms of Maxalt/Maxalt MLT. Nevertheless, the current invention provides the T_max which is much lesser than that of the oral dosage forms. As per one of the aspects of invention, the T_max of the present nasal compositions is in the range of about less than about 30 minutes.

As used herein, all numerical values relating to amounts, weights, and the like, that are defined as "about” each value is plus or minus 10%. For example, the phrase "about 10% w/w” is to be understood as “9%w/w to 11% w/w.” Therefore, amounts within 10% of the claimed value are encompassed by the scope of the claims.

As used herein, “% w/w” refers to the percent weight of the total formulation.

As used herein, the term “effective amount” refers to the amount necessary to treat a patient in need thereof.

As used herein, the term “solvent” refers to any substance that has an ability to dissolve one or several substances to form a solution. Further, as used herein, the term “co-solvent” refers to any substance added in addition to a solvent to increase the solubility of one or more substances. Furthermore, as used herein, the term “solvent system” refers to the combination of one or more solvents or a combination of one or more solvents with one or more co-solvents.

As used herein, the term “permeation enhancer” refers to a functional excipient included in formulations to improve the absorption of a pharmacologically active drug. This term usually refers to an agent whose function is to increase absorption by enhancing mucosal permeation.

As used herein, the term “isotonicity agent” refers to a functional excipient included in formulations to adjust the tonicity of the solutions.

As used herein, the term “stabilizing agent” refers to a functional excipient included in formulations to help the active pharmaceutical ingredient maintain its original form in the desirable formulation until the administration. As used herein, the term “preservative” refers to a functional excipient included in formulations to prolong the shelf life of the formulation.

As used herein, the term “viscosity modifier” refers to a functional excipient included in formulations to transform the rheological properties of liquids and to control the thickness or texture of the formulation.

As used herein, the term “antioxidant” refers to a functional excipient included in formulations to decrease or prevent the oxidation of the pharmaceutical components in the formulation.

As used herein, the term “buffering agent” refers to a functional excipient included in formulations to adjust the pH of the formulation as desired.

As used herein, the term “treatment” or “treating" refers to reversing, alleviating, inhibiting, or slowing the progress of the disease, disorder, or condition to which such terms apply, or one or more symptoms of such disease, disorder, or condition.

As used herein, the term “subject” refers but is not limited to a person that suffers from migraines.

As used herein, the term “migraine” refers to a chronic and/or episodic condition including moderate to severe pulsating unilateral headaches lasting between 4 hours and 72 hours, which includes migraine without aura and migraine with aura.

As used herein, the phrase “migraine without aura” refers to at least five attacks fulfilling the following criteria:

(a) the headache attack lasts 4 - 72 hours with the headache having at least two of the following features: unilateral location, pulsating quality, moderate or severe intensity with direct influence on activities of daily living, and aggravation by daily activities; and (b) During the headache at least one of the following occurs: nausea and/or vomiting, and pho tophobia and phonophobia.

As used herein, "migraine with aura” refers to at least two attacks accompanied by at least 3 of the 4 following features:

(a) one or more fully reversible aura symptoms.

(b) at least one aura symptom which develops gradually over more than four minutes or two or more symptoms which occur in succession.

(c) no aura symptom which lasts more than 60 minutes.

(d) a headache occurs prior to, simultaneously with or following the aura, with a free interval between aura and headache of less than about 60 minutes.

As used herein, the term “aura” refers to a perceptual disturbance experienced before a headache begins. Perceptual disturbances include, but are not limited to, perception of a strange light including flashing lights or blind spots, an unpleasant smell, confusing thoughts, or experiences or tingling on one side of the face or one extremity.

As used herein, the phrase "pharmaceutically acceptable” refers to ingredients that are not biologically or otherwise undesirable the pharmaceutical dosage forms.

As used herein, the term “stable” includes but is not limited to physical and chemical stability.

The processes for the preparation of Rizatriptan or its pharmaceutically acceptable salts thereof are well documented earlier.

In the composition of the present invention, the Rizatriptan or its pharmaceutically acceptable salt is present in the range of about 1% w/w to about 20% w/w, preferably from about 1% w/w to about 15%w/w, more preferably about 5% w/w to about 10% w/w. Specifically, the Rizatriptan or its pharmaceutically acceptable salt is present in the amount of about 2.5% w/w or about 5% w/w or about 7.5% w/w or about 10% w/w. The present invention can be administered via a nasal spray. The nasal spray devices may include unit dose, bi-dose or multi-dose system. The Rizatriptan dose dispensed from the nasal spray per actuation is in the range of about 50 pL to about 100 pL. The fill volume of the nasal spray may vary from about 100 pLto about 20 mL and spray volumes may range from about 50 pL to about 125 pL depending upon the dose.

The present composition may further have the pharmaceutically acceptable excipients or the inactive ingredients. Without limitations, the possible inactive ingredients are permeation enhancers, solvent(s), co-solvent(s), isotonicity agent(s), stabilizing agent(s), preservative(s), viscosity modifier(s), antioxidant(s), buffer(s), pH adjustment agent(s), etc.

The permeation enhancers suitable for the present invention include, but are not limited to, alcohol, glycols, stearyltri ethanol amine, aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramides, cetylpyridinium chloride, chitosan, cyclodextrins, deoxycholic acid, decanoyl, dimethyl sulfoxide, glyceryl monooleate, glycerin monostearate, glycofurol, glycosylated sphingosines, glycyrrhetinic acids, 2 - hydroxypropyl-L-cyclodextrin, laureth - 9, lauric acid, lauroyl carnitine, poloxamer 407 or F68, poly - L arginine, L - lysine polyoxyethylene - 9 - lauryl ether, isopropyl myristate, isopropyl palmitate, lanolin, light mineral oil, linoleic acid, menthol, myristic acid, myristyl alcohol, oleic acid, or salt thereof, octanoic acid, citric acid, oleyl alcohol, palmitic acid, polysorbate 20, polysorbate 80, propylene glycol, polyoxyethylene alkyl ethers, polyoxylglycerides, pyrrolidone, quillaia saponin, sodium lauryl sulfate, sucrose cocoate, taurocholic acid, taurodeoxycholic acid, taurodihydrofusidic acid, thymol, tricaprylin, triolein, menthol, sodium edetate, cetylpyridinium chloride, sodium desoxycholate , sodium deoxyglycolate , glyceryl oleate, cellulose polymers as well as the alkylglycosides or alkylsaccharides. Alkyl glycosides of the present invention include, but are not limited to, octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl-, pentade cyl-, hexadecyl-, heptadecyl-, and octadecyl-a- or P-D- maltoside, -glucoside or -Sucroside, alkyl thiomaltosides, such as heptyl, octyl, dodecyl-, tridecyl-, andtetradecyl-P-D-thiomaltoside, alkylthioglucosides such as heptyl- or octyl 1-thio-a- or P-D-glucopyranoside, alkyl maltotriosides, long chain aliphatic carbonic acid amides of Sucrose P-amino alkyl ethers, derivatives of palatinose and isomaltamine linked by amide linkage to an alkyl chain, derivatives of isomaltamine linked by urea to an alkyl chain, long chain aliphatic carbonic acid ureides of Sucrose P-amino-alkyl ethers, and long chain aliphatic carbonic acid amides of Sucrose B-amino-alkyl ethers. The preferred permeation enhancers are glycols or their derivatives such as ethylene glycol, propylene glycol, polyethylene glycol (PEG), or polypropylene glycol. The most preferred permeation enhancer of the current invention is polyethylene glycol -6-m ethyl ether. The other preferred permeation enhancers include alkyl maltosides such as n-dodecyl-P-D-maltoside.

The permeation enhancers can be present in the range of about 0.1% w/w to about 60% w/w. As per one of the aspects of invention, the PEG-6-methyl ether is preferably present in the range of about 35% w/w to about 55% w/w or about 40% w/w to about 50% w/w or about 45% w/w to about 50% w/w. Most preferably, the PEG-6-methyl ether of the current invention is present in the amount of about 48.5% w/w.

As per another aspect of invention, n-dodecyl-P-D-maltoside is present in the range of about 0.01% w/w to about 1 % w/w or about 0.1% w/w to about 0.5% w/w or about 0.2% w/w to about 0.4% w/w or about 0.2% w/w to about 0.3% w/w. Most preferably, n-dodecyl-P-D-maltoside is present in the range of about 0.25% w/w.

The solvents or a solvent system suitable for the current invention include, but are not limited to, water, alcohols such as ethanol, glycols such as propylene glycol, polyethylene glycol, PEG-6-methyl ether, medium chain glycerides, diethylene glycol monoethyl ether etc. The most preferred solvent according to the present invention is propylene glycol. The composition of the current invention may sometimes have a solvent system comprising of one or more solvent. Preferably, the first solvent according to the present invention is propylene glycol and the second solvent is ethanol or the first solvent according to the present invention is ethanol and the second solvent is propylene glycol.

The co-solvents suitable for the current invention include, but are not limited to, water, small quantities of alcohols such as ethanol, glycols such as propylene glycol, polyethylene glycol, PEG-6-methyl ether, medium chain glycerides, diethylene glycol monoethyl ether etc. The most preferred co-solvent according to the present invention is propylene glycol or ethanol. Another preferred system of solvents/co-solvents according to the present invention includes a combination of one or more solvents/co-solvents, for example, a combination of propylene glycol with ethanol.

The solvents and/or co-solvents or a combination thereof can be present in the range of about 1% w/w to about 50% w/w. As per one aspect of the invention, the solvent and/or co-solvent or a combination thereof is present in the range of about 1% w/w to about 15% w/w. Preferably, the solvent and/or co-solvent or a combination thereof is present in the range of about 5% w/w to about 15% w/w. Most preferably, propylene glycol is selected as the solvent, and it is present in the amount of about 5.8% w/w.

As per another aspect of invention, the solvent and/or co-solvent or a combination thereof is present in the range of about 30% w/w to about 50% w/w. More preferably, the solvent and or co-solvent or a combination thereof is present in the range of about 35% w/w to about 45% w/w. Most preferably, propylene glycol is selected as the solvent, and it is present in the amount of about 40% w/w.

As per the additional aspect of the invention, a combination of solvents or a combination of solvents with co-solvents in the composition is present such that the first solvent is present in the range of about 1% w/w to about 10% w/w and the second solvent or a co-solvent is present in the range of about 1% w/w to about 10% w/w. More preferably, a combination of solvents and/or co-solvents in the composition is present such that the first solvent is present in the range of about 1% w/w to about 6% w/w and the second solvent is present in the range of about 5% w/w to about 10% w/w. Most preferably, the combination of co-solvents is selected such that the first solvent is ethanol, and it is present in the amount of about 6.65% w/w; and the second solvent and/or co-solvent is selected as the propylene glycol and it is present in the amount of about 5.8% w/w.

As per the current invention, the compositions may include the permeation enhancer and the solvent system in such a way that the ratio of the amount of permeation enhancer to the cumulative amount of solvent system is 0.01 :5 to 60:5.

As per one of the aspects of invention, the ratio of the amount of permeation enhancer to the amount of solvent system is preferably 10:5 - 30:5. More preferably, the ratio of the amount of permeation enhancer to the cumulative amount of solvent system is 10:5 - 20:5. Even more preferably, the ratio of the amount of permeation enhancer to the cumulative amount of solvent system is 15:5 to 20:5. Most preferably, the ratio of the amount of permeation enhancer to the cumulative amount of solvent system is 19.45:5.

As per the another aspect of invention, the ratio of the amount of permeation enhancer to the cumulative amount of solvent system is preferably 30:5 - 60:5. More preferably, the ratio of the amount of permeation enhancer to the cumulative amount of solvent system is 35:5 - 50:5. Even more preferably, the ratio of the amount of permeation enhancer to the cumulative amount of solvent system is 40:5 to 45:5. Most preferably, the ratio of the amount of permeation enhancer to the cumulative amount of solvent system is 41.8:5.

As per the another aspect of invention, the ratio of the amount of permeation enhancer to the cumulative amount of solvent system is preferably 0.001 :5 to 1 :5. More preferably, the ratio of the amount of permeation enhancer to the cumulative amount of solvent system is 0.001:5 - 0.05:5. Most preferably, the ratio of the amount of permeation enhancer to the cumulative amount of solvent system is 0.03:5. The pH of the composition of the current invention is in the range of about 5 to about 9.

Optionally, the stabilizing agents/stabilizers include, but are not limited to, ethylenediaminetetraaceticacid (EDTA) or a salt thereof, cyclodextrin, D, L - alpha tocopherol, butylated hydroxytoluene, methionine, ascorbyl palmitate, ascorbic acid, butylated hydroxy anisole, citric acid, sodium bisulfate, tertbutylhydroquinone and propyl gallate. Stabilizers may be present in the compositions of the invention at a concentration preferably from about 0.001% w/w to about 0.5 % w/w and more preferably from about 0.0002% to about 0.2% or about 0.05% w/w to about 0.4% w/w. The stabilizer concentrations can be optimized by the one ordinarily skilled in the art.

Optionally, the preservatives include, but are not limited to, benzalkonium chloride, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, sodium benzoate, benzoic acid, phenol, m-cresol, ortho-cresol, meta-cresol, par-cresol, thiomersal, chlorobutanol, benzethonium chloride, sodium benzoate, sorbic acid. Preservatives may be present in the compositions of the invention at a concentration from about 0.005% w/w to about 0.2% w/w. The preservative concentrations can be optimized by the one ordinarily skilled in the art. The compositions of the current invention may be preservative-free.

Optionally, the antioxidant selected from alpha tocopherol, arachidonic acid, ascorbic acid, ascorbyl palmitate, benzethonium chloride, benzethonium bromide, benzalkonium chloride, butylated hydroxyanisole(BHA), butylated hydroxytoluene (BHT), capric acid, caproic acid, carbon dioxide, cetylpyridium chloride, chelating agents, chitosan derivatives, citric acid monohydrate, dodecyl dimethyl aminopropionate, enanthic acid, erythorbic acid, ethyl oleate, fumaric acid, glycerol oleate, glyceryl monostearate, lauric acid, limonene, linolenic acid, lysine, malic acid, menthol, methionine, monothioglycerol, myristic acid, oleic acid, palmitic acid, pelargonic acid, peppermint oil, phosphoric acid, polysorbates, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate sodium bisulfite, sodium caprate, sodium desoxycholate, sodium deoxyglycolate, sodium formaldehyde sulfoxylate, sodium glycocholate, sodium hydroxybenzoyal amino caprylate, sodium lauryl sulfate, sodium metabisulfite, sodium sulfite, sodium taurocholate, sodium thiosulfate stearic acid, sulfur dioxide and a combination thereof. Antioxidants may be present in the compositions of the invention at a concentration from about 0.05% w/w to about 1% w/w. The antioxidant concentrations can be optimized by the one ordinarily skilled in the art.

Optionally, the viscosity modifiers include, but are not limited to, gelatin; methylcellulose (MC); hydroxypropylmethylcellulose (HPMC) and derivatives thereof; carboxymethylcellulose (CMC); cellulose; starch; heta starch; poloxamers; pluronics; sodium CMC; sorbitol; acacia; povidone; carbopol (as used herein, carbopol is a carbomer; carbopol is also known as Carbomer Homopolymer Type B, or Carbopol® 974P NF Polymer); polycarbophil; chitosan; chitosan microspheres; alginate microspheres; chitosan glutamate; amberlite resin; hyaluronan; ethyl cellulose; maltodextrin DE; drum-dried way maize starch (DDWM); degradable starch microspheres (DSM); deoxyglycocholate (GDC); hydroxyethyl cellulose (HEC); hydroxypropyl cellulose (HPC); microcrystalline cellulose (MCC); polymethacrylic acid and polyethylene glycol; sulfobutylether B cyclodextrin; cross-linked eldexomer starch biospheres; sodiumtaurodihydrofusidate (STDHF); N-trimethyl chitosan chloride (TMC); degraded starch microspheres; amberlite resin; chistosan nanoparticles; spray-dried crospovidone; spray-dried dextran microspheres; spray-dried microcrystalline cellulose; and cross-linked eldexomer starch microspheres. The viscosity modifiers may be present in the compositions of the invention at a concentration from about 0.05% w/w to about 10% w/w. The viscosity modifier concentrations can be optimized by the one ordinarily skilled in the art.

Optionally the buffering agents include, but are not limited to, adipic acid, boric acid, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate, tribasic, citric acid monohydrate, dibasic sodium phosphate, diethanolamine, glycine, maleic acid, malic acid, methionine, monobasic sodium phosphate, monoethanolamine, monosodium glutamate, phosphoric acid, potassium citrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate dihydrate, sodium hydroxide, sodium lactate, and triethanolamine.

Optionally, the isotonicity agents include, but are not limited to, dextrose, glycerin, mannitol, potassium chloride, or sodium chloride. Isotonicity agents may be present in the compositions of the invention at a concentration from about 0.5% w/w to about 5% w/w. The isotonicity agent concentrations can be optimized by the one ordinarily skilled in the art.

Analysis and characterization of the nasal spray composition is an important aspect of the pharmaceutical development of a product. Without limitations, the characterization of the nasal spray includes the testing of description, identification, assay, impurities and degradation products, preservatives and stabilizing agents assay, microbial limits, antimicrobial effectiveness, pH, osmolality, viscosity, pump delivery, droplet size distribution, spray pattern, plume geometry, net content, particulate matter, dose proportionality and spray characterization.

The present invention is further illustrated with the help of working examples. In no way do the working examples limit the scope of the invention. The nasal spray compositions of the current invention can be manufactured using the processes well established in art.

Example 1 - 10:

Table 1

Preparation of the composition illustrated in Table 1.

Step 1 : The propylene glycol and the purified water in the amount of 40% of the total batch size was mixed under the stirring. Step 2: Rizatriptan benzoate was dissolved in the solution of Step 1.

Step 3 : A separate solution was made by adding the n-dodecyl-beta-D-maltoside to the purified water quantified as 5% of the total batch size.

Step 4: The solution of Step 3 was then added to the solution of Step 2 under the stirring. Step 5. The container of the solution of Step 3 was further rinsed by the purified water quantified as 5% of the total batch size and the rinsate was added to the solution prepared in Step 4.

Step 6: The purified water remaining after Step 5 was then added to the Step 5 solution and the total volume was made up. Step 7. The bulk of the Step 6 was then filtered using 0.45 pm PVDF filter and filled in the glass vials fitted with nasal spray pump actuator assembly.

Example 11:

Table 2

Preparation of the composition illustrated in Table 2.

Step 1 : The PEG-6-methyl ether as quantified in Table 1 was weighed and added to the propylene glycol under stirring, followed by the addition of purified water in the amount of 10% of the total batch size. Step 2: Rizatriptan benzoate was dissolved in the solution of Step 1.

Step 3. The purified water remaining after Step 2 was then added to the Step 3 and the total volume was made up.

Step 4. The bulk of the Step 3 was then filtered using 0.45 pm PVDF filter and filled in the glass vials fitted with nasal spray pump actuator assembly. Example 12:

Table 3

Preparation of the composition illustrated in Table 3. Step 1 : The PEG-6-methyl ether quantified in Table 1 was weighed and added to the propylene glycol under stirring, followed by the addition of ethanol and purified water in the amount of 10% of the total batch size.

Step 2: Rizatriptan benzoate was dissolved in the solution of Step 1.

Step 3. The purified water remaining after Step 2 was then added to the Step 3 solution and the total volume was made up.

Step 4. The bulk of the Step 3 was then filtered using 0.45 pm PVDF filter and filled in the glass vials fitted with nasal spray pump actuator assembly. Example 13.

The pharmacokinetic parameters of the pharmaceutical compositions described in the present invention were evaluated in comparison with MAXALT® (10 mg) oral tablets. The study involved seven groups, each consisting of three subjects, who received a single intranasal dose of the composition described in Example 3, 4, 5, 11 and 12. The results are shown in below Table 4

Table 4

Claims

CLAIMS:

1. A pharmaceutical composition for intranasal administration comprising, about 2.5% (w/w) to 10% (w/w) of rizatriptan benzoate; about 0.01% (w/w) to about 1% (w/w) of n-dodecyl-P-D-maltoside; about 35% (w/w) and about 45% (w/w) of propylene glycol; and water in an amount sufficient to achieve a final volume of about 50 pL to about 150 pL.

2. The pharmaceutical composition of claim 1, comprising about 2.5% (w/w) of rizatriptan benzoate.

3. The pharmaceutical composition of claim 1, comprising about 5% (w/w) of rizatriptan benzoate.

4. The pharmaceutical composition of claim 1, comprising about 7.5% (w/w) of rizatriptan benzoate.

5. The pharmaceutical composition of claim 1, comprising about 0.025% (w/w) of n-dodecyl-P-D-maltoside.

6. The pharmaceutical composition of claim 1, comprising about 0.05% (w/w) of n-dodecyl-P-D-maltoside.

7. The pharmaceutical composition of claim 1, comprising about 0.1% (w/w) of n-dodecyl-P-D-maltoside.

8. The pharmaceutical composition of claim 1, wherein the composition is used for the treatment of migraine.

9. The pharmaceutical composition of claim 1, wherein the time to reach maximum plasma concentration (Tmax) following intranasal administration is less than about 20 minutes.

10. The pharmaceutical composition of claim 1, wherein the composition is administered using a nasal spray device configured for unit dose, bi-dose, or multi-dose delivery.