Oromucosal solutions of zolpidem or a pharmaceutically acceptable salt thereof

Abstract

The present invention relates to buccal or sublingual formulations of Zolpidem or a pharmaceutically acceptable salt thereof. The formulations minimize the amount of permeation enhancers while providing rapid transmucosal penetration of the drug. These formulations not only provide the desired drug concentration (0.5% to 10% w / v) in the form of clear solutions, but also achieve stable formulations throughout a shelf life of at least about 2 years. The pH of the stable non-aqueous solutions of the present invention is in the range of 5 to 9, preferably in the range of 6 to 9, more preferably in the range of 7 to 9.

Description

Technical Field

[0001] The present invention relates to a stable non-aqueous solution of Zolpidem or a pharmaceutically acceptable salt or salts thereof. The solution of the present invention is suitable for administration by an oromucosal route. More particularly, the present invention relates to a stable non-aqueous solution of Zolpidem or a pharmaceutically acceptable salt or salts thereof which will have a rapid onset of action when administered into the oral cavity via a buccal, sublingual or oromucosal route, wherein the pH of the formulation is in the range of 5 to 9. Background Art

[0002] Sleep plays an important role in the regulation of the central nervous system (CNS) and physiological functions of the human body, including metabolism, catabolism, body temperature, learning and memory consolidation. Insomnia is a sleep disorder characterized by one or more of the following features: difficulty falling asleep (e.g., sleep onset latency (SOL) greater than 30 minutes), insufficient sleep (e.g., total sleep time (TST) less than 5.5-6 hours), multiple nighttime awakenings, early morning awakenings and inability to fall asleep again, or non-restorative sleep after awakening from usual sleep.

[0003] Insomnia is more prevalent in women, older adults, shift workers, and patients with medical and psychiatric illnesses. Difficulty falling asleep is more common in younger adults, whereas problems maintaining sleep are more common in middle-aged and older adults. The importance of insomnia is often underestimated due to its high prevalence and because its symptoms are often mild and transient. However, as a chronic disorder affecting approximately 10% of the population, insomnia is often challenging to treat and is associated with considerable comorbid symptoms (i.e., depression, anxiety).

[0004] There are two main goals in the treatment of insomnia. These goals include improving sleep quality or quantity and improving daytime impairment.

[0005] Initial treatment usually includes at least one behavioral intervention, such as stimulus control therapy or relaxation therapy. Medications used to treat insomnia include benzodiazepines BZD, non-benzodiazepine Class, melatonin agonists, tricyclic antidepressants, barbiturates, etc.

[0006] Zolpidem and BDZ share GABA A The BDZ receptor is a molecule that binds to the alpha subunit of the BDZ receptor / chloride channel complex. However, there are decisive differences in the selectivity of the relevant subtypes. For example, BDZ is relatively non-selective in this regard and causes anti-excitatory hyperpolarization in many parts of the CNS. These effects lead to more widespread neural inhibition and a variety of effects beyond sedation and sleep promotion, such as anxiolytic, anticonvulsant and relaxant effects.

[0007] Zolpidem tartrate is chemically N,N,6-trimethyl-2-p-methylphenylimidazo[1,2-a]pyridine-3-acetamide L-(+)-tartrate (2:1) and exhibits strong hypnotic and sedative effects with negligible anxiolytic, muscle relaxant, or anticonvulsant properties. Zolpidem tartrate is widely used in the short-term treatment of insomnia. Zolpidem tartrate is relatively well tolerated and has few side effects typically associated with BDZs.

[0008] Attempts have been made to provide Zolpidem or its salts in solid oral dosage forms such as tablets. These dosage forms are relatively more stable due to the absence of water. Stable liquid formulations not only exist as clear solutions, but also remain clear upon storage without precipitation of the drug.

[0009] The drug is administered in solid form, so larger amounts of the drug can be delivered through these solid dosage forms. and CR tablets (Sanofi Aventis, USA) provide 10 and 12.5 mg of drug per tablet, respectively.

[0010] The problem with solid dosage forms is that the drug in them needs to be broken down and dissolved before being transported into the system, so these solid dosage forms have a much slower onset of action compared to liquid dosage forms, where the drug is readily available in solution to penetrate the mucous membranes. Another disadvantage of these tablet formulations is that they can cause daytime sleepiness, affecting the patient's quality of life.

[0011] WO9916417 (WO'417) discloses a buccal spray composition for transmucosal administration of a pharmaceutically active compound selected from the group comprising a sleep inducing agent. WO'417 discloses two types of formulations. The buccal polar composition comprises formulation (I): aqueous polar solvent 30%-99.89%, active compound 0.001%-60%, optionally containing flavoring agent 0.1%-10%. The non-polar composition of the present invention comprises formulation (II): non-polar solvent 20%-85%, active compound 0.005%-50%, optional flavoring agent 0.1%-10%, and propellant 50%-80%. The specification does not disclose any specific formulation of Zolpidem or its salts. It should be noted that the formulation without propellant disclosed in WO'417 contains a large amount of water. The presence of water will greatly shorten the shelf life of the formulation, so it is desirable to prepare anhydrous formulations.

[0012] WO 2005079761 (WO'761) and WO 2006128022 (WO'022) disclose oral solid compositions for delivering hypnotic agents across the oral mucosa. It is noted that WO'761 provides about 1.0 to about 5.5 weight percent of Zolpidem in a solid dosage form that takes a long time to be absorbed. WO'761 and WO'022 do not achieve a drug concentration of 0.5% to 10% w / v in a solution formulation, wherein the drug is ready for absorption.

[0013] WO 2006046041 (WO'041) discloses a fast-acting solid dosage formulation of Zolpidem in the form of a mucoadhesive tablet suitable for transmucosal administration. The present PCT-disclosed invention in solid dosage form frequently contacts the oral mucosa, which can cause considerable discomfort to the patient.

[0014] WO 2005032519 (WO'519) discloses buccal aerosol sprays or capsules using polar and non-polar solvents, which provide zolpidem for rapid absorption through the oral mucosa for rapid onset of action. The buccal polar composition of the present invention comprises a formulation aqueous polar solvent, zolpidem and optional flavoring agent; formulation II: aqueous polar solvent, zolpidem, optional flavoring agent, and propellant; formulation III: non-polar solvent, zolpidem, and optional flavoring agent; formulation IV: non-polar solvent, zolpidem, optional flavoring agent, and propellant; formulation V: a mixture of polar and non-polar solvents, zolpidem, and optional flavoring agent; formulation VI: a mixture of polar and non-polar solvents, zolpidem, optional flavoring agent, and propellant.

[0015] The "propellant-free" buccal spray of Zolpidem in WO '519 uses polar and / or non-polar solvents to rapidly deliver Zolpidem or a pharmaceutically acceptable salt thereof in an amount between 0.01% and 20% (w / w) of the total formulation.

[0016] Although a solvent system containing a high proportion of polar solvents (propylene glycol and ethanol in the ratio of 30% and 99%) is used in the formulation of WO'519, the drug cannot be completely dissolved, thus resulting in a turbid solution. In addition, the proportion of alcohol (which also acts as a penetration enhancer) is very high, resulting in an unpleasant feeling in the mouth. WO'519 does not disclose the pH of the formulation. When measured by the inventors of the present invention, the pH was about 5. A liquid formulation of Zolpidem sold by Novadel Pharma US (the applicant of WO'519) Having a pH of 3 to 4, at which the drug remains dissolved, suggests that the invention is only feasible in the range of pH <5.

[0017] The invention disclosed in WO'519 teaches that 8% citrate buffer is essential for drug dissolution in a propellant-free formulation containing 2.5% w / w Zolpidem and a polar solvent comprising 15% propylene glycol and about 64% ethanol, with the pH maintained at <5. When the pH of these solutions increases to 5 and above, turbid solutions are formed. In addition, a relatively high proportion of water is used as an essential ingredient. WO'519 fails to provide a liquid formulation that is stable for storage. The invention disclosed in WO'519 also teaches a "propellant-free" formulation prepared using an oily component and lemon oil, in which the drug concentration achieved is only 0.5%. The pH of this formulation is also less than 5. It has been found that such a formulation is not feasible for a drug concentration of 2.5% w / v.

[0018] WO 2007123955 (WO'955) discloses stable hydroalcoholic formulations of active pharmaceutical preparations suitable for oral spray administration. WO'955 uses water as an essential component of the solvent system for the propellant-free buccal formulations. The pH of these formulations is maintained in the range of 7 to 12 to deliver the various active pharmaceutical ingredients in the aqueous formulations. However, it has been found that it is not possible to prepare a clear solution of Zolpidem tartrate using the solvent system disclosed in WO'955 (pH in the range of 7 to 12).

[0019] WO 2008141264 (WO'264) discloses oral spray formulations for transmucosal absorption of zolpidem using a combination of polar and non-polar solvents. These formulations may optionally use a propellant. The formulations mentioned in this reference are commercially available under the trade name get.

[0020] Typically, WO'264 discloses oral spray formulations comprising 0.05%-10% Zolpidem or a pharmaceutically acceptable salt thereof; a polar or non-polar solvent or a mixture thereof. These formulations may further comprise 0-1% of a taste masking agent and / or flavoring agent; and 0-1% of a preservative; and a propellant. All exemplary formulations of Zolpidem contain water. All exemplary formulations disclosed in WO'264 have a pH of 3-4. The inventors of the present invention have found that when the pH of these formulations is increased to about 5, the drug precipitates as a curd-like white mass, indicating that these formulations are not suitable for oral mucosal administration. In addition, the inventors of the present invention have found that the transmucosal penetration T of the formulations disclosed in WO'264 is max It's 20 minutes.

[0021] The prior art that discloses the invention of improving the transmucosal permeability of Zolpidem by providing a liquid dosage form with or without a propellant has the following limitations:

[0022] • They are unable to provide the desired drug concentration (0.5% to 10% w / v) in the form of a clear solution with a desired shelf life of at least about 2 years. Therefore, most formulations available in the market are solid dosage forms.

[0023] • They require water as an essential ingredient which results in reduced drug stability where precipitation of the drug occurs in solution upon storage.

[0024] They use very high proportions of penetration enhancers, such as alcohol, which has the potential to cause side effects, such as an unpleasant sensation in the mouth.

[0025] They do not achieve a more rapid onset of action through rapid transmucosal penetration of the drug over the pH range of 5 to 9 (T max Less than 20 minutes). Therefore, the pH of commercially available liquid formulations is kept at less than 5.

[0026] In order to address the long-standing need to provide a stable non-aqueous liquid formulation for effective transmucosal administration of Zolpidem or a pharmaceutically acceptable salt thereof, the following technical problems associated with such liquid dosage forms need to be simultaneously addressed:

[0027] 1. Providing the drug at a concentration of 0.5% to 10% w / v in a clear non-aqueous solution;

[0028] 2. Provide a formulation that remains stable over a wide pH range of 5 to 9 throughout a storage period of at least two years; and

[0029] 3. Minimize the amount of one or more penetration enhancers used in the formulation up to 30% v / v without affecting the transmucosal penetration of the drug.

[0030] 4. Provide rapid transmucosal penetration of drugs over a pH range of 5 to 9, thereby allowing the drug to take effect more quickly.

[0031] Purpose of the invention:

[0032] The primary object of the present invention is to provide stable non-aqueous solutions of Zolpidem or its pharmaceutically acceptable salts, wherein these formulations provide rapid transmucosal penetration of the drug.

[0033] Yet another object of the present invention is to provide stable non-aqueous solutions of Zolpidem or a pharmaceutically acceptable salt thereof, wherein the formulations provide 0.5% to 10% w / v, preferably 2.5% to 10% w / v of Zolpidem or a pharmaceutically acceptable salt thereof, wherein the pH of the formulation is in the range of 5 to 9, preferably in the range of 6 to 9, more preferably in the range of 7 to 9.

[0034] Another object of the present invention is to provide stable non-aqueous formulations of Zolpidem or a pharmaceutically acceptable salt thereof suitable for administration via buccal, sublingual or oromucosal routes, wherein these formulations have a rapid onset of action due to rapid transmucosal penetration.

[0035] Another object of the present invention is to provide a stable non-aqueous formulation of Zolpidem or a pharmaceutically acceptable salt thereof, wherein rapid transmucosal penetration of the drug is achieved by minimizing the amount of one or more penetration enhancers used in the formulation.

[0036] The present invention addresses the above and other needs by providing a stable non-aqueous formulation of Zolpidem or a pharmaceutically acceptable salt thereof in synergistic combination with components such as a judiciously selected solvent system, one or more penetration enhancers and other ingredients, the pH of the combination being in the range of 5 to 9, preferably in the range of 6 to 9, more preferably in the range of 7 to 9. Unexpectedly, the formulations of the present invention achieve rapid transmucosal penetration compared to formulations known in the art. DETAILED DESCRIPTION

[0037] The present invention provides a stable non-aqueous solution of Zolpidem or a pharmaceutically acceptable salt thereof, wherein the drug can be rapidly absorbed through the oral mucosa.

[0038] The challenge faced by the present inventors is to dissolve Zolpidem or a pharmaceutically acceptable salt thereof at a desired concentration in a non-aqueous liquid formulation while maintaining its stability throughout the shelf life of the formulation.

[0039] The synergistic combination of the components of the present invention not only provides a stable non-aqueous liquid solution of Zolpidem or a pharmaceutically acceptable salt thereof, but also maintains the drug in a dissolved state over a pH range of 5 to 9 throughout a storage period of at least 2 years.

[0040] Surprisingly, the solutions of the present invention achieve rapid transmucosal penetration of the drug compared to formulations disclosed in the prior art. In animals, this results in a more rapid onset of action when administered by the sublingual route. The present invention provides a T max <20 minutes of solution. Most surprisingly, the present invention achieves the above advantages by minimizing the use of penetration enhancers in the solution.

[0041] The solution of the present invention comprises Zolpidem or a pharmaceutically acceptable salt thereof, one or more penetration enhancers, a non-aqueous solvent system, optionally a pH adjuster and optionally a polymer, wherein the pH of the solution is in the range of 5 to 9, preferably in the range of 6 to 9, more preferably in the range of 7 to 9.

[0042] The present invention provides a stable non-aqueous solution of Zolpidem or a pharmaceutically acceptable salt thereof, wherein the concentration of Zolpidem or a pharmaceutically acceptable salt thereof is in the range of 0.5% to 10% w / v of the solution, preferably in the range of 2.5% to 10% w / v of the solution.

[0043] The one or more penetration enhancers are selected from one or more low-chain alcohols with a carbon chain length of 1 to 5, preferably ethanol, isopropanol or a mixture thereof. The one or more penetration enhancers of the formulation may also be selected from: one or more low-chain alcohols, sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, oleic acid, capric acid, lauric acid, lecithin, myristic acid, palmitic acid, lysophosphatidylcholine, phosphatidylcholine, azone, cyclodextrin, sodium lauryl sulfate, polyoxyethylene-9-lauryl ether, polyoxyethylene-20-hexadecyl ether, benzalkonium chloride, cetylpyridinium chloride, vitamin ETPGS, caprylocaproyl polyoxyglycerol, stearyl macrogol glyceride, propylene glycol dicaprylate caprate, propylene glycol monocaprylate, propylene glycol monolaurate, N-methyl-2-pyrrolidone or a mixture thereof.

[0044] In one embodiment, the solution comprises ethanol as one or more penetration enhancers. The present invention attempts to minimize the proportion of one or more penetration enhancers to be incorporated into the solution. The present invention comprises up to 30% v / v of the solution (preferably in the range of 2% to 30% v / v of the solution, more preferably in the range of 10% to 30% v / v of the solution) of one or more penetration enhancers. In one embodiment, the present invention comprises less than 25% v / v (preferably in the range of 2% to 25% v / v of the solution) of one or more penetration enhancers.

[0045] The non-aqueous solvent system of the present invention is selected from glycerol, propylene glycol, polyethylene glycol, propylene carbonate, glycogen, isopropyl myristate, isopropyl palmitate, dimethyl sulfoxide, triethyl citrate, dimethylacetamide, benzyl alcohol, N-methyl-pyrrolidone, dimethyl isosorbide, ethyl acetate or a combination thereof. Preferably, the present invention comprises a non-aqueous solvent system in a proportion of at least 40% v / v, preferably at least 50% v / v, more preferably at least 55% v / v of the formulation. In one embodiment, the non-aqueous solvent system of the present invention is 40% v / v to 99.5% v / v of the solution.

[0046] The present invention provides a solution having a pH in the range of 5 to 9, preferably in the range of 6 to 9, more preferably in the range of 7 to 9. In order to adjust the pH of the solution within the desired range, a pH adjusting agent known in the art is also included. The agent can be selected from pH adjusting compounds known in the art. The pH adjusting agent is preferably selected from meglumine, sodium bicarbonate, sodium carbonate, sodium hydroxide, triethanolamine, tromethamine, diethanolamine, monoethanolamine, sodium borate, sodium citrate dihydrate, calcium hydroxide, potassium bicarbonate, potassium citrate, potassium carbonate, tromethamine or a combination thereof. The pH adjusting agent of the present invention is used in an amount sufficient to adjust the pH of the formulation within the range of 5 to 9, preferably within the range of 6 to 9, more preferably within the range of 7 to 9.

[0047] The present invention may further comprise various auxiliary ingredients, such as sweeteners, flavoring agents, taste masking agents, etc. known in the art. The flavoring agents of the present invention are selected from menthol, peppermint oil, maltol, ethyl maltol, ethyl vanillin, vanillin, green mint, strawberry, cherry, raspberry, wintergreen, watermelon, grape flavoring agents, etc. The sweeteners of the present invention are selected from neotame, sucrose, alitame, acesulfame potassium, aspartame, trehalose, xylitol, sucralose, sorbitol, saccharin sodium, neohesperidin dihydrochalcone, mannitol, maltitol, lactitol, fructose, etc.

[0048] In another embodiment, the formulation may further comprise a polymer such as polyvinylpyrrolidone, poly(vinylpyrrolidone-co-vinyl acetate), polyvinylpolypyrrolidone, polymethacrylate, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl beta-cyclodextrin, polyvinyl alcohol, polyacrylic acid, or a combination thereof. The polymer is incorporated in a range of up to 5% w / v of the solution. When used, the polymer is preferably incorporated in a range of 0 to 2% w / v of the solution or more preferably in a range of 1% to 2% w / v of the solution.

[0049] The present invention provides a stable non-aqueous solution of Zolpidem or a pharmaceutically acceptable salt thereof, which achieves rapid transmucosal absorption of the drug across the mucosa, thereby providing a rapid onset of action.

[0050] Furthermore, the present invention avoids the use of organic propellants and high proportions of one or more penetration enhancers that may result in deleterious side effects or oral discomfort to the patient.

[0051] The present invention provides stable non-aqueous solutions suitable for administration via oromucosal routes including buccal or sublingual routes.

[0052] Non-limiting examples of formulations of the present invention are provided below:

[0053] Preparation 1:

[0054]

[0055] Preparation 2:

[0056] Element Percentage (%) Zolpidem tartrate 2.5%w / v Meglumine 1.4%w / v Ethanol 10%v / v Neotame 0.01%w / w glycerin 25%v / v Neohesperidin 0.001%w / w Propylene glycol Appropriate amount to 100% pH 8.1

[0057] Comparative Formulation 3: (Zolpimist)

[0058]

[0059] The pH of the preparation prepared once according to the recipe is 3.5

[0060] Preparation 4:

[0061] Element Percentage (%) Zolpidem tartrate 1% w / v Meglumine 1.4%w / v Ethanol 5% v / v PVP K30 2%w / v Neotame 0.01%w / w Propylene glycol Appropriate amount to 100% pH 7.5

[0062] Preparation 5:

[0063]

[0064]

[0065] Preparation 6:

[0066] Element Percentage (%) Zolpidem tartrate 2.5%w / v Meglumine 1.4%w / v Ethanol 20%v / v PVP K30 2%w / v Neotame 0.01%w / w Propylene glycol Appropriate amount to 100% pH 7.5

[0067] Preparation 7:

[0068] Element Percentage (%) Zolpidem tartrate 2.5%w / v Meglumine 1.4%w / v Ethanol 30%v / v PVP K30 2%w / v Neotame 0.01%w / w Propylene glycol Appropriate amount to 100% pH 7.3

[0069] Preparation 8:

[0070]

[0071]

[0072] Preparation 9:

[0073] Element Percentage (%) Zolpidem tartrate 2.5%w / v Meglumine 1.4%w / v Ethanol 8%v / v Lecithin 2%w / v PVP K30 2%w / v glycerin 25%v / v Neotame 0.01%w / w Propylene glycol Appropriate amount to 100% pH 7.8

[0074] Preparation 10:

[0075] Element Percentage (%) Zolpidem tartrate 2.5%w / v Meglumine 1%w / v PVP K30 2%w / v Ethanol 10%v / v glycerin 25%v / v Neotame 0.01%w / w Propylene glycol Appropriate amount to 100% pH 6.2

[0076] Preparation 11:

[0077]

[0078]

[0079] Preparation 12:

[0080] Element Percentage (%) Zolpidem tartrate 2.5%w / v Meglumine 1.8%w / v PVP K30 2%w / v Ethanol 10%v / v glycerin 25%v / v Neotame 0.01%w / w Propylene glycol Appropriate amount to 100% pH 8.6

[0081] Preparation 13:

[0082] Element Percentage (%) Zolpidem tartrate 2.5%w / v Meglumine 1.4%w / v PVP K30 2%w / v Ethanol 10%v / v DMSO 50%v / v Neotame 0.01%w / w Propylene glycol Appropriate amount to 100% pH 9.0

[0083] Preparation 14:

[0084] Element Percentage (%) Zolpidem tartrate 2.5%w / v Meglumine 1.4%w / v PVP K30 2%w / v Ethanol 10%v / v PEG 400 34%v / v Neotame 0.01%w / w Propylene glycol Appropriate amount to 100% pH 8.2

[0085] Preparation 15:

[0086] Element Percentage (%) Zolpidem tartrate 2.5%w / v Meglumine 1.4%w / v PVP K30 2%w / v Ethanol 10%v / v Glycogen 38%v / v Neotame 0.01%w / w Propylene glycol Appropriate amount to 100% pH 7.8

[0087] Preparation 16:

[0088]

[0089]

[0090] Preparation 17:

[0091] Element Percentage (%) Zolpidem tartrate 2.5%w / v Meglumine 1.4%w / v PVP K30 2%w / v Ethanol 10%v / v Ethyl acetate 20%v / v Neotame 0.01%w / w Propylene glycol Appropriate amount to 100% pH 7.7

[0092] Preparation 18:

[0093] Element Percentage (%) Zolpidem tartrate 2.5%w / v Meglumine 1.4%w / v PVP K30 2%w / v Ethanol 10%v / v Dimethyl Isosorbide 24%v / v Neotame 0.01%w / w Propylene glycol Appropriate amount to 100% pH 7.5

[0094] Preparation 19:

[0095]

[0096]

[0097] Preparation 20:

[0098] Element Percentage (%) Zolpidem tartrate 2.5%w / v Meglumine 1.4%w / v PVP K30 2%w / v Ethanol 10%v / v Benzyl alcohol 40%v / v Neotame 0.01%w / w Propylene glycol Appropriate amount to 100% pH 7.6

[0099] Preparation 21:

[0100] Element Percentage (%) Zolpidem tartrate 4%w / v Meglumine 2.24% w / v PVP K30 2%w / v Ethanol 20%v / v glycerin 20%v / v Propylene glycol Appropriate amount to 100% pH 8.0

[0101] Preparation 22:

[0102]

[0103]

[0104] Preparation 23:

[0105]

[0106] Preparation 24:

[0107] Element Percentage (%) Zolpidem tartrate 2.5%w / v Ethanol 10%v / v glycerin 25%v / v Propylene glycol Appropriate amount to 100% pH 5.2

[0108] Auxiliary ingredients such as sweeteners, flavoring agents, and taste masking agents may be added to the preparation.

[0109] All solutions prepared according to the invention appeared as clear solutions and were found to be stable throughout the storage period.The stable non-aqueous solutions of the invention are suitable for administration by the oromucosal route (across the oral mucosa).

[0110] The solutions of the present invention are prepared using methods known in the art without being limited to any particular method or order of addition of ingredients.

[0111] Comparative Pharmacokinetic Studies:

[0112] The examples disclosed above are representative of the formulations encompassed in the present invention. The scope of the present invention is not limited to any one of these examples. The advantageous features provided by these representative formulations of the present invention are also provided by all formulations encompassed within the scope of the present invention.

[0113] A cross-comparison pharmacokinetic study of the formulations of the present invention (Formulations 1 and 2) was performed with a commercially available formulation (Comparison Formulation 3 - Zolpimist) to compare the pharmacokinetics of Zolpidem after buccal or sublingual administration following single-dose administration to male New Zealand white rabbits. A dose equivalent to a 10 mg human dose (0.52 mg / kg by wt) was administered to rabbits via buccal or sublingual routes. Sampling was performed at various time points during each study, such as before dosing, 5 min, 10 min, 20 min, 30 min, 45 min, 1 hr, 2 hr, and 3 hr after dosing. Plasma samples were analyzed for Zolpidem quantification using a validated LC-MS / MS method. The pharmacokinetics of Zolpidem were analyzed using a validated Phoenix The non-compartmental analysis tool of the software was used to perform pharmacokinetic analysis and obtain T max , C max and AUC 0-3hr Use Software, statistical analysis was performed by ANOVA method (p < 0.05).

[0114] Results: Among all the formulations tested, the T max The shortest is about 5 minutes. It was found that the T of formulations 1 and 2 max The difference between the two was not statistically significant. max It was found that the T of Formulations 1 and 2 and Comparative Formulation 3 max The differences between the tested formulations were statistically significant. max and AUC 0-3hr No significant differences were observed in the values ​​of .

[0115] Prior art formulations fail to provide higher concentrations of a drug in a stable non-aqueous liquid dosage form while using a minimal proportion of a penetration enhancer and still achieve enhanced transmucosal penetration of the drug.

[0116] In contrast, the present formulation provides a stable liquid dosage form of Zolpidem or a pharmaceutically acceptable salt thereof, wherein the drug not only remains in a fully dissolved state, but also remains stable throughout the storage period of the solution, and achieves rapid transmucosal penetration of the drug. The non-aqueous liquid solution of the present invention not only provides a stable solution with a desired drug concentration, but also unexpectedly leads to a significantly faster onset of action due to faster transmucosal penetration of the drug. Unexpectedly, the above advantages of the present invention are achieved by minimizing the amount of one or more penetration enhancers in the solution.

[0117] The present invention surprisingly found that a stable non-aqueous solution of Zolpidem comprising 0.5% to 10% w / v of Zolpidem or a pharmaceutically acceptable salt thereof, a penetration enhancer, and a non-aqueous solvent having a pH in the range of 5 to 9 can provide enhanced transmucosal penetration, thereby resulting in a rapid onset of action. Preferably, the pH of the solution of the present invention is in the range of 6 to 9, more preferably, the pH of the solution of the present invention is in the range of 7 to 9.

Claims

1. A stable non-aqueous oromucosal solution of zolpidem or a pharmaceutically acceptable salt thereof, the solution comprising: 0.5% to 10% w / v of Zolpidem or a pharmaceutically acceptable salt thereof; 2% v / v to 30% v / v of a penetration enhancer selected from the group consisting of a low linear alcohol having a carbon chain length of 1 to 5, sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, oleic acid, capric acid, lauric acid, lecithin, myristic acid, palmitic acid, lysophosphatidylcholine, phosphatidylcholine, azone, cyclodextrin, sodium lauryl sulfate, polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether, benzalkonium chloride, cetylpyridinium chloride, vitamin E TPGS, caprylocaproyl polyoxyglycerol, stearyl macrogol glyceride, propylene glycol dicaprylate caprate or a mixture thereof; 40% v / v to 99.5% v / v of a non-aqueous polar solvent, wherein the non-aqueous solvent system is selected from glycerol, propylene glycol, polyethylene glycol, propylene carbonate, glycogen, isopropyl myristate, isopropyl palmitate, dimethyl sulfoxide, triethyl citrate, dimethylacetamide, benzyl alcohol, N-methyl-pyrrolidone, dimethyl isosorbide, ethyl acetate or a mixture thereof; and pH adjuster meglumine; in, The oromucosal solution has a pH of 5 to 9.

2. The stable non-aqueous oromucosal solution of claim 1, wherein the solution comprises 2.5% to 10% w / v of Zolpidem or a pharmaceutically acceptable salt thereof.

3. The stable non-aqueous oromucosal solution of claim 1, wherein the pH of the oromucosal solution is in the range of 6 to 9.

4. The stable non-aqueous oromucosal solution of claim 1, wherein the low linear alcohol is ethanol, isopropanol or a mixture thereof.

5. The stable non-aqueous oromucosal solution of any one of claims 1 to 4, wherein the penetration enhancer is in the range of 10% to 30% v / v of the solution.

6. The stable non-aqueous oromucosal solution of any one of claims 1 to 4, wherein the solution further comprises up to 5% w / v of a polymer selected from the group consisting of polyvinylpyrrolidone, poly(vinylpyrrolidone-co-vinyl acetate), polyvinylpolypyrrolidone, polymethacrylates, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl β-cyclodextrin, polyvinyl alcohol, polyacrylic acid, or mixtures thereof.

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