OA20536A - Oromucosal solutions of zolpidem or pharmaceutically acceptable salts thereof. - Google Patents

Oromucosal solutions of zolpidem or pharmaceutically acceptable salts thereof. Download PDF

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Publication number
OA20536A
OA20536A OA1202100148 OA20536A OA 20536 A OA20536 A OA 20536A OA 1202100148 OA1202100148 OA 1202100148 OA 20536 A OA20536 A OA 20536A
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OAPI
Prior art keywords
aqueous
stable
formulation
zolpidem
range
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OA1202100148
Inventor
Ketan R. Patel
Asheel K. PATEL
Nisheel K. PATEL
Milan R. Patel
Kush M. PATEL
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Troikaa Pharmaceuticals Limited
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Publication of OA20536A publication Critical patent/OA20536A/en

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Abstract

The present invention relates to buccal or sublingual formulations of Zolpidem or pharmaceutically acceptable salt thereof. The formulations minimize the amount of penetration enhancers and yet provide rapid transmucosal penetration of the drug. These formulations not only provide desired a concentration (0.5 % to 10% w/v) of the drug in the form of clear solution, but also achieve stable formulations throughout the 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 range of 5 to 9, preferably 6 to 9 more preferably 7 to 9.

Description

OROMUCOSAL SOLUTIONS OF ZOLPIDEM OR PHARMACEUTICALLY ACCEPTABLE SALTSTHEREOF
FIELD OF THE INVENTION
The présent invention relates to a stable, non-aqueous solutions of Zolpidem or pharmaceutically acceptable salt(s) thereof. The solutions of the présent invention are suitable for administration via oromucosal route. More particularly, the présent invention relates to stable, non-aqueous solutions of Zolpidem or pharmaceutically acceptable salt(s) that provide rapid onset of action when administered into the oral cavity via buccal, sublingual or oromucosal route, wherein the pH of the formulation is in the range of 5 to 9.
BACKGROUND OF THE INVENTION
Sleep has an important rôle in the régulation of the central nervous System (CNS), and the body’s physiological fonctions including regulating metabolism, catabolism, température, leaming and memory consolidation. Insomnia is a sleep disorder characterized by one or more of the foliowing traits: difficulty falling asleep (e.g., sleep onset latency (SOL) of more than 30 minutes), insufficient sleep (e.g., total sleep time (TST) of less that 5.5-6 hours), numerous noctumal awakenings, early moming awakenings with the inability to résumé sleep, or non-restorative sleep.
Insomnia is more prévalent in women, older adults, shift workers and patients with medical and psychiatrie îllness. Difficulties of sleep initiation are more common in young adults while problems of maintaining sleep are more common in middle-aged and older adults. Because of its high incidence, and because its symptoms are usually mild and transient, the importance of insomnia is frequently underestimated. However, as a chronic disorder affecting about 10% of the population, its treatment is often challenging and assocîated with a substantial number of co-morbid symptoms (i.e., dépréssion, anxiety).
The treatment of insomnia has two primary objectives. These objectives include improving quality or quantity of sleep and improving daytime impainnents.
Initial approaches of treatment usually include at least one behavioral intervention, such as stimulus control therapy or relaxation therapy. The médication for the treatment of insomnia includes benzodiazépines (BZD), non-benzodiazepines, Melatonin-agonîst, Tricyclic antidepressant, barbiturates, etc.
Zolpidem and BDZs share the property of binding to a subunits (the BDZ receptor) of the GABAa receptor/chloride channel complex. However, there is a décisive différence in selectivity concerning the subtypes. For example, BDZs are relatively non-sélective in this regard causing antiexcitatory hyper-polarizations in many places in the CNS. These actions lead to more generalized neuronal inhibitions and numerous effects exceeding sédation and sîeep promotion, such as anxiolytic, anticonvulsant and relaxant actions.
Zolpidem Tartrate is chemically, N, N, 6-trimethyl-2-p-tolylimidazo [ 1,2-a] pyridine-3-acetamide L(+)-tartrate (2:1) and exhibits strong hypnotic and sédative actions with negligible anxiolytic, muscle relaxing, or anticonvulsant properties. Zolpidem Tartrate is widely prescribed for the shortterm treatment of insomnia. It is relatively well-tolérâted and almost devoîd of the side effects typically associated with BDZs.
Attempts hâve been made to provide Zolpidem or its sait in solid oral dosage forms such as tablets. Due to absence of water, these dosage forms are relatively more stable. A stable liquid formulation will not only be in the form of a clear solution but also will remain clear, without précipitation of the drug, on storage.
The drug is administered in solid form, and therefore it is possible to deliver higher amount of drug through these solid dosage forms. Accordingly Ambien® and Ambien® CR tablets (Sanofi Aventis, USA) provides 10 and 12.5 mg drug per tablet respectively.
The issue with solid dosage form is that it needs to get dîsintegrated and dissolved before the drug therein can be transported into tire System, and therefore the onset of action for these solid dosage forms will be much slower compared to the liquid dosage forms, wherein the drug is readily available in solution for pénétration across mucosa. Another drawback of these tablet formulations is daytîme drowsiness which affects the quality of life of the patient.
WO9916417 (WO’417) discloses buccal spray composition for transmucosal administration of a pharmacologically active compound selected from a group including sleep inducers. WO’417 discloses two-type 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 invention comprises formulation (II): non-polar solvent 20-85 %, active compound 0.005-50 % and optionally flavoring agent 0.1-10 % and propellant 50-80 %. The spécification does not disclose any spécifie formulation ofZolpidem or its salts. It is to be noted that the propellant-free formulations disclosed in WO’417 contain substantial quantity of water. The presence of water would substantially reduce the shelf-life of the formulations and hence it is désirable to préparé formulations without water.
WO2005079761 (WO’761) and WO200612S022 (WO’022) disclose oral solid compositions for the delivery of a hypnotic agent across oral mucosa. It is to be noted that WO’761 provides about 1.0 to about 5.5 weight percent zolpidem in a solid dosage form which, takes a long time to get absorbed. WO’761 and WO’022, faîl to achieve the drug concentration of 0.5% to 10% w/v in a solution formulation, wherein the drug is ready for absorption.
WO2006046041 (WO’041) discloses fast acting solid dose formulations ofZolpidem in the form of mucoadhesive tablets suitable for transmucosal administration. The invention in this PCT Publication which is in a solid dosage form remains in constant contact with the oral mucosa which causes considérable discomfort to the patient.
WO2005032519 (WO’519) discloses buccal aérosol sprays or capsules using a polar and non-polar solvent, which provide Zolpidem for rapid absorption through oral mucosa, resulting in fast onset of action. The buccal polar compositions of the invention comprise formulation aqueous polar solvent, zolpidem, and optional flavoring agent; formulation II: aqueous polar solvent, zolpidem, optionally 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 a polar solvent and a non-polar solvent, zolpidem, and optional flavoring agent; formulation VI: a mixture of a polar solvent and a non-polar solvent, zolpidem, optional flavoring agent, and propellant.
The “propellant-free” buccal spray of Zolpidem in WO’519 uses a polar and/or non-polar solvent to quickly deliver Zolpidem or a pharmaceutically acceptable sait thereof in an amount between 0.01 to 20% (w/w) of the total formulation.
Despite using a solvent System containing the polar solvents in very high proportion (of propylene glycol and éthanol 30 and 99 %) in formulation of in WO’519, it was not possible to solubilise the drug completely, thereby producing hazy solutions. Further very high proportion of alcohol, which also acts as a pénétration enhancer, leads to unpleasant sensation in the oral cavity. WO’519 does not disclose the pH of the formulations. When measured by the présent inventors, the pH was ~5.
The liquid formulation of Zolpidem (Zolpimist®) marketed by Novadel Pharma US (the applicant of WO’5I9), has a pH of 3 to 4 at which the drug remains solubîlized indicating that the invention is workable only in the pH range <5.
The invention disclosed in WO’519 teaches that 8% of citrate buffer is crucial for solubilisation of S the drug in propellant-free formulation containing 2.5 % w/w Zolpidem and a polar solvent comprising 15% Propylene glycol and -64% éthanol maintained at pH of <5. When the pH of these solutions is increased to 5 and above, a hazy solution is formed. Further, water in fairly high proportions is used as an essential ingrédient. WO’519 fails to provide liquid formulations that are stable on storage. The invention disclosed in WO’519 also teaches “propellant-free” formulations 10 prepared using oily components and lemon oil wherein the drug concentration achieved is only 0.5%. The pH of this formulation is also less than 5. It has been found that such formulations are not workable for drug concentrations of 2.5 % w/v.
WO2007123955 (WO’955) discloses stable hydro-alcoholic formulations of an active pharmaceutical agent suitable for oral spray administration. WO’955 uses water as an essential 15 component of the solvent System for the propellant-free buccal formulations. The pH for these formulations is maintained in the range of 7 to 12 to deliver a variety of active pharmaceutical ingrédients in aqueous formulations. However, it has been found that it is not possible to préparé a clear solution of Zolpidem Tartrate using the solvent System disclosed in WO’955 in the pH range of7 to 12.
WO2008141264 (WO’264) discloses oral sprays formulations for transmucosal absorption of
Zolpidem using a combination of polar and non-polar solvents. These formulations may optionally use propellants. The formulations covered in this reference are available in the market under the brand naine Zolpimist®.
Typically, WO’264 discloses oral spray formulations comprising 0.05-10% Zolpidem or a 25 pharmaceuticaliy acceptable sait thereof; a polar or non-polar solvent or mixture thereof. These formulations may further comprise 0-1% taste mask and/or flavoring agents; and 0-1% preservative; and a propellant. Ail the exemplified formulations of Zolpidem contain water. Ail the exemplified formulations disclosed in WO’264 hâve a pH of 3-4. The présent inventors hâve found that when the pH of these formulations are increased to about 5, the drug précipitâtes as curdy white mass 30 demonstrating that these formulations are not suitable for oromucosal administration. Further the présent înventors hâve found that the transmucosal pénétrations of the formulations disclosed in WO’264 has Tmax of 20 minutes.
The prior art disclosing inventions to improve transmucosal pénétration of Zolpidem b y providing a liquid dosage form with or without propellants has the foliowing limitations:
• They fail to provide a desired drug concentration (0.5 % to 10 % w/v) m the form of a clear solution with the desired shelflife of at least about 2 years. Hence, most formulations available in the market are in solid dosage foims.
• They need water as an essential ingrédient which results in lower stability of the drug, wherein the drug précipitâtes from the solution on storage.
• They use very high proportion of pénétration enhancers such as alcohol, in these formulations that lead to a possibility of sîde effects such as unpleasant sensation in the oral cavity.
• They fail to achieve faster onset of action (Tmax of less than 20 minutes) by providing rapid transmucosal pénétration of the drug over a pH range of 5 to 9. Hence the liquid formulations available in the market are maintained at pH less than 5.
To address the long-felt need of providing stable non-aqueous liquid formulations for effective transmucosal administration of Zolpidem or its pharmaceutically acceptable salts, the foliowing technical issues with regard to such liquid dosage forms need to concurrently address:
1. Provide a concentration of 0.5 % to 10% w/v of the drug in clear non-aqueous solutions;
2. Provide formulations that are stable for the entire shelf-life of at least two years over a broad pH range of 5 to 9; and
3. Minimize the amount of pénétration enhancer(s) used in the formulation upto 30% v/v without compromising on the transmucosal pénétration of the drug.
4. Provide rapid transmucosal pénétration of the drug over a pH range of 5 to 9 thereby leading to faster onset of action.
OBJECTS OF THE INVENTION:
The main object of the présent invention is to provide stable, non-aqueous solutions ofZolpidem or pharmaceutically acceptable salts thereof wherein the formulations provide rapid transmucosal pénétration of the drug.
It is yet another object of the présent invention to provide stable, non-aqueous solutions ofZolpidem or pharmaceutically acceptable salts thereof wherein the formulations provide 0.5 to 10% w/v, preferably 2.5% to 10% w/v, ofZolpidem or pharmaceutically acceptable salts thereof wherein 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.
Another object of the présent invention is to provide stable, non-aqueous formulations of Zolpidem or pharmaceutically acceptable salts thereof suitable for administration by buccal or sublingual or oromucosal route, wherein the formulations provide rapid onset of action due to rapid transmucosal pénétration.
Another object of the présent invention is to provide stable non-aqueous formulations of Zolpidem or pharmaceutically acceptable salts thereof, wherein rapid transmucosal pénétration of the drug is achîeved, by minîmizing the amount of pénétration enhancer(s) used in the formulation.
The présent invention addresses the abovementioned and other needs by providing stable nonaqueous formulation of Zolpidem or its pharmaceutically acceptable sait by synergistic combination of components such as a judiciously selected solvent System, pénétration enhancer(s) and other ingrédients in a pH range of 5 to 9, preferably in the range of 6 to 9, more preferably in the range of 7 to 9. The formulations of the présent invention surprisingly results in rapid transmucosal pénétration as compared to the formulations known in the art.
DETAILED DESCRIPTION OF THE INVENTION:
The présent invention provides stable, non-aqueous solutions of Zolpidem or pharmaceutically acceptable salts thereof with rapid oromucosal absorption of the drug,
The challenge for the présent inventors was to solubilise the desîred concentration ofZolpidem or its pharmaceutically acceptable salts in non-aqueous liquid formulation and at the same time keeping it stable for the entire shelf life of the formulation.
The synergistic combination of the components of the présent invention not only achieves stable non-aqueous liquid solutions of Zolpidem or its pharmaceutically acceptable salts, but it also maintains the drug in a solubilîzed State over a pH range of 5 to 9 for the entire shelf-life of at least 2 years.
Surprisingly, the solutions of the présent invention achieve rapid transmucosal pénétration of the drug as compared to the formulations disclosed in the prior-art. This leads to a faster onset of action when administered through sublingual route in animais. The présent invention provides a solution with Tmax < 20 minutes. Most surprisingly, the présent invention achieves the above mentioned advantages with minimized use of pénétration enhancers in the solutions.
The solutions of the présent invention comprises Zolpidem or pharmaceutically acceptable salts thereof, pénétration enhancer(s), a non-aqueous solvent system, optionally pH adjusting agents and optionally a Polymer, wherein the pH of the solution is în the range of 5 to 9, preferably in the range of 6 to 9, more preferably in the range of 7 to 9.
The présent invention provides a stable, non-aqueous solution of Zolpidem or its pharmaceutically acceptable salts wherein the concentration of Zolpidem or its pharmaceutically acceptable salts is in the range of 0.5 to 10% w/v of the solutions, preferably in the range of 2.5% to 10% w/v of the solutions.
The pénétration enhancer(s) are selected from lower chain alcohol(s) with a carbon chain length of 1 to 5, preferably éthanol, isopropyl alcohol or mixtures thereof. The pénétration enhancer(s) of the présent formulation may also be selected from the lower chain alcohol(s), 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 sulphate, Polyoxyethylene-9-laurylether, Polyoxythylene-20-cetylether, Benzalkonium chloride, cetylpyridinium chloride, Vitamin E TPGS, Caprylocaproyl polyoxylglycerides, Stearoyl Macro golglyceri des, Propylene Glycol Dicaprylocaprate, Propylene Glycol Monocaprylate, Propylene Glycol monoiaurate, N-Methyl-2pyrrolidone or mixtures thereof.
In an embodiment, the solution comprises éthanol as pénétration enhancer(s). The présent invention attempts to minimize the proportion of pénétration enhancer(s) to be încorporated in the solutions. The présent invention comprises pénétration enhancer(s) up to 30% v/v of the solutions, preferably in the range of 2 to 30% v/v of the solutions, more preferably in the range of 10 to 30% v/v of the 7 solutions. In one of the embodiments, the présent invention comprises less than 25% v/v of pénétration enhancer(s), preferably in the range of 2 to 25% v/v of the solutions.
The non-aqueous solvent system of the présent invention is selected from glycerol, propylene glycol, polyethylene glycol, propylene carbonate, glycofurol, isopropyl myristate, isopropyl palmîtate, dimethyl sulfoxide, triethyl citrate, dimethylacetamide, benzyl alcohol, N-methylpyrrolidone, dimethyl isosorbide, ethyl acetate or combination thereof Preferably, the présent invention comprises the 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 of the embodiments the non-aqueous solvent System of the présent invention is from 40% v/v to 99.5 % v/v of the solutions.
The présent invention provides solutions in the pH 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 solutions in the desired range, a pH adjusting agent known in the art may be included. The said agent may be selected from the pH adjustîng compounds known in the art. The pH adjusting agent are preferably selected from meglumine, sodium bicarbonate, sodium carbonate, sodium hydroxîde, triethanolamine, tromethamine, diethano lamine, monoethanoïamine, sodium borate, sodium citrate dihydrate, calcium hydroxîde, potassium bicarbonate, potassium citrate, potassium carbonate, tromethamine or combination thereof. The pH adjusting agent of the présent invention are used in a quantity suffi ci ent to adjust the pH of the formulation in the range of 5 to 9, preferably in the range of 6 to 9, more preferably in the range of 7 to 9.
The présent invention may further comprise varions auxiliary ingrédients such as sweeteners, flavoring agents, taste masking agents etc known in the art. The flavoring agents of the présent invention are selected from menthol, peppermint oil, mal toi, ethyl maltol, ethyl vanillin, vanillin, spearmint, strawberry, cherry, raspberry, wintergreen, watermelon, grape flavors and theîr like. The sweeteners of the présent invention are selected from neotame, sucrose, alitame, acesulfame potassium, aspartame, trehalose, xylitol, sucralose, sorbitol, saccharin sodium, neobesperidin dihydrochalcone, mannitol, maltitol, lactitol, fructose and theîr like.
In another embodiment, the formulation may further comprises a polymer such as polyvinylpyrrolidone, poly(vinyl pyrrolidone-co-vinyl acetate), polyvinylpolypyrrolidone, polymethacrylates, hydroxypropylmethyl cellulose, hydroxypropylmethylcellulose acetate succinate, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl betadex, polyvinyl alcohol, polyacrylic acid or combination thereof. The Polymer is incorporated in the range of up to
5% w/v of the solution, The Polymer, when used, is preferably incorporated in the range of 0 to 2% w/v of the solution or more preferably in the range of 1 to 2% w/v of the solution.
The présent invention provides stable, non-aqueous solution of Zolpidem or pharmaceuticaliy acceptable sait thereof that achieves rapid transmucosal absorption of the drug across the mucosa 5 leading to fast onset of action.
Further, the présent invention avoids the use of organic propellants and high proportion of pénétration enhancer(s) which may lead to harmful side effects or dîscomfort in the mouth of the patient.
The présent invention provides stable non-aqueous solutions suitable for administration through 10 oromucosal route including buccal or sublingual route.
Non-limiting examples of the formulations of the présent invention are provided below:
Formulation 1 :
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 2.5% w/v
Meglumine 1.4 % w/v
Ethanol 10% v/v
PVP K30 2 % w/v
Neotame 0.01% w/w
Glycerol 25 % v/v
Neohespiridine 0.001% w/w
Propylene glyco! q.s to 100%
pH 8
Formulation 2:
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 2.5% w/v
Meglumine 1.4 % w/v
Ethanol 10%v/v
Neotame 0.01% w/w
Glycerol 25 % v/v
Neohespirîdine 0.001% w/w
Propylene glycol q.s to 100%
pH 8.1
Comparative Formulation 3 : (Zolpimist)
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 2.5% w/v
Propylene glycol 18.73% w/w
Benzoic acid 0.0265 % w/v
Citric acid monohydrate 5.12% w/v
(Citric acid Anhydrous ) (4.655% w/v)
Neotame 0.0005 % w/v
Hydrochloric acid Qs to adjust the pH 3 to 4
Flavoured fruit DC 0.135 % w/v
Purifîed water q.s to 100 %
The pH of the formulation once prepared as per the formula was 3.5
Formulation 4:
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 1 % w/v
Meglumine 1.4 % w/v
Ethanol 5% v/v
P VP K30 2 % w/v
Neotame 0.01% w/w
Propylene glycol q.sto 100%
pH 7.5
Formulation 5:
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 5 %
Meglumine 2.8 % w/v
Ethanol 20%v/v
Neotame 0.01% w/w
Propylene glycol q.s to 100%
PH 7.9
Formulation 6:
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 2.5 % w/v
Meglumine 1.4% w/v
Ethanol 20%v/v
P VP K30 2 % w/v
Neotame 0.01% w/w
Propylene glycol q.s to 100%
pH 7.5
Formulation 7:
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 2.5 % w/v
Meglumine 1.4% w/v
Ethanol 30%v/v
P VP K30 2 % w/v
Neotame 0.01% w/w
Propylene glycol q.s to 100%
pH 7.3
Formulation 8:
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 2.5 % w/v
Meglumine 1.4 % w/v
Ethanol 8% v/v
Cyclodextrin 2 % w/v
PVP K30 2 % w/v
Glycerol 25% v/v
Neotame 0.01% w/w
Propylene glycol q.s to 100%
pH 7.6
Formulation 9:
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 2.5 % w/v
Meglumine 1.4 % w/v
Ethanol 8% v/v
Lecithîn 2 % w/v
PVP K30 2 % w/v
Glycerol 25% v/v
Neotame 0.01% w/w
Propylene glycol q.s to 100%
pH 7.S
Formulation 10:
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 2.5 % w/v
Meglumine 1 % w/v
PVP K30 2 % w/v
Ethanol 10% v/v
Glycerol 25% v/v
Neotame 0.01% w/w
Propylene glycol q.s to 100%
pH 6.2
Formulation 11:
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 2.5 % w/v
Meglumine 1.24 % w/v
PVP K30 2 % w/v
Ethanol 10% v/v
Glycerol 25% v/v
Neotame 0.01% w/w
Propylene glycol q.s to 100%
pH 6.9
Formulation 12:
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 2.5 % w/v
Meglumine 1.8 % w/v
P VP K30 2 % w/v
Ethanol 10% v/v
Glycerol 25% v/v
Neotame 0.01% w/w
Propylene glycol q.s to 100%
pH 8.6
Formulation 13:
Ingrédients Quantity in 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 q.s to 100%
pH 9.0
Formulation 14:
Ingrédients Quantity in 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 q.s to 100%
pH 8,2
Formulation 15:
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 2.5 % w/v
Meglumine 1.4% w/v
PVP K30 2 % w/v
Ethanol 10% v/v
Glycofurol 38% v/v
Neotame 0.01% w/w
Propylene glycol q.s to 100%
pH 7.8
Formulation 16:
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 2.5 % w/v
Meglumine 1.4% w/v
PVP K30 2 % w/v
Ethanol 10% v/v
N-Methyl Pyrrolidone 34 %v/v
Neotame 0.01 % w/w
Propylene glycol q.s to 100%
pH 7.9
Formulation 17:
Ingrédients Quantity in 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 q.s to 100%
pH 7.7
Formulation 18:
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 2.5 % w/v
Meglumine 1.4 % w/v
PVP K30 2 % w/v
Ethanol 10% v/v
DiMethylsosorbide 24% v/v
Neotame 0.01% w/w
Propylene glycol q.s to 100%
pH 7.5
Formulation 19:
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 2.5 % w/v
Megiumine 1.4 % w/v
P VP K30 2 % w/v
Ethanol 10% v/v
Dimethyl Acetamide 30% v/v
Neotame 0.01% w/w
Propylene glycol q.s to 100%
pH 7.9
Formulation 20:
ingrédients Quantity in Percentage (%)
Zolpidem tartrate 2.5 % w/v
Megiumine 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 q.s to 100%
pH 7.6
Formulation 21 :
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 4 % w/v
Meglumine 2.24% w/v
PVP K30 2 % w/v
Ethanol 20 % v/v
Glycerol 20 % v/v
Propylene glycol q.s to 100 %
pH 8.0
Formulation 22:
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 1.25 % w/v
Ethanol 20 % v/v
Glycerol 40 % v/v
Propylene glycol q.s to 100 %
pH 5.6
Formulation 23:
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 1.25 % w/v
Sodium lauryl Sulfate (SLS) 2 % w/v
Glycerol 20% v/v
Propylene glycol q.s to 100 %
pH 5.3
Formulation 24:
Ingrédients Quantity in Percentage (%)
Zolpidem tartrate 2.5 % w/v
Ethanol 10% v/v
Glycerol 25 % v/v
Propylene glycol q.s to 100 %
pH 5.2
Auxiliary ingrédients such as sweetener, flavoring agent, taste masking agents etc may be added in the formulation.
Ail the solutions prepared in accordance with the présent invention were in the form of clear solutions and were found to be stable throughout theîr shelf-life. The stable non-aqueous solutions of the présent invention are suitable for administration by oromucosal route (across oral mucosa).
Without limiting to any particular procès s or sequence of addition of ingrédients, the solutions of the présent invention are prepared using the processes known in the art.
Comparative pharmacokinetic study:
The examples disclosed above are représentative of the formulations covered in the présent invention. The scope of the présent invention is not limited to any of these examples. The advantageous features provided by these représentative formulations of the présent invention are also provided b y ail the formulations covered in the scope of the présent invention.
A cross-over comparative pharmacokinetic study of the formulations of the présent invention (Formulations 1 & 2) with those of the formulations available in the market (Comparative Formulation 3 - Zolpimist) was carried out following single dose administration in male New Zealand white rabbits to compare the pharmacokinetics of Zolpidem following buccal or sublingual administration. A dose équivalent to 10 mg of human dose (0.52 mg/kg by wt) was administered to rabbits by buccal or sublingual route. Sampling was carried out at different time points such as predose, 5 min, 10 min, 20 min, 30 min, 45 min, 1 hr, 2 hr & 3 hr post dosing in each study period. The plasma samples were analyzed for quantification of Zolpidem using a validated LC-MS/MS method. Pharmacokinetic analysis was carried out using the non-compartmental analysis tool of the validated 19
Phoenix WinNonlin® software and the values of Tmax , Cmax and AUC0-3 u, were obtained. The statistical analysis was carried out by ANOVA method at p <0.05 using SAS® software.
Results: Among ail the formulations tested, Formulation 1 provided the shortest Tmax of about 5 minutes. The différence between the Tmax of Formulations 1 and 2 was found to be statistically insignificant. The comparative Formulation 3 resulted in the T max of 20 minutes. The différence between the Tmax of the Formulation 1 and 2 with comparative Formulation 3 was found to be statistically significant. No significant différence was observed in the values of Cmx and AUC0-3 hr between the formulations tested.
Pri or-art formulations fail to provide a higher concentration of drug in stable, non-aqueous liquid dosage fonn and at the same tîme use minimised proportion of pénétration enlrancer and yet achieve enhanced transmucosal pénétration of the drug.
In contrast, the présent formulation provides stable, liquid, dosage form of Zolpidem or its pharmaceutically acceptable salts wherein the drug not only remains in completely solubilized State, but also remains stable throughout the shelf life of the solutions and achieves rapid transmucosal pénétration of the drug. The non-aqueous liquid solutions of the présent invention not only provide a stable solutions with désirable drug concentration but surprisingly resuit in significantly rapid onset of action due to quîcker transmucosal pénétration of the drug. Surprisingly, the présent invention provides the above advantage by minimizing the amount of pénétration enhancer(s) in the solutions.
The présent invention has surprisingly found that stable, non-aqueous solutions of Zolpidem comprising 0.5 to 10 % w/v of Zolpidem or Pharmaceutically acceptable salts thereof, a pénétration enhancer and a non-aqueous solvent in the pH range of 5 to 9 provides enhanced transmucosal pénétration leading to fast onset of action. Preferably the pH ofthe solutions ofthe présent invention is in the range of 6 to 9, more preferably the pH of the solutions of the présent invention is in the range of 7 to 9.

Claims (9)

1. A stable, non-aqueous oromucosal solution of Zolpidem or its pharmaceutically acceptable salts comprising: 0.5 to 10 % w/v of Zolpidem or pharmaceutically 5 acceptable salts thereof. a pénétration enhancer, and a non-aqueous solvent System, wherein the pH of the formulation is 5 to 9.
2. The stable, non-aqueous oromucosal solution as claimed in claim 1, wherein the solution comprises 2.5% to 10 % w/v ofZolpidem or pharmaceutically acceptable salts thereof.
10
3. The stable, non-aqueous oromucosal solution as claimed in claims 1-2, wherein the pH of the formulation is in the range of 6 to 9, preferably in the range of 7 to 9,
4. The stable, non-aqueous oromucosal solution as claimed in claims 1-3, wherein the pénétration enhancer is selected from a group comprising lower chain alcohol
15 with a carbon chain iength of 1 to 5, sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, oleic acid, capric acid, lauric acid, lecithin, myristîc acid, palmitic acid, lysophosphatidylcholine, phosphatidylcholine, azone, cyclodextrin, sodium lauryl sulphate, Polyoxyethylene-9-lauryl ether, Polyoxythylene-20-cetylether,
20 Benzalkonîum chloride, cetylpyridinîum chloride, Vitamin E TPGS, Caprylocaproyl polyoxylglycerides, Stearoyl Macrogolglycerides, Propylene Glycol Dicaprylocaprate or mixtures thereof.
5. The stable, non-aqueous oromucosal solution as claimed in claim 4, wherein the lower chain alcohol is éthanol, isopropyl alcohol or mixtures thereof.
25
6. The stable, non-aqueous oromucosal solution as claimed in claims 1-5, wherein the pénétration enhancer is upto 30% v/v of the formulation.
2.1
7. The stable, non-aqueous oromucosal solution as claimed in daims 1-6, wherein the pénétration enhancer is in the range of 2 to 30% v/v of the formuiation, preferably in the range of 10 to 30% v/v ol the formulation.
8. The stable, non-aqueous oromucosal solution as claimed m daims 1-7, wherein 5 the pénétration enhancer is in the range of 2 to 25% v/v ol the formulation.
9 The stable, non-aqueous oromucosal solution as claimed in daims 1-8, wherein the non-aqueous suivent System is selected from glycerol, propylene glycol, polyethylene glycol, propylene carbonate, glycofurol, isopropyl mynstate, isopropyl palmitate, dimethyl sulfoxide, triethyl Citrate, dimethyl acetamide, 10 benzyl alcohol, N-methyl-pyrrolidone, dimethyl isosorbide, ethyl acetate or mixture thereof.
10. The stable, non-aqueous oromucosal solution as claimed m daims 1-9, wherein tire solution further comprises upto 5% w/v of a polymer selected from poly vinypyrolidone, poly(vinyl pyrrolidone-co-vmyl acetate),
15 polyvinylpolypyrrolidone, polymethacrylates, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, hydroxyetbyl cellulose, hydroxypropyl cellulose, hydroxypropyl betadex, polyvinyl alcohol, polyacrylic acid or mixtures thereof.
OA1202100148 2018-10-08 2019-10-07 Oromucosal solutions of zolpidem or pharmaceutically acceptable salts thereof. OA20536A (en)

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