Patent Application
20070286902
The present invention is directed to a controlled release pharmaceutical dosage form comprising a sedative hypnotic, preferably zolpidem tartrate. The formulation may include a first portion of the active agent, in order to induce sleep without the necessity to have an extended “lag time” for drug absorption. The formulation may also include a second portion of the active agent in a controlled release component, in order to maintain sleep throughout the night without the need to administer a second dose.
Preferably, the dosage form releases not less than about 70% or not less than about 75% of the short-acting sedative-hypnotic within 30 minutes, utilizing USP Apparatus II paddle method at 50 rpm in 0.01N HCL solution; and from about 70% to about 90% of the hypnotic at 0.5 hour; from about 80% to about 100% at 2 hours and greater than 90% at 4 hours, when subjected to in-vitro dissolution utilizing USP Apparatus I paddle method at 50 rpm, in a pH 6.8 buffer solution.
The controlled release dosage forms of the present invention preferably provide effective blood levels of a short acting sedative-hypnotic or pharmaceutically acceptable salt thereof for a suitable time, e.g., about 8 hours, to maintain sleep in the treatment of insomnia.
“Pharmaceutically acceptable salts” of a sedative-hypnotic, as used herein, is meant to encompass all pharmaceutically acceptable salts, including, but not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, fumarate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts such as arginate, asparginate, glutamate and the like. The preferred salt form for use in accordance with the present invention is the tartrate salt.
Suitable short acting sedative-hypnotics useful in the present invention include compounds (including their salt forms) such as pyrazolopyrimidines (e.g., zaleplon); cyclopyrrolones, (e.g., zopiclone and its enantiomers); benzodiazepines (e.g., triazolam, temazepam and brotizolam); phenothiazines (e.g.; alimemazine); and imidazopyridines (e.g., zolpidem). The preferred short acting sedative-hypnotic for use in the present invention is zolpidem tartrate.
When the formulation of the present invention include zolpidem or a pharmaceutically acceptable salt thereof, the active agent can be included in an amount, e.g., from about 1 mg to about 25 mg, or from about 5 to 20 mg.
In certain embodiments, the dosage form of the present invention comprises a first portion of a short acting sedative-hypnotic in an immediate release component; and a second portion of the sedative-hypnotic in a controlled release component, the controlled release component comprising (i) a unitary core comprising the second portion of sedative-hypnotic dispersed in a controlled release matrix and (ii) a delayed release coating surrounding the unitary core.
The immediate release portion allows for the short acting sedative-hypnotic to be immediately released, thus inducing a quick onset of sleep. Further release of the sedative-hypnotic is delayed by virtue of the delayed release coating layer. Once the delayed release coating is dissolved, the remainder of the dosage form is released at a controlled rate by virtue of the controlled release matrix. The controlled release of the sedative-hypnotic preferably provides a hypnotic effect throughout the night without the need to awaken to administer an additional dose.
A non-limiting list of suitable controlled-release materials which may be included in the matrix core according to the invention include hydrophilic and/or hydrophobic materials such as polymers, protein derived materials, waxes, shellac, gums, hydrogels, and oils such as hydrogenated castor oil and hydrogenated vegetable oil. Suitable polymers include alkylcelluloses (such as ethylcellulose), acrylic and methacrylic acid polymers and copolymers (such as Eudragit® commercially available by Rohm Pharma), alkylvinyl polymers, cellulose ethers, (such as hydroxyalkylcelluloses e.g., hydroxypropylmethylcellulose) and carboxyalkylcelluloses. Examples of acrylic and methacrylic acid polymers and copolymers include methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, ethyl acrylate, trimethyl ammonioethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. Waxes include, for example, natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures of the same (e.g., beeswax, carnauba wax, stearic acid and stearyl alcohol). Certain embodiments of the present invention utilize mixtures of any of the foregoing controlled release materials in the matrix core. However, any pharmaceutically acceptable hydrophobic or hydrophilic controlled-release material which is capable of imparting controlled-release of the active agent may be used in accordance with the present invention.
Cellulosic polymers which may be used in the core of the present invention include hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, and mixtures thereof. A preferred controlled release carrier is hydroxypropylmethylcellulose (“HPMC”). HPMC polymers are available from Dow Chemical under the trade name METHOCEL®.
In certain embodiments, the controlled release material further comprises effective amounts of different grades of hydroxypropylmethylcellulose (HPMC), commercially available as Methocel K4M® and Methocel E5® by The Dow Chemical Company (Midland, Mich.).
Another example of a class of polymers that may be used in the present invention is carbomers. Carbomers are synthetic high-molecular-weight polymers of acrylic acid that are cross-linked with either allylsucrose or allyl ethers of pentaerythritol. Carbomers are typically used as dry or wet binders and as a rate controlling excipient. Certain carbomers for use in certain embodiments of the present invention include for example, Carbopol® 941, 971 PNF, 981 and 71G manufactured by Noveon, Inc.
In addition to the above ingredients, in certain embodiments the controlled release matrix core of the present invention may further include a wide variety of additives and excipients that enhance drug solubility or, that promote stability, tableting or processing. Such additives and excipients include tableting aids, lubricants, surfactants, fillers or diluents, water-soluble polymers, pH modifiers, binders, pigments, disintegrants, glidants, plasticizer, solvents, flow conditioning agents, suspending agents, viscosity-increasing agents, anti-caking agents, antioxidants, lubricants and flavorants. Examples of such components are metallic salts of acids such as aluminum stearate, calcium stearate, magnesium stearate, sodium stearate, and zinc stearate; fumed or colloidal silica which is commercially available as Cab-O-Sil M5®, by Cabot Corporation; povidone, fatty acids, hydrocarbons and fatty alcohols such as stearic acid, palmitic acid, liquid paraffin, stearyl alcohol, and palmitol; fatty acid esters such as glyceryl (mono- and di-) stearates, triglycerides, glyceryl (palmiticstearic) ester, sorbitan monostearate, saccharose monostearate, saccharose monopalmitate, and sodium stearyl fumarate; alkyl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; polymers such as polyethylene glycols, polyoxethylene glycols, and polytetrafluoroethylene; and inorganic materials such as talc and dicalcium phosphate; sugars such as lactose, xylitol, sucrose, dextrose, fructose, sorbitol, mannitol, starches, other polyols, mixtures thereof and the like; and sodium starch glycolate. The quantities of these additional materials will be sufficient to provide the desired effect to the desired formulation. Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986), incorporated by reference herein.
Examples of lubricants include stearic acid, magnesium stearate, carnauba wax, glyceryl behenate, talc, mineral oil (in polyethylene glycol), mixtures thereof, and the like. Magnesium stearate and carnauba wax are preferred lubricants.
Examples of binders include water-soluble polymers, such as modified starch, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, povidone, sodium carboxymethylcellulose, alginic acid, polyethylene glycol, polypropylene glycol, guar gum, polysaccharides, bentonite clay, sugar, poloxamer, collagen, albumin, gelatin, mixtures thereof, and the like.
Examples of fillers or diluents for use in the present invention include lactose, microcrystalline cellulose, dextrin, dextrose, starch, mixtures thereof and the like.
Examples of glidants for use in the present invention include calcium phosphate tribasic, calcium silicate, powdered cellulose, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, talc, mixtures thereof and the like.
Direct compression vehicles may be used in the present invention and include, for example, processed forms of cellulose, sugars, and dicalcium phosphate dihydrate, among others. Microcrystalline cellulose is an example of a processed cellulose that is suitable as a direct compression vehicle for solid dosage forms.
Silicified microcrystalline cellulose is a particularly useful direct compression vehicle. Silicified microcrystalline cellulose is a particulate agglomerate of coprocessed microcrystalline cellulose and from about 0.1% to about 20% silicon dioxide, by weight of the microcrystalline cellulose, the microcrystalline cellulose and silicon dioxide being in intimate association with each other, and the silicon dioxide portion of the agglomerate being derived from a silicon dioxide having a particle size from about 1 nanometer (nm) to about 100 microns (μm), based on average primary particle size. Preferably, the silicon dioxide comprises from about 0.5% to about 10% of the silicified microcrystalline cellulose, and most preferably from about 1.25% to about 5% by weight relative to the microcrystalline cellulose. Moreover, the silicon dioxide preferably has a particle size from about 5 nm to about 40 μm, and most preferably from about 5 nm to about 50 μm. Moreover, the silicon dioxide preferably has a surface area from about 10 m2 g to about 500 m2/g, preferably from about 50 m2/g to about 500 m2/g, and more preferably from about 175 m2/g to about 350 m2/g.
In certain embodiments of the present invention, the controlled release matrix core may further include an effective amount of a pharmaceutically acceptable organic acid. The pharmaceutically acceptable organic acid can be chosen, for example, among maleic, tartaric, malic, fumaric, lactic, citric, adipic or succinic acid and their acid salts where these exist, in the form of racemates or isomers, where these exist.
In preferred aspects of the invention, the organic acid is tartaric acid, and its acid salts.
In certain aspects of the present invention, the controlled release matrix core is coated with a delayed release coating, e.g., an enteric coating. Examples of suitable enteric polymers to be used for the enteric coating include cellulose acetate phthalate, hydroxypropyl-methylcellulose phthalate, polyvinylacetate phthalate, methacrylic acid copolymer, shellac, hydroxypropylmethylcellulose succinate, cellulose acetate trimellitate, and mixtures of any of the foregoing. An example of a suitable commercially available enteric material is available under the trade name Eudragit® L30D55 or Acryl-Eze®.
The enteric coating may be applied in any pharmaceutically acceptable manner known to those skilled in the art. For example, in one embodiment, the coating is applied via a fluidized bed. In another embodiment, the coating is applied via a coating pan. In certain embodiments, the enteric coating further includes a binder. Examples of suitable binders for use in the present invention are listed above.
In certain embodiments, the dosage form of the present invention further includes an immediate release portion. In one embodiment, the immediate release portion is over the delayed release coating disclosed above (with or without an intermediate layer, such as a film coat). The immediate release portion of the dosage form includes a portion of the short acting sedative-hypnotic. In another embodiment, the immediate release component can be separate and distinct from the enteric coated matrix, e.g., in the form of mutliparticulate, a tablet, or a powder. This separate and distinct component can be included with the enteric coated matrix in a capsule.
In certain embodiments, the immediate release portion of the dosage form of the present invention further includes a film coat that rapidly disintegrates or dissolves in water or the environment of use. The film coat may be a conventional sugar or polymeric film coating which is applied in a coating pan or by conventional spraying techniques. Preferred materials for the film coat are hydroxypropylmethylcellulose, polyvinyl alcohol, or mixtures thereof. An example of a commercially available film coat is under the Opadry tradename (e.g., Opadry® II, Yellow), from Colorcon, West Point, Pa.
The following examples illustrate various aspects of the present invention. They are not to be construed to limit the claims in any manner whatsoever.
In Example 1, zolpidem tartrate 6.25 mg delayed release tablets including a delayed release portion (A) and an immediate release portion (B), were prepared in accordance with the present invention in three steps as follows:
The ingredients of the controlled release matrix core of the formulation of Example 1 are set forth in Table 1 below:
The controlled release matrix core of the formulation of Example 1 was prepared as follows:
The ingredients of the enteric coated formulation of Example 1 are listed in Table 2 below:
The enteric coated formulation of Example 1 was prepared as follows:
The ingredients of the final formulation of Example 1, including the immediate release portion, are listed in Table 3 below:
The final formulation of by Example 1, including the immediate release portion was prepared as follows:
The tablets prepared in accordance with Example 1 were dissolution tested in USP dissolution Apparatus type II paddle method, in 0.01 NHCL with an agitation of 50 rpm. The dissolution results are illustrated in
The tablets prepared in accordance with Example 1 were dissolution tested in USP dissolution Apparatus type I basket method, in a pH of 6.8 buffer solution with an agitation of 50 rpm. The dissolution results are illustrated in
In Example 2, zolpidem tartrate 12.5 mg delayed release tablets including a delayed release portion and an immediate release portion, were prepared in accordance with the present invention in three steps as follows:
The ingredients of the controlled-release matrix core of the formulation of Example 2 are listed in Table 4 below:
The controlled-release matrix core of the formulation of Example 2 was prepared in accordance with the process of Example 1.
The ingredients of the enteric coated formulation of Example 2 are listed in Table 5 below:
The enteric coated formulation of Example 2 was prepared in accordance with the process of Example 1.
The ingredients of the final formulation of Example 2, including the immediate release portion are listed in Table 6 below:
The final formulation of Example 2, including the immediate release portion was prepared in accordance with the process of Example 1.
The tablets prepared in accordance with Example 2 were dissolution tested in USP dissolution Apparatus type II paddle method, in 0.01 NHCL with an agitation of 50 rpm. The dissolution results are illustrated in
The tablets prepared in accordance with Example 2 were dissolution tested in USP dissolution Apparatus type I basket method, in a pH of 6.8 buffer solution with an agitation of 50 rpm. The dissolution results are illustrated in
