Sustained release pharmaceutical preparations and methods for producing the same

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to sustained release pharmaceutical preparations and methods for producing the same. In particular, this invention relates to albuterol sulfate pharmaceutical sustained release formulations and their preparation.

[0003] 2. Discussion of Background Information

[0004] Albuterol sulfate is a bronchodilator which is believed to be a beta-adrengenic agonist which stimulates beta-adrengeric receptor, which leads to relaxation of bronchial smooth muscle and inhibits hypersensitivity of mast cells. Albuterol sulfate is indicated for the relief of bronchospasm for the management of asthma and reversible obstructibe airway disease.

[0005] Albuterol sulfate is also known as, (±) ∝, −[(tert-butylamino) methyl]-4-hydroxy-m-xylene-∝,∝′-diol sulfate (2:1) salt, and has an empirical formula (C13H21NO3)2.H2SO4, a molecular weight of 576.7, and has the following structural formula:

[0006] Albuterol sulfate extended release tablets are currently available as Volmax® Tablets, which are available in two strengths, 4 and 8 mg, and manufactured by Glaxo Wellcome Ltd. UK England, Muro Pharmaceutical Inc., Tewksbury, Mass. The oral administration of Volmax® tablets provides a duration of action up to 12 hours, with the maximum concentration of drug in plasma being reached within 6 hours, and the plasma half-life being about 9 hours. Volmax® releases the drug from polymeric coated tablets through a laser drilled hole on one side of the tablet (OROS™ technology). The tablets include a rate controlling semi-permeable membrane, and a core of albuterol and osmotic agent. An osmotic gradient caused by core components draws water only into the tablet, where albuterol and osmotic agent dissolve, and albuterol is released through the laser drilled hole.

[0007] As disclosed in U.S. Pat. No. 5,837,379, the disclosure of which is incorporated by reference herein in its entirety, extended release tablets containing osmotic tablets are known which have had an osmotically active drug core surrounded by a semi-permeable membrane. As disclosed therein, the core can be divided into two layers, one containing the active drug and the other containing a push layer of pharmacologically inactive ingredients which are osmotically active in the presence of gastrointestinal fluids. Also, as disclosed therein, an outer water permeable coating provided with an aperture covers the tablet to allow the drug to be pushed out of the tablet. Products of this type are disclosed in U.S. Pat. Nos. 4,327,725, 4,612,008, 4,751,071, 4,765,989, 4,777,049. 4,783,337 and 4,851,229. The disclosures of which are each incorporated by reference herein in their entireties.

[0008] U.S. Pat. No. 4,503,030, the disclosure of which is incorporated by reference herein in its entirety, discloses an osmotic device for delivering drugs to the stomach and the intestine. The device disclosed therein includes a shaped wall around a compartment described as a compartment which maintains its physical and chemical integrity in the stomach but loses its chemical and physical integrity in the intestine.

[0009] U.S. Pat. No. 4,587,117, the disclosure of which is incorporated by reference herein in its entirety, discloses an oral osmotic device which has a shaped wall which loses its integrity at a pH of 3.5 to 8.0, a passageway from a compartment to the exterior of the device.

[0010] U.S. Pat. No. 5,837,379, the disclosure of which is incorporated by reference herein in its entirety, also discloses the belief that its osmotic tablet operates by water passing through the membrane on the surface of the tablet which causes the core to swell and increase the pressure inside the tablet. This is disclosed to cause a very slight expansion of the partially hydrated core which is controlled by the use of a relatively small amount of water swellable polymer. It is disclosed that the expansion of the core will cause the membrane to open to relieve the internal pressure, and that once the initial opening or openings are formed, the swelling effect of the core components will cause the contents of the core to extrude through the initial opening without complete disintegration of the membrane. It is further disclosed that the internal pressure which is exerted on the membrane by the swelling and expanding osmotic core is relieved by the passage of the first portions of the core contents through the initial openings.

[0011] Moreover, sustained release tablets are known, such as disclosed in U.S. Pat. Nos. 5,500,227, 6,024,982 and 6,210,714, the disclosures of which are each incorporated by reference herein in their entireties, wherein release of the drug is controlled by means of the resistance of a coating layer or matrix against the diffusion of the drug therethrough. The release of drugs from such formulations is disclosed to be driven, e.g., by the gradient of the drug concentration resulting from penetration of, e.g., gastric fluid, by diffusion into the formulation.

[0012] Still further, U.S. Pat. No. 6,245,351, the disclosure of which is incorporated by reference herein in its entirety, discloses a drug-containing core coated with a coating composition containing a water-insoluble substance and a swellable polymer having no basis groups.

[0013] U.S. Pat. No. 5,254,347, the disclosure of which is incorporated by reference herein in its H entirety, discloses a controlled release pharmaceutical preparation, comprising a core containing a pharmaceutically active ingredient, and a porous film of a hydrophobic polymeric substance or a hydrophobic polymeric substance and a hydrophilic polymeric substance, the core being coated with the porous film. It is further disclosed that the hydrophobic polymeric substance may be ethyl cellulose and that the hydrophilic polymer may be a water-soluble polymeric substance such as methyl cellulose.

[0014] U.S. Pat. Nos. 5,674,895, 5,840,754, 5,912,268, 6,124,355 and 6,262,115, the disclosures of which are each incorporated by reference herein in their entireties, disclose a dosage form for delivering oxybutynin in a rate-controlled dose.

SUMMARY OF THE INVENTION

[0015] The present invention is directed to extended release pharmaceutical preparations.

[0016] The present invention is also directed to methods for producing extended release pharmaceutical preparations.

[0017] The present invention provides a stable formulation of extended release tablets of albuterol in albuterol sulfate extended release tablets which are bioequivalent to Volmax® tablets, including the 4 and 8 mg tablets, manufactured by Glaxo Wellcome Muro Pharmaceutical Inc.

[0018] The present invention provides a diffusion controlled formulation that achieves bioequivalence to formulations utilizing osmotic devices.

[0019] The present invention is also directed to controlled release pharmaceutical preparations having desired dissolution rates that can be obtained in a diffusion controlled tablet.

[0020] The present invention provides an extended release tablet comprising a core including albuterol sulfate and extended release agent; and an extended release coating associated with the core to provide for sustained release of the albuterol sulfate.

[0021] The extended release agent can comprise a hydophobic polymer. The hydrophobic polymer can comprise ethyl cellulose.

[0022] The extended release coating can comprise hydrophobic polymer and hydrophilic polymer. The hydrophobic polymer can comprise ethyl cellulose and the hydrophilic polymer can comprise hi methyl cellulose.

[0023] The extended release coating can comprise ethyl cellulose and methyl cellulose, and the extended release agent can comprise ethyl cellulose.

[0024] The hydrophobic polymer and hydrophilic polymer of the extended release coating can be present in a weight ratio of 55-65:45-35 of the hydrophobic polymer to the hydrophilic polymer, preferably in a weight ratio of 53:47 of the hydrophobic polymer to the hydrophilic polymer.

[0025] The hydrophobic polymer and hydrophilic polymer of the extended release coating can comprise ethyl cellulose and methyl cellulose, respectively.

[0026] The extended release coating can have a weight of about 5 to 25 mg, more preferably about 8 to 13 mg.

[0027] Ethanol is preferably utilized as a solvent for preparing the core and the extended release coating.

[0028] The core can also include an anhydrous sulfate, such as calcium sulfate and/or lactose monohydrate.

[0029] The extended release tablet can have an albuterol dissolution profile for a formulation containing 8 mg of albuterol of:

1 2nd HourNot more than 30% 6th Hour50-75% 10th HourNot less than 75%.

[0030] The extended release tablet can have an albuterol dissolution profile for a formulation containing 4 mg of albuterol of:

2 2nd HourNot more than 20% 6th Hour45-70% 10th HourNot less than 75%.

[0031] The extended release tablet can have bioequivalency to an albuterol sulfate osmotic device formulation.

[0032] The present invention is also directed to a diffusion controlled tablet for extended release of albuterol sulfate comprising albuterol sulfate in a diffusion controlled formulation structured and arranged to provide an albuterol dissolution profile for a formulation containing 8 mg of albuterol of:

3 2nd HourNot more than 30% 6th Hour50-75% 10th HourNot less than 75%.

[0033] The present invention is also directed to a diffusion controlled tablet for extended release of albuterol sulfate comprising albuterol sulfate in a diffusion controlled formulation structured and arranged to provide an albuterol dissolution profile for a formulation containing 4 mg of albuterol of:

4 2nd HourNot more than 20% 6th Hour45-70% 10th HourNot less than 75%.

[0034] The present invention is also directed to a diffusion controlled formulation for extended release of albuterol sulfate comprising albuterol sulfate in a diffusion controlled formulation structured and arranged to provide bioequivalency to an albuterol sulfate osmotic device formulation.

[0035] The bioequivalency can be measured in a randomized, single dose, 2-way cross-over bioavailability study of healthy adult males under fasting conditions, based upon 36 individuals and plasma albuterol levels, for a formulation containing 4 mg of albuterol, and ln AUC 0-t is within 80-125% of 53074 pg.h/mL, ln AUCinf is within 80-125% of 55606 pg.h/mL, and ln Cmax is within 80-125% of 4383 pg/mL.

[0036] The bioequivalency can be measured in a randomized, single dose, 3-way cross-over bioavailability study of healthy adult males under fed and fasting conditions, based upon 16 individuals and plasma albuterol levels, for a formulation containing 8 mg of albuterol, and wherein, for fed adult males, ln AUC 0-t is within 80-125% of 106139 pg.h/mL, ln AUCinf is within 80-125% of 109692 pg.h/mL, and ln Cmax is within 80-125% of 7149 pg/mL.

[0037] The bioequivalency can be measured in a randomized, 2-way cross-over steady state bioavailability study of healthy adult males under fasting conditions, based upon 37 individuals and plasma albuterol levels, for a formulation containing 8 mg of albuterol, and wherein ln AUC 0-T is within 80-125% of 1125573 pg.h/mL and ln Cmax is within 80-125% of 14522 pg/mL.

BRIEF DESCRIPTION OF THE DRAWINGS

[0038] The present invention is further described in the detailed description which follows, in reference to the noted plurality of non-limiting drawings, wherein:

[0039]
FIG. 1 shows a semi-log plot of mean plasma albuterol concentrations for plasma albuterol concentration vs. time for data shown in Table 16;

[0040]
FIG. 2 shows a linear plot of mean plasma albuterol concentrations for plasma albuterol concentration vs. time for data shown in Table 16;

[0041]
FIG. 3 shows a semi-log plot of mean plasma albuterol concentrations for plasma albuterol concentration vs. time for data shown in Table 17;

[0042]
FIG. 4 shows a linear plot of mean plasma albuterol concentrations for plasma albuterol concentration vs. time for data shown in Table 17;

[0043]
FIG. 5 shows a semi-log plot of mean plasma albuterol concentrations for plasma albuterol concentration vs. time for data shown in Table 18; and

[0044]
FIG. 6 shows a linear plot of mean plasma albuterol concentrations for plasma albuterol concentration vs. time for data shown in Table 18.

DETAILED DESCRIPTION OF THE INVENTION

[0045] The particulars shown herein are by way of example and for purposes of illustrative discussion of the various embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

[0046] All percent measurements in this application, unless otherwise stated, are measured by weight based upon 100% of a given sample weight. Thus, for example, 30% represents 30 weight parts out of every 100 weight parts of the sample.

[0047] Unless otherwise stated, a reference to a compound or component, includes the compound or component by itself, as well as in combination with other compounds or components, such as if mixtures of compounds.

[0048] Before further discussion, a definition of the following terms will aid in the understanding of the present invention.

[0049] Osmotic formulation device or osmotic tablet device is utilized herein to refer to formulations or tablets wherein one or more osmotic agents are configured and arranged to provide osmotic pressure or force associated with the formulation or tablet so as to cause active ingredient to be released from the formulation or tablet primarily due to the osmotic pressure or force, such as, but not limited to, pressure causing the active ingredient to be released by being pushed by pressure through an aperture in the formulation or tablet, or by causing pressure to expand a tablet layer.

[0050] Diffusion controlled is utilized herein to refer to formulations or tablets wherein the active ingredient is not released due to pressure or force, but is primarily released by diffusion according to Fick's laws.

[0051] Without being wished to be bound by theory, diffusion includes processes wherein molecules intermingle as a result of their kinetic energy of random motion. In contrast, osmosis is a selective diffusion process driven, e.g., forced, by the internal energy of the solvent molecules.

[0052] When referring to dissolution and dissolution profiles in the present specification and claims, the dissolution is performed utilizing the dissolution procedure set forth in the Examples, or a dissolution technique that is equivalent thereto. As an overview, the present invention relates to extended (sustained) release pharmaceutical preparations. These preparations are especially useful for the extended release of albuterol sulfate. In particular, the present invention is directed to a tablet formulation including a core containing albuterol sulfate and an extended release agent; an extended release coating combining a hydrophilic agent and a hydrophobic agent; and can have one or coatings. The core and extended release coating is are formulated with respect to each other in order to provide a pharmaceutically acceptable in vitro dissolution profile, and particularly a dissolution profile and characteristics that are bioequivalent to that of albuterol obtainable with osmotic devices.

[0053] The tablet according to the present invention achieves desired dissolution in vitro profiles and bioequivalence to FDA approved albuterol tablet formulations, i.e., Volmax® tablets, in a tablet that is diffusion controlled as compared to being osmotically operated, such as Volmax® tablets.

[0054] In accordance with the present invention, the preferred percent of labeled amount of albuterol released at each specified time interval utilizing the dissolution test set forth in the Examples, for 8 mg albuterol tablets, is:

5 2nd HourNot more than 30% 6th Hour50-75% 10th HourNot less than 75%

[0055] Moreover, in accordance with the present invention, the preferred percent of labeled amount of albuterol released at each specified time interval utilizing the dissolution test set forth in the Examples, for 4 mg albuterol tablets, is:

6 2nd HourNot more than 20% 6th Hour45-70% 10th HourNot less than 75%

[0056] The moisture content of the tablet is preferably not more than 0.5 wt %. Moreover, residual alcohol content of alcohols utilized in preparing the formulation is preferably less than 0.5 wt %.

[0057] According to the present invention, the core includes the active pharmaceutical ingredient and an extended release agent. The active pharmaceutical ingredient preferably comprises albuterol sulfate.

[0058] The core according to the present invention preferably is prepared by a granulation process, with the granules containing the active pharmaceutical ingredient and the extended release agent. These granules preferably have an average particle diameter of about 125μ to 1700μ, more preferably about 180μ to 1000μ, and most preferably about 250μ to 600 μ.

[0059] The active pharmaceutical ingredient content of the core is preferably about 4 to 8 mg based upon active ingredient. For example, for albuterol sulfate, the content is the core would preferably be about 4.8 to 9.6 mg.

[0060] The core is preferably constructed to provide overall dosages of 4 or 8 mg of albuterol. The core is preferably formulated with 4.8 mg of albuterol sulfate to provide an overall dosage of 4 mg of albuterol, and the core is preferably formulated with 9.6 mg of albuterol sulfate to provide an overall dosage of 8 mg of albuterol. Thus, the tablet of the present invention can be described by either the amount of active ingredient contained therein, e.g., albuterol, or by pharmaceutically acceptable salts thereof, preferably albuterol sulfate.

[0061] The albuterol sulfate utilized in the formulation preferably has a particle size distribution, determined using a Malvern Mastersizer (Malvern 2600c with PS64 dry powder feeder, lens 100 mm obscuration 0.1 to 0.4) using particle in air method. Preferably, at least 50% of the particles of albuterol sulfate that are to be added to the core is not more than (NMT) 25 μm, and at least 90% is not more than 55 μm. Without wishing to be bound by theory, it is believed that particles within these parameters provide a good combination of dissolution and core hardness. Specific batches of albuterol sulfate tested had the following particle size distribution denoted in Table 1 below.

7TABLE 1Particle Size Distribution of Albuterol SulfateSample 1Sample 2Sample 3Sample 450%, NMT 25 μm 9% 8%11%11%90%, NMT 55 μm24%22%31%32%

[0062] The extended release agent can comprise one or more ingredients which in combination with the extended release coating control the release of the active pharmaceutical ingredient, especially albuterol sulfate, from the core in order to achieve a desired dissolution profile, and, in particular, bioequivalency with FDA approved formulations of albuterol sulfate. The extended release agent can comprise various water-insoluble materials, Examples of such water insoluble materials include hydrophobic polymers including, but are not limited to, one or more of ethyl cellulose, butyl cellulose, cellulose acetate, cellulose propionate, polyvinyl acetate, polyvinyl butyrate, ethyl acrylate-methyl methacrylate-ethyl ammonium trimethyl chloride methacrylate copolymer and N-vinyl-2-pyrrolidonecellulose ether, cellulose ester, polyvinyl ester, acrylic acid type polymer having a quaternary ammonium-alkyl group, and Plasdone® K-90, Povidone, homopolymer of N-vinyl-2-pyrrolidone. Preferably, the extended release agent comprises one or more of ethyl cellulose, butyl cellulose, cellulose acetate, cellulose propionate, polyvinyl acetate, polyvinyl butyrate, ethyl acrylate-methyl methacrylate-ethyl ammonium trimethyl chloride methacrylate copolymer and N-vinyl-2-pyrrolidone. Most preferably, the extended release agent comprises ethyl cellulose, such as Ethocel N-10 which is obtainable from Dow Chemical, Midland, Mich.

[0063] The core can be prepared in any manner, such as by utilizing any conventional manufacturing technique. Thus, the core can be produced by combining the active pharmaceutical ingredient and at least one agent capable of restricting release of the active ingredient with each other, and other ingredients. For example, the core may contain a wide variety of excipients, such as those ingredients that are conventionally included in the core of tablets, including diluents, glidents, binders, granulating solvent, granulating agents, anti-aggregating agents, buffers, lubricants.

[0064] For example, diluents can include, but are not limited to, one or more of sugars such as sucrose, lactose, mannitol, glucose; starch; microcrystalline cellulose; sorbitol, maltodextrin, whey, calcium phosphate; calcium sulfate; sodium sulfate or similar anhydrous sulfate; calcium lactate; lactose anhydrous; and lactose monohydrate. Preferably, the diluents comprise calcium sulfate and/or lactose monohydrate. Preferably, lactose anhydrous is not included in the core, because of its ability to absorb water from solvents, such as ethanol, thereby contributing to undesirable weight gain.

[0065] Examples of binders include, but are not limited to, one or more of polyvinyl alcohol, polyacrylic acid, polymethacryic acid, polyvinyl pyrrolidone, sucrose, sorbitol, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyethylene glycols, gum arabic, gelatin, agar, starch, etc.

[0066] Lubricants and anti-aggregating agents include, but are not limited to, one or more of talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, waxes, hydrogenated vegetable oil, polyethylene glycols, sodium benzoate, sodium laurylsulfate, magnesium laurylsulfate and dl-leucine. Preferably, the lubricants include stearic acid and/or magnesium stearate.

[0067] Solvents include, but are not limited to, one or more of acetone, ethanol, isopropyl alcohol (IPA) and/or methylene chloride. Preferably, the solvent for the core comprises ethanol. The use of chlorinated solvents, such as methylene chloride is preferably avoided. Therefore, the tablets preferably do not contain a chlorinated solvent, such as methylene chloride. The amount of solvent can be adjusted to provide a sufficient amount to achieve the formation of granules while not being of such a high amount as to turn the mixture into a large mass instead of granular in nature. Moreover, it is preferred to control the solvent addition time to effect adequate granulation. It is preferred that the temperature of granulating solution is preferably not be more than 26° C. at the time of addition to avoid lumping.

[0068] The ingredients can be combined and/or granulated in one or more procedures utilizing any appropriate techniques, such as by granulating in a low shear granulator, fluidized bed granulation, high shear granulator.

[0069] It is noted that during development of granulation, formulations were prepared with and Without the use of calcium sulfate to study its impact on dissolution profile of the product. Based on a fast drug release of albuterol sulfate from tablets without calcium sulfate, it is preferred that calcium sulfate be incorporated in the core to control drug release from the tablets.

[0070] Following production of the granules for the core, the granules are dried under sufficient conditions to provide granules preferably having not more than 0.5 wt % alcohol, and preferably not more than 0.5 wt % water. Therefore, for commercial batches, it is preferred that the batches be dried at a preferred temperature of at about 50° C. preferably for at least 16 hours to ensure solvent removal, such as ethanol and/or water.

[0071] The cores are compressed into tablets to a hardness of preferably between about 2 and 6 kP, with a preferred value being about 4 kP.

[0072] The extended release coating is deposited on the tablets in a location that is external to the core, and is preferably layered directly onto the core. The extended release coating is formulated to provide in conjunction with the extended release agent in the core a desired dissolution profile, and bioequivalency to commercially available albuterol sulfate tablet formulations, such as Volmax® tablets.

[0073] The extended release coating comprises a film preferably a combination of hydrophobic and hydrophilic polymers. Preferably, the active pharmaceutical ingredient, which is preferably albuterol sulfate, is not present in the extended release coating. In this regard, preferably the active a pharmaceutical ingredient, which is preferably albuterol sulfate, is only present in the core.

[0074] The hydrophobic polymer constituting the film is not particularly limited, provided that it has film forming ability, and is insoluble in water, but soluble in a water-miscible organic solvent. Examples of hydrophobic polymers include, but are not limited to, one or more of ethyl cellulose, butyl cellulose, cellulose acetate, cellulose propionate, polyvinyl acetate, polyvinyl butyrate, ethyl acrylate-methyl methacrylate-ethyl ammonium trimethyl chloride methacrylate copolymer and N-vinyl-2-pyrrolidonecellulose ether, cellulose ester, polyvinyl ester, acrylic acid type polymer having a quaternary ammonium-alkyl group, and Plasdone® K-90, Povidone, homopolymer of N-vinyl-2-pyrrolidone. Preferably, there may be included, for example, ethyl cellulose, butyl cellulose, cellulose acetate, cellulose propionate, polyvinyl acetate, polyvinyl butyrate, ethyl acrylate-methyl methacrylate-ethyl ammonium trimethyl chloride methacrylate copolymer and N-vinyl-2-pyrrolidone. Most preferably, the hydrophobic polymeric substance comprises ethyl cellulose, such as Ethocel N-10, which is obtainable from Dow Chemical, Midland, Mich.

[0075] The hydrophilic polymer maybe a water-soluble polymeric substance, including, but are not limited to, one or more of methyl cellulose, polysaccharides optionally having a sulfuric acid group such as pullulan, dextrin, alkali metal alginate, etc.; polysaccharides having ahydroxy-alkyl group or a carboxyalkyl group such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose sodium, etc.; methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol or polyethylene glycol, etc. may be included. Preferably, the hydrophilic polymeric substance comprises methyl cellulose, such as Methocel E-15, which is obtainable from Dow Chemical, Midland, Mich.

[0076] Changing the weight ratio of hydrophobic polymer to hydrophilic polymer in the extended release coating affects the dissolution of the albuterol from the tablet. Therefore, the weight ratio of hydrophobic polymer to hydrophilic polymer can be varied for each specific formulation to obtain desired dissolution profiles for the formulation. Preferable weight ratios for the hydrophobic polymer to hydrophilic polymer include weight ratios of 55-65:45-35, with one preferred weight ratio of hydrophobic polymer to hydrophilic polymer being 57:43.

[0077] The solvent for the extended release coating can comprise various solvents including, but are not limited to, acetone, ethanol, isopropyl alcohol (IPA) and/or methylene chloride. Preferably, the solvent for the extended release coating comprises ethanol. The use of chlorinated solvents, such as methylene chloride is preferably avoided. Various combinations of solvents can be used, such as, but not limited to, ethanol and isopropyl alcohol, and combinations of isopropyl alcohol:water, denatured alcohol:water and ethyl alcohol:water.

[0078] Tablets prepared using isopropyl alcohol were found to have a drug release that is slower than when ethanol is used as coating solvent. In addition, when isopropyl alcohol is used for both, granulation and coating, the drug release is found to be slower compared to that of the product made using ethanol for granulation and coating. Accordingly, ethanol is a preferred solvent for both granulation and coating.

[0079] To obtain a product that is bioequivalent to Volmax®, the hydrophobic polymer and the hydrophilic polymer are blended with each other to provide an extended release coating that has desired dissolution profiles and/or bioequivalence properties in conjunction with the extended release agent and active ingredient included in the core. For example, using the preferred formulations as disclosed herein, a weight ratio of 57 parts by weight of Ethocel N-10 to 43 parts by weight of Methocel E-15, a coating weight gain of about 5-25 mg per tablet is preferred. Preferably, a coating weight gain of 20 mg per tablet, for 4 mg and 8 mg tablets, using R&D equipment provides a drug release profile similar to that of Volmax® tablets. Commercial tablets preferably have a weight gain of 8.7 and 12.4 mg, respectively, for 4 mg and 8 mg albuterol sulfate tablets. A preferred weight gain for the extended release coating is about 5 to 25 mg, more preferably about 8 to 13 mg.

[0080] Coating of the extended release coating can be performed using various techniques, such as conventional coating techniques such as perforated pan, or using fluidized bed technique. These methods are commonly understood by individuals who are practicing the art tablet manufacture. The angle of spray guns utilized in spayed on the coating can be varied, such as, but not limited to between 300 and 75°, with one preferred angle being 65°.

[0081] Without being wished to be bound by theory, it is believed that the hydrophilic polymer provides a porous layer for diffusion of the active ingredient from the core. In this regard, the hydrophilic polymer is believed to be dissolved to leave pores through which diffusion takes place.

[0082] In the formulation of the present invention, by adequately controlling the weight of the extended release coating, and the ratio of hydrophobic polymer to hydrophilic polymer as well as the extended release agent in the core, it is possible to make a tablet having a desired in vitro dissolution rate. For example, and without wishing to be bound by theory, when the pharmaceutically active ingredient contained in the core is a drug which is desired to exhibit a pharmaceutical effect within a short period of time after administration, it is preferred to make the film thinner and the porosity thereof greater upon dissolving of the hydrophilic polymeric substance, while in the case of a drug which is desired to be released persistently for a prolonged period of time, it is preferred to make the film thicker and the porosity thereof smaller upon dissolving of the hydrophilic polymeric substance.

[0083] For a set composition for the extended release coating, a difference in dissolution rate of the active pharmaceutical ingredient can be obtained by varying the weight of the coating. Thus, a higher coating weight of the extended release coating provides for a greater time to dissolve an equivalent concentration of active pharmaceutical ingredient as compared to a lower weight of the extended release coating. Therefore, the weight of the extended release coating is preferably accurately monitored during production of the tablet to ensure a desired dissolution rate for an extend release coating composition. For example, the weight of the extended release coating can be monitored by determining core weight prior to applying the extended release coating, and then determining the total weight of the core and extended release coating. The difference between these two values would be the weight gain due to the extended release coating. For example, a weight gain of 10 mg would provide a slower dissolution rate than a weight gain of 9 mg.

[0084] The tablet can include optional coatings, such as coatings to provide cosmetic elegance and/or to facilitate packaging of the product. For example, an optional coating can comprise a color coating including, but not limited to, Opadry Green. Another optional coating can include, for example, a clear solution, such as, but not limited to, Opadry Clear. These optional coatings can be utilized in combination, such as a clear coat being applied over a color coating.

[0085] The active pharmaceutical ingredient according to the present invention preferably comprises albuterol sulfate, but can comprise other active ingredients. However, the present invention is particularly suited to albuterol sulfate as the active pharmaceutical ingredient. In this regard, as noted above, the present invention provides for the extended release of albuterol sulfate having similar dissolution profiles to that of pharmaceutical tablets operating on osmotic principles and provides bioequivalency thereto.

[0086] The present invention will be further illustrated by way of the following Examples. These Examples are non-limiting and do not restrict the scope of the invention.

[0087] Unless stated otherwise, all percentages, parts, etc. presented in the examples are by weight.

EXAMPLES

[0088] The following procedures are utilized in connection with the present invention:

[0089] A. Dissolution Procedure—For Determining Dissolution Rates and Profiles in Accordance with the Present Invention:

[0090] The dissolution procedure utilized in connection with the present invention includes the following:

[0091] The dissolution apparatus is a Van Kel Model VK-7000 utilized according to USP 24, Method <724>. The dissolution units have paddle shafts or equivalent dissolution unit to meet USP 24 Method<711> criteria on six samples, and using an HPLC system equipped with UV detector. The following reagents and standards are used in the dissolution procedure:

[0092] Reagents and Standards:

8WaterPurified waterSodium ChlorideACS reagent1-Octane sulfonic acid sodium saltReagent GradeAmmonium acetateACS reagent2-PropanolHPLC gradeMethanolHPLC gradeGlacial Acetic AcidACS reagentAlbuterol SulfateStandard withknown purity or USP RS

[0093] Preparation of Dissolution Medium:

[0094] Dissolve 9.0 grams of sodium chloride in 1000 mL of water, heat to 37° C.±0.5° C., filter and degas, to thereby form 0.9% sodium chloride solution.

[0095] Preparation of Mobile Phase:

[0096] Dissolve 600 mg of 1-Octane sulfonic acid sodium salt, and 20.0 g of ammonium acetate into 920 mL of water. Add 30 mL of 2-propanol, 10 mL of methanol, and 40 mL of glacial acetic acid, mix well.

[0097] Filter with vacuum and degas by sonication for 5 minutes. Helium sparging is also suitable.

[0098] Preparation of Standard Solution:

[0099] A. Stock Standard Solution:

[0100] Accurately weigh about 24 mg of albuterol sulfate, and transfer quantitatively into 100 mL volumetric flask with the aid of about 50 mL dissolution medium. Dissolve the standard by sonication, dilute with dissolution medium to volume, and mix.

[0101] B. Working Standard Solution:

[0102] Pipet 4.0 mL of stock standard solution into a volumetric flask, a 200 ml volumetric flask for 4 mg tablet, and a 100 mL volumetric flask for 8 mg tablet.

[0103] Dilute with dissolution medium to volume and mix. Filter a portion of the solution through nylon disk filter of 0.45 gm porosity SR1 (Scientific Resources, Inc. catalog: #44525-NC) or equivalent, discarding a first few mL. Fill 1 mL HPLC glass vials with the filtered material.

[0104] Chromatographic System for Dissolution Measurement:

[0105] Prepare a liquid chromatographic system according to Table 2 below:

9TABLE 2Chromatographic System for Dissolution Measurement:Equipment and Conditions:ColumnSymmetry C18, 5 μm, 3.9 × 150 mm, Waterscatalog # WAT 046980, which represents USPpacking L1 type or equivalentColumn TemperatureThermostatically controlled at 30° C.Flow Rate1.0 mL per minute using a Waters 600 seriespump or equivalentDetectorUV at 276 nm using a Waters 486 or equivalentIntegratorWaters Millennium System or equivalentInjector Volume50 μL with a Waters Model 717 or an equivalentautosamplerRetention TimeAbout 5 minutesRun Time8 minutes

[0106] The dissolution tests are performed using 900 mL of dissolution medium (0.9% sodium chloride solution) and a paddle rotational speed of 50 rpm, and sampling is conducted in accordance with USP 24 Method <711>. For each withdrawal of 10 mL of sample for testing, 10 mL of dissolution medium preheated to 37° C.±0.5° C. is added to the dissolution vessel thereby replacing the withdrawn dissolution solution.

[0107] Analysis of the samples is performed using standard HPLC techniques to conform the average value of the following parameters to:

[0108] The relative standard deviation (RSD) of albuterol peak area response for replicate injections should not be more than 3.0%.

[0109] The tailing factor for albuterol peak area should not be more than 2.0.

[0110] The number of theoretical plates per column for albuterol peak should not be less than 2000.

[0111] Particle size and powder fineness can be determined using sieve analysis according to USP-23 NF 18, such as by using an ATM Sonic Sifter Model L3P.

EXAMPLES 1-7

[0112] The following Tables 3 and 4 illustrate formulations of 4 and 8 mg tablets according to the present invention which were used in the Examples which follow.

10TABLE 3ALBUTEROL SULFATE ER TABLETS, 4 MG AND 8 MGStrength8 mg4 mg4 mg8 mg8 mg8 mg8 mg4 mg4 mgExample #Example-IExample-IExample-IIExample-IIIExample-IVExample-VExample-VExample-VIExample VIIngredients (in mg)ABCI COREAlbuterol Sulfate USP 9.60 4.80 4.80 9.60 9.60 9.60 9.60 4.80 4.80Lactose monohydrate NF 66.00 70.80 70.80 74.40 66.00 66.00 66.00 70.80 70.80powderCalcium Sulfate powder 8.40 8.40 8.40— 8.40 11.40 15.07 8.40 8.40USPEthocel N-10 premium 12.50 12.50 13.00 12.50— 9.17 5.83 13.00 13.00Ethocel N-10 premium 2.00 2.00 1.50 2.00— 2.00 2.00 1.50 1.50PVP K-90———— 14.50————Isopropyl alcohol USP 15.00*——————Ethyl alcohol, 95% USP *15.00 *15.00n/a *20.0 *20.0 *20.0 *20.0— 15.00*Denatured Alcohol——————— 15.00*—(SDA-3A)Stearic Acid NF 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00Magnesium Stearate NF 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50Total (Solids in mg) 100.00 100.00100.00 100.00 100.00 99.67 100.00100.00100.00II ER Coating solutionMethocel E-15 premium 8.325 8.325 2.14 4.20 4.20 4.00 4.00 2.14 2.14Ethocel N-10 premium 11.25 11.25 2.88 4.20 4.20 5.40 5.40 2.88 2.88Triacetin USP 2.50 2.50 0.64 1.00 1.00 1.20 1.20 0.64 0.64Purified water USP 32.50* 32.50* *8.40 *13.33 *13.33 *15.0 *15.0 *8.40 *8.40Ethyl alcohol USP 292.50* 292.50**74.67*113.33*113.33*134.0*134.0*74.67*74.67Total (Solids in mg) 22.075 22.075 5.66 9.40 9.40 10.60 10.60 5.66 5.66III White F/C suspensionand clear solutionOpadry white YS-1-7003***1.67***1.67 1.65 1.67 1.67 2.00 2.00 1.65 1.65Purified water USP 16.67* 16.67* 16.67* *16.67 *16.67 *20.00 *20.00 16.67* 16.67*Opadry clear YS-1-7006 0.167 0.167 0.17 0.167 0.167 0.20 0.20 0.17 0.17Propylene Glycol USP 0.167 0.167 0.17 0.167 0.167 0.20 0.20 0.17 0.17Purified water USP 8.33* 8.33* 8.33* *8.33 *8.33 *10.0 *10.0 8.33* 8.33*Carnuba wax Powder 0.167 0.167 0.1 0.167 0.167 0.20 0.20 0.1 0.1NFTotal (Solids in mg) 2.171 2.171 2.11** 2.171 2.171 2.60 2.60 2.11** 2.11**

[0113]

11

TABLE 4

ALBUTEROL SULFATE ER TABLETS, 4 MG

4 mg

Control #
Example-VII

Ingredients (in mg)
A
B
C
D

I CORE

Albuterol Sulfate USP
4.80

Lactose monohydrate NF powder
70.80

Calcium Sulfate powder USP
8.40

Ethocel N-10 premium
12.50

Ethocel N-10 premium
2.00

Isopropyl alcohol USP

Ethyl alcohol, 95% USP
*15.00

Stearic Acid NF
1.00

Magnesium Stearate NF
0.50

Total (Solids in mg)
100.00

II ER Coating solution

Methocel E-15 premium
1.56
3.12
4.68
5.475

Ethocel N-10 premium
14.08
12.52
10.96
10.165

Triacetin USP
2.00
2.00
2.00
2.00

Purified water USP
26.00*
26.00*
26.00*
26.00*

Ethyl alcohol USP
234.00*
234.00*
234.00*
234.00*

Total (Solids in mg)
17.64
17.64
17.64
17.64

III White F/C suspension

and clear solution

Opadry green
1.67
1.67
1.67
1.67

Purified water USP
*16.67
*16.67
*16.67
*16.67

Opadry clear YS-1-7006
0.167
0.167
0.167
0.167

Propylene Glycol USP
0.167
0.167
0.167
0.167

Purified water USP
*8.33
*8.33
*8.33
*8.33

Carnauba wax Powder NF
0.167
0.167
0.167
0.167

Purified water USP

Total (Solids in mg)
2.171
2.171
2.171
2.171

*= Ingredient will be removed

**= Blue and Yellow dye were mixed in formula

***= opadry green instead of Opadry white

[0114] The following procedure is utilized to produce tablets according to the present invention unless otherwise stated:

[0115] Core Preparation

[0116] Screen ingredients including lactose monohydrate, albuterol sulfate and calcium sulfate through #18 mesh and the extended release agent (Ethocel N-10) through #12 mesh. The ingredients are mixed in a twin shell blender without I-bar to a uniform blend. The contents are emptied into an AMF mixer and set at 45±5 RPM.

[0117] Prepare a solution of the extended release agent (Ethocel N-10, 2 kg.) in of warm (50° C.±5° C.) solvent (Ethyl Alcohol). Stir the solution until clear, such as for a minimum time of one hour. Then, cool the solution to not more than 26° C. Start the mixer and pump the Ethocel N-10 solution to granulate ingredients, such as by delivering the solution over a period of three minutes. Mix to achieve adequate granulation, such as for about 6 to 9 minutes. Dry by spreading, such as on a stainless steel tray at 50° C.±5° C. for not more than 16 hours and until the average loss on drying at 75° C. is less than 0.5%.

[0118] Mill the dried granulation in a Fitzmill having screwfeeder, perforated Stainless Steel plate #0065, set for medium speed, knives forward and feeder at 3.5±0.5 kg.

[0119] Screen remaining ingredients of the stearic acid and magnesium stearate through #18 mesh and collect in a suitable container. Transfer milled granulation, screened ingredients through twin shell without I-bar blender, and blend until uniform, preferably about 5 minutes.

[0120] Set the tablet press for ¼″ round, deep concave, plain tooling, and compress the blend at a nominal value of at 100 mg±7 mg. Compress at 4 kp (range 2-6 kp) hardness. The cores in these examples are at a thickness and 0.130″-0.155″, and have a friability less than 1%.

[0121] Preparation of Extended Release Coating Solution

[0122] Prepare Extended Release (ER) coating solution by dissolving Methocel E-15 and Ethocel N-10 in a mixture of ethyl alcohol and purified water, mixing until clear, such as for a minimum of 5 hours. Add Triacetin and stir for preferably 15 more minutes to equally distribute. Store this solution for minimum time of 10 hours before application, such as 15 to 16 hours.

[0123] Preparation of Film Coating Solutions

[0124] Prepare film coating colored solution using Opadry Green and purified water, stirring the suspension until dispersed, such as for 2 hours.

[0125] Prepare film coating clear solution using Opadry Clear and purified water, stirring the suspension until dispersed and clear, such as for 2 hours.

[0126] Add Propylene Glycol into the solution and stir for 15 more minutes.

[0127] Coating Core with Extended Release Coating Solution

[0128] Transfer the core tablets into a 48″ perforated pan. Set spray guns at 65° angle, and adjust the atomizing air pressure at 25 PSI atomizing air pressure. Set the pump for extended release coating solution to provide solution at 130 ml/min/gun (RANGE: 100-130 ml/min/gun). Set the air temperature at 75° C. or less to warm the core tablets. Turn the coating pan at 6 RPM pan speed (range 4-8 RPM). Dry the extended release solution coated tablets for 30 minutes at 70° C.±5° C. inlet air temperature. Determine the coating weight gain.

[0129] Coating with Film Coating Solutions

[0130] Apply coatings as above, except liquid rate is at 90±15 ml/min/gun. Dry the tablets for 10 minutes at 70° C.±5° C. Determine the coating weight gain.

Example 1

[0131] Example 1 is directed to an 8 mg tablet produced utilizing the ingredients and processes indicated above and in Table 3. Dissolution testing was performed using the dissolution procedure m0 as discussed above. The coating weight ratio of Ethocel E-10 to Methocel E-15 was 57:43 in this 4a; example. The results are illustrated in Table 5 below. In particular, the release of albuterol sulfate in the tablet according to the present invention was found to be comparable to that of the commercial product.

[0132] Table 3 also shows an example of a formulation of a 4 mg tablet according to the present invention.

12TABLE 5Time, Hrs1246810Invention, 8 mg01154748794Volmax, 8 mg102247708693

Example 2

[0133] Example 2 is directed to a 4 mg tablet produced utilizing the ingredients and processes indicated above and in Table 3. Dissolution testing was performed using the dissolution procedure as discussed above. In particular, this example is similar to that of Example 1 with isopropyl alcohol being used instead of ethyl alcohol in granulation and coating, and a 4 mg formulation being utilized. The results are illustrated in Table 6 below. The release of albuterol sulfate in the tablet according to the present invention was found to be slower than the commercial product.

13TABLE 6Time, Hrs1246810Invention, 4 mg1538627989Volmax, 4 mg82247698792

Example 3

[0134] Example 3 is directed to an 8 mg tablet produced utilizing the ingredients and processes indicated above and in Table 3. Dissolution testing was performed using the dissolution procedure as discussed above. In particular, this example is similar to that of Example 1 with CaSO4 being omitted, and the amount of lactose monohydrate being correspondingly increased to bring the core to 100 mg. The results are illustrated in Table 7 below. The coating weight ratio of Ethocel E-10 to Methocel E-15 was 50:50 in this example. The release of albuterol sulfate in the tablet according to the present invention was found to be faster than the commercial product.

14TABLE 7Time, Hrs1246810Invention, 8 mg28518096100101Volmax, 8 mg10224770 86 93

Example 4

[0135] Example 4 is directed to an 8 mg tablet produced utilizing the ingredients and processes indicated above and in Table 3. Dissolution testing was performed using the dissolution procedure as discussed above. In particular, this example is similar to that of Example 1 with PVP K-90 replacing Ethocel N-10 as binder. The coating weight ratio of Ethocel E-10 to Methocel E-15 was −50:50 in this example. For tablets having the same thickness of Exampe 1, the hardness was found to be 12 Kp. The results are illustrated in Table 8 below. The release of albuterol sulfate in the tablet according to the present invention was found to be faster than the commercial product.

15TABLE 8Time, Hrs1246810Sidmak, 8 mg 425658798100Volmax, 8 mg1022477086 93

Example 5

[0136] Example 5 is directed to an 8 mg tablet produced utilizing the ingredients and processes indicated above and in Table 3. Dissolution testing was performed using the dissolution procedure as discussed above. In particular, this example is similar to that of Example 1 with a portion of Ethocel N-10 in granulation being replaced with CaSO4. The results are illustrated in Table 9 below. The release of albuterol sulfate in the tablet according to the present invention was found to be faster than the commercial product.

16TABLE 9Time, Hrs1246810Invention, 8 mg1040729198100Volmax, 8 mg1022477086 93

Example 6

[0137] Example 6 is directed to a 4 mg tablet produced utilizing the ingredients and processes indicated above and in Table 3. Dissolution testing was performed using the dissolution procedure as discussed above. In particular, this example is similar to that of Example 1 with core tablets being manufactured using denatured alcohol (100 parts by weight of ethyl alcohol, 95% USP and 5 parts by weight of methyl alcohol, USP) instead of ethyl alcohol. The results are illustrated in Table 10 below. The release of albuterol sulfate in the tablet according to the present invention was found to be comparable to that using ethyl alcohol.

17TABLE 10Time, Hrs1246810Invention, Denatured alcohol, 4 mg295384969797Invention, ethyl alcohol, 4 mg315787979999

Example 7

[0138] Example 7 is directed to 4 mg tablets produced utilizing the ingredients and processes indicated above and in Table 4. Dissolution testing was performed using the dissolution procedure as discussed above. In particular, this example is similar to that of Example 1 with core tablets being coated with varying weight ratios of Ethocel N-10 and Methocel E-15, as indicated in Table 4 and indicated below, as follows:

[0139] Tablets were coated with extended release coating suspension having—

18Methocel Ethocel weight ratio of:A10:90B20:80C30:70D35:65

[0140] The extended release coating for all four ratios was applied to same weight gain, except for D where 50% coating suspension applied sample was studied for dissolution. The results are illustrated in Table 11 below. The release of albuterol sulfate in the tablet according to the present invention was found to be too slow for comparison.

19TABLE 11Time, Hrs1246810A(10:90)000000B(20:80)000000C(30:70)000001D(35:65), 50%1434597687Volmax ®, 4 mg82247698792

Example 8

Dissolution Profiles of Volmax® Tablets

[0141] 4 and 8 mg Volmax® tablets were subjected to dissolution testing according to the dissolution procedure set forth herein, with the exception that 12 tablets were tested for the 4 mg tablet whereas 6 tablets were tested for the 8 mg tablets. Solutions of different pH were prepared according to USP 25. The data for the tests using 0.90% NaCl were obtained from outside data. The dissolution results are shown in Tables 12 and 13 below.

20TABLE 12Dissolution Profile of Volmax ® tablet, 4 mg in Various Media.Method: USP 23, 2 (paddle) at 50 RPM, 900 M, 37° C. (12 Tablets)%, Dissolved1246810MediumhourhourshourshourshourshoursRecoveryPH 1.2 buffer11265681929698PH 4.5 buffer12295983929597PH 6.4 buffer12285882929598PH 7.4 buffer112653779094970.90% NaCl11255376919599

[0142]

21

TABLE 13

Dissolution Profile of Volmax ® tablet, 8 mg in Various Media.

Method: USP 23, 2 (paddle) at 50 RPM, 900 M, 37° C. (6 Tablets)

%, Dissolved

Medium
1 hour
2 hours
4 hours
6 hours
8 hours
10 hours
Recovery

PH 1.2 buffer
12
25
52
78
92
96
99

PH 4.5 buffer
12
27
56
80
92
94
96

PH 6.4 buffer
13
30
60
86
93
95
98

PH 7.4 buffer
12
27
53
78
92
95
97

0.90% NaCl
11
25
52
78
93
98
101

Example 9

[0143] 4 and 8 tablets according to Exampl 1 wre subjected to controlled accelerated conditions of 40° C. and 75% Relative Humidity for indication of the stability of tablets according to the present invention. The results are shown in Tables 14 and 15.

22TABLE 14Stability data of Albuterol Sulfate ER tablets, 8 mgCondition: 40° C./75% RH100's500'sDrug Release, %Initial1 month2 month3 month1 month2 month3 month1st hour32322222nd hour192022182121194th hour504848464948476th hour696867656967668th hour8381857883808110th hour92878788908987Assay, %98.298.098.397.098.298.097.5Moisture, %3.63.83.73.83.73.83.6

[0144]

23

TABLE 15

Stability data of Albuterol Sulfate ER tablets, 4 mg

Condition: 40° C./75% RH

100's
500's

Drug Release, %
Initial
1 month
2 month
3 month
1 month
2 month
3 month

2nd hour
9
7
7
3
7
6
7

4th hour
45
43
41
39
43
40
43

6th hour
65
65
61
61
65
61
64

8th hour
79
80
77
76
79
76
78

10th hour
88
89
86
86
88
86
88

Assay, %
98.9
98.7
97.2
98.2
98.8
97.6
98.6

Moisture, %
3.4
3.3
3.4
3.4
3.4
3.4
3.3

Example 10

[0145] This example is directed to bioequivalence study of both 4 & 8 mg products under fed and fasting conditions in healthy subjects.

[0146] The objective of the clinical study was to compare the relative steady state bioavailability of Sidmak products with Reference products. The study design was comparative randomized 2 way crossover steady state studies of Sidmak and Muro (Volmax) 4 and 8 mg Albuterol Sulfate Extended Release tablets in healthy adult males under fed and fasting conditions. Clinical supplies for the test product according to the present invention were according to Example 1, and Reference Product, Volmax manufactured by Glaxo Wellcome were Lot No: 10460727 for 8 mg tablets and Lot No. D008194 for 4 mg tablets.

[0147] Blood samples were collected during each study period before the initial drug administration and up to 12 hours post dose at appropriate times. Overall, data for the number of subjects indicated in the tables were analyzed in accordance with FDA guidance “Bioavailability and Bioequivalence Studies for Orally administered Drug Products—General Considerations.

[0148] Albuterol ion plasma was analyzed using a validated LC/MS/MS method developed at MDS Pharma Services, Inc. The following Pharmacokinetic parameters for plasma Albuterol were calculated.

24AUC 0-tThe area under the plasma concentration versus timecurve, from time 0 to the last measurable concentration,as calculated by the linear trapezoidal method.AUCinfThe area under the plasma concentration versus timecurve from time 0 to infinity. AUCinf was calculated asthe sum of the AUC O-t plus the ratio of the lastmeasurable plasma concentration to the elimination rateconstant.AUC/AUCinfThe ratio of AUC O-t to AUCinf.CmaxMaximum measured plasma concentration over the timespan Specified.tmaxTime of the maximum measured plasma concentration. Ifthe maximum value occurred at more than one timepoint, tmax was defined as the 1st time point with thisvalue.kel:Apparent first-order terminal elimination rate constantcalculated from a semi-log plot of the plasmaconcentration versus time curve. The parameter wascalculated by linear least-squares regression analysisusing the last three (or more) non-zero plasmaconcentrations.T½The apparent first-order terminal elimination half-lifeis calculated as 0.693/kel

[0149] Statistical analysis was performed using ANOVA on the transformed AUC 0-t; AUC inf; and Cmax pharmacokinetic parameters.

25AlbuterolParameterSidmak Fed Vs FastingSidmak Fed Vs. Muro FedAUC O-t97.6%97.3%AUC inf97.7%97.1%Cmax78.5%98.8%

[0150] Whereas, the following data was obtained under steady state fasting conditions

26ParameterAlbuterolln AUC O-t99.1% (95-103.3%)ln Cmax104.8%(98.2-111.8%)

[0151] The ratios of LSM, least square means, and 90% confidence intervals for the transformed parameters AUC and Cmax were within the 80-125% FDA acceptance range Based on these results, the present invention and Muro 4 and 8 mg albuterol sulfate extended release tablets are bioequivalent under fed as well as steady state fasting conditions.

[0152] Table16 and FIGS. 1 and 2, and Table 17 and FIGS. 3 and 4 identify the data under each study for 8 mg product.

[0153] Similar studies were conducted using 4 mg of the invention product and compared with Muro 4 mg Albuterol sulfate extended release products. Table 18 and FIGS. 5 and 6 identify the data under each study for 4 mg product.

27TABLE 16Summary of Results - Albuterol in PlasmaPharmacokinetic Parameters(N = 17)In AUC 0-t*In AUCinf*In Cmax*tmaxHalf-lifekel(pg · h/mL)(pg · h/mL)(pg/mL)(h)(h)(1/h)Sidmak (fast) (A)Mean105616.66109041.139075.4874.55611.9580.06393CV23.523.829.533.532.032.2n171717171717Sidmak (fed) (B)Mean102950.39106529.817081.6066.69111.8390.06759CV28.928.835.034.642.935.1n171717171717Kuro (fed) (C)Mean106138.68109692.477149.8177.52611.4200.07171CV16.416.817.720.751.636.4n161616161616Least-Squares MeansSidmak (fast) (A)105313.16108875.049001.416Sidmak (fed) (B)102747.86106368.827066.553Muro (fed) (C)105608.89109554.927155.965Ratio ofLeast-Squares Means(B/A) %97.697.778.5(B/C) %97.397.198.8*For In-transformed parameters, the antilog of the mean (i.e. the geometric mean) is reported. Subject No. 13 did not complete period 3, Formulation C PhAST STAB 2.3-000

[0154]

28

TABLE 17

Summary of Results - Albuterol in Plasma

Pharmacokinetic Parameters

(N = 36)

In AUC 0-t*
In Cmax*
Cssav
Cmin
tmax
Flux1
Flux2

(pg · h/mL)
(pg/mL)
(pg/ml)
(pg/mL)
(h)
(%)
(%)

Sidmak (A)

Mean
123488.78
15201.994
10539.18
7462.51
4.276
78.16
113.95

CV
22.9
21.6
21.5
25.7
20.7
23.3
31.3

n
36
36
36
36
36
36
36

Kuro (B)

Mean
125572.85
14521.762
10693.54
7508.92
4.576
70.77
103.02

CV
21.7
21.4
20.6
22.3
26.1
25.6
31.4

n
35
36
35
35
36
35
35

Least-Squares Means

Sidmak (A)
126622.28
15431.180

Kuro (B)
127783.42
14726.983

Ratio of

Least-Squares Means

(A/B) %
99.1
104.8

90% Confidence Intervals

(A/B) %

lower limit:
95.0%
98.2%

upper limit:
103.3%
111.8%

p-value (ANOVA)

A vs B
0.7149
0.2319

Intrasubject CV %
10.2
16.1

*For In-transformed parameters, the antilog of the mean (i.e. the geometric mean) is reported.

For Subject No. 37, period 2, formulation B, parameters AUC 0-t, Cssav, Cmin, Flux1 and Flux2 could not be calculated

PhAST STAB 2.3-000

[0155]

29

TABLE 18

Summary of Results - Albuterol in Plasma

Pharmacokinetic Parameter

(N = 36)

In AUC 0-t*
In AUCinf*
In Cmax*
tmax
Half-life
kel

(pg · h/mL)
(pg · h/mL)
(pg/mL)
(h)
(h)
(1/h)

Sidmak (A)

Mean
51116.63
54777.81
4237.615
4.458
14.297
0.05633

CV
20.7
22.8
32.0
27.4
41.0
37.6

n
36
36
36
36
36
36

Kuro (B)

Mean
53073.89
55606.14
4383.472
4.660
12.614
0.06426

CV
20.3
21.1
26.5
20.3
42.8
38.0

n
36
36
36
36
36
36

Least-Squares Means

Sidmak (A)
51116.63
54777.81
4237.615

Kuro (B)
53073.89
55606.14
4383.472

Ratio of

Least-Squares Means

(A/B) %
96.3
98.5
96.7

90% Confidence Intervals

(A/B) %

lower limit:
92.0%
94.1%
87.7%

upper limit:
100.8%
103.1%
106.6%

p-Value (ANOVA)

A vs B
0.1715
0.5816
0.5613

Period
0.0267
0.0262
0.5056

Sequence
0.0356
0.0782
0.4380

Intrasubject
11.4
11.5
24.8

*For In-transformed parameters, the antilog of the mean (i.e. the geometric mean) is reported.

See Section 3 of Report for details on calculation of parameters.

PhAST STAB 2.3-000

Example 11

Dissolution Examples at Differing pH

[0156] 4 mg and 8 mg albuterol sulfate extended release tablets were prepared according Example 1. These tablets according to the invention, and Volmax® 4 and 8 mg tablets were studied using the dissolution procedure set forth above for 12 tablets. The tablets were dissolved in (900 ml) deionized water, 0.1 N HCl, pH buffer 4.5 and pH Buffer 6.8 prepared according to USP 25. Samples were taken at 1, 2, 4, 6, 8 and 10 hours. The results are shown in Tables 19-22 for 4 mg tablets, and Tables 23-26 for 8 mg tablets.

30TABLE 19% OF LABEL CLAIM RELEASED AT SPECIFIED TIME INTERVAL IN DEIONIZED WATER4 mg Tablet of Invention4 mg Volmax ® TabletUnitUnitUnitWeight1246810Weight1246810#(mg)HourHoursHoursHoursHoursHours(mg)HourHoursHoursHoursHoursHoursMin.111.22205270829186.4112346668791Max.117.93306278899690.5153365929696Avg.115.02245674869288.8132755819194% RSD2.027.213.45.13.22.31.41.412.410.710.18.22.61.7

[0157]

31

TABLE 20

% OF LABEL CLAIM RELEASED AT SPECIFIED TIME INTERVAL IN 0.1 N HC

4 mg Tablet of Invention
4 mg Volmax ® Tablet

Unit

Unit

Unit
Weight
1
2
4
6
8
10
Weight
1
2
4
6
8
10

#
(mg)
Hour
Hours
Hours
Hours
Hours
Hours
(mg)
Hour
Hours
Hours
Hours
Hours
Hours

Min.
113.3
2
9
53
72
84
90
89.2
8
21
43
62
84
92

Max
117.5
4
28
60
78
89
96
93.5
13
27
53
81
94
98

Avg.
115.1
3
19
56
75
87
93
91.3
11
24
49
72
90
95

% RSD
1.2
19.8
30.2
3.8
2.3
1.7
2.2
1.6
15.0
7.6
6.5
7.3
3.2
2.1

[0158]

32

TABLE 21

% OF LABEL CLAIM RELEASED AT SPECIFIED TIME INTERVAL IN pH 4.5 BUFFER

4 mg Tablet of Invention
4 mg Volmax ® Tablet

Unit

Unit

Unit
Weight
1
2
4
6
8
10
Weight
1
2
4
6
8
10

#
(mg)
Hour
Hours
Hours
Hours
Hours
Hours
(mg)
Hour
Hours
Hours
Hours
Hours
Hours

Min.
114.0
1
5
44
66
79
87
85.9
10
22
44
63
86
90

Max
119.6
2
21
52
71
83
91
91.9
14
32
64
89
98
99

Avg.
116.5
2
15
49
68
81
89
89.7
12
26
52
77
91
94

% RSD
1.2
28.3
34.8
4.5
2.4
1.5
1.4
2.2
8.6
10.8
10.7
11.2
4.2
2.5

[0159]

33

TABLE 22

% OF LABEL CLAIM RELEASED AT SPECIFIED TIME INTERVAL IN pH 6.8 BUFFER

4 mg Tablet of Invention
4 mg Volmax ® Tablet

Unit

Unit

Unit
Weight
1
2
4
6
8
10
Weight
1
2
4
6
8
10

#
(mg)
Hour
Hours
Hours
Hours
Hours
Hours
(mg)
Hour
Hours
Hours
Hours
Hours
Hours

Min.
113.2
1
3
37
58
72
81
87.5
9
20
39
57
75
87

Max
120.6
1
12
46
65
78
87
92.6
12
26
52
81
92
96

Avg.
115.6
1
6
42
62
75
85
90.3
11
23
46
68
87
92

% RSD
1.9
25.6
56.0
6.0
3.6
2.6
2.3
1.8
8.7
8.7
9.2
11.4
5.7
2.7

[0160]

34

TABLE 23

% OF LABEL CLAIM RELEASED AT SPECIFIED TIME INTERVAL IN DEIONIZED WATER

8 mg Tablet of Invention
8 mg Volmax ® Tablet

Unit

Unit

Unit
Weight
1
2
4
6
8
10
Weight
1
2
4
6
8
10

#
(mg)
Hour
Hours
Hours
Hours
Hours
Hours
(mg)
Hour
Hours
Hours
Hours
Hours
Hours

Min.
108.8
3
29
58
77
88
94
162.0
12
28
56
77
84
82

Max
113.6
13
36
66
85
95
99
175.3
15
37
72
94
99
99

Avg.
111.4
9
32
62
80
91
96
172.2
13
33
62
85
93
95

% RSD
1.3
32.2
6.3
3.6
2.8
2.2
1.7
2.2
8.6
9.9
8.1
6.1
4.2
4.9

[0161]

35

TABLE 24

% OF LABEL CLAIM RELEASED AT SPECIFIED TIME INTERVAL IN 0.1 N HCl

8 mg Tablet of Invention
8 mg Volmax ® Tablet

Unit

Unit

Unit
Weight
1
2
4
6
8
10
Weight
1
2
4
6
8
10

#
(mg)
Hour
Hours
Hours
Hours
Hours
Hours
(mg)
Hour
Hours
Hours
Hours
Hours
Hours

Min.
110.0
3
28
58
76
87
94
168.4
8
22
45
66
79
76

Max
115.2
11
37
66
84
94
99
182.8
14
30
61
87
96
99

Avg.
112.1
7
32
63
81
91
97
174.8
11
26
54
78
91
95

% RSD
1.2
38.8
7.5
4.2
3.0
2.2
1.6
2.2
16.2
11.1
8.5
7.2
5.0
6.6

[0162]

36

TABLE 25

% OF LABEL CLAIM RELEASED AT SPECIFIED TIME INTERVAL IN pH 4.5 BUFFER

8 mg Tablet of Invention
8 mg Volmax ® Tablet

Unit

Unit

Unit
Weight
1
2
4
6
8
10
Weight
1
2
4
6
8
10

#
(mg)
Hour
Hours
Hours
Hours
Hours
Hours
(mg)
Hour
Hours
Hours
Hours
Hours
Hours

Min.
107.6
2
24
52
70
84
91
166.9
11
22
46
67
88
91

Max
113.8
9
30
59
78
91
97
178.7
15
35
70
91
98
99

Avg.
111.1
5
27
55
74
86
94
173.5
13
30
59
82
92
95

% RSD
1.8
55.2
8.1
4.1
3.1
2.3
1.7
1.7
12.9
12.6
10.9
8.2
3.1
2.3

[0163]

37

TABLE 26

% OF LABEL CLAIM RELEASED AT SPECIFIED TIME INTERVAL IN pH 6.8 BUFFER

8 mg Tablet of Invention
8 mg Volmax ® Tablet

Unit

Unit

Unit
Weight
1
2
4
6
8
10
Weight
1
2
4
6
8
10

#
(mg)
Hour
Hours
Hours
Hours
Hours
Hours
(mg)
Hour
Hours
Hours
Hours
Hours
Hours

Min.
107.8
1
17
43
61
74
84
162.2
10
21
45
68
87
91

Max
116.0
6
27
53
71
83
91
181.9
15
34
68
89
96
100

Avg.
111.0
2
22
49
67
80
88
173.4
12
27
57
80
92
96

% RSD
2.1
54.6
11.9
5.2
3.9
3.2
2.3
3.0
12.8
12.3
9.5
6.3
2.7
2.8

[0164] While the invention has been described in connection with certain preferred embodiments so that aspects thereof may be more fully understood and appreciated, it is not intended to limit the invention to these particular embodiments. On the contrary, it is intended to cover all alternatives, modifications and equivalents as may be included within the scope of the invention as defined by the appended claims.

Sustained release pharmaceutical preparations and methods for producing the same

Information

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Abstract

Description

Claims