WO2008155620A1

WO2008155620A1 - Dosage form containing dispersible matrix of sustained release granules

Info

Publication number: WO2008155620A1
Application number: PCT/IB2008/001561
Authority: WO
Inventors: Mathias Scheer; Helene Rey; Dirk Kramer; Marc Fischer
Original assignee: Develco Pharma Schweiz Ag
Priority date: 2007-06-20
Filing date: 2008-06-11
Publication date: 2008-12-24

Abstract

A tablet has a dispersible matrix of granules each containing an active agent in a sustained release matrix, wherein the tablet is monolithic and adapted to release the active agent over a predetermined time period according to a profile of dissolution including a zero order release phase. The tablet can further contain tablet excipients and/or a non-functional film coating. A method for providing a tablet of the invention is also disclosed.

Description

DOSAGE FORM CONTAINING DISPERSIBLE MATRIX OF SUSTAINED RELEASE GRANULES

SPECIFICATION BACKGROUND OF THE INVENTION

1. FIELD OF INVENTION

[0001 ] This invention relates to sustained release pharmaceutical formulations, methods for making them and methods for using them.

2. DESCRIPTION OF RELATED ART

[0002] Drug delivery systems having zero order release profiles are considered very desirable for use in sustained release pharmaceutical formulations. In a drug delivery system having a zero order release profile, the amount of drug released is independent of the amount of drug remaining in the delivery system and remains constant over the entire delivery profile. A plot of percent of drug released against time is a straight line for a drug delivery system having a zero order release profile. A variety of drug delivery systems having zero (or substantially zero) order release profiles have been proposed.

[0003] For example, U.S. Patents Nos.3,995,631 and 3,977,404 disclose osmotic pumps in which osmotic pressure pushes the drug out of an almost microscopic orifice. The zero order profile is achieved due to the constant, small, cross-section of the orifice being the rate determining step in the drug release.

[0004] U.S. Patents Nos.4,839,177 and 5,422,123 disclose zero order drug delivery systems comprising a drug delivery layer sandwiched between two layers that are impermeable. Only the drug delivery layer is eroded and the cross-section of the eroding layer is constant.

[0005] U.S. PatentNo. 7,195,778 discloses a drug delivery device comprising a core of drug and excipient that has a cylindrical plug embedded therein, and a drug-impermeable coating that at least partially surrounds the core. The cylindrical plug expands upon absorbing water that permeates the coating, punching a hole in the impermeable coating. Drug dissolution or erosion is designed to be the rate determining step of drug release and is said to be constant because of the constant cross-section of the hole formed in the coating.

[0006] The manufacture of the foregoing drug delivery systems is complex and can require special equipment to produce complex drug delivery systems comprising multiple structural components.

[0007] Landgraf et al., "New Polymer Enables Near Zero-Order Release of Drugs." Drug

Delivery Technology 5(2), 48-55 (2005) discloses porous polymer microcarriers that exhibit near zero order kinetics of drug release following an initial burst. The polymers are not reactive. Drug delivery is accomplished through diffusion of fluid into the pores, which carry the drug. [0008] U.S. Patent No.6,090,411 discloses sustained release tablets that are said to be easily manufactured. The tablets are monolithic and comprise a swellable hydrophilic matrix and a salt adapted to control outward diffusion of the active agent by an inwardly progressing hardening reaction between the salt and the matrix. Each of the examples comprises the use of a carbonate or a bicarbonate as the salt to release the active agent over 6-8 hours or more. [0009] U.S. Patent Application Publication No. 20060062846 Al discloses a monolithic composition including alfuzosin as an active agent in a sustained release matrix comprising lactose monohydrate, hydroxypropylmethylcellulose, polyvinylpyrrolidone and magnesium stearate. The composition is designed to release 13-33% of the alfuzosin within 2 hours, 40-60% of the alfuzosin within 7 hours, and greater than 80% of the alfuzosin within 20 hours of administration.

[0010] U.S. Patent Application Publication No. 20050042289 Al discloses a sustained release tablet comprising active agent granules blended in a sustained release matrix. This tablet is said to achieve nearly zero order release kinetics.

[0011 ] Despite the foregoing developments, it is desired to provide an improved zero order drug delivery system that is easy to manufacture. It is further desired to provide a monolithic tablet adapted to release an active agent with a zero order release profile. It is still further desired to provide such a monolithic tablet capable of achieving a relatively low release of active agent over 30 minutes and complete release within about 2-6 hours. [0012] All references cited herein are incorporated herein by reference in their entireties.

BRIEF SUMMARY OF THE INVENTION

[0013] Accordingly, a first aspect of the invention is a tablet comprising a dispersible matrix comprising a plurality of granules each containing an active agent in a sustained release matrix, wherein the tablet is monolithic and adapted to release the active agent over a predetermined time period according to a profile of dissolution when measured in a USP type II dissolution apparatus with a paddle rotation speed of 75 rpm in 0.0 IM hydrochloric acid buffer at 37°C and pH 6.8, said profile including a zero order release phase.

[0014] A second aspect of the invention is a tablet comprising: (a) a dispersible matrix comprising: (i)a plurality of granules each containing an active agent in a sustained release matrix; and (ii) tablet excipients; and (b) a non-functional film coated on a surface of the dispersible matrix, wherein the tablet is monolithic and adapted to release the active agent over a predetermined time period according to a profile of dissolution when measured in a USP type H dissolution apparatus with a paddle rotation speed of 75 rpm in 0.01M hydrochloric acid buffer at 37°C and pH 6.8, said profile including a zero order release phase beginning when 39% or less active agent has been released and ending when 60% or more active agent has been released.

[0015] A third aspect of the invention is a tablet comprising: (a) a dispersible matrix comprising: (i)a plurality of granules each containing an active agent in a sustained release matrix; and (ii) tablet excipients; and (b) a non- functional film coated on a surface of the dispersible matrix, wherein the tablet is monolithic and adapted to release 20-35% of the active agent within 30 minutes, 4059% of the active agent within 60 minutes and more than 90% of the active agent within 4 hours of adding the tablet to a 0.01M hydrochloric acid buffer at 37°C and pH 6.8 in a USP type II dissolution apparatus with a paddle rotation speed of 75 rpm. [0016] A fourth aspect of the invention is a method for providing a tablet of the invention, said method comprising: (a) providing a granulation composition comprising the active agent and a sustained release agent; (b) granulating the granulation composition to form the granules;

(c) forming the dispersible matrix from the granules and optionally tablet excipients; and

(d) compressing the dispersible matrix to form the tablet.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The invention will be described in conjunction with the following drawings wherein Figs. 1, 2, 3 and 4 are graphs of the dissolution profiles of certain preferred embodiments of the invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION [0018] The invention was driven by the desire to provide an easily manufactured dosage form capable of achieving a controlled release of active agent over a relatively short duration and complete release of the active agent within about 2-6 hours. The invention was further driven by the desire to provide a system in which the slope of the dissolution profile can be easily adjusted. The inventors were able to fulfill these desires by providing a dispersible matrix tablet. The matrix is dispersible in the sense that it is disintegrated into its granules or particles within 30 minutes after being exposed to aqueous media. Such a property of the matrix and of any optional non-functional film coating shall be referred to hereinafter as "dispersible". The expression "non-functional film coating" as used herein means that the film coating has no effect or substantially no effect on the dissolution profile. The expression is not intended to exclude from the invention film coatings having functions (e.g., taste masking, etc.) other than dissolution modification.

[0019] The term "tablet" is used herein in its broadest sense to encompass solid dosage forms of various sizes and shapes. Suitable shapes include but are not limited to discs, ovoids, ellipsoids, rhomboids, and the like. The size of the tablet should be large enough to delivery at least one dose of the active agent but not so large as to hinder oral, anal and/or vaginal administration in a human or other animal.

[0020] The tablet is preferably monolithic. The term "monolithic" denotes that the tablet (or other object) is not layered. The term monolithic is not intended to require that the tablet be formed from a single material or comprise a completely homogeneous mixture, although such embodiments are within the scope of the invention.

[0021 ] The tablet comprises a plurality of granules, wherein each of the granules contains an active agent in a sustained release matrix. The granules are compressed together with tablet excipients to provide uncoated embodiments of the tablet. In such embodiments, the granules and the tablet excipients together constitute the dispersible matrix of the tablet. In other embodiments, the dispersible matrix consists of granules compressed together without any tablet excipients. In certain embodiments, the granules comprise 10-90% or 25-75% or 40-60% of the total tablet weight, with the balance of the tablet weight being optional excipients and an optional external film coating. (All percentages referenced herein are in weight percent unless otherwise noted.)

[0022] The active agent can be a drug, a nutritional additive (e.g., vitamin), or a diagnostic substance. The active agent is preferably at least one substance which induces or impedes a biological process in an organism to which it is administered. It is particularly preferred that the active agent be a substance that is ideally administered over a prolonged period of time. Non-limiting examples of suitable active agents include Zolpidem, metoprolol, carvedilol, valsartane, amlodipine, nimodipine, felodipine, methylphenidate, paroxetine, fluoxetine, metformine, simvastatine, fluvastatine, oxycodone, hydromorphone, salts thereof, enantiomers thereof, diastereomers thereof, and racemic mixtures thereof.

[0023] The amount of active agent in the composition can be determined with routine experimentation using the present disclosure as a guide. The active agent preferably ranges from 0.1 to 25% or 5 to 15% based on the total weight of the granules, and/or constitutes about 1-1000 mg or 10-500 mg or 50-250 mg of the total tablet weight. In a preferred embodiment of the invention, each tablet of the composition preferably contains from 1 mg to 25 mg, preferably 5 to 15 mg, most preferably about 6.25 mg (i.e., 6.25 mg ± 0.1 mg) or about 12.5 mg (i.e., 12.5 mg ± 0.1 mg) Zolpidem tartrate as the active agent.

[0024] The sustained release matrix of the granules comprises at least one sustained release agent and at least one granule excipient. The sustained release agent is preferably a hydrophilic polymer that gels or swells upon contact with gastrointestinal fluids, such that passage of the formulation from the stomach (duodenum, jejunum, etc.) is delayed. In addition, the sustained release agent provides a matrix from which the active agent cannot readily escape. [0025] Suitable sustained release agents are biocompatible. They are slowly soluble and/or slowly gelable and/or swell rapidly or at a different rate in aqueous liquids and then may optionally be broken down. Preferred polymers for use as sustained release agents include hydroxymethylcellulose, hydroxyethyl-cellulose, hydroxypropylmethylcellulose having a molecular weight of from 1000 to 4,000,000, hydroxypropylcellulose having a molecular weight of from 2000 to 2,000,000, carboxyvinyl polymers, chitosans, mannans, galactomannans, xanthans, carrageenans, amylose, alginic acid, its salts and its derivatives, pectins, acrylates, methacrylates, acrylic/methacrylic copolymers, polyanhydrides, polyamino acids, poly(methyl vinyl ether/maleic anhydride) polymers, polyvinyl alcohols, glucans, scleroglucans, polyethylene oxides, carboxymethylcellulose and its derivatives, ethylcellulose, methylcellulose and, in general, hydrophilic cellulose derivatives.

[0026] HPMC is the most preferred sustained release agent, as it is pharmaceutically acceptable and non-ionic, such that no interactions between the polymer and other constituents are to be expected. HPMC provides a hydrophilic matrix in which the active agent is preferably distributed homogeneously (or uniformly), and is released over a sustained period of time. [0027] The various HPMC quality grades commercially available differ in their molecular weight. The molecular weight of the polymer used and its concentration in the tablet are of particular importance for the release of the drug substance. Adjustment of these parameters to achieve desired results is possible with routine experimentation using the present disclosure as a guide. A higher molecular weight leads to an increase in gel strength and increased viscosity, reducing the release of the drug substance due to a greater barrier to diffusion and slower dispersion of the tablet. Increasing the polymer concentration in the preparation, i.e., the ratio HPMC/drug substance, results in an increase of gel viscosity on the surface of the tablets. This delays the release of drug substance from the gel layer. The concentration effect is, however, of limited relevance for HPMC grades of high molecular weight. [0028] The content of sustained release agent can range from 5 to 95% relative to the total weight of the granules, but is preferably from' 25 to 75% and more preferably about 40 to 60%. [0029] In addition to the sustained release agent, the granules also contain at least one pharmacologically inert ingredient, referred to as a granule excipient. Excipients can be broadly classified according to their intended function, although many excipients have more than one function. It should be noted that the expressions "granule excipient" and "tablet excipient" are not necessarily intended to convey any information about the function of an excipient so characterized. A granule excipient is an excipient that is present in the granule. A tablet excipient is any excipient that is present in the tablet other than in the granules. All, none or some of the granule excipients can be identical to the tablet excipients. [0030] Suitable granule excipients include but are not limited to binders, flow enhancers, lubricants, fillers, stabilizers, and other pharmaceutically acceptable additives. Soluble granule excipients usually increase the release rate of embodied active ingredients, whereas the release rate is reduced by insoluble granule excipients. The total amount of excipients in the granules can range from 5 to 95% relative to the total weight of the granules, but is preferably from 25 to 75% and more preferably about 40-60%.

[0031] Preferred binders include povidone (e.g., Plasdone K 29-32), hydroxypropylmethylcellulose (eg., Methocel K5), starch, etc. Required quantities of binders can be determined by persons skilled in the art using the present disclosure as a guide. [0032] Preferred flow enhancers and lubricants include silicas (e.g., anhydrous colloidal silica), talc, magnesium stearate, sodium stearyl fumarate, etc. Required quantities can be determined by persons skilled in the art using the present disclosure as a guide. [0033] Preferred fillers include cellulose (e.g., macrocrystalline cellulose, such as AVICEL PH 200), lactose monohydrate, sorbitol, mannitol, maize starch, starch, pregelatinized maize starch, calcium phosphate etc. Required quantities can be determined by persons skilled in the art using the present disclosure as a guide.

[0034] Preferred stabilizers include pharmaceutically acceptable organic acids, such as 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. According to the invention, acids particularly preferred are tartaric, fumaric, citric, and succinic and their acid salts. Preferred stabilizers also include antioxidants such as Vitamin E, BHT, etc. It can also contain alkalizing agents for stabilization such as sodium triphosphate and calcium carbonate, are also suitable for use in the invention. [00351 The granules are combined with tablet excipients, tableted to form tablets, and optionally coated with a film as discussed in further detail below. The tablet excipients can be the same as or different from the granule excipients. The tablet excipients form the dispersible matrix in which the sustained release granules are contained, and thus, the tablet excipients should be selected and combined so as to achieve immediate dispersion of the granules.

[0036] Preferably, the tablet excipients include at least a disintegrant, a flow enhancer and a lubricant. Preferred disintegrants include but are not limited to microcrystalline cellulose, povidone XL, croscarmellose sodium, sodium starch glycolate, etc. Depending on the disintegration power or amount of disintegrants, the slope of the release profile can be adjusted.

Higher disintegration power will lead to a steeper profile whereas lower disintegration power or lower amount of disintegrant reduces the slope of the release profile.

[0037] Preferred lubricants include but are not limited to magnesium stearate, sodium stearyl fumarate, hydrogenated castor oil, etc.

[0038] Preferred flow enhancers can be selected from the same list of flow enhancers discussed above with respect to granule excipients.

[0039] The invention further comprises a method for providing the tablets. The method comprises providing the sustained release granules, combining the granules with excipients and compressing them to form uncoated tablets, and optionally coating the uncoated tablets to form a coated tablet in accordance with the invention.

[0040] The granules are provided by granulating a composition comprising the active agent and a sustained release agent. In certain embodiments, the granulation composition can further comprise at least one granule excipient and/or at least one solvent.

[0041 ] The granulation composition can be granulated using any suitable methods known in the art. A binder is preferably included in the granulation composition to improve the granulation process. Examples of a suitable binder include povidone, hydroxypropyl cellulose

(HPC), a mixture of polyethylene oxide and polyethylene glycol, acacia, carbomer, carboxymethylcellulose sodium, ethylcellulose, dextrin, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl methylcellulose, maltodextrin, povidone, pregelatinized starch, zein, starch, and the like.

[0042] Optionally, water and/or other solvents can be added to aid the granulation process.

The amount of solvent added depends on, e.g., the selection of a granulation process, and is readily determinable by those of skill in the art. The solvent may be added at any suitable time point during the granulation process. For example, a binder may be mixed with a solvent to form a binder solution, and then the binder solution can be sprayed onto the remaining quantity of the granulation composition. Alternatively, if a binder solution is too viscous to be uniformly sprayed, the binder can be blended with the active agent and then be sprayed with solvent. [0043] Any suitable granulation method can be used to produce the granules. For example, either wet granulation or dry granulation methods can be used.

[0044] Dry granulation refers to the granulation of a formulation without the use of heat and solvent. In certain dry granulation embodiments, the blended granulation composition is compacted into a slug or a sheet and then comminuted into compacted granules. Dry granulation technique is particularly useful when the active agent is sensitive to heat or solvent. [0045] Alternatively, wet granulation can be used. In wet granulation, solvents and binders are typically added to a formulation to provide larger aggregates of granules. The temperature during granulation can be set at any suitable point, generally not exceeding the melting point of any components of the granulation composition. In certain embodiments, the granulation composition is granulated at a temperature of about 35-65°C for about 20-90 minutes. The granules are optionally air dried for a suitable duration (e.g., one or more hours). [0046] Preferably, the granules are formed by high shear mixer granulation or more preferably, fluidized bed granulation. In fluidized bed granulation, a binder solution is sprayed from, e.g., a spray gun positioned at any suitable manner (e.g., top or bottom). The spray position and the rate of spray may depend on the nature of the active agent and the binder used, and are readily determinable by those skilled in the art.

[0047] The granules are screened and/or milled, dried and then screened and/or milled to the desired particle size. Milling can be performed using any commercially available apparatuses (e.g., Comil equipped with a 0.0787 inch screen). The mesh size for the screen can be selected depending on the size of the granules desired. Preferably, the mesh size can range from 0.0331 inch screen (mesh 20) to 0.0098 inch screen (mesh 60). The milling process aids in providing relatively uniform granules. After the granulated active agents are milled, they may be further dried (e.g., with preheated or dried air) if desired.

[0048] In certain embodiments, the mean size of the granules can range from about 50 μm to about 3 mm, or about 100 μm to about 2 mm, or about 300 μm to about 1 mm. Typically, the bulk density or the tap density of the active agent granules ranges from about 0.1 g/ml to about 1.5 g/ml, or about 0.2 to about 0.8 g/ml, or about 0.3 g/ml to about 0.6 g/ml. Bulk density is measured based on USP method (see US Pharmacopoeia, edition XXTV, pages 1913-1914, testing method 616). [0049J The granules are combined with at least one tablet excipient and compressed to form an uncoated tablet comprising a plurality of granules. This tablet shaping can be done by any suitable means, with or without compressive force. For example, compression of the formulation after the granulation step can be accomplished using any tablet press, provided that the tablet composition is adequately lubricated. The level of lubricant in the formulation is typically in the range of 0.5-2.0%, with magnesium stearate being the most preferred lubricant. Many alternative means to effectuate this step are available, and the invention is not limited by the use of any particular apparatus.

[0050] The diameter and shape of the tablet depends on the molds, dies, and punches selected for the shaping or compression of the granulation composition. Tablets can be discoid, oval, oblong, round, cylindrical, triangular, and the like. The tablets maybe scored to facilitate breaking. The top or lower surface can be embossed or debossed with a symbol or letters. [0051] The compression force can be selected based on the type/model of press, what physical properties are desired for the tablets (e.g., desired, hardness, friability, etc.), the desired tablet appearance and size, and the like. The compression force applied is such that the compressed tablets have a suitable hardness and strength to be packaged, shipped and handled by the user. If desired, a higher compression force can be applied to the tablet to increase the tablet hardness. However, the compression force is preferably selected so that it does not hinder the disintegration of the tablet or lead to undesired results (e.g., cracking, capping or breaking). Preferably, the compression force applied is such that the compressed tablet has a resistance against crushing force of 20 - 250 N.

[0052] In certain embodiments, the uncoated tablet will have a weight of about 10 mg to about 2000 mg, or about 50 mg to about 500 mg, or 114±10 mg to about 228±20 mg. [0053] The uncoated tablet is optionally coated with a non-functional external film. The external film is preferably immediately dissolved. Polymers suitable for use in the external film include but are not limited to HPMC, polyvinylacetate, povidone, carageenan, hydroxypropylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, methylcellulose, ethylcellulose, cellulose acetate, sodium carboxymethylcellulose, polymers and copolymers of acrylic acid and methacrylic acid and esters thereof, polyethylene glycols and polyethylene oxides.

[0054] The external film can also include excipients, such as colorants, flavorants, taste-masking agents, light protection agents, lubricants, etc. [0055] In another aspect, the present invention provides a method for generating a predetermined sustained release profile of an active agent. The release profile can be in vitro or in vivo. The most preferred release profile achieved by tablets of the invention is zero order. The expression "zero order" as used herein refers to at least a portion of a release profile in which a plot of active ingredient release against time is sufficiently linear such that release rate for each test point within a given time interval does not deviate by more than 30% from the mean release rate within that interval. Table 1 and Fig. 1 of Example 1 below demonstrate an embodiment wherein the zero order portion of the release profile does not deviate by more than 30% from the mean release rate. A zero order release profile is one in which the active agent release rate is constant or near-constant for a given time interval.

[0056] All active agent release values referenced herein are stated with reference to measurements conducted in a USP type II dissolution apparatus with a paddle rotation speed of 75 rpm in 0.01M hydrochloric acid buffer at 37°C and pH 6.8.

[0057] Release profiles other than zero order are also within the scope of the invention, as are release profiles having different phases with different release kinetics. Thus, for example, as shown in Fig.2, it is possible for tablets of the invention to exhibit a zero order phase over only a portion of the release profile. In certain embodiments, the zero order release phase begins when 39% or less active agent has been released and ends when 60% or more active agent has been released. Preferably the zero order release profile begins when 30% or less active agent has been released and ends when 80% or more active agent has been released. More preferably, the zero order release phase begins within 30 minutes of adding the tablet to the dissolution media.

[0058] The release characteristics of the tablets can also be characterized as a function of time with or without reference to the kinetics of active agent release. Thus, in certain embodiments, less than 40% or less than 30% of the active agent is released within 30 minutes of adding the tablet to the dissolution media. In certain embodiments, less than 30% of the active agent is released within 30 minutes of adding the tablet to the dissolution media and more than 90% of the active agent is released within 4 hours of adding the tablet to the dissolution media. In certain embodiments, 20-35% of the active agent is released at 30 minutes, 40-59% of the active agent is released at 60 minutes and more than 90% of the active agent is released at 4 hours. [0059] The invention will be illustrated in more detail with reference to the following Examples, but it should be understood that the present invention is not deemed to be limited thereto.

EXAMPLES [0060] Example 1

[0061 ] Tablets in accordance with the invention were prepared from the ingredients listed in Tables 1 and 2. [0062] Table 1. Dispersible Film Coated Tablet Formulation

[0063] Table 2. Dispersible Tablet Formulations And Dispersible Film Coated Tablet Formulations

[0064] The tablets were prepared from the foregoing ingredients by a six-step process. [0065] Step 1 : Zolpidem tartrate, Hypromellose 5cP, microcrystalline cellulose (Avicel PH 101), Silica colloidal (Aerosil 200) and Plasdone K 29 - 32 were spray granulated in a fluidized bed with a granulation liquid consisting of tartaric acid, Plasdone K29 - 32 and water. [0066] Step 2: The fluid bed granules of step 1 were screened through sieve # 20. [0067] Step 3 : The granules of step 2 were mixed with colloidal silica and microcrystalline cellulose (Avicel PH 200).

[0068] Step 4: The granules of step 3 were lubricated with magnesium stearate. [0069] Step 5: The final blend of step 4 was compressed into tablets with the properties listed in Table 3. [0070] Table 3. Tablet Properties

[0071] Step 6: The tablets were coated with a non-functional coating.

[0072] The active agent release properties of the 12.5 mg dispersible tablets and film coated tablets (Figure 2) as well as active release properties of the 6.25 mg dispersible tablets and 6.25 mg film coated tablets (Figure 3) were tested in a USP type II dissolution apparatus with a paddle rotation speed of 75 rpm in 0.01M hydrochloric acid and pH 6.8 buffer at 37°C. The tablets of the invention exhibited a substantially zero order release phase from about 20% to about 80% active agent released.

[0073] Example 2

[0074] Tablets in accordance with the invention were prepared from the ingredients listed in

Table 4 using the same manufacturing method as described for Example 1. In this example, the sustained release granule formulation remains unchanged whereas the amount of disintegrant in the dispersible tablet varies.

[0075] Table 4. Dispersible Tablet Formulations With Different Amount Of Disintegrant.

[0076] The active agent release properties of the formulation Zolpidem 12.5 dispersible tablets 31 Tl , 31 T3 and 31 T5 were tested in a USP type II dissolution apparatus with a paddle rotation speed of 75 rpm in pH 6.8 buffer at 37°C. The tablets of the invention exhibited a substantially zero order release phase with different slope depending on the amount of disintegrant (Figure 4).

[0077] Preferred embodiments of the tablets also exhibited dose proportionality (see Example 1). Unlike certain sustained release tablets in the prior art, dose proportional tablets of the invention can be divided into smaller doses, which contain an amount of active agent proportional to the size of the fragment relative to the whole.

[0078] While the invention has been described in detail and with reference to specific examples thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A tablet comprising a dispersible matrix comprising: a plurality of granules each containing an active agent in a sustained release matrix; wherein the tablet is monolithic and adapted to release the active agent over a predetermined time period according to a profile of dissolution when measured in a USP type II dissolution apparatus with apaddle rotation speed of 75 rpm in 0.01M hydrochloric acid buffer at 37°C and pH 6.8, said profile including a zero order release phase.

2. A tablet comprising:

(a) a dispersible matrix comprising:

(i) a plurality of granules each containing an active agent in a sustained release matrix; and (ii) tablet excipients; and

(b) a non-functional film coated on a surface of the dispersible matrix, wherein the tablet is monolithic and adapted to release the active agent over a predetermined time period according to a profile of dissolution when measured in a USP type II dissolution apparatus with a paddle rotation speed of 75 rpm in 0.0 IM hydrochloric acid buffer at 37°C and pH 6.8, said profile including a zero order release phase beginning when 39% or less active agent has been released and ending when 60% or more active agent has been released.

3. A tablet comprising:

(a) a dispersible matrix comprising:

(b) a non-functional film coated on a surface of the dispersible matrix, wherein the tablet is monolithic and adapted to release 20-35% of the active agent within 30 minutes, 40-59% of the active agent within 60 minutes and more than 90% of the active agent within 4 hours of adding the tablet to a 0.0 IM hydrochloric acid buffer at 37°C and pH 6.8 in a USP type II dissolution apparatus with a paddle rotation speed of 75 rpm.

4. The tablet of claim 1 , wherein the zero order release phase begins when 30% or less active agent has been released and ends when 80% or more active agent has been released.

5. The tablet of claim 1, wherein the zero order release phase begins within 30 minutes of adding the tablet to the buffer.

6. The tablet of claim 1 , wherein less than 40% of the active agent is released within 30 minutes of adding the tablet to the buffer.

7. The tablet of claim 6, wherein less than 30% of the active agent is released within 30 minutes of adding the tablet to the buffer and more than 90% of the active agent is released within 4 hours of adding the tablet to the buffer.

8. The tablet of claim 6, wherein 20-35% of the active agent is released at 30 minutes, 40-59% of the active agent is released at 60 minutes and more than 90% of the active agent is released at 4 hours.

9. The tablet of claim 1, wherein the active agent is at least one member selected from the group consisting of Zolpidem, metoprolol, carvedilol, valsartane, amlodipine, nimodipine, felodipine, methylphenidate, paroxetine, fluoxetine, metformine, simvastatine, fluvastatine, oxycodone, hydromorphone, salts thereof, enantiomers thereof, diastereomers thereof, and racemic mixtures thereof.

10. The tablet of claim 1, wherein the active agent is at least one member selected from the group consisting of Zolpidem, zoplidem tartrate, Zolpidem hydrochloride, Zolpidem hydrobromide, Zolpidem maleate, Zolpidem fumarate, Zolpidem tartrate, Zolpidem sulfate and Zolpidem sulfonate.

11. The tablet of claim 1, wherein the tablet excipients are members selected from the group consisting of disintegrants, flow enhancers, lubricants, sustained release agents, fillers, stabilizers, disintegrants, film forming agents, colorants and plasticizers.

12. The tablet of claim 1, further comprising an immediate release film coating an entire surface of the tablet.

13. The tablet of claim 12, comprising: 4-6 % Zolpidem or a salt thereof;

3-6 % povidone;

25-40 % hypromellose 5cP;

0.5-1.5 % anhydrous colloidal silica;

45-55 % microcrystalline cellulose;

5-7 % Tartaric acid;

1-2% Magnesium stearate;

1-5% Colorant; and

0.1-1% Polyethylene oxide 6000.

14. The tablet of claim 12, wherein the active agent is homogeneously distributed throughout the entire tablet other than the film.

15. The tablet of claim 1 , wherein the tablet is dose proportional.

16. The tablet of claim 1, wherein the tablet is free of sustained release films.

17. The tablet of claim 1, wherein the tablet is free of carbonate and bicarbonate salts.

18. The tablet of claim 1, wherein the tablet consists essentially of an immediate release film coated on the dispersible matrix of the granules and the tablet excipients.

19. The tablet of claim 1, wherein the tablet excipients comprise a disintegrant, a flow enhancer and a lubricant, and a slope of the zero order release phase is adjustable as a function of the distintegrant and distintegrant concentration, the flow enhancer and flow enhancer concentration, and the lubricant and lubricant concentration.

20. A method for providing the tablet of claim 1 , said method comprising: providing a granulation composition comprising the active agent and a sustained release agent; granulating the granulation composition to form the granules; forming the dispersible matrix from the granules and optionally tablet excipients; and compressing the dispersible matrix to form the tablet.

21. The method of claim 20, wherein the active agent is at least one member selected from the group consisting of Zolpidem, zoplidem tartrate, Zolpidem hydrochloride, Zolpidem hydrobromide, Zolpidem maleate, Zolpidem fumarate, Zolpidem tartrate, Zolpidem sulfate and Zolpidem sulfonate.

22. The method of claim 20, further comprising coating the tablet with an immediate release film.

23. The method of claim 20, wherein the dispersible matrix includes tablet excipients comprising a disintegrant, a flow enhancer and a lubricant, and the method further comprises adjusting a slope of the zero order release phase by adjusting the distintegrant and distintegrant concentration, the flow enhancer and flow enhancer concentration, and the lubricant and lubricant concentration.

24. The method of claim 20, wherein the tablet is adapted to release 20-35% of the active agent within 30 minutes, 40-59% of the active agent within 60 minutes and more than 90% of the active agent within 4 hours of adding the tablet to a 0.01M hydrochloric acid buffer at 37°C and pH 6.8 in a USP type II dissolution apparatus with a paddle rotation speed of 75 rpm.

CLAIMS WHAT IS CLAIMED IS:

1. A tablet comprising a dispersible matrix comprising: a plurality of granules each containing an active agent in a sustained release matrix; wherein the tablet is monolithic and adapted to release the active agent over a predetermined time period according to a profile of dissolution when measured in a USP type π dissolution apparatus with a paddle rotation speed of 75 rpm in 0.01M hydrochloric acid buffer at 37°C and pH 6.8, said profile including a zero order release phase.

2. A tablet comprising:

(a) a dispersible matrix comprising:

3. A tablet comprising:

(a) a dispersible matrix comprising:

(b) a non-functional film coated on a surface of the dispersible matrix, wherein the tablet is monolithic and adapted to release 20-35% of the active agent within 30 minutes, 40-59% of the active agent within 60 minutes and more than 90% of the active agent within 4 hours of adding the tablet to a 0.0 IM hydrochloric acid buffer at 37°C and pH 6.8 in a USP type π dissolution apparatus with a paddle rotation speed of 75 rpm.

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7. The tablet of claim 6, wherein less than 30% of the active agent is released within 30 minutes of adding the tablet to the buffer and more than 90% of the active agent is released wrthin 4 hours of adding the tablet to the buffer.

13. The tablet of claim 12, comprising: 4-6 % Zolpidem or a salt thereof;

3-6 % povidone;

25-40 % hypromellose 5cP;

0.5-1.5 % anhydrous colloidal silica;

45-55 % microcrystalline cellulose;

5-7 % Tartaric acid;

1-2% Magnesium stearate;

1-5% Colorant; and

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0.1-1% Polyethylene oxide 6000.

15. The tablet of claim 1 , wherein the tablet is dose proportional.

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24. The method of claim 20, wherein the tablet is adapted to release 20-35% of the active agent within 30 minutes, 40-59% of the active agent within 60 minutes and more than 90% of the active agent within 4 hours of adding the tablet to a 0.01 M hydrochloric acid buffer at 37°C and pH 6.8 in a USP type II dissolution apparatus with a paddle rotation speed of 75 rpm.

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