Trimodal precision timed release tablets

Abstract

A trimodal precision timed release tablet is provided that delivers a trimodal release profile. The tablet contains at least three immediate release components of buspirone whose release times are controlled by erodible barrier layers.

Description

[Background technology]

[0001] 2. Background of the Invention Buspirone is an immediate release dosage form administered up to three times daily for the treatment of generalized anxiety disorder (GAD). A once-daily dosage form remains highly desirable to achieve improved efficacy and patient compliance. Past efforts to achieve a multiple release single dosage form of buspirone have failed. Buspirone, selective serotonin reuptake inhibitors (SSRIs), and selective non-serotonin reuptake inhibitors (SNRIs) are the only first-line drugs for the treatment of GAD. Currently, buspirone is administered two to three times daily at intervals of 4, 6, 8, or 12 hours, which poses significant challenges to patients, and non-adherence to such regimens results in suboptimal outcomes.

[0002] There remains a need for a single, once-daily oral dosage form that delivers multiple releases of buspirone in a manner that provides a safe and effective therapeutic response sustained throughout the day in the patient. Summary of the Invention

[0003] Summary of the Invention Provided herein is a trimodal precision timed release tablet that provides three release profiles. According to one embodiment, the tablet contains three release components in the final tablet. By providing a single tablet with multiple release components, administration frequency is reduced, patient compliance is improved, and precise blood levels of active pharmaceutical ingredient (API; e.g., anxiolytic or anxiety reducing drug) are precisely achieved over a long period of time. Further advantages include improved efficacy.

[0004] The trimodal precision timed release tablets disclosed herein provide a pharmacologic precise amount of buspirone to the patient via a first release component to achieve a desired pharmacological response, and deliver the remaining predetermined amount of buspirone via second and third release components, maintaining effective therapeutic pharmacological activity for a period of time that exceeds that expected from a single immediate release drug formulation.

[0005] According to one embodiment, the tablet provides a trimodal precise time-release tablet for oral administration of buspirone, or a pharma- ceutically acceptable salt thereof, which comprises three release components.

[0006] In certain embodiments, the first release component comprises: (i) about 15% w / w to about 25% w / w of buspirone as a first precise timed release in which about 10% to about 50% of the total buspirone in the tablet is released at time 0 after oral administration of the tablet to a patient; (ii) about 1% w / w to about 5% w / w of croscarmellose sodium; (iii) about 65% w / w to about 78% w / w of microcrystalline cellulose; (iv) about 0.5% w / w to about 1.5% w / w of magnesium stearate; (v) about 2.0% w / w to about 6% w / w of sodium starch glycolate; and (vi) about 0.25% w / w to about 0.75% w / w of colloidal silicon dioxide.

[0007] In certain embodiments, the second release component comprises: (i) about 15% w / w to about 25% w / w of buspirone as a second precision timed release where about 30% to about 40% of the total buspirone in the tablet is released at about 3 to about 5 hours after oral administration of the tablet to a patient; (ii) about 1% w / w to about 4% w / w of croscarmellose sodium; (iii) about 65% w / w to about 78% w / w of microcrystalline cellulose; (iv) about 0.5% w / w to about 1.5% w / w of magnesium stearate; (v) about 2.0% w / w to about 6% w / w of sodium starch glycolate; and (vi) about 0.25% w / w to about 0.75% w / w of colloidal silicon dioxide.

[0008] In certain embodiments, the third release component comprises: (i) about 15% w / w to about 25% w / w buspirone as a third precision timed release where about 10% to about 40% of the total buspirone in the tablet is released at about 6 to about 12 hours after oral administration of the tablet to a patient; (ii) about 1% w / w to about 4% w / w croscarmellose sodium; (iii) about 65% w / w to about 78% w / w microcrystalline cellulose; (iv) about 0.5% w / w to about 1.5% w / w magnesium stearate; (v) about 2.0% w / w to about 6% w / w sodium starch glycolate; and (vi) about 0.25% to about 0.75% colloidal silicon dioxide.

[0009] According to one embodiment, the tablet comprises a first release component providing a first precise timed release of about 10% to about 50% of the total buspirone in the tablet; a second release component providing a second precise timed release of about 30% to about 40% of the total buspirone in the tablet; and a third release component providing a third precise timed release of about 10% to about 40% of the total buspirone in the tablet, such that the total dose or label claim of buspirone in the final tablet is 100%.

[0010] According to one embodiment, the tablet is structured such that a first release component is disposed on the exterior surface of the tablet and on the outer erosion barrier layer; a second release component is disposed between the outer and inner erosion barrier layers such that it is surrounded by the outer and inner erosion barrier layers; and a third release component is disposed in the center of the tablet and surrounded by the inner erosion barrier layer. In some embodiments, the release components are arranged substantially as in FIG.

[0011] By disposing the first release component on the exterior surface of the tablet, the first precisely timed release of buspirone can be released within about 5 to about 45 minutes after administration to a patient. In some embodiments, the first precisely timed release is 90% complete within 30 minutes. By surrounding the second and third release components with an erodible barrier layer, the second and third precisely timed releases of buspirone can be delayed releases. Delivery of the second precisely timed release of buspirone can be delayed until about 3 to about 5 hours after administration of the tablet to a patient. Delivery of the third precisely timed release of buspirone can be delayed until about 6 to about 12 hours after oral administration of the tablet to a patient.

[0012] The outer and inner erosion barrier layers each comprise about 30% to about 50% by weight glyceryl behenate, about 40% to about 60% by weight of two or more varieties of low-substituted hydroxypropylcellulose (L-HPC), and about 4% to about 8% by weight of hydroxypropylcellulose. The two or more varieties of L-HPC can be LH-21 and LH-32.

[0013] The tablet described herein is orally administered to patients once a day in a pharmacologic effective amount to treat or prevent various disorders, conditions and diseases.According to some embodiments, the administration of at least one anxiety-reducing drug can be carried out to treat any disorder, condition or disease for which anxiety-reducing drugs are generally indicated, now or in the future.Such disorders, conditions and diseases include, for example, generalized anxiety disorder.

[0014] The tablets described in this invention may be an effective way to provide day-long therapeutic duration of buspirone and may offer compelling safety and tolerability advantages. [Brief description of the drawings]

[0015] [Figure 1A] FIG. 1A is a plan view of one embodiment of a trimodal precision timed release tablet disclosed herein.

[0016] [Figure 1B]FIG. 1B is a perspective view of one embodiment of a trimodal precision timed release tablet disclosed herein.

[0017] [Diagram 2] FIG. 2 is a cross-sectional view of one embodiment of a trimodal precision timed release tablet disclosed herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Detailed Description of the Invention As used in this specification and the appended claims, the singular terms "a," "an," and similar terms include plural references unless the context clearly dictates otherwise.

[0019] "Active ingredient" and "pharmacologically active ingredient" are used herein to refer to a chemical compound or compound that induces a desired pharmacological effect.

[0020] As used herein, "anxiety relieving drug" refers to any active pharmaceutical ingredient that is administered to relieve anxiety.Anxiety relieving drug can also refer to "anxiety medication" that treats anxiety-related disorders and related psychological or physical symptoms.In some embodiments, anxiety medication can include, but is not limited to, benzodiazepines, buspirone, meprobamate, and hydroxyzine.

[0021] As used herein, "buspirone" refers to 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione. Buspirone also includes all pharma- ceutically acceptable salts, metabolites, and prodrugs thereof, such as buspirone hydrochloride. The hydrochloride salt is a white crystalline, water-soluble compound. Buspirone is sold under the trade names BUSPAR® and NAMANSPIN®.

[0022] As used herein, "one day" refers to 16 to 24 hours. In some embodiments, one day can be 18 to 24 hours. In some embodiments, one day can be 24 hours.

[0023] An "effective amount" or "pharmacologically effective amount" of an agent provided herein is meant to refer to a sufficient amount of the active ingredient to provide the desired therapeutic effect.

[0024] As used herein, "precise time" refers to the release of an ingredient as immediate release or delayed immediate release. In some embodiments, the term "release" refers to oral administration to a patient, where oral administration is time zero.

[0025] As used herein, "release component" or "component" refers to the elements of a tablet that contain an API, e.g., buspirone, and non-active additives. Each release component is separated by an erosion barrier. In some embodiments, the first and second release components are layers. In some embodiments, the third release component is a core with one "outer" surface that contacts an inner erosion barrier.

[0026] First and foremost, it should be noted that terms such as "first," "second," "third," "top," "bottom," "upper," "lower," etc. are applied for the purposes of clarity and to distinguish one element or object from another. Such terms, particularly "top," "lower," "above," and "lower," are relative and depend on the orientation of the object (e.g., tablet), which may be the same as or different from the orientation of the same object shown in the figures provided herein.

[0027] 1A and 1B provide plan and perspective views, respectively, of an embodiment of tablet 100. FIG. 1A shows a round, biconvex tablet. As shown in FIG. 1B, tablet (100) includes a cylindrical central band (102) or "belly bend" around the center of tablet (100). In FIG. 1B of tablet (100), top (101) and bottom (103), facing left and right, respectively, are shown as convex with multiple radii, giving tablet (100) a contrasting appearance. Each convex has the same characteristics, so any reference to the structure of one convex may be taken as a reference to the other convex, unless otherwise noted. Each end of the convex curves from band (102) toward the plane of the convex. As shown in FIG. 1B, the portion of first release component (104) identified as the "blended land" is the flat area between the cup and the belly bend. The size of the blend lands aids in the structural integrity of the tablet. Without adequately sized "lands", compression forces across the erosion barrier layer will be uneven and relaxation forces after compression may cause delamination / cracks, affecting release timing.

[0028] The diameter of the tablet (100) can be from about 9.00 mm to about 13.00 mm, or from about 10.00 mm to about 12.00 mm. In one embodiment, as shown in Figures 1A and 1B, the diameter is 11.00 mm.

[0029] The distance between the centers of the respective convex portions (i.e., peak points A and B at the top (101) and bottom (103) of the tablet), which defines the overall thickness of the tablet (100), is about 5.00 mm to about 8.00 mm, or about 6.00 mm to about 7.00 mm. In one embodiment, as shown in FIG. 1B, the distance between peak points A and B is about 6.30 mm. The width of the central band (102) can be about 40% to about 60%, or about 45% to about 55%, or about 50% of the distance between peak points A and B. In one embodiment, as shown in FIG. 1B, the width of the central band (102) is 50% of the distance between peak points A and B, or 3.15 mm.

[0030] As shown in FIG. 2, tablet (100) may include three release components (104), (106), and (108), respectively, separated by erosion barrier layers (outer erosion barrier layer (120) and inner erosion barrier layer (122)). The three release components are separated and spaced apart from one another in tablet (100); for example, located at specific and controlled locations within the tablet. As shown in FIG. 2, first release component (104), which includes a first precisely timed release of buspirone, is located on the outside, or top (101) of tablet (100). The unit immediately below first release component (104) is outer erosion barrier layer (120). A second release component (106) comprising a second precisely timed release of buspirone is disposed between the outer erosion barrier layer (120) and the inner erosion barrier layer (122) such that the second release component (106) is completely surrounded by the outer and inner erosion barrier layers. A third release component (108) comprising a third precisely timed release of buspirone is disposed in the center or core of the tablet. The inner erosion barrier layer (122) completely surrounds the third release component (108). As shown in FIG. 2, that release component is disposed between the first and third release components.

[0031] The first release component (104) is designed to release a first precise timed release portion of buspirone immediately after oral administration of the tablet (100) to a patient (i.e., immediate release or IR). The IR may be substantially complete within about 5 minutes to about 45 minutes after oral administration of the tablet to a patient, or within about 20 minutes to about 30 minutes after oral administration of the tablet to a patient. In some embodiments, the IR is substantially complete within 30 minutes after oral administration of the tablet to a patient. In this context, "substantially complete" may mean release of not less than 90% of the first precise timed release.

[0032] The second and third release components (106) and (108) are designed to delay release of second and third precise timed releases of buspirone, respectively. The second and third release are delayed relative to the first release component, but each layer is fully released in its entirety within 30 minutes. The delayed release is achieved by the erodible barrier layer and the placement of the second and third release components within the tablet.

[0033] Because the first release component (104) is designed for immediate release of a first precise timed release of buspirone, the first release component (104) is located on the exterior surface (100) of the tablet, e.g., on the top surface (101). As a result, the first release component (104) is immediately available to dissolve immediately upon administration to a patient, thereby releasing a first precise timed release portion of buspirone. The bottom surface of the first release component is bounded by an outer erosion barrier layer (120).

[0034] The first release component is approximately 549-600 microns thick and covers the entire top surface of the tablet (100) following the contour of the outer tablet surface (101).

[0035] According to certain embodiments, the first release component (104) releases from about 10% to about 50%, or from about 30% to about 40%, or about 33% of the total buspirone in the tablet.

[0036] The second release component (106) is delayed immediate release and is designed for release of a second precision timed release portion of buspirone beginning about 3 to about 6 hours after oral administration of the tablet to a patient. In certain embodiments, release of the second precision timed release portion of buspirone begins about 3 to about 5 hours after oral administration of the tablet to a patient. In certain embodiments, release of the second precision timed release portion of buspirone begins about 3.5 to about 4.5 hours after oral administration of the tablet to a patient. In certain embodiments, release of the second precision timed release portion of buspirone begins about 4 hours after administration of the tablet to a patient. The second release component can be about 549 to 750 microns thick.

[0037] According to certain embodiments, the second precise timed release is about 25% to about 45%, or about 30% to about 40% of the total buspirone in the tablet. In some embodiments, the second precise timed release is about 33% of the total buspirone in the tablet.

[0038] The third release component (108) may be a delayed immediate release containing a third precisely timed release of buspirone and may be located in the center of the tablet. The third release component is approximately 1.97-2.03 mm thick by 4.95-5.05 mm in diameter with a flat radius end.

[0039] According to one embodiment, the third release component (108) comprises a third precision timed release of buspirone, the release of which is delayed until about 6 hours to about 12 hours after oral administration of the tablet to a patient. According to another embodiment, the release of the third precision timed release portion of buspirone begins about 6 hours to about 9 hours after oral administration of the tablet to a patient. According to another embodiment, the release of the third precision timed release portion of buspirone begins about 7 hours to about 8 hours after oral administration of the tablet to a patient. According to another embodiment, the release of the third precision timed release portion of buspirone is delayed until about 8 hours after oral administration of the tablet to a patient. The third precision timed release of buspirone can be a delayed immediate release precision timed release.

[0040] According to one embodiment, the third precise timed release is about 10% to about 40%, or about 25% to about 35%, or about 30% to about 35% of the total buspirone in the tablet (100). According to another embodiment, the third precise timed release of buspirone can be about 33% of the total buspirone in the tablet.

[0041] The outer and inner erosion barrier layers (120) and (122), collectively referred to as the "erosion barrier layers", can have the same composition. Although the outer erosion barrier layer (120) and the inner erosion barrier layer (122) are shown as separate structures in FIG. 2, in embodiments in which the erosion barrier layers have the same composition, there may be no clear physical boundary or distinction between the erosion barrier layers in the finished tablet.

[0042] The outer and inner erosion barrier layers may each comprise a mixture of glyceryl behenate, low-substituted hydroxypropyl cellulose (L-HPC) and hydroxypropyl cellulose. L-HPC is insoluble in water and contains a glucose backbone that is minimally substituted by hydroxypropyl groups. This chemistry prevents L-HPC from dissolving, but it swells in the presence of water. In certain embodiments, the erosion barrier layer may comprise two or more grades of L-HPC, such as LH-21 and LH-32. LH-21 is moderately fibrous and has an average particle size of 45 μm. LH-21 has a molecular weight of about 120,000 and a hydroxypropyl content of about 11%. LH-32 is micronized and has an average particle size of 20 μm. LH-32 has a molecular weight of 115,000 and a hydroxypropyl cellulose content of 8%.

[0043] In some embodiments, the outer and inner erosion barrier layers each comprise about 30% to about 50% glyceryl behenate, 35% to about 45% glyceryl behenate, or about 37.5% to about 42.5% glyceryl behenate by weight.

[0044] The outer and inner erosion barrier layers may each comprise a total of about 40% to about 60% by weight, or about 45% to about 55% by weight, or about 47.5% to about 52.5% by weight of two or more grades of L-HPC. In some embodiments, the outer and inner erosion barrier layers each comprise about 15% to about 25% by weight of a first grade of L-HPC, such as LH-21, and about 25% to about 35% by weight of a second grade of L-HPC, such as LH-32; about 20% to about 23% by weight of LH-21 and about 27.5% to about 32.5% by weight of LH-32.

[0045] The outer and inner erosion barrier layers may each comprise about 4% to about 8% by weight of hydroxypropyl cellulose. In certain embodiments, the outer and inner erosion barrier layers may comprise about 5% to about 7% by weight of hydroxypropyl cellulose. In certain embodiments, the hydroxypropyl cellulose of the outer and inner erosion barrier layers may be hydroxypropyl cellulose type L.

[0046] The erosion barrier layer may further comprise silicon dioxide, e.g., colloidal silicon dioxide such as AEROSIL® 200 Pharma. In certain embodiments, the outer and inner erosion barrier layers each comprise up to about 1% by weight colloidal silicon dioxide, about 0.2% to 0.8% by weight colloidal silicon dioxide, or about 0.2% to 0.6% by weight colloidal silicon dioxide.

[0047] The precise timed release profile of the described tablets is due in part to the composition of the outer and inner erosion barrier layers. The erosion barrier layer (EBL) contains a combination of a waxy additive, glyceryl dibehenate, and a mixture of three disintegrants that are various iterations of low-substituted hydroxypropylcellulose (L-HPC). Glyceryl dibehenate is an inert compound that is non-water soluble and has minimal chemical interaction with water. In contrast, L-HPC is water soluble and expands rapidly upon contact with water. Due to the manufacturing by the compression method, the particles in the EBL are tightly packed, limiting the penetration of liquid into the EBL matrix. When the surface particles come into contact with the liquid medium, they expand, the surface becomes brittle, and the particles fall off the tablet. This process is repeated until a "fresh" layer of particles becomes exposed and the underlying API layer is exposed and released.

[0048] In certain embodiments, the trimodal precision timed release tablet comprises about 200-300 mg, about 225-275 mg, about 230-260 mg, or about 235-245 mg of an outer erosion barrier layer. In certain embodiments, the precision timed release tablet comprises about 100-150 mg, about 115-135 mg, or about 120-130 mg of an inner erosion barrier layer.

[0049] In certain embodiments, the thickness of the outer erosion barrier layer is about 574 to 888 microns.

[0050] In certain embodiments, the thickness of the inner erosion barrier layer is between about 862 and 1071 microns.

[0051] The distance between the first and third emissive components (104, 108) is about 1,436 to 1,906 microns. As shown in FIG. 2, the distance between the first and third emissive components (104, 108) is about 1,567 to 1,932 microns.

[0052] Similarly, the distance between the second and third emissive components (106, 108) is approximately 862-1071 microns. As shown in FIG. 2, the distance between the second and third emissive components (106, 108) is approximately 862-1071 microns.

[0053] In certain embodiments, each release component contains additives and diluents in addition to the dosage amount of the substance. The amount of additives and diluents in each release component depends on the total amount of buspirone in the tablet. Exemplary additives include croscarmellose sodium, microcrystalline cellulose, and magnesium stearate.

[0054] In certain embodiments, the first release component may comprise about 15% w / w to about 25% w / w buspirone.In some embodiments, the first release component may comprise about 75% w / w to about 85% w / w of excipients including croscarmellose sodium, microcrystalline cellulose, magnesium stearate, sodium starch glycolate, and colloidal silicon dioxide.

[0055] In certain embodiments, the second release component may comprise about 15% w / w to about 25% w / w buspirone.In some embodiments, the second release component may comprise about 75% w / w to about 85% w / w of additives including croscarmellose sodium, microcrystalline cellulose, magnesium stearate, sodium starch glycolate, and colloidal silicon dioxide.

[0056] In certain embodiments, the third release component may comprise about 15% w / w to about 25% w / w buspirone.In some embodiments, the third release component may comprise about 75% w / w to about 85% w / w of additives including croscarmellose sodium, microcrystalline cellulose, magnesium stearate, sodium starch glycolate, and colloidal silicon dioxide.

[0057] The tablets disclosed herein are suitable for delivery of an effective amount of at least one anxiety-reducing drug and its salts. At least one other active ingredient may be combined with the anxiety-reducing drug in a single release component in the tablet, or one or more release components in the tablet may contain additional active ingredients. The salts of the active ingredients used with the tablets of the present invention may be commercially available or may be prepared using standard procedures known to those skilled in the art of synthetic organic science. The anxiety-reducing drugs provided herein may be in the form of pharma-ceutically acceptable salts, prodrugs, or other derivatives or active metabolites. According to certain embodiments, the anxiety-reducing drug is buspirone or a pharma-ceutically acceptable salt thereof. According to another embodiment, the anxiety-reducing drug is buspirone hydrochloride.

[0058] Optional ingredients present in the trimodal precision time-release tablet may include, but are not limited to, additional binders, lubricants, disintegrants, stabilizers, surfactants, colorants, coatings, and diluents.Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, hydrolyzed starch, silicon dioxide, titanium dioxide, alumina, talc, microcrystalline cellulose, and powdered sugar.Suitable binder materials include, but are not limited to, starch (including cornstarch and pregelatinized starch), gelatin, sugar (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, wax, natural and synthetic gums (e.g., acacia, tragacanth, sodium alginate, polyvinylpyrrolidone, cellulose, and Veegum), and synthetic polymers such as polymethacrylate and polyvinylpyrrolidone. Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, and polyethylene glycol. Suitable disintegrants include, but are not limited to, starch, clay, cellulose, algins, gums, or crosslinked polymers. Suitable surfactants include, but are not limited to, those containing carboxylate, sulfonate, and sulfate ions in combination with cations such as sodium, potassium, and ammonium ions; long chain alkyl sulfonates and alkylaryl sulfonates such as sodium dodecylbenzenesulfonate; dialkyl sodium sulfosuccinates such as sodium bis-(2-ethylhexyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and preservatives may also be included in the tablet or in the individual drug-containing release components.

[0059] In some embodiments, the trimodal precision timed release tablet is a film-coated tablet. Suitable film coatings include aqueous film coatings such as OPADRY® II (Colorcon, Inc., Harleysville, PA).

[0060] The trimodal precise timed release tablets described herein may be useful in a method of treating disorders, conditions or diseases for which anxiety-relieving medications are generally indicated, by administering the trimodal precise timed release tablets to a patient in need thereof. In some embodiments, the disorder, condition or disease is anxiety or an anxiety-related disorder.

[0061] The trimodal precise timed release tablets described herein can be useful in a method for extending the therapeutic period of buspirone by administering the tablets to a patient in need thereof. As a result of the balanced trimodal release of buspirone, the therapeutic period of buspirone is effective for greater than 12 hours, at least 14 hours, and up to the entire day, following oral administration of the tablets to a patient.

[0062] The trimodal precise timed release tablet described herein can be manufactured through a series of tablet-within-a-tablet compression operations.For example, the third release component is compressed, and then surrounded by or covered with an inner erosion barrier layer.Then, the second release component is compressed on top of the inner erosion barrier layer, and then surrounded by or covered with an outer erosion barrier layer.Then, the first release component is compressed on top of the outer erosion barrier layer.In another embodiment, the second release component is compressed at the bottom of the inner erosion barrier layer, so that the third release component is disposed between the first release component and the second release component. EXAMPLES

[0063] Example 1 Trimodal precision timed release tablets, such as those shown in Figures 1A, 1B and 2, can be manufactured using the apparatus and steps as provided herein. The precision timed release tablets can contain a total of 30 mg of buspirone. The three release components of the trimodal precision timed release tablet can have the following compositions: [Table 1]

[0064] The first release component comprises a first precisely timed release of buspirone that is about 33% of the total buspirone dose in the tablet. The second release component comprises a second precisely timed release of buspirone that is about 33% of the total buspirone dose in the tablet. The third release component comprises a third precisely timed release of buspirone that is about 33% of the total buspirone amount in the tablet.

[0065] In certain embodiments, each of the three release components of the trimodal precision timed release tablet may have the following composition: [Table 2]

[0066] The outer and inner erosion barrier layers have the following composition: [Table 3]

[0067] Trimodal precision timed release tablets are generally structured as shown in Figure 2. Three release components are incorporated into the tablet at specific and controlled locations. The first release component is located on the surface of the tablet and on the outer erosion barrier layer. The second release component is located between the outer and inner erosion barrier layers. The third and final release component is located in the center of the tablet and is surrounded by the inner erosion barrier layer. The tablet contains 240 mg of the outer erosion barrier layer and 125 mg of the inner erosion barrier layer.

[0068] Although the present invention has been described in detail, it is not limited to the above-described embodiments, and modifications can be made without departing from the concept of the present invention.

Claims

1. 1. A trimodal precision time-release tablet for oral administration of buspirone or a pharmaceutically acceptable salt thereof, comprising: (a) a first-release component comprising: (i) about 15% w / w to about 25% w / w buspirone as a first precision timed release, wherein about 10% to about 50% of the total buspirone in the tablet is released at time 0 after oral administration of the tablet to a patient; (ii) about 1% w / w to about 4% w / w croscarmellose sodium; (iii) about 65% w / w to about 78% w / w microcrystalline cellulose; (iv) about 0.5% w / w to about 1.5% w / w magnesium stearate; (v) about 2.0% w / w to about 6% w / w sodium starch glycolate; and (vi) about 0.25% w / w to about 0.75% w / w colloidal silicon dioxide; (b) a second release component comprising: (i) about 15% w / w to about 25% w / w buspirone as a second precision timed release, wherein about 30% to about 40% of the total buspirone in the tablet is released from about 3 hours to about 5 hours after oral administration of the tablet to a patient; (ii) about 1% w / w to about 4% w / w croscarmellose sodium; (iii) about 65% w / w to about 78% w / w microcrystalline cellulose; (iv) about 0.5% w / w to about 1.5% w / w magnesium stearate; (v) about 2.0% w / w to about 6% w / w sodium starch glycolate; and (vi) about 0.25% w / w to about 0.75% w / w colloidal silicon dioxide; and (c) a third release component comprising: (i) about 15% w / w to about 25% w / w of buspirone as a third precision timed release tablet, wherein about 10% to about 40% of the total buspirone in the tablet is released from about 6 hours to about 12 hours after oral administration of the tablet to a patient; (ii) about 1% w / w to about 4% w / w of croscarmellose sodium; (iii) about 70% w / w to about 80% w / w of microcrystalline cellulose; (iv) about 0.5% w / w to about 1.5% w / w of magnesium stearate; (v) about 2.0% w / w to about 6% w / w of sodium starch glycolate; and (vi) about 0.25% w / w to about 0.75% w / w of colloidal silicon dioxide; wherein the tablet is structured such that a first release component is disposed on the surface of the tablet and on the outer erosion barrier layer, a second release component is disposed between the outer and inner erosion barrier layers so as to be surrounded by the outer and inner erosion barrier layers, and a third release component is disposed in the center of the tablet and surrounded by the inner erosion barrier layer. Trimodal precision time-release tablets.

2. 10. The tablet of claim 1, wherein the first-release component releases approximately 33% of the total buspirone in the tablet.

3. 10. The tablet of claim 1, wherein the second release component releases approximately 33% of the total buspirone in the tablet.

4. 10. The tablet of claim 1, wherein the third release component releases approximately 33% of the total buspirone in the tablet.

5. 10. The tablet of claim 1, wherein release of the second precise timed release portion begins about 3 hours to about 5 hours after oral administration of the tablet to a patient.

6. 10. The tablet of claim 1, wherein release of the third precise timed release portion begins about 7 hours to about 9 hours after oral administration of the tablet to a patient.

7. 10. The tablet of claim 1, wherein the outer and inner erosion barrier layers each comprise about 35% to about 45% by weight of glyceryl behenate, about 15% to about 25% by weight of LH-21, about 25% to about 35% by weight of LH-32, and about 4% to about 8% by weight of hydroxypropyl cellulose.

8. 10. The tablet of claim 1, wherein the outer and inner erosion barrier layers each comprise about 37.5% to about 42.5% by weight of glyceryl behenate, about 20% to about 23% by weight of LH-21, about 27.5% to about 32.5% by weight of LH-32, and about 5% to about 7% by weight of hydroxypropyl cellulose.

9. 8. The tablet of claim 7, wherein the hydroxypropyl cellulose is hydroxypropyl cellulose type L.

10. 8. The tablet of claim 7, wherein the outer erosion barrier layer and the inner erosion barrier layer each further comprise about 1% by weight or less of colloidal silicon dioxide.

11. 10. The tablet of claim 1, wherein the first release component is about 600 microns thick, the second release component is about 750 microns thick, and the third release component is about 2.03 mm thick with flat radiused edges.

12. 10. The tablet of claim 1, wherein the third release component is disposed between the first release component and the second release component.

13. The total buspirone dose of the tablet is 30 mg; the first-release component comprising 17.5% w / w to 23.0% w / w of buspirone and 77.0% w / w to 82.5% w / w of a total of croscarmellose sodium, microcrystalline cellulose, magnesium stearate, sodium starch glycolate, and colloidal silicon dioxide; the second release component comprises 17.5% w / w to 23.0% w / w of buspirone and 77.0% w / w to 82.5% w / w of a total of croscarmellose sodium, microcrystalline cellulose, magnesium stearate, sodium starch glycolate, and colloidal silicon dioxide; and the third release component comprises 17.5% w / w to 23.0% w / w of buspirone and 77.0% w / w to 82.5% w / w of a total of croscarmellose sodium, microcrystalline cellulose, magnesium stearate, sodium starch glycolate, and colloidal silicon dioxide; The tablet according to claim 1.

14. A tablet according to any one of claims 1 to 13, wherein the therapeutic effect of buspirone persists for at least 14 hours after oral administration to a patient.

15. A tablet according to any one of claims 1 to 13 for treating a disorder, condition or disease for which buspirone is generally indicated.

16. 16. The tablet of claim 15, wherein the disorder, condition, or disease is generalized anxiety disorder or an anxiety-related disorder.

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