Oral Formulations

Abstract

The present invention relates to a solid pharmaceutical formulation suitable for oral administration, comprising: (a) an active agent, which is S-pindolol or a pharma- ceutical acceptable salt thereof; (b) a starch additive in an amount of at least 15.0% by weight based on the total weight of the formulation; and (c) a cellulose additive in an amount of at least 30.0% by weight based on the total weight of the formulation. Also provided is a solid pharmaceutical formulation for use in therapy, e.g., in the treatment of cachexia.

Description

[Technical field]

[0001] The present invention relates to a solid oral formulation comprising S-pindolol or a salt thereof, in particular a tablet comprising S-pindolol or a salt thereof. The present invention also relates to the use of the solid oral formulation in therapy, for example in the treatment or prevention of cachexia. [Background technology]

[0002] S-pindolol has β1 receptor antagonistic action, β2 receptor partial agonist action and central 5-HT 1A It is an anabolic / catabolic agent that exhibits antagonistic effects. S-pindolol is also known as (-)-pindolol or S(-)-pindolol, and has the systematic name (2S)-1-(1H-indol-4-yloxy)-3-(1-methylethylamino)propan-2-ol. The structure of S-pindolol is shown below. [ka]

[0003] The racemate of S-pindolol (i.e. pindolol racemate) is described in US 3,471,515 and is marketed for the treatment of hypertension. The treatment of wasting diseases such as cachexia and sarcopenia with enantiomerically enriched S-pindolol is described in WO2008 / 068477A1, WO2010 / 125348A1 and WO2014 / 016585A1.

[0004] S-pindolol and its salts are typically administered orally, for example as tablets. Tablet formulations containing S-pindolol are described in WO2014 / 016585A1.

[0005] The formulation of pharmaceutical compounds as oral dosage forms is a complex process: different excipients may interact differently with the active substance, and it is impossible to predict what these interactions and the resulting properties of the dosage form will be.

[0006] There is a need to develop an oral formulation of S-pindolol or a salt thereof that is stable during storage. It is also desirable to produce a solid oral dosage form that has a favorable dissolution profile. Summary of the Invention

[0007] A surprising discovery of the present invention is that certain solid oral dosage forms comprising S-pindolol or a pharma- ceutically acceptable salt thereof and substantial proportions of both starch and microcrystalline cellulose as excipients are stable and have advantageous dissolution profiles.

[0008] Accordingly, the present invention provides a solid pharmaceutical formulation suitable for oral administration comprising: (a) an active agent, which is S-pindolol or a pharma- ceutical acceptable salt thereof; (b) a starch excipient in an amount of at least 15.0% by weight, based on the total weight of the formulation; and (c) a cellulose excipient in an amount of at least 30.0% by weight, based on the total weight of the formulation.

[0009] Accordingly, the present invention provides a solid pharmaceutical formulation suitable for oral administration comprising: (a) an active agent, which is S-pindolol or a pharma- ceutical acceptable salt thereof; (b) a starch excipient in an amount of at least 15.0% by weight, based on the total weight of the formulation; and (c) a cellulose excipient in an amount of at least 40.0% by weight, based on the total weight of the formulation.

[0010] The solid pharmaceutical formulation of the present invention is typically a tablet.

[0011] The invention also provides solid pharmaceutical formulations for use in the treatment of the human or animal body. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The solid pharmaceutical formulation comprises an active agent that is S-pindolol or a pharma- ceutical acceptable salt thereof. S-pindolol is preferably formulated as a salt since the free base may, in some cases and under certain conditions, decompose or discolor during storage.

[0013] Typically, the active substance is a pharma- ceutically acceptable salt of S-pindolol. Pharmaceutically acceptable salts typically have a pK a1 It is an acid addition salt formed with an acid having a pK of 1.5 or more or 2.5 or more. a1 is the acid dissociation constant of the first proton that dissociates from the acid. For acids with one acidic proton, the pK a1 is simply the acid dissociation constant pK a The pK a1 The value is measured at 25°C. a and pK a1 Values ​​are readily available to one of skill in the art.

[0014] The active agent is typically a pharma- ceutically acceptable salt of (i) S-pindolol and (ii) an organic acid, the organic acid having a pK of 1.5 or greater. a1 ; and C x H y (CO2H) z (OH) q where x is 1-10, y is 2-20, z is 1, 2 or 3, and q is 0, 1 or 2. The organic acid can be, for example, benzoic acid, succinic acid, fumaric acid, malonic acid, acetic acid, propionic acid, glutaric acid, adipic acid, phenylacetic acid, toluic acid (including o-, m- and p-toluic acid) and naphthoic acid (including 1- and 2-naphthoic acid), citric acid or tartaric acid.

[0015] The active agent is preferably a pharma- ceutically acceptable salt of (i) S-pindolol and (ii) an organic acid, the organic acid having a pK of 2.5 or greater. a1 ; and C x H y (CO2H) z where x is 1 to 10, y is 2 to 20, and z is 1 or 2. Thus, the organic acid has a hydrocarbyl moiety (C x H y , hydrogen and carbon) and one or two carboxylic acid groups (COH). Typically, x is 2 to 7 and H is 2 to 6. x H yThe group can be an arenyl group, an alkyl group, or an alkenyl group. For example, C x H y The group is a divalent C optionally substituted with one or two methyl groups. 2-7 Alkyl group, divalent C 2-7 It may be an alkenyl group or a divalent phenyl group.

[0016] The organic acid may be, for example, benzoic acid, succinic acid, fumaric acid, malonic acid, acetic acid, propionic acid, glutaric acid, adipic acid, phenylacetic acid, toluic acid (including o-, m- and p-toluic acid) or naphthoic acid (including 1- and 2-naphthoic acid). Preferably, the organic acid is benzoic acid, succinic acid or fumaric acid. More preferably, the organic acid is benzoic acid or succinic acid. Typically, the organic acid is S-pindolol benzoate.

[0017] The active substance may be present in an amount of 1.0-45.0% by weight based on the total weight of the formulation. The active substance is typically present in an amount of 1.0-25.0% by weight, for example 3.0-25.0% by weight based on the total weight of the formulation. Preferably, the active substance is present in an amount of 10.0-20.0% by weight based on the total weight of the formulation. For example, a solid pharmaceutical formulation may contain S-pindolol benzoate in an amount of 10.0-20.0% by weight based on the total weight of the formulation. The active substance may be present, for example, in an amount of 13.0-17.0% by weight. Alternatively, the active substance may be present in an amount of 6.0-9.0% by weight or 20.0-24.0% by weight.

[0018] The active substance may be present in an amount equivalent to 0.1-50 mg of S-pindolol free base. Typically, the active substance is present in an amount equivalent to 0.5-20 mg of S-pindolol free base. Preferably, the active substance is present in an amount equivalent to 3.0-15.0 mg of S-pindolol free base, more preferably in an amount equivalent to 4.0-6.0 mg of S-pindolol free base. The active substance may be present in an amount equivalent to 1.0 mg, 2.5 mg, 5.0 mg, 7.5 mg, 10.0 mg, 12.5 mg or 15.0 mg of S-pindolol free base. For example, the solid pharmaceutical formulation may contain about 7.44 mg of S-pindolol benzoate (equivalent to 5.0 mg of S-pindolol free base).

[0019] The solid pharmaceutical formulation typically comprises an enantiomeric excess (e.g., at least 50%, at least 90% or at least 99% enantiomeric excess) of S-pindolol or its pharma- ceutically acceptable salt. Typically, the solid pharmaceutical formulation is substantially free of R-pindolol or its pharma-ceutically acceptable salt. For example, the solid pharmaceutical formulation may comprise less than 1.0% by weight, less than 0.1% by weight, or less than 0.01% by weight of R-pindolol or its pharma-ceutically acceptable salt, based on the total weight of the composition.

[0020] The solid pharmaceutical formulation comprises a starch additive. The solid pharmaceutical formulation may comprise one or more starch additives. The starch additive is an additive derived from starch and may be starch or modified starch. Starch comprises two components: amylose (typically 20-25% by weight) and amylopectin (typically 75-80% by weight). Modified starch is starch whose hydroxyl groups have been chemically treated to change the properties of the starch, for example by esterification or etherification.

[0021] Preferably, the starch additive comprises starch (optionally pregelatinized as described below). The starch additive typically comprises starch obtained from a natural source. For example, the starch additive may comprise one or more of maize starch, wheat starch, rice starch, cassava starch and cocoyam starch. Preferably, the starch additive comprises maize starch. Maize starch is also known as corn starch.

[0022] The starch additive (i.e., starch or modified starch) may further be pregelatinized. For example, the starch additive may comprise an at least partially pregelatinized starch (e.g., corn starch).

[0023] At least partially pregelatinized starch corresponds to starch granules that have been suspended in water, slowly heated to cause the starch granules to absorb water, and then at least partially dried. The starch is typically partially pregelatinized. Partially pregelatinized starch is commercially available, for example as partially pregelatinized corn starch.

[0024] The partially pregelatinized starch present in the solid pharmaceutical formulation may have a loss on drying of 1.0 to 15.0% by weight, for example 5.0 to 10.0% by weight. The weight percentage of any partially pregelatinized starch present in the solid pharmaceutical formulation is based on the weight of the partially pregelatinized starch present in the formulation without further drying (i.e. the weight of the partially pregelatinized starch added during manufacture of the formulation).

[0025] The starch additive is typically present in an amount of at least 20.0% by weight, for example 20.0-40.0% by weight, based on the total weight of the formulation. Preferably, the starch additive is present in an amount of 25.0-35.0% by weight, based on the total weight of the formulation. For example, a solid pharmaceutical formulation may contain starch or partially pregelatinized starch in an amount of 25.0-30.0% by weight, based on the total weight of the formulation.

[0026] The solid pharmaceutical formulation comprises a cellulose additive. The solid pharmaceutical formulation may comprise one or more cellulose additives. The cellulose additive is an additive derived from cellulose and may be cellulose or modified cellulose. Cellulose is a polysaccharide formed of D-glucose units linked in β(1→4). Modified cellulose is cellulose whose hydroxyl groups have been chemically treated to change the properties of the cellulose, for example by esterification or etherification. Preferably, the cellulose additive comprises cellulose.

[0027] More preferably, the cellulose additive comprises microcrystalline cellulose, which is commercially available and is a partially depolymerized cellulose synthesized from α-cellulose.

[0028] Microcrystalline cellulose typically has a degree of polymerization of less than 400 or less than 300. Microcrystalline cellulose may have a degree of polymerization of 200-250. The degree of polymerization may be measured by the intrinsic viscosity method (confirmatory test A) of the United States Pharmacopeia monograph for crystalline cellulose. The method involves first forming a solution by transferring 1.3 g of microcrystalline cellulose, weighed accurately to the nearest 0.1 mg, into a 125 mL Erlenmeyer flask; adding 25.0 mL of water and 25.0 mL of 1.0 M caprylethylenediamine hydroxide solution; immediately purging the solution with nitrogen; inserting a stopper; and determining the intrinsic viscosity by shaking on a wrist-action shaker until completely dissolved. Transfer an appropriate amount of the solution to a calibrated No. 150 Cannon-Fenske viscometer. The solution is allowed to equilibrate at 25 ± 0.1 °C for at least 5 minutes to determine the intrinsic viscosity [η]. c The degree of polymerization P is calculated using the formula (95) [η] c / W S [(100-%LOD) / 100], where W S is the weight in grams of the collected microcrystalline cellulose, and %LOD is the value obtained from the loss on drying test.

[0029] The crystalline cellulose typically has a particle size distribution (median particle size) of D50 of 80 to 160 μm, preferably 90 to 140 μm, more preferably 100 to 130 μm. The D50 value used in this specification is typically the Dv50 value (median volume particle size). The D50 or Dv50 value described in this specification is typically measured by laser diffraction, for example, by laser diffraction using a dry dispersion cell.

[0030] The cellulose additive is typically present in an amount of at least 35.0% by weight based on the total weight of the formulation or at least 40.0% by weight based on the total weight of the formulation. The cellulose additive is typically present in an amount of at least 45.0% by weight based on the total weight of the formulation, for example, 45.0-70.0% by weight. Preferably, the cellulose additive is present in an amount of 50.0-60.0% by weight based on the total weight of the formulation. For example, the solid pharmaceutical formulation may contain 50.0-60.0% by weight of crystalline cellulose based on the total weight of the formulation.

[0031] The solid pharmaceutical formulation typically comprises a starch additive which is starch (preferably partially pregelatinized starch); and a cellulose additive which is microcrystalline cellulose. The solid pharmaceutical formulation may comprise one or more additional starch additives and cellulose additives in addition to starch and crystalline cellulose. Alternatively, the solid pharmaceutical formulation may comprise one starch additive which is starch and one cellulose additive which is a microcrystalline cellulose. The solid pharmaceutical formulation may comprise one starch additive which is partially pregelatinized corn starch and one cellulose additive which is microcrystalline cellulose.

[0032] The solid pharmaceutical formulations may contain one or more further additives selected from, for example, silica; lubricants, such as talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycol; binders, such as gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrants, such as starch, alginic acid, alginates or sodium starch glycolate; effervescent mixtures; dyes; sweeteners; and wetting agents, such as lecithin, polysorbates, lauryl sulfate.

[0033] The solid pharmaceutical formulation typically further comprises colloidal silica. The colloidal silica may be present in an amount of 0.1-1.0% by weight based on the total weight of the formulation. For example, the solid pharmaceutical formulation may comprise 0.15-0.35% by weight of colloidal silica.

[0034] The solid pharmaceutical formulation typically further comprises a lubricant. The lubricant may be, for example, one or more of talc, stearic acid, magnesium stearate or calcium stearate. The lubricant is preferably magnesium stearate. The lubricant is typically present in an amount of 0.1-1.0% by weight based on the total weight of the formulation. For example, the solid pharmaceutical formulation may comprise 0.15-0.35% by weight of a lubricant, for example magnesium stearate.

[0035] Typically, the solid pharmaceutical formulation does not contain a significant amount of lactose. For example, the solid pharmaceutical formulation may contain less than 10.0% by weight of lactose based on the total weight of the formulation. The solid pharmaceutical formulation may contain less than 10.0% by weight of lactose monohydrate. Preferably, the solid pharmaceutical formulation contains less than 1.0% by weight of lactose. The solid pharmaceutical formulation is typically substantially free of lactose. The solid pharmaceutical formulation is typically free of lactose.

[0036] Typically, the solid pharmaceutical formulation comprises: (a) 3.0 to 35.0 wt. % of a pharma- ceutically acceptable salt of S-pindolol as defined herein; (b) at least 20.0 wt. % of a starch excipient as defined herein; and (c) at least 45.0 wt. % of a cellulose excipient as defined herein, wherein the wt. % are based on the total weight of the formulation.

[0037] Typically, the solid pharmaceutical formulation comprises: (a) 5.0-25.0% by weight of a pharma- ceutically acceptable salt of S-pindolol as defined herein; (b) at least 20.0% by weight of a starch excipient as defined herein; and (c) at least 45.0% by weight of a cellulose excipient as defined herein, where the weight percentages are based on the total weight of the formulation. The solid pharmaceutical formulation may comprise at least 90%, at least 95%, or at least 99% by weight of components (a)-(c) based on the total weight of the composition.

[0038] The solid pharmaceutical preparation is (a) 3 to 25% by weight of S-pindolol benzoate; (b) 20 to 35% by weight of starch, optionally partially pregelatinized starch; (c) 50-65% by weight of crystalline cellulose; (d) optionally, colloidal silica; and (e) optionally, magnesium stearate where the weight percentages are based on the total weight of the formulation.

[0039] The solid pharmaceutical preparation is (a) 3 to 20% by weight of S-pindolol benzoate; (b) 20 to 35% by weight of starch, optionally partially pregelatinized starch; (c) 50-60% by weight of crystalline cellulose; (d) optionally, colloidal silica; and (e) optionally, magnesium stearate where the weight percentages are based on the total weight of the formulation.

[0040] Solid pharmaceutical formulations include, for example: (a) 10-20% by weight of S-pindolol benzoate; (b) 20 to 30% by weight of starch, optionally partially pregelatinized starch; (c) 50-60% by weight of crystalline cellulose; (d) optionally, colloidal silica; and (e) optionally, magnesium stearate where the weight percentages are based on the total weight of the formulation.

[0041] The solid pharmaceutical formulation may comprise at least 90% by weight of components (a)-(e) based on the total weight of the composition. For example, the solid pharmaceutical formulation may comprise at least 95% by weight or at least 99% by weight of components (a)-(e) based on the total weight of the composition. The solid pharmaceutical formulation may consist of or consist essentially of components (a)-(e).

[0042] The solid pharmaceutical formulations may be prepared by standard pharmaceutical techniques such as mixing, granulating or tabletting the ingredients present in the composition.

[0043] The solid pharmaceutical formulation is typically in the form of a tablet, caplet or granules. The solid pharmaceutical formulation is preferably in the form of a tablet.

[0044] The solid pharmaceutical preparation is (a) 6 to 24% by weight of S-pindolol benzoate; (b) 22 to 32% by weight of corn starch; (c) 50-63% by weight of crystalline cellulose; (d) 0.1 to 0.5 weight percent colloidal silica; and (e) 0.1 to 0.5% by weight of magnesium stearate wherein the weight percentages are based on the total weight of the formulation.

[0045] The solid pharmaceutical preparation is (a) 10-20% by weight of S-pindolol benzoate; (b) 22 to 32% by weight of corn starch; (c) 50-60% by weight of crystalline cellulose; (d) 0.1 to 0.5 weight percent colloidal silica; and (e) 0.1 to 0.5% by weight of magnesium stearate wherein the weight percentages are based on the total weight of the formulation.

[0046] The solid pharmaceutical preparation is (a) 10-20% by weight of S-pindolol benzoate; (b) 22 to 30% by weight of corn starch; (c) 50-60% by weight of crystalline cellulose; (d) 0.1 to 0.5 weight percent colloidal silica; and (e) 0.1 to 0.5% by weight of magnesium stearate wherein the weight percentages are based on the total weight of the formulation.

[0047] The solid pharmaceutical preparation is (a) 10-20% by weight of S-pindolol benzoate; (b) 22 to 30% by weight of partially pregelatinized corn starch; (c) 50-60% by weight of crystalline cellulose; (d) 0.1 to 0.5 weight percent colloidal silica; and (e) 0.1 to 0.5% by weight of magnesium stearate wherein the weight percentages are based on the total weight of the formulation.

[0048] The solid pharmaceutical preparation is (a) 13-17% by weight of S-pindolol benzoate; (b) 24 to 30% by weight of partially pregelatinized corn starch; (c) 54-58% by weight of crystalline cellulose; (d) 0.15 to 0.35 weight percent colloidal silica; and (e) 0.15 to 0.35% by weight of magnesium stearate wherein the weight percentages are based on the total weight of the formulation.

[0049] The solid pharmaceutical preparation is (a) 6-9 wt. % S-pindolol benzoate; (b) 28 to 33% by weight of partially pregelatinized corn starch; (c) 59-63% by weight crystalline cellulose; (d) 0.15 to 0.35 weight percent colloidal silica; and (e) 0.15 to 0.35% by weight of magnesium stearate wherein the weight percentages are based on the total weight of the formulation.

[0050] The solid pharmaceutical preparation is (a) 20-24% by weight of S-pindolol benzoate; (b) 23 to 28% by weight of partially pregelatinized corn starch; (c) 49-54% by weight of crystalline cellulose; (d) 0.15 to 0.35 weight percent colloidal silica; and (e) 0.15 to 0.35% by weight of magnesium stearate wherein the weight percentages are based on the total weight of the formulation.

[0051] The tablets may be prepared by any standard tableting technique. Preferably, the tablets are prepared by direct compression of a powder mixture of the components. The tablets may be prepared by direct compression of a powder mixture of the components, i.e., components (a)-(c) and, optionally, (d) and (e).

[0052] Medical Use The solid pharmaceutical formulation is useful in the treatment or prevention of a disease or condition selected from cachexia, sarcopenia, neuromuscular disorders, muscle weakness, hypertension, heart failure, atrial fibrillation, heart attack, angina, glaucoma and anxiety. Typically, the disease or condition is selected from cachexia and muscle weakness.

[0053] Cachexia may be caused by an underlying disease. For example, cachexia may be caused by cancer, heart failure, chronic obstructive pulmonary disease (COPD), liver failure, kidney failure, stroke, rheumatoid arthritis, severe burns, or HIV / AIDS. Muscle weakness may be caused by an underlying disease. For example, muscle weakness may be caused by trauma, musculoskeletal injury, surgery, or immobilization. Muscle weakness may be intensive care unit acquired muscle weakness (ICUAW). Neuromuscular disorders may be, for example, amyotrophic lateral sclerosis.

[0054] The present invention also provides a method for treating or preventing a disease or condition selected from cachexia, sarcopenia, neuromuscular disorders, muscle weakness, hypertension, heart failure, atrial fibrillation, heart attack, angina, glaucoma and anxiety in a subject, comprising administering to the subject a therapeutically effective amount of a solid pharmaceutical formulation.

[0055] The present invention also provides the use of a solid pharmaceutical formulation in the manufacture of a medicament for the treatment or prevention of a disease or condition selected from cachexia, sarcopenia, neuromuscular disorders, muscle weakness, hypertension, heart failure, atrial fibrillation, heart attack, angina, glaucoma and anxiety.

[0056] Pharmaceutically solid pharmaceutical formulations are typically administered orally.

[0057] An effective amount of a solid pharmaceutical formulation typically contains an amount of S-pindolol or a pharma- ceutically acceptable salt thereof equivalent to 0.1-1000 mg of S-pindolol free base per single dose. For example, a single dose of a solid pharmaceutical formulation may contain an amount of S-pindolol or a pharma- ceutically acceptable salt thereof equivalent to 2.5-50 mg or 80-160 mg of S-pindolol free base. A single dose may be an amount of S-pindolol or a pharma- ceutically acceptable salt thereof equivalent to 2.5-15 mg of S-pindolol free base. A dose may be administered once, twice or three times a day. A dose may contain 1, 2 or 3 solid pharmaceutical formulations (e.g. 1, 2 or 3 tablets).

[0058] The following examples illustrate the invention. EXAMPLES

[0059] Example 1 Tablet Formulation Three tablet formulations containing S-pindolol benzoate (Formulations A, B and C) were prepared according to the formulas shown below in Tables 1, 2 and 3. The tablets were prepared by direct compression of powder blends of the ingredients. [Table 1] [Table 2] [Table 3]

[0060] Example 2 Dissolution test The dissolution profiles of the three tablet formulations were evaluated in 0.1 M hydrochloric acid for 15 minutes and the results are shown in Table 4. [Table 4]

[0061] Formulation A consistently demonstrated higher dissolution rates than Formulations B or C.

[0062] Formulation A exhibited a rapid disintegration time of 15 seconds. Formulations B and C exhibited disintegration times of 27 and 30 seconds, respectively.

[0063] Example 3 Stability Test The stability of Formulations A and C during storage at 25°C / 60% RH or 40°C / 75% RH conditions was evaluated over a 6-month period.

[0064] Formulation A was observed to perform well under both storage conditions for all stability properties tested. Formulation A also maintained a dissolution rate of at least 97% after 15 minutes over the course of the stability evaluation at 25° C. / 60% RH.

[0065] Formulation C gave lower assay results for the active ingredient than Formulation A, and this remained true throughout the storage evaluation.

[0066] The friability of the tablets was evaluated and Formulation A was found to have excellent friability (0.0%).

[0067] conclusion Of the three formulations evaluated, Formulation A was found to have the most favorable dissolution and stability properties.

[0068] Example 4 Tablets of 5 mg, 10 mg and 15 mg S-pindolol equivalent were prepared with the composition in Table 5. The tablets were prepared by blending the ingredients and compressing. Starch 1500 is a partially pregelatinized corn starch. MCC 102 is a microcrystalline cellulose. [Table 5]

[0069] All tablets demonstrated rapid disintegration and dissolution and had good friability characteristics.

Claims

1. (a) An active substance that is S-pindolol or a pharmaceutically acceptable salt thereof; (b) A starch additive in an amount of at least 15.0% by weight based on the total weight of the formulation; and (c) A cellulose additive in an amount of at least 30.0% by weight based on the total weight of the formulation A solid pharmaceutical formulation suitable for oral administration, comprising the above.

2. The solid pharmaceutical composition is (a) An active substance that is S-pindolol or a pharmaceutically acceptable salt thereof; (b) A starch additive in an amount of at least 15.0% by weight based on the total weight of the formulation; and (c) A cellulose additive in an amount of at least 40.0% by weight based on the total weight of the formulation The solid pharmaceutical formulation according to Claim 1, comprising the above.

3. The solid pharmaceutical formulation according to Claim 1, wherein the active substance is a pharmaceutically acceptable salt of S-pindolol.

4. The active substance is (i) S-pindolol and (ii) a pharmaceutically acceptable salt of an organic acid, and the organic acid has a pK of 2.5 or more a1 ; and C x H y (CO 2 H) z having a chemical formula of, where x is from 1 to 10, y is from 2 to 20, and z is 1 or 2, Preferably, the organic acid is benzoic acid, succinic acid, fumaric acid, malonic acid, glutaric acid, adipic acid, acetic acid, propionic acid, phenylacetic acid, toluic acid or naphthoic acid. The solid pharmaceutical formulation according to Claim 1.

5. The solid pharmaceutical formulation according to Claim 1, wherein the active substance is S-pindolol benzoate.

6. The active substance is present in an amount of 1.0 to 25.0% by weight based on the total weight of the formulation, Preferably, the active substance is present in an amount of 10.0 to 20.0% by weight based on the total weight of the formulation. The solid pharmaceutical formulation according to Claim 1.

7. The starch additive is present in an amount of at least 20.0% by weight based on the total weight of the formulation, Preferably, the starch additive is present in an amount of 25.0 to 35.0% by weight based on the total weight of the formulation. The solid pharmaceutical formulation according to Claim 1.

8. The starch additive contains starch, Preferably, the starch additive contains one or more of corn starch, wheat starch, rice starch, cassava starch and cocoyam starch, More preferably, the starch additive contains corn starch. The solid pharmaceutical formulation according to Claim 1.

9. The solid pharmaceutical formulation according to Claim 1, wherein the starch additive contains at least partially gelatinized starch.

10. The cellulose additive is present in an amount of at least 45.0% by weight based on the total weight of the formulation, Preferably, the cellulose additive is present in an amount of 50.0 to 60.0% by weight based on the total weight of the formulation. The solid pharmaceutical formulation according to Claim 1.

11. The solid pharmaceutical preparation according to claim 1, wherein the cellulose additive contains crystalline cellulose.

12. The solid pharmaceutical preparation according to claim 1, wherein the solid pharmaceutical preparation contains a starch additive that is starch; and a cellulose additive that is crystalline cellulose.

13. The solid pharmaceutical preparation further contains colloidal silica, and the colloidal silica may be present in an amount of 0.1 to 1.0% by weight based on the total weight of the preparation, The solid pharmaceutical preparation according to claim 1.

14. The solid pharmaceutical preparation further contains a lubricant, preferably the lubricant is magnesium stearate, and the lubricant may be present in an amount of 0.1 to 1.0% by weight based on the total weight of the preparation, The solid pharmaceutical preparation according to claim 1.

15. The solid pharmaceutical preparation contains less than 10.0% by weight of lactose based on the total weight of the preparation, preferably, the solid pharmaceutical preparation contains less than 1.0% by weight of lactose, The solid pharmaceutical preparation according to claim 1.

16. The solid pharmaceutical preparation is (a) a pharmaceutically acceptable salt of 5.0 to 25.0% by weight of S-pindolol; (b) at least 20.0% by weight of a starch additive; and (c) at least 45.0% by weight of a cellulose additive wherein the % by weight is based on the total weight of the preparation, The solid pharmaceutical preparation according to claim 1.

17. The solid pharmaceutical preparation is (a) 10 to 20% by weight of S-pindolol benzoate; (b) 20 to 30% by weight of starch; (c) 50 to 60% by weight of crystalline cellulose; (d) optionally, colloidal silica; and (e) optionally, magnesium stearate wherein the % by weight is based on the total weight of the preparation, The solid pharmaceutical preparation according to claim 1.

18. The solid pharmaceutical preparation according to claim 1, wherein the solid pharmaceutical preparation is a tablet.

19. The solid pharmaceutical preparation is (a) 10 to 20% by weight of S-pindolol benzoate; (b) 22 to 30% by weight of corn starch, preferably partially pregelatinized corn starch; (c) 50 to 60% by weight of crystalline cellulose; (d) 0.1 to 0.5% by weight of colloidal silica; and (e) 0.1 to 0.5% by weight of magnesium stearate and is a tablet, wherein the % by weight is based on the total weight of the preparation, The solid pharmaceutical preparation according to claim 1.

20. The solid pharmaceutical preparation according to any one of claims 1 to 19 for the treatment or prevention of a disease or condition selected from cachexia, sarcopenia, neuromuscular disorder, muscle weakness, hypertension, heart failure, atrial fibrillation, heart attack, angina pectoris, glaucoma and anxiety.

21. The solid pharmaceutical preparation according to claim 20, wherein the disease or condition is cachexia or muscle weakness.