Pharmaceutical oral solid dosage forms including phenobarbital and methods of making and using the same

Abstract

Pharmaceutical oral solid dosage forms including at least one of phenobarbital and phenobarbital salt and methods of making and using the pharmaceutical oral solid dosage forms are disclosed.

Description

Docket No.230332PCT TITLE PHARMACEUTICAL ORAL SOLID DOSAGE FORMS INCLUDING PHENOBARBITAL AND METHODS OF MAKING AND USING THE SAME FIELD OF THE TECHNOLOGY

[0001] The present disclosure relates to pharmaceutical oral solid dosage forms comprising at least one of phenobarbital and phenobarbital salt and to methods of making and using the oral solid dosage forms. DESCRIPTION OF THE BACKGROUND OF THE TECHNOLOGY

[0002] Seizures are one of the most frequently reported neurological conditions in dogs. A seizure is a temporary involuntary disturbance of normal brain function that is usually accompanied by uncontrollable muscle activity. Epilepsy is a term used to describe repeated episodes of seizures. With epilepsy, the seizures can be single or may occur in clusters, and they can be infrequent and unpredictable or may occur at regular intervals.

[0003] There are many causes of seizures. Idiopathic epilepsy, the most common cause of seizures in the dog, is an inherited disorder, but its exact cause is unknown. Other causes include liver disease, kidney failure, brain tumors, brain trauma, and toxins. Seizures often occur at times of changing brain activity, such as during excitement or feeding, or as a dog is falling asleep or waking up. Affected dogs can appear completely normal between seizures.

[0004] Phenobarbital is a classical barbiturate with sedative, hypnotic, and antiepileptic properties. It is white or almost white crystalline powder or colorless crystals with an empirical formula C12H12N2O3and a molecular weight of 232.24. It is very slightly soluble in water, freely soluble in alcohol, and soluble in solutions of potassium and sodium hydroxide. It forms water-soluble compounds with alkali hydroxides and carbonates and with ammonia.

[0005] Phenobarbital is used in veterinary medicine as a seizure control therapy in dogs. Despite long-term and widespread use, there are no approved products for veterinary or human use. So that dogs receive a desired amount of phenobarbitalDocket No.230332PCT and / or phenobarbital salt when treated for idiopathic epilepsy, it is important that solid dosage forms including phenobarbital and / or phenobarbital salt are suitably stable such that they retain a desired minimum amount of the active drug compound after the dosage forms have been stored for a period of time.

[0006] Accordingly, there is a need for a pharmaceutical oral solid dosage form including at least one active ingredient selected from phenobarbital and phenobarbital salt and which exhibits advantageous stability and improved shelf life. SUMMARY

[0007] It is understood that the inventions disclosed and described in this specification are not limited to the embodiments described in this Summary.

[0008] One non-limiting aspect according to the present disclosure is directed to a pharmaceutical oral solid dosage form comprising, in weight percentages: at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%; about 34% to about 51% lactose monohydrate; about 20% to about 30% microcrystalline cellulose; and about 1% to about 5% colloidal silicon dioxide. In various non-limiting embodiments, the pharmaceutical oral solid dosage form is stable such that, for example, a total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form is at least 90%, at least 92%, at least 95%, or at least 97% of an original total content of phenobarbital and phenobarbital salt after the pharmaceutical oral solid dosage form has been stored for 12 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%.

[0009] A further non-limiting aspect according to the present disclosure is directed to pharmaceutical oral solid dosage form comprising, in weight percentages: at least one of phenobarbital and phenobarbital salt, wherein the total content of phenobarbital and phenobarbital salt is about 24% to about 30%; about 38% to about 47% lactose monohydrate; about 22.5% to about 27.5% microcrystalline cellulose; about 1.5% to about 5% sodium starch glycolate; about 1% to about 3% colloidal silicon dioxide; and about 0.5% to about 2.0% magnesium stearate. In various non-limiting embodiments, the pharmaceutical oral solid dosage form is stable such that, for example, a total content of phenobarbital and phenobarbital saltDocket No.230332PCT in the pharmaceutical oral solid dosage form is at least 90%, at least 92%, at least 95%, or at least 97% of an original total content of phenobarbital and phenobarbital salt after the pharmaceutical oral solid dosage form has been stored for 12 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%.

[0010] An additional non-limiting embodiment according to the present disclosure is directed to a packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form; and a container closure system comprising a container and a sealing closure. The pharmaceutical oral solid dosage form comprises, in weight percentages: at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%; about 34% to about 51% lactose monohydrate; about 20% to about 30% microcrystalline cellulose; and about 1% to about 5% colloidal silicon dioxide. A plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure, and each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 12 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%.

[0011] An additional non-limiting embodiment according to the present disclosure is directed to a packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form; and a container closure system comprising a container and a sealing closure. The pharmaceutical oral solid dosage form comprises, in weight percentages: at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%; about 34% to about 51% lactose monohydrate; about 20% to about 30% microcrystalline cellulose; and about 1% to about 5% colloidal silicon dioxide. A plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure, and each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in theDocket No.230332PCT pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 18 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%.

[0012] An additional non-limiting aspect according to the present disclosure is directed to a packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form; and a container closure system comprising a container and a sealing closure. The pharmaceutical oral solid dosage form comprises, in weight percentages: at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%; about 34% to about 51% lactose monohydrate; about 20% to about 30% microcrystalline cellulose; and about 1% to about 5% colloidal silicon dioxide. A plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure, and each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 36 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%.

[0013] An additional non-limiting aspect according to the present disclosure is directed to a packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form; and a container closure system comprising a container and a sealing closure. The pharmaceutical oral solid dosage form comprises, in weight percentages: at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%; about 34% to about 51% lactose monohydrate; about 20% to about 30% microcrystalline cellulose; and about 1% to about 5% colloidal silicon dioxide. A plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure, and each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosageDocket No.230332PCT form has been stored for 48 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%.

[0014] Another non-limiting aspect according to the present disclosure is directed to a packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form; and a container closure system comprising a container and a sealing closure. The pharmaceutical oral solid dosage form comprises, in weight percentages: at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%; about 34% to about 51% lactose monohydrate; about 20% to about 30% microcrystalline cellulose; and about 1% to about 5% colloidal silicon dioxide. A plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure, and each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%.

[0015] Yet another non-limiting aspect according to the present disclosure is directed to a packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form; and a container closure system comprising a container and a sealing closure. The pharmaceutical oral solid dosage form comprises, in weight percentages: at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%; about 34% to about 51% lactose monohydrate; about 20% to about 30% microcrystalline cellulose; and about 1% to about 5% colloidal silicon dioxide. A plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure, and each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 3 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%.Docket No.230332PCT

[0016] Yet an additional non-limiting aspect according to the present disclosure is directed to a packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form; and a container closure system comprising a container and a sealing closure. The pharmaceutical oral solid dosage form comprises, in weight percentages: at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%; about 34% to about 51% lactose monohydrate; about 20% to about 30% microcrystalline cellulose; and about 1% to about 5% colloidal silicon dioxide. A plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure, and each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%.

[0017] An additional non-limiting aspect according to the present disclosure is directed to method of treatment to address seizures in animals, the method comprising administering a pharmaceutical oral solid dosage form according to the present disclosure to an animal in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Various features and characteristics of non-limiting and non-exhaustive embodiments disclosed and described in this specification may be better understood by reference to the accompanying figures, in which:

[0019] Figures 1A and 1B, respectively, are side and section views of an embodiment of a 60 cm3(2.0 oz.) internal volume high-density polyethylene (“HDPE”) bottle used to contain oral solid dosage forms, as described herein.

[0020] Figure 1C is a side view of Detail “A” in Figure 1A.Docket No.230332PCT

[0021] Figures 2A and 2B, respectively, are side and section views of an embodiment of a 120 cm3(4.0 oz.) internal volume high-density polyethylene (“HDPE”) bottle used to contain oral solid dosage forms, as described herein.

[0022] Figure 2C is a side view of Detail “A” in Figure 2A.

[0023] Figures 3A and 3B are views of an embodiment of a container closure that can be used with the container shown in Figures 1A, 1B, and 1C, and with the container shown in Figures 2A, 2B, and 2C, and wherein Figure 3A is an exterior top view of a ribbed, threaded closure cap and Figure 3B is a side sectional view of the cap shown in Figure 3A.

[0024] Figures 4A and 4B, respectively, are side and section views of an embodiment of a 200 cm3(6.75 oz.) internal volume high-density polyethylene (“HDPE”) bottle used to contain oral solid dosage forms, as described herein.

[0025] Figure 4C is a side view of Detail “A” in Figure 4A.

[0026] Figures 5A and 5B are views of an embodiment of a container closure that can be used with the container shown in Figures 2A, 2B, and 2C, and with the container shown in Figures 4A, 4B, and 4C, and wherein Figure 5A is an exterior top view of a ribbed, threaded closure cap and Figure 5B is a side sectional view of the cap shown in Figure 5A.

[0027] Figures 6A and 6B, respectively, are side and section views of an embodiment of a 400 cm3(13.5 oz.) internal volume high-density polyethylene (“HDPE”) bottle used to contain oral solid dosage forms, as described herein.

[0028] Figure 6C is a side view of Detail “A” in Figure 6A.

[0029] Figures 7A and 7B, respectively, are side and section views of an embodiment of a 625 cm3(21.1 oz.) internal volume high-density polyethylene (“HDPE”) bottle used to contain oral solid dosage forms, as described herein.

[0030] Figure 7C is a side view of Detail “A” in Figure 7A.

[0031] Figures 8A-8C are views of an embodiment of a container closure that can be used with the container shown in Figures 6A, 6B, and 6C, and with the containerDocket No.230332PCT shown in Figures 7A, 7B, and 7C, and wherein Figure 8A is an exterior elevational view of a ribbed, threaded closure cap, Figure 8B is an exterior top view of the ribbed, threaded closure cap, and Figure 8C is a side sectional view of the cap shown in Figure 8B.

[0032] Dimensions shown in Figures 1-8 that are not in brackets are in inches. Dimensions shown in Figures 1-8 in brackets are in millimeters.

[0033] The reader will appreciate the foregoing details, as well as others, upon considering the following detailed description of various non-limiting and non- exhaustive embodiments according to the present disclosure. DESCRIPTION OF CERTAIN NON-LIMITING EMBODIMENTS

[0034] Various embodiments are described and illustrated in this specification to provide an overall understanding of the disclosed compositions, dosage forms, and methods. It is understood that the various embodiments described and illustrated in this specification are non-limiting and non-exhaustive. Thus, the present invention is not limited by the description of the various non-limiting and non-exhaustive embodiments disclosed in this specification. Rather, the invention is defined solely by the claims. Certain features and characteristics illustrated and / or described in connection with various embodiments may be combined with the features and characteristics of other embodiments. Such modifications and variations are intended to be included within the scope of this specification. As such, the claims may be amended to recite any features or characteristics expressly or inherently described in, or otherwise expressly or inherently supported by, this specification. Further, Applicant reserves the right to amend the claims to affirmatively disclaim features or characteristics that may be found present in the prior art. The various embodiments disclosed and described in this specification can comprise, consist of, or consist essentially of the features and characteristics as variously described herein.

[0035] All percentages provided herein are weight percentages based on the total weight of the respective composition, dosage form, mixture, etc., unless otherwise indicated.Docket No.230332PCT

[0036] Any numerical ranges recited in this specification are intended to include all sub-ranges of the same numerical precision subsumed within the recited range. For example, a range of "1.0 to 10.0" is intended to include all sub-ranges between (and including) the recited minimum value of 1.0 and the recited maximum value of 10.0, that is, having a minimum value equal to or greater than 1.0 and a maximum value equal to or less than 10.0, such as, for example, 2.4 to 7.6. Any maximum numerical limitation recited in this specification is intended to include all lower numerical limitations subsumed therein and any minimum numerical limitation recited in this specification is intended to include all higher numerical limitations subsumed therein. Applicant reserves the right to amend this specification, including the claims, to expressly recite any sub-range subsumed within the ranges expressly recited herein.

[0037] As generally used herein, the term “about” refers to an acceptable degree of error for the quantity measured, given the nature or precision of the measurement. Typical exemplary degrees of error may be within 20%, 10%, or 5% of a given value or range of values.

[0038] The terms “subject” and “patient” are used interchangeably herein, and it is intended that both refer to a recipient on whom a method is conducted according to the present disclosure or another method, as the case may be.

[0039] The terms “stability” and “stable” as used herein refer to each oral solid dosage form retaining at least 90%, at least 95%, at least 97%, at least 99%, or at least 100% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for a period of time under indicated conditions.

[0040] Disclosed herein are storage stable, pharmaceutical oral solid dosage forms comprising phenobarbital and / or phenobarbital salt as an active ingredient. In certain of the embodiments herein, the pharmaceutical oral solid dosage forms (e.g., tablets) comprise phenobarbital and / or phenobarbital salt (i.e., at least one of phenobarbital and phenobarbital salt), lactose monohydrate, microcrystalline cellulose, and colloidal silicon dioxide. The present inventors observed that certain embodiments of the pharmaceutical oral solid dosage forms according to the presentDocket No.230332PCT disclosure exhibit unexpectedly advantageous stability of the active pharmaceutical ingredient.

[0041] In certain non-limiting embodiments, the present pharmaceutical oral solid dosage forms can comprise phenobarbital (illustrated below) as an active pharmaceutical ingredient.

[0042] In certain other non-limiting embodiments, the present pharmaceutical oral solid dosage forms can comprise salts of phenobarbital as an active pharmaceutical ingredient. One such salt, a sodium salt of phenobarbital, is illustrated below.

[0043] It is further contemplated that in other non-limiting embodiments, oral solid dosage forms according to the present disclosure may include both phenobarbital and a salt form of phenobarbital. Accordingly, although the following description may refer at times to one or the other of phenobarbital and phenobarbital salt, it will be understood that oral solid dosage forms according to the present disclosure my include phenobarbital, phenobarbital salt, or a combination of the two.

[0044] In certain non-limiting embodiments, phenobarbital and / or phenobarbital salt is present in the oral solid dosage forms according to the present disclosure, andDocket No.230332PCT the total concentration of phenobarbital and phenobarbital salt in the oral solid dosage forms is 21% to 33%, such as, for example, 22% to 33%, 23% to 33%, 24% to 33%, 25% to 33%, 26% to 33%, 27% to 33%, 22% to 30%, 22% to 28%, 24% to 30%, 24% to 28%, 26% to 30%, or 26% to 28%, all in weight percent based on total weight of the oral solid dosage form. In various embodiments, phenobarbital and / or phenobarbital salt is present in the oral solid dosage forms according to the present disclosure, and the total concentration of phenobarbital and phenobarbital salt in the oral solid dosage forms may be about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, or about 33%, in weight percent based on the total weight of the oral solid dosage form.

[0045] In certain non-limiting embodiments, depending on the desired strength of the particular oral solid dosage form, the total mass of phenobarbital and phenobarbital salt included in an oral solid dosage form according to the present disclosure can range from about 12 mg to about 20 mg, from about 13 mg to about 20 mg, from about 14 mg to about 20 mg, from about 15 mg to about 20 mg, from about 12 mg to about 19 mg, from about 12 mg to about 18 mg, from about 12 mg to about 17 mg, from about 24 mg to about 40 mg, from about 24 mg to about 38 mg, from about 24 mg to about 36 mg, from about 24 mg to about 34 mg, from about 28 mg to about 40 mg, from about 30 mg to about 40 mg, from about 28 mg to about 34 mg, from about 49 mg to about 81 mg, from about 49 mg to about 78 mg, from about 49 mg to about 72 mg, from about 49 mg to about 68 mg, from about 52 mg to about 78 mg, from about 56 mg to about 74 mg, from about 60 mg to about 68 mg, from about 73 mg to about 122 mg, from about 73 mg to about 114 mg, from about 73 mg to about 106 mg, from about 80 mg to about 116 mg, from about 86 mg to about 110 mg, from about 90 mg to about 102 mg, from about 94 mg to about 100 mg, or from about 96 mg to about 162 mg.

[0046] Various non-limiting embodiments of a pharmaceutical oral solid dosage form according to the present disclosure can comprise one or more diluents. Diluents may be included as fillers in the pharmaceutical oral solid dosage form (e.g., tablet) to increase dosage form weight and improve content uniformity. Non-limiting examples of suitable diluents that can be used in the pharmaceutical oral solidDocket No.230332PCT dosage forms disclosed herein include at least one of microcrystalline cellulose (MCC) (e.g., AVICEL®PH-102 MCC powder), AVICEL®HFE-102 powder (a blend of microcrystalline cellulose and mannitol, available from FMC BioPolymer, Philadelphia, PA), confectioner’s sugar (including corn starch), croscarmellose sodium, dicalcium phosphate, inulin, carbohydrates (for example, arabinose, sucrose, dextrose, fructose, maltose, lactose, lactose monohydrate, trehalose, isomalt, starch, monosaccharides, disaccharides, polysaccharides, and sugar alcohols (e.g., sorbitol, mannitol, erythritol, xylitol, lactitol)), derivatives of the foregoing, and combinations of any thereof.

[0047] In certain non-limiting embodiments, diluent may be present in pharmaceutical oral solid dosage forms according to the present disclosure in a concentration of about 20% to about 30%, such as, for example, 21% to 30%, 22% to 30%, 22.5% to 27.5%, 23% to 30%, 24% to 30%, 20% to 29%, 20% to 28%, 20% to 27%, 20% to 26%, or 24% to 26%, or in a concentration of about 34% to about 51%, such as, for example, 34% to 50%, 34% to 49%, 34% to 48%, 34% to 47%, 34% to 46%, 34% to 45%, 34% to 44%, 36% to 50%, 36% to 48%, 36% to 46%, 36% to 44%, 38% to 50%, 38% to 48%, 38% to 47%, 38% to 46%, 38% to 44%, 41% to 45%, or 41% to 44%, all in weight percent based on total weight of the pharmaceutical oral solid dosage form. In other embodiments, diluent may be present in the pharmaceutical oral solid dosage forms according to the present disclosure in a concentration of about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, or about 51%, all in weight percent based on total weight of the pharmaceutical oral solid dosage form.

[0048] In certain non-limiting embodiments according to the present disclosure, the amount of diluent included in a pharmaceutical oral solid dosage form can range from about 12 mg to about 99 mg, such as from about 12 mg to about 18 mg, from about 24 mg to about 36 mg, from about 48 mg to about 72 mg, from about 81 mg to about 99 mg, from about 84 mg to about 96 mg, or from about 86 mg to about 94Docket No.230332PCT mg, or can range from about 20 mg to about 170 mg, such as from about 20 mg to about 30 mg, from about 22 mg to about 28 mg, from about 40 mg to about 60 mg, from about 46 mg to about 54 mg, from about 80 mg to about 120 mg, from about 90 mg to about 110 mg, from about 95 mg to about 105 mg, from about 135 mg to about 170 mg, from about 140 mg to about 165 mg, or from about 145 mg to about 160 mg.

[0049] In certain non-limiting embodiments, microcrystalline cellulose (MCC) may be present in pharmaceutical oral solid dosage forms according to the present disclosure in a concentration of about 20% to about 30%, such as, for example, 21% to 30%, 22% to 30%, 22.5% to 27.5%, 23% to 30%, 24% to 30%, 20% to 29%, 20% to 28%, 20% to 27%, 20% to 26%, or 24% to 26%, all in weight percent based on total weight of the pharmaceutical oral solid dosage form. In other embodiments, MCC may be present in the pharmaceutical oral solid dosage forms according to the present disclosure in a concentration of about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%, all in weight percent based on total weight of the pharmaceutical oral solid dosage form.

[0050] In certain non-limiting embodiments, the amount of MCC included in a pharmaceutical oral solid dosage form can range from about 12 mg to about 99 mg, such as from about 12 mg to about 18 mg, from about 24 mg to about 36 mg, from about 48 mg to about 72 mg, from about 81 mg to about 99 mg, from about 84 mg to about 96 mg, or from about 86 mg to about 94 mg.

[0051] In certain non-limiting embodiments, lactose monohydrate may be present in pharmaceutical oral solid dosage forms according to the present disclosure in a concentration of about 34% to about 51%, such as, for example, 34% to 50%, 34% to 49%, 34% to 48%, 34% to 47%, 34% to 46%, 34% to 45%, 34% to 44%, 36% to 50%, 36% to 48%, 36% to 46%, 36% to 44%, 38% to 50%, 38% to 48%, 38% to 47%, 38% to 46%, 38% to 44%, 41% to 45%, or 41% to 44%, all in weight percent based on total weight of the pharmaceutical oral solid dosage form. In other embodiments, MCC may be present in the pharmaceutical oral solid dosage forms according to the present disclosure in a concentration of about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%,Docket No.230332PCT about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, or about 51%, all in weight percent based on total weight of the pharmaceutical oral solid dosage form.

[0052] In certain non-limiting embodiments, the amount of lactose monohydrate included in a pharmaceutical oral solid dosage form can range from about 20 mg to about 170 mg, such as from about 20 mg to about 30 mg, from about 22 mg to about 28 mg, from about 40 mg to about 60 mg, from about 46 mg to about 54 mg, from about 80 mg to about 120 mg, from about 90 mg to about 110 mg, from about 95 mg to about 105 mg, from about 135 mg to about 170 mg, from about 140 mg to about 165 mg, or from about 145 mg to about 160 mg.

[0053] Various non-limiting embodiments of a pharmaceutical oral solid dosage form according to the present disclosure comprise one or more lubricants. Lubricants may be included in the pharmaceutical oral solid dosage forms, for example, to improve powder processing properties when manufacturing the pharmaceutical solid dosage forms. Non-limiting examples of suitable lubricants that can be used in the pharmaceutical oral solid dosage forms according to the present disclosure include sodium stearyl fumarate, polyethylene glycols, mineral oil, medium chain triglycerides, sodium stearyl sulfate, cocoa butter, sodium benzoate, stearic acid (and its derivatives or esters such as, for example, sodium stearate, magnesium stearate, calcium stearate), and combinations of any thereof.

[0054] The concentration of lubricant in a pharmaceutical oral solid dosage form in certain non-limiting embodiments according to the present disclosure can range from about 0.5% to about 2%, from about 0.75% to about 2%, from about 0.75% to about 1.75%, from about 0.75% to about 1.5%, from about 0.5% to about 1.75%, from about 0.5% to about 1.5%, or from about 0.75% to about 1.25%, all in weight percent based on total weight of the oral solid dosage form.

[0055] In certain non-limiting embodiments, the amount of lubricant included in a pharmaceutical oral solid dosage form can range from about 0.5 mg to about 5 mg, such as from about 0.5 mg to about 0.7 mg, from about 0.5 mg to about 0.65 mg, from about 0.55 mg to about 0.7 mg, from about 0.55 mg to about 0.65 mg, from about 1.0 mg to about 1.4 mg, from about 1.1 mg to about 1.4 mg, from about 1.0Docket No.230332PCT mg to about 1.3 mg, from about 1.1 mg to about 1.3 mg, from about 1.15 mg to about 1.25 mg, from about 2.0 mg to about 2.6 mg, from about 2.0 mg to about 2.5 mg, from about 2.1 mg to about 2.6 mg, from about 2.2 mg to about 2.6 mg, from about 2.2 mg to about 2.5 mg, from about 2.3 mg to about 2.5 mg; from about 3.2 mg to about 5 mg, from about 3.4 mg to about 4.8 mg, from about 3.2 mg to about 4.6 mg, from about 3.2 mg to about 4.4 mg, from about 3.2 mg to about 4 mg, from about 3.2 mg to about 3.8 mg, or from about 3.4 mg to about 3.8 mg.

[0056] Various non-limiting embodiments of a pharmaceutical oral solid dosage form according to the present disclosure can comprise one or more glidants. Glidants may be included to enhance flowability of the powder ingredients during production of the dosage forms by reducing interparticle friction, particle surface charge, and / or particle cohesion. Non-limiting examples of suitable glidants that can be used in oral solid dosage forms according to the present disclosure include talc, silicon dioxide, colloidal silicon dioxide, and combinations of any thereof.

[0057] The concentration of glidant in a pharmaceutical oral solid dosage form according to certain non-limiting embodiments of the present disclosure can range from about 1% to about 5%, from about 1% to about 4.5%, from about 1% to about 4%, from about 1% to about 3.5%, from about 1% to about 3.25%, from about 1% to about 3%, from about 1.25% to about 3%, from about 1% to about 2.75%, from about 1% to about 2.5%, from about 1% to about 2.25%, from about 1% to about 2%, from about 1% to about 1.75%, from about 1.25% to about 2%, from about 1.2% to about 1.8%, all in weight percent based on total weight of the pharmaceutical oral solid dosage form.

[0058] In certain non-limiting embodiments, the amount of glidant included in a pharmaceutical oral solid dosage form according to the present disclosure can range from about 0.5 mg to about 6 mg, such as from about 0.5 mg to about 1.5 mg, from about 0.7 mg to about 1.5 mg, from about 0.7 mg to about 1.3 mg, from about 0.7 mg to about 1.1 mg, from about 1.0 mg to about 3.0 mg, from about 1.4 mg to about 3.0 mg, from about 1.4 mg to about 2.6 mg, from about 1.4 mg to about 2.4 mg, from about 1.0 mg to about 2.4 mg, from about 2.5 mg to about 4.5 mg, from about 2.8 mg to about 4.5 mg, from about 2.5 mg to about 4.0 mg, from about 2.8 mg to about 3.8 mg, from about 3.2 mg to about 3.8 mg, from about 4.0 mg to about 6.0 mg; fromDocket No.230332PCT about 4.4 mg to about 6.0 mg, from about 4.8 mg to about 6.0 mg, from about 5.0 mg to about 6.0 mg, from about 5.2 mg to about 6.0 mg, or from about 5.2 mg to about 5.8 mg.

[0059] Various non-limiting embodiments of a pharmaceutical oral solid dosage form according to the present disclosure can comprise one or more disintegrant. Disintegrants may be included in the pharmaceutical oral solid dosage forms, for example, to facilitate disintegration after oral administration. Non-limiting examples of suitable disintegrants that can be used in pharmaceutical oral solid dosage forms according to the present disclosure include sodium starch glycolate and / or croscarmellose sodium.

[0060] The concentration of disintegrants in a pharmaceutical oral solid dosage form according to certain non-limiting embodiments of the present disclosure can range from about 1.5% to about 5%, from about 1.5% to about 4.5%, from about 1.5% to about 4%, from about 1.5% to about 3.5%, from about 1.5% to about 3.25%, from about 1.5% to about 3%, from about 2% to about 3.5%, from about 2.25% to about 3.5%, from about 2.5% to about 3.5%, or from about 2.2% to about 3.4%, all in weight percent based on total weight of the pharmaceutical oral solid dosage form.

[0061] In certain non-limiting embodiments, the amount of disintegrant included in a pharmaceutical oral solid dosage form according to the present disclosure can range from about 1 mg to about 12 mg, such as from about 1.0 mg to about 2.0 mg, from about 1.25 mg to about 2.0 mg, from about 1.5 mg to about 2.0 mg, from about 2.5 mg to about 4.0 mg, from about 2.75 mg to about 3.75 mg, from about 3.0 mg to about 3.75 mg, from about 3.25 mg to about 3.75 mg, from about 5.0 mg to about 7.5 mg, from about 5.5 mg to about 7.5 mg, from about 6.0 mg to about 7.5 mg, from about 5.75 mg to about 7.0 mg, from about 6.0 mg to about 7.0 mg, from about 6.5 mg to about 7.0 mg, from about 9.0 mg to about 11.0 mg, from about 9.5 mg to about 11.0 mg, from about 9.5 mg to about 10.5 mg, or from about 9.0 mg to about 10.5 mg.

[0062] Various non-limiting embodiments of a pharmaceutical oral solid dosage form according to the present disclosure optionally can comprise one or more coloring agents. Examples of a coloring agent that may be used in oral dosageDocket No.230332PCT forms according to the present disclosure include, but are not limited to, one or more of FD&C Blue #1 Aluminum Lake (11-13%), D&C Yellow #10 Aluminum Lake (14- 18%), and FD&C Red #40 Aluminum Lake (14-16%).

[0063] Various non-limiting embodiments of a pharmaceutical oral solid dosage form according to the present disclosure optionally can further comprise one or more coatings. Coatings may be included on the pharmaceutical oral solid dosage forms, for example, to mask taste, facilitate swallowing, and / or protect active pharmaceutical ingredients. Non-limiting examples of suitable coatings that can be applied to various non-limiting embodiments of the pharmaceutical oral solid dosage forms according to the present disclosure include OPADRY®white coating and OPADRY®II 85F19316 clear coating (available from Colorcon, Inc., West Point, PA USA).

[0064] In various non-limiting embodiments, the pharmaceutical oral solid dosage forms according to the present disclosure may be provided as tablets, caplets, capsules, powders, lozenges, or other suitable solid dosage forms.

[0065] In certain embodiments according to the present disclosure, a pharmaceutical oral solid dosage form comprises at least one of phenobarbital and phenobarbital salt (i.e., phenobarbital and / or phenobarbital salt), lactose monohydrate, microcrystalline cellulose, and colloidal silicon dioxide. In various embodiments, the pharmaceutical oral solid dosage form is prepared by a method comprising a dry blending process. In various embodiments, the pharmaceutical oral solid dosage form retains at least 90% of an original total content of phenobarbital and phenobarbital salt in the solid dosage form when the dosage form is stored under one or more of the following storage conditions: stored for 48 months under standard testing conditions (25oC ± 2oC and 60% ± 5% relative humidity); stored for 6 months under accelerated testing conditions (40oC ± 2oC and 75% ± 5% relative humidity).

[0066] In certain embodiments according to the present disclosure, a pharmaceutical oral solid dosage form comprises at least one of phenobarbital and phenobarbital salt, lactose monohydrate, microcrystalline cellulose, and colloidal silicon dioxide. In various embodiments, the pharmaceutical oral solid dosage formDocket No.230332PCT is prepared by a method comprising a dry blending process. In various embodiments, the pharmaceutical oral solid dosage form retains at least 95% of an original total content of phenobarbital and phenobarbital salt in the solid dosage form when the dosage form is stored under one or more of the following storage conditions: stored for 48 months under standard testing conditions (25oC ± 2oC and 60% ± 5% relative humidity); stored for 6 months under accelerated testing conditions (40oC ± 2oC and 75% ± 5% relative humidity).

[0067] In certain embodiments according to the present disclosure, a pharmaceutical oral solid dosage form comprises at least one of phenobarbital and phenobarbital salt, lactose monohydrate, microcrystalline cellulose, and colloidal silicon dioxide. In various embodiments, the pharmaceutical oral solid dosage form is prepared by a method comprising a dry blending process. In various embodiments, the pharmaceutical oral solid dosage form retains at least 97% of an original total content of phenobarbital and phenobarbital salt in the solid dosage form when the dosage form is stored under one or more of the following storage conditions: stored for 48 months under standard testing conditions (25oC ± 2oC and 60% ± 5% relative humidity); stored for 6 months under accelerated testing conditions (40oC ± 2oC and 75% ± 5% relative humidity).

[0068] In certain embodiments according to the present disclosure, a pharmaceutical oral solid dosage form comprises at least one of phenobarbital and phenobarbital salt, lactose monohydrate, microcrystalline cellulose, and colloidal silicon dioxide. In various embodiments, the pharmaceutical oral solid dosage form is prepared by a method comprising a dry blending process. In various embodiments, the pharmaceutical oral solid dosage form retains at least 99% of an original total content of phenobarbital and phenobarbital salt in the solid dosage form when the dosage form is stored under one or more of the following storage conditions: stored for 48 months under standard testing conditions (25oC ± 2oC and 60% ± 5% relative humidity); stored for 6 months under accelerated testing conditions (40oC ± 2oC and 75% ± 5% relative humidity).

[0069] In various embodiments, pharmaceutical oral solid dosage forms according to the present disclosure can be prepared by a method comprising a dry blending process that provides for uniform blending of ingredients. The dry uniformDocket No.230332PCT blending of the ingredients can comprise techniques known in the art, such as one or more of blending, mixing, sieving, co-milling, grinding, granulation, and power granulation.

[0070] In certain non-limiting embodiments according to the present disclosure, a prepackaged drug product is provided comprising pharmaceutical oral solid dosage forms according to the present disclosure contained in a container closure system including a container and a sealing closure. In certain non-limiting embodiments according to the present disclosure, the container has an internal volume of about 50 cm3to about 70 cm3and includes therein about 90 to about 110 oral solid dosage forms according to the present disclosure and, optionally, at least one silica gel desiccant canister containing, for example, about 2 grams of desiccant per canister. In various embodiments, the container closure system can also include at least one oxygen absorber containing, for example, about 2 grams of oxygen absorbing material. In certain non-limiting embodiments according to the present disclosure, a prepackaged drug product according to the present disclosure comprises a container closure system wherein the container has an internal volume of about 50 cm3to about 70 cm3and in which are contained about 90 to about 110 oral solid dosage forms according to the present disclosure and at least one oxygen absorber canister or other container type (including, for example, about 2 grams of oxygen absorbing material).

[0071] In certain non-limiting embodiments according to the present disclosure, a prepackaged drug product is provided comprising pharmaceutical oral solid dosage forms according to the present disclosure contained in a container closure system including a container and a sealing closure. In certain non-limiting embodiments according to the present disclosure, the container has an internal volume of about 110 cm3to about 130 cm3and includes therein about 90 to about 110 oral solid dosage forms according to the present disclosure and, optionally, at least one silica gel desiccant canister containing, for example, about 2 grams of desiccant per canister. In various embodiments, the container closure system can also include at least one oxygen absorber canister or other container type containing, for example, about 2 grams of oxygen absorbing material. In certain non-limiting embodiments according to the present disclosure, a prepackaged drug product according to theDocket No.230332PCT present disclosure comprises a container closure system wherein the container has an internal volume of about 110 cm3to about 130 cm3and in which are contained about 90 to about 110 oral solid dosage forms according to the present disclosure and at least one oxygen absorber canister or other container type (including, for example, about 2 grams of oxygen absorbing material).

[0072] In certain non-limiting embodiments according to the present disclosure, a prepackaged drug product is provided comprising pharmaceutical oral solid dosage forms according to the present disclosure contained in a container closure system including a container and a sealing closure. In certain non-limiting embodiments according to the present disclosure, the container has an internal volume of about 110 cm3to about 130 cm3and includes therein about 900 to about 1100 oral solid dosage forms according to the present disclosure and, optionally, at least one silica gel desiccant canister containing, for example, about 2 grams of desiccant per canister. In various embodiments, the container closure system can also include at least one oxygen absorber canister or other container type containing, for example, about 2 grams of oxygen absorbing material. In certain non-limiting embodiments according to the present disclosure, a prepackaged drug product according to the present disclosure comprises a container closure system wherein the container has an internal volume of about 110 cm3to about 130 cm3and in which are contained about 900 to about 1100 oral solid dosage forms according to the present disclosure and at least one oxygen absorber canister or other container type (including, for example, about 2 grams of oxygen absorbing material).

[0073] In certain non-limiting embodiments according to the present disclosure, a prepackaged drug product is provided comprising pharmaceutical oral solid dosage forms according to the present disclosure contained in a container closure system including a container and a sealing closure. In certain non-limiting embodiments according to the present disclosure, the container has an internal volume of about 180 cm3to about 220 cm3and includes therein about 900 to about 1100 oral solid dosage forms according to the present disclosure and, optionally, at least one silica gel desiccant canister containing, for example, about 2 grams of desiccant per canister. In various embodiments, the container closure system can also include at least one oxygen absorber containing, for example, about 2 grams of oxygenDocket No.230332PCT absorbing material. In certain non-limiting embodiments according to the present disclosure, a prepackaged drug product according to the present disclosure comprises a container closure system wherein the container has an internal volume of about 180 cm3to about 220 cm3and in which are contained about 900 to about 1100 oral solid dosage forms according to the present disclosure and at least one oxygen absorber canister or other container type (including, for example, about 2 grams of oxygen absorbing material).

[0074] In certain non-limiting embodiments according to the present disclosure, a prepackaged drug product is provided comprising pharmaceutical oral solid dosage forms according to the present disclosure contained in a container closure system including a container and a sealing closure. In certain non-limiting embodiments according to the present disclosure, the container has an internal volume of about 360 cm3to about 440 cm3and includes therein about 900 to about 1100 oral solid dosage forms according to the present disclosure and, optionally, at least one silica gel desiccant canister containing, for example, about 2 grams of desiccant per canister. In various embodiments, the container closure system can also include at least one oxygen absorber canister or other container type containing, for example, about 2 grams of oxygen absorbing material. In certain non-limiting embodiments according to the present disclosure, a prepackaged drug product according to the present disclosure comprises a container closure system wherein the container has an internal volume of about 360 cm3to about 440 cm3and in which are contained about 900 to about 1100 oral solid dosage forms according to the present disclosure and at least one oxygen absorber canister or other container type (including, for example, about 2 grams of oxygen absorbing material).

[0075] In certain non-limiting embodiments according to the present disclosure, a prepackaged drug product is provided comprising pharmaceutical oral solid dosage forms according to the present disclosure contained in a container closure system including a container and a sealing closure. In certain non-limiting embodiments according to the present disclosure, the container has an internal volume of about 575 cm3to about 675 cm3and includes therein about 900 to about 1100 oral solid dosage forms according to the present disclosure and, optionally, at least one silica gel desiccant canister containing, for example, about 2 grams of desiccant perDocket No.230332PCT canister. In various embodiments, the container closure system can also include at least one oxygen absorber containing, for example, about 2 grams of oxygen absorbing material. In certain non-limiting embodiments according to the present disclosure, a prepackaged drug product according to the present disclosure comprises a container closure system wherein the container has an internal volume of about 575 cm3to about 675 cm3and in which are contained about 900 to about 1100 oral solid dosage forms according to the present disclosure and at least one oxygen absorber canister or other container type (including, for example, about 2 grams of oxygen absorbing material).

[0076] The container of the container closure system of certain non-limiting embodiments of a prepackaged drug product according to the present disclosure can comprise at least one of glass, plastic, or other suitable polymeric material. For example, in certain embodiments the container of the container closure system of certain non-limiting embodiments of a prepackaged drug product according to the present disclosure can comprise polypropylene or high-density polyethylene. In certain embodiments of a prepackaged drug product according to the present disclosure, the pharmaceutical oral solid dosage forms can be stored in a container of a container closure system that has been purged with an inert gas to replace at least a portion of environmental oxygen within the container prior to sealing the container with the closure. In certain embodiments according to the present disclosure, the inert gas used to purge the container can comprise nitrogen, argon, a mixture of nitrogen and argon, or another inert gas or inert gas mixture. In certain embodiments of a prepackaged drug product according to the present disclosure, the pharmaceutical oral solid dosage forms can be stored in a container of a container closure system that has not been purged with an inert gas prior to sealing the container with the closure. In certain embodiments according to the present disclosure, at least a portion of air space within the container may be filled with a pill packing material such as, for example, rayon or cotton, prior to sealing the container with the closure.

[0077] An aspect of the present disclosure is directed to methods of treatment to address the occurrence of seizures in animals resulting from idiopathic epilepsy or another cause. According to one method, a pharmaceutical oral solid dosage formDocket No.230332PCT according to the present disclosure is administered to an animal in need thereof such that that the animal receives a total of about 15 mg to about 100 mg of phenobarbital and / or phenobarbital salt per dosage. In certain embodiments according to the present disclosure, the animal is a dog. In certain other embodiments according to the present disclosure, the animal has idiopathic epilepsy.

[0078] According to certain non-limiting embodiments, oral solid dosage forms according to the present disclosure may be prepared using a dry layering / mixing process generally including the following steps. A dry layered blend is prepared by first screening a diluent (e.g., AVICEL®PH-102 MCC powder) through a #30 mesh screen and then mixing the diluent using a V-blender to form a first layer in the V- blender. Next, a screened blend is prepared by screening together the remaining diluent (e.g., AVICEL®PH-102 MCC powder), a second diluent (e.g., lactose monohydrate), at least one of phenobarbital and phenobarbital salt, glidant (e.g., colloidal silicon dioxide), and disintegrant (e.g., sodium starch glycolate), to form a screened blend. The screened blend is deposited on the first layer to form a second layer in the V-blender. Next, a third layer is formed on the second layer by screening a lubricant (e.g., magnesium stearate) through a #30 mesh screen and depositing it on the second layer in the V-blender. The dry layered arrangement comprising the first, second, and third layers of powdered materials is then uniformly mixed in the V- blender to provide a uniform powder mixture. Predetermined quantities of the dry mixture are compressed to form tablets having a desired mass and including desired quantities of at least one of phenobarbital and phenobarbital salt per tablet. Alternatively, predetermined quantities of the dry oral solid dosage mixture may be, for example, disposed in capsules such as, for example, hard gelatin capsules, or used to prepare other suitable oral solid dosage forms.

[0079] The present inventors observed that various embodiments of pharmaceutical oral solid dosage forms according to the present disclosure including at least one of phenobarbital and phenobarbital salt exhibited advantageous stability.

[0080] For example, the present inventors observed that certain non-limiting embodiments of pharmaceutical oral solid dosage forms according to the present disclosure retained at least 90% of an original total content of phenobarbital and phenobarbital salt after storage for 12 months, 18 months, 36 months, or 48 monthsDocket No.230332PCT under standard testing conditions including a temperature of about 23°C to about 27°C and a relative humidity from about 55% to about 65%. The present inventors also observed that certain embodiments of pharmaceutical oral solid dosage forms according to the present disclosure retained at least 90% of an original total content of phenobarbital and phenobarbital salt after storage for two months, three months, or six months under accelerated testing conditions including a temperature of about 38°C to about 42°C and a relative humidity from about 70% to about 80%.

[0081] In addition, the present inventors observed that certain non-limiting embodiments of pharmaceutical oral solid dosage forms according to the present disclosure retained at least 92% of an original total content of phenobarbital and phenobarbital salt after storage for 12 months, 18 months, 36 months, or 48 months under standard testing conditions including a temperature of about 23°C to about 27°C and a relative humidity from about 55% to about 65%. The present inventors also observed that certain embodiments of pharmaceutical oral solid dosage forms according to the present disclosure retained at least 92% of an original total content of phenobarbital and phenobarbital salt after storage for two months, three months, or six months under accelerated testing conditions including a temperature of about 38°C to about 42°C and a relative humidity from about 70% to about 80%.

[0082] In addition, the present inventors observed that certain non-limiting embodiments of pharmaceutical oral solid dosage forms according to the present disclosure retained at least 95% of an original total content of phenobarbital and phenobarbital salt after storage for 12 months, 18 months, 36 months, or 48 months under standard testing conditions including a temperature of about 23°C to about 27°C and a relative humidity from about 55% to about 65%. The present inventors also observed that certain embodiments of pharmaceutical oral solid dosage forms according to the present disclosure retained at least 95% of an original total content of phenobarbital and phenobarbital salt after storage for two months, three months, or six months under accelerated testing conditions including a temperature of about 38°C to about 42°C and a relative humidity from about 70% to about 80%.

[0083] In addition, the present inventors observed that certain non-limiting embodiments of pharmaceutical oral solid dosage forms according to the present disclosure retained at least 97% of an original total content of phenobarbital andDocket No.230332PCT phenobarbital salt after storage for 12 months, 18 months, 36 months, or 48 months under standard testing conditions including a temperature of about 23°C to about 27°C and a relative humidity from about 55% to about 65%. The present inventors also observed that certain embodiments of pharmaceutical oral solid dosage forms according to the present disclosure retained at least 97% of an original total content of phenobarbital and phenobarbital salt after storage for two months, three months, or six months under accelerated testing conditions including a temperature of about 38°C to about 42°C and a relative humidity from about 70% to about 80%.

[0084] In addition, the present inventors observed that certain non-limiting embodiments of pharmaceutical oral solid dosage forms according to the present disclosure retained at least 99% of an original total content of phenobarbital and phenobarbital salt after storage for 12 months, 18 months, 36 months, or 48 months under standard testing conditions including a temperature of about 23°C to about 27°C and a relative humidity from about 55% to about 65%. The present inventors also observed that certain embodiments of pharmaceutical oral solid dosage forms according to the present disclosure retained at least 99% of an original total content of phenobarbital and phenobarbital salt after storage for two months, three months, or six months under accelerated testing conditions including a temperature of about 38°C to about 42°C and a relative humidity from about 70% to about 80%.

[0085] Following are non-limiting examples of pharmaceutical oral dosage forms including at least one of phenobarbital and phenobarbital salt and methods of making pharmaceutical oral dosage forms including at least one of phenobarbital and phenobarbital salt, all according to the present disclosure.Docket No.230332PCT Examples Example 1

[0086] This example describes a non-limiting embodiment of a dry layering / mixing and tableting process that may be used to make embodiments of pharmaceutical oral solid dosage forms according to the present disclosure.

[0087] Half of a total required amount of a powdered diluent (for example, AVICEL®PH-102 MCC powder) was screened through a #30 mesh screen, and the screened material was mixed in a first V-blender for 1 minute at 20 RPM. The screened and mixed portion of the diluent powder formed a first powder layer in the first V-blender. Next, a screened blend was prepared by adding the remainder portion of the powdered diluent to a container including an amount of an additional diluent (for example, lactose monohydrate), phenobarbital, powdered glidant (for example, colloidal silicon dioxide), and powdered disintegrant (for example, sodium starch glycolate), and screening the resulting blend of powders through a #30 mesh screen into a high-density polyethylene (HDPE) bag. The screened blend of diluent powder, phenobarbital, glidant powder, and disintegrant powder from the HDPE bag was then mixed in a second V-blender for 10 minutes at 20 RPM. The screened and mixed mixture of the diluent powder, phenobarbital, glidant powder, and disintegrant powder formed a second layer in the first V-blender, on top of the first layer. Next, an amount of lubricant (for example, magnesium stearate) was screened through a #30 mesh screen and mixed in a third V-blender for 2 minutes at 20 RPM. The screened and mixed portion of the lubricant material was disposed on the second layer in the first V-blender, and formed a third layer. The layered arrangement was then mixed in the first V-blender until uniformly combined to form a final powder blend.

[0088] Multiple small quantities of the final powder blend were removed from the V-blender using a cradle discharge method over short time periods to prevent segregation of the ingredients. Measured portions of the final powder blend removed from the V-blender were compressed to a hardness of 1.9 to 11.0 Kp using a PROTABTM300 tableting press (available from ProTab Laboratories, Foothill Ranch, CA USA) into 15.0 mg, 16.2 mg, 30 mg, 32.4 mg, 60 mg, 64.8 mg, 97.2 mg,Docket No.230332PCT and 100 mg tablets. The tablets were packaged in high density polyethylene (HDPE) containers (i.e., bottles) having an internal volume of about 60 cm3, about 120 cm3, about 200 cm3, about 400 cm3, or about 625 cm3.

[0089] About 90 to about 110 of the tablets were disposed in the 60 cm3HDPE containers (shown in Figures 1A, 1B, and 1C). The 60 cm3containers were sealed with a sealing closure (depicted in Figures 3A and 3B), providing a packaged pharmaceutical oral solid dosage form product.

[0090] About 90 to about 110 of the tablets were disposed in the 120 cm3HDPE containers (shown in Figures 2A, 2B, and 2C). The 120 cm3containers were sealed with a sealing closure (depicted in Figures 3A and 3B), providing a packaged pharmaceutical oral solid dosage form product.

[0091] About 900 to about 1100 of the tablets were disposed in the 120 cm3HDPE containers (shown in Figures 2A, 2B, and 2C). The 120 cm3containers were sealed with a sealing closure (depicted in Figures 5A and 5B), providing a packaged pharmaceutical oral solid dosage form product.

[0092] About 900 to about 1100 of the tablets were disposed in the 200 cm3HDPE containers (shown in Figures 4A, 4B, and 4C). The 200 cm3containers were sealed with a sealing closure (depicted in Figures 5A and 5B), providing a packaged pharmaceutical oral solid dosage form product.

[0093] About 900 to about 1100 of the tablets were disposed in the 400 cm3HDPE containers (shown in Figures 6A, 6B, and 6C). The 400 cm3containers were sealed with a sealing closure (depicted in Figures 8A, 8B, and 8C), providing a packaged pharmaceutical oral solid dosage form product.

[0094] About 900 to about 1100 of the tablets were disposed in the 625 cm3HDPE containers (shown in Figures 7A, 7B, and 7C). The 625 cm3containers were sealed with a sealing closure (depicted in Figures 8A, 8B, and 8C), providing a packaged pharmaceutical oral solid dosage form product. Example 2Docket No.230332PCT

[0095] Pharmaceutical oral solid dosage forms were prepared by compressing portions of several uniform mixtures made using the method generally described in Example 1. Each of the tablets included phenobarbital, microcrystalline cellulose (MCC) powder, lactose monohydrate, colloidal silicon dioxide, sodium starch glycolate, and magnesium stearate. Table 1 below provides the mass and weight / weight concentration of the ingredients in individual tablets comprising 15.0 mg, 16.2 mg, 30 mg, 32.4 mg, 60 mg, 64.8 mg, 97.2 mg, and 100.0 mg phenobarbital per tablet. The amount of phenobarbital in a dosage form is referred to as the “strength” of an individual tablet. All tablets of a particular strength listed in Table 1 included the same ingredients in the same weight percentage concentrations Table 1: Composition of tabletsExample 3

[0096] A study was conducted to assess the stability of embodiments of oral solid dosage forms according to the present disclosure.Docket No.230332PCT

[0097] Tablets including 16.2 mg of phenobarbital were prepared by compressing portions of several uniform mixtures made using the method generally described in Example 1. Each of the mixtures included phenobarbital, microcrystalline cellulose (MCC), lactose monohydrate, colloidal silicon dioxide, sodium starch glycolate, and magnesium stearate. The MCC used was AVICEL®PH-102 MCC powder. Table 2 below provides the mass and weight / weight concentration of the ingredients in individual tablets comprising 16.2 mg phenobarbital per tablet produced in Batches S54100118C and S54100118D. Table 2: Composition of tablets in Batches S54100118C and S54100118D

[0098] For purposes of conducting the stability study, the tablets of Batch S54100118C were disposed in container closure systems including a container comprising an internal volume of either about 60 cm3(including 90 to 110 tablets) and a sealing closure. For purposes of conducting the stability study, the tablets of Batch S54100118D were disposed in container closure systems including a container comprising an internal volume of either about 120 cm3(including 900 to 1100 tablets) and a sealing closure.

[0099] Two studies were conducted to assess the stability of the phenobarbital in the tablets produced in Batches S54100118C and S54100118D. The stability studies involved the following testing periods and conditions:Docket No.230332PCT • Storing under standard testing conditions (25oC ± 2oC and 60% ± 5% relative humidity) for up to 48 months. • Storing under accelerated testing conditions (40oC ± 2oC and 75% ± 5% relative humidity) for up to 6 months.

[0100] A standard testing conditions stability study of the tablets of Batches S54100118C and S54100118D contained in the container closure system was conducted over a period of 48 months to determine the rate of physical or chemical degradation of the phenobarbital included in tablets when stored under the standard environmental conditions.

[0101] Container closure systems prepared as described above containing tablets including about 16.2 mg of phenobarbital per tablet were placed upright in a calibrated environmental chamber and maintained in an upright position during the stability study. The sealed containers including either 90 to 110 or 900 to 1100 tablets were maintained at 25oC ± 2oC and 60% ± 5% relative humidity, uninterrupted (except for the addition or withdrawal of test samples), for a period of 12 months, 18 months, 36 months, or 48 months. Tablets were removed from the storage conditions at the specified time points and tested for phenobarbital content using high pressure liquid chromatography.

[0102] Considering phenobarbital content, shelf life of tablets of Batches S54100118C and S54100118D was estimated to be at least 48 months when stored under standard testing conditions. Table 3 provides the 48-month stability assay results for tablets of Batches S54100118C and S54100118D. The stability assay showed that greater than 98 percent of the original phenobarbital content was retained in tablets stored under standard testing conditions for 48 months.

[0103] Accelerated condition stability samples were placed upright in an environmental chamber and maintained in an upright position during the stability testing. As discussed, each tablet was disposed in the sealed container containing either 90 to 110 or 900 to 1100 tablets from Batches S54100118C and S54100118D, and each tablet included about 16.2 mg of phenobarbital per tablet. The sealed containers were maintained at 40oC ± 2oC and 75% ± 5% relative humidity, uninterrupted, (except for the addition or withdrawal of test samples) for a period ofDocket No.230332PCT two months, three months, or six months. Tablets were removed from the storage conditions at the specified time points and tested for phenobarbital content using high pressure liquid chromatography.

[0104] Considering phenobarbital content, shelf life of tablets of Batches S54100118C and S54100118D was estimated to be at least 6 months when stored under accelerated testing conditions. Table 3 provides the 6-month stability assay results for tablets of Batches S54100118C and S54100118D stored under accelerated testing conditions. The stability assay showed that greater than 99 percent of the original phenobarbital content was retained in tablets stored under accelerated testing conditions for 6 months.

[0105] Table 3 reports stability data for the oral solid dosage form samples (Batches S54100118C and S54100118D) tested under standard and accelerated conditions. Table 3 identifies the bottle size for storing each test sample. The assay percentages listed in Table 3 are based on expected (“label claim”) contents of 16.2 mg phenobarbital per tablet of Batches S54100118C and S54100118D.Docket No.230332PCT Table 3: Stability assay results for tablets of Batches S54100118C and S54100118D

[0106] With reference to the results shown in Table 3, the present inventors surprisingly observed that oral solid dosage forms produced in Batches S54100118C and S54100118D retained more than about 98% of the original content of phenobarbital when stored under standard testing conditions at 25°C ± 2oC and 60% ± 5% relative humidity for a period of 48 months. Even when tablets were stored under accelerated conditions (40°C ± 2°C and 75% ± 5% relative humidity) for 6 months, tablets produced in Batches S54100118C and S54100118D retained over 99% of the original phenobarbital content (a decrease in the phenobarbital content of the tablets of less than one percent).Docket No.230332PCT Example 4

[0107] An additional study was conducted to assess the stability of oral solid dosage forms comprising phenobarbital according to the present disclosure.

[0108] Tablets including 32.4 mg of phenobarbital were prepared by compressing portions of several uniform mixtures made using the method generally described in Example 1. Each of the mixtures included phenobarbital, microcrystalline cellulose (MCC), lactose monohydrate, colloidal silicon dioxide, sodium starch glycolate, and magnesium stearate. The MCC was AVICEL®PH-102 MCC powder. Table 4 below provides the mass and weight / weight concentration of the ingredients in individual tablets comprising 32.4 mg phenobarbital per tablet produced in Batches S54200119A and S54200119C. Table 4: Composition of tablets in Batches S54200119A and S54200119C

[0109] For purposes of conducting the stability study, the tablets of Batch S54200119A were disposed in container closure systems including a container comprising an internal volume of either about 60 cm3(including 90 to 110 tablets) and a sealing closure. For purposes of conducting the stability study, the tablets of Batch S54200119C were disposed in container closure systems including a container comprising an internal volume of either about 200 cm3(including 900 to 1100 tablets) and a sealing closure.Docket No.230332PCT

[0110] Two studies were conducted to assess the stability of the phenobarbital in the tablets produced in Batches S54200119A and S54200119C. The stability studies involved the following testing periods and conditions: • Storing under standard testing conditions (25oC ± 2oC and 60% ± 5% relative humidity) for up to 48 months. • Storing under accelerated testing conditions (40oC ± 2oC and 75% ± 5% relative humidity) for up to 6 months.

[0111] A standard testing conditions stability study of the tablets of Batches S54200119A and S54200119C contained in the container closure system was conducted over a period of 48 months to determine the rate of physical or chemical degradation of the phenobarbital included in tablets when stored under the standard environmental conditions.

[0112] Container closure systems prepared as described above containing tablets including about 32.4 mg of phenobarbital per tablet were placed upright in a calibrated environmental chamber and maintained in an upright position during the stability study. The sealed containers including either 90 to 110 or 900 to 1100 tablets were maintained at 25oC ± 2oC and 60% ± 5% relative humidity, uninterrupted (except for the addition or withdrawal of test samples), for a period of 12 months, 18 months, 36 months, or 48 months. Tablets were removed from the storage conditions at the specified time points and tested for phenobarbital content using high pressure liquid chromatography.

[0113] Considering phenobarbital content, shelf life of tablets of Batches S54200119A and S54200119C was estimated to be at least 48 months when stored under standard testing conditions. Table 5 provides the 48-month stability assay results for tablets of Batches S54200119A and S54200119C. The stability assay showed that 100% percent of the original phenobarbital content was retained in tablets stored under standard testing conditions for 48 months.

[0114] Accelerated condition stability samples were placed upright in an environmental chamber and maintained in an upright position during the stability testing. As discussed, each tablet was disposed in the sealed container containing either 90 to 110 or 900 to 1100 tablets from Batches S54200119A and S54200119C,Docket No.230332PCT and each tablet included about 32.4 mg of phenobarbital per tablet. The sealed containers were maintained at 40oC ± 2oC and 75% ± 5% relative humidity, uninterrupted, (except for the addition or withdrawal of test samples) for a period of two months, three months, or six months. Tablets were removed from the storage conditions at the specified time points and tested for phenobarbital content using high pressure liquid chromatography.

[0115] Considering phenobarbital content, shelf life of tablets of Batches S54200119A and S54200119C was estimated to be at least 6 months when stored under accelerated testing conditions. Table 5 provides the 6-month stability assay results for tablets of Batches S54200119A and S54200119C stored under accelerated testing conditions. The stability assay showed that 100 percent of the original phenobarbital content was retained in tablets stored under accelerated testing conditions for 6 months.

[0116] Table 5 reports stability data for the oral solid dosage form samples (Batches S54200119A and S54200119C) tested under standard and accelerated conditions. Table 5 identifies the bottle size for storing each test sample. The assay percentages listed in Table 5 are based on expected (“label claim”) contents of 32.4 mg phenobarbital per tablet of Batches S54200119A and S54200119C.Docket No.230332PCT Table 5: Stability assay results for tablets of Batches S54200119A and S54200119C

[0117] With reference to the results shown in Table 5, the present inventors surprisingly observed that oral solid dosage forms produced in Batches S54200119A and S54200119C retained about 100% of the original content of phenobarbital when stored under standard testing conditions at 25°C ± 2oC and 60% ± 5% relative humidity for a period of 48 months. Even when tablets were stored under accelerated conditions (40°C ± 2°C and 75% ± 5% relative humidity) for 6 months, tablets produced in Batches S54200119A and S54200119C retained about 100% of the original phenobarbital content.Docket No.230332PCT Example 5

[0118] A study was conducted to assess the stability of embodiments of oral solid dosage forms according to the present disclosure.

[0119] Tablets including 64.8 mg of phenobarbital were prepared by compressing portions of several uniform mixtures made using the method generally described in Example 1. Each of the mixtures included phenobarbital, microcrystalline cellulose (MCC), lactose monohydrate, colloidal silicon dioxide, sodium starch glycolate, and magnesium stearate. The MCC was AVICEL®PH-102 MCC powder. Table 6 below provides the mass and weight / weight concentration of the ingredients in individual tablets comprising 64.8 mg phenobarbital per tablet produced in Batches S54300119A and S54300119B. Table 6: Composition of tablets in Batches S54300119A and S54300119B

[0120] For purposes of conducting the stability study, the tablets of Batch S54300119A were disposed in container closure systems including a container comprising an internal volume of either about 120 cm3(including 90 to 110 tablets) and a sealing closure. For purposes of conducting the stability study, the tablets of Batch S54300119B were disposed in container closure systems including a container comprising an internal volume of either about 400 cm3(including 900 to 1100 tablets) and a sealing closure.Docket No.230332PCT

[0121] Two studies were conducted to assess the stability of the phenobarbital in the tablets produced in Batches S54300119A and S54300119B. The stability studies involved the following testing periods and conditions: • Storing under standard testing conditions (25oC ± 2oC and 60% ± 5% relative humidity) for up to 48 months. • Storing under accelerated testing conditions (40oC ± 2oC and 75% ± 5% relative humidity) for up to 6 months.

[0122] A standard testing conditions stability study of the tablets of Batches S54300119A and S54300119B contained in the container closure system was conducted over a period of 48 months to determine the rate of physical or chemical degradation of the phenobarbital included in tablets when stored under the standard environmental conditions.

[0123] Container closure systems prepared as described above containing tablets including about 64.8 mg of phenobarbital per tablet were placed upright in a calibrated environmental chamber and maintained in an upright position during the stability study. The sealed containers including either 90 to 110 or 900 to 1100 tablets were maintained at 25oC ± 2oC and 60% ± 5% relative humidity, uninterrupted (except for the addition or withdrawal of test samples), for a period of 12 months, 18 months, 36 months, or 48 months. Tablets were removed from the storage conditions at the specified time points and tested for phenobarbital content using high pressure liquid chromatography.

[0124] Considering phenobarbital content, shelf life of tablets of Batches S54300119A and S54300119B was estimated to be at least 48 months when stored under standard testing conditions. Table 7 provides the 48-month stability assay results for tablets of Batches S54300119A and S54300119B. The stability assay showed that greater than 99 percent of the original phenobarbital content was retained in tablets stored under standard testing conditions for 48 months.

[0125] Accelerated condition stability samples were placed upright in an environmental chamber and maintained in an upright position during the stability testing. As discussed, each tablet was disposed in the sealed container containing either 90 to 110 or 900 to 1100 tablets from Batches S54300119A and S54300119B,Docket No.230332PCT and each tablet included about 64.8 mg of phenobarbital per tablet. The sealed containers were maintained at 40oC ± 2oC and 75% ± 5% relative humidity, uninterrupted, (except for the addition or withdrawal of test samples) for a period of two months, three months, or six months. Tablets were removed from the storage conditions at the specified time points and tested for phenobarbital content using high pressure liquid chromatography.

[0126] Considering phenobarbital content, shelf life of tablets of Batches S54300119A and S54300119B was estimated to be at least 6 months when stored under accelerated testing conditions. Table 7 provides the 6-month stability assay results for tablets of Batches S54300119A and S54300119B stored under accelerated testing conditions. The stability assay showed over 99 percent of the original phenobarbital content was retained in tablets stored under accelerated testing conditions for 6 months.

[0127] Table 7 reports stability data for the oral solid dosage form samples (Batches S54300119A and S54300119B) tested under standard and accelerated conditions. Table 7 identifies the bottle size for storing each test sample. The assay percentages listed in Table 7 are based on expected (“label claim”) contents of 64.8 mg phenobarbital per tablet of Batches S54300119A and S54300119B.Docket No.230332PCT Table 7: Stability assay results for tablets of Batches S54300119A and S54300119B

[0128] With reference to the results shown in Table 7, the present inventors surprisingly observed that oral solid dosage forms produced in Batches S54300119A and S54300119B retained over 99% of the original content of phenobarbital when stored under standard testing conditions at 25°C ± 2oC and 60% ± 5% relative humidity for a period of 48 months. Even when tablets were stored under accelerated conditions (40°C ± 2°C and 75% ± 5% relative humidity) for 6 months,Docket No.230332PCT tablets produced in Batches S54300119A and S54300119B retained over 99% of the original phenobarbital content. Example 6

[0129] A study was conducted to assess the stability of embodiments of oral solid dosage forms according to the present disclosure.

[0130] Tablets including 97.2 mg of phenobarbital were prepared by compressing portions of several uniform mixtures made using the method generally described in Example 1. Each of the mixtures included phenobarbital, microcrystalline cellulose (MCC), lactose monohydrate, colloidal silicon dioxide, sodium starch glycolate, and magnesium stearate. The MCC was AVICEL®PH-102 MCC powder. Table 8 below provides the mass and weight / weight concentration of the ingredients in individual tablets comprising 97.2 mg phenobarbital per tablet produced in Batches S54400119A and S54400119B. Table 8: Composition of tablets in Batches S54400119A and S54400119B

[0131] For purposes of conducting the stability study, the tablets of Batch S54400119A were disposed in container closure systems including a container comprising an internal volume of either about 120 cm3(including 90 to 110 tablets) and a sealing closure. For purposes of conducting the stability study, the tablets of Batch S54400119B were disposed in container closure systems including aDocket No.230332PCT container comprising an internal volume of either about 625 cm3(including 900 to 1100 tablets) and a sealing closure.

[0132] Two studies were conducted to assess the stability of the phenobarbital in the tablets produced in Batches S54400119A and S54400119B. The stability studies involved the following testing periods and conditions: • Storing under standard testing conditions (25oC ± 2oC and 60% ± 5% relative humidity) for up to 48 months. • Storing under accelerated testing conditions (40oC ± 2oC and 75% ± 5% relative humidity) for up to 6 months.

[0133] A standard testing conditions stability study of the tablets of Batches S54400119A and S54400119B contained in the container closure system was conducted over a period of 48 months to determine the rate of physical or chemical degradation of the phenobarbital included in tablets when stored under the standard environmental conditions.

[0134] Container closure systems prepared as described above containing tablets including about 97.2 mg of phenobarbital per tablet were placed upright in a calibrated environmental chamber and maintained in an upright position during the stability study. The sealed containers including either 90 to 110 or 900 to 1100 tablets were maintained at 25oC ± 2oC and 60% ± 5% relative humidity, uninterrupted (except for the addition or withdrawal of test samples), for a period of 12 months, 18 months, 36 months, or 48 months. Tablets were removed from the storage conditions at the specified time points and tested for phenobarbital content using high pressure liquid chromatography.

[0135] Considering phenobarbital content, shelf life of tablets of Batches S54400119A and S54400119B was estimated to be at least 48 months when stored under standard testing conditions. Table 9 provides the 48-month stability assay results for tablets of Batches S54400119A and S54400119B. The stability assay showed that 100 percent of the original phenobarbital content was retained in tablets stored under standard testing conditions for 48 months.Docket No.230332PCT

[0136] Accelerated condition stability samples were placed upright in an environmental chamber and maintained in an upright position during the stability testing. As discussed, each tablet was disposed in the sealed container containing either 90 to 110 or 900 to 1100 tablets from Batches S54400119A and S54400119B, and each tablet included about 97.2 mg of phenobarbital per tablet. The sealed containers were maintained at 40oC ± 2oC and 75% ± 5% relative humidity, uninterrupted, (except for the addition or withdrawal of test samples) for a period of two months, three months, or six months. Tablets were removed from the storage conditions at the specified time points and tested for phenobarbital content using high pressure liquid chromatography.

[0137] Considering phenobarbital content, shelf life of tablets of Batches S54400119A and S54400119B was estimated to be at least 6 months when stored under accelerated testing conditions. Table 9 provides the 6-month stability assay results for tablets of Batches S54400119A and S54400119B stored under accelerated testing conditions. The stability assay showed 100 percent of the original phenobarbital content was retained in tablets stored under accelerated testing conditions for 6 months.

[0138] Table 9 reports stability data for the oral solid dosage form samples (Batches S54400119A and S54400119B) tested under standard and accelerated conditions. Table 9 identifies the bottle size for storing each test sample. The assay percentages listed in Table 9 are based on expected (“label claim”) contents of 97.2 mg phenobarbital per tablet of Batches S54400119A and S54400119B.Docket No.230332PCT Table 9: Stability assay results for tablets of Batches S54400119A and S54400119B

[0139] With reference to the results shown in Table 9, the present inventors surprisingly observed that oral solid dosage forms produced in Batches S54400119A and S54400119B retained 100% of the original content of phenobarbital when stored under standard testing conditions at 25°C ± 2oC and 60% ± 5% relative humidity for a period of 48 months. Even when tablets were stored under accelerated conditions (40°C ± 2°C and 75% ± 5% relative humidity) for 6 months, tablets produced inDocket No.230332PCT Batches S54400119A and S54400119B retained 100% of the original phenobarbital content.

[0140] The following numbered clauses are directed to various non-limiting embodiments of inventions according to the present disclosure: 1. A pharmaceutical oral solid dosage form comprising, by weight: at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%; about 34% to about 51% lactose monohydrate; about 20% to about 30% microcrystalline cellulose; and about 1% to about 5% colloidal silicon dioxide. 2. The pharmaceutical oral solid dosage form of Clause 1, wherein the total content of phenobarbital and phenobarbital salt is about 24% to about 30%. 3. The pharmaceutical oral solid dosage form of any of Clauses 1 or 2, wherein the total content of phenobarbital and phenobarbital salt is about 26% to about 28%. 4. The pharmaceutical oral solid dosage form of any of Clauses 1-3, comprising, by weight, about 38% to about 47% lactose monohydrate. 5. The pharmaceutical oral solid dosage form of any of Clauses 1-4, comprising, by weight, about 41% to about 45% lactose monohydrate. 6. The pharmaceutical oral solid dosage form of any of Clauses 1-5, comprising, by weight, about 22.5% to about 27.5% microcrystalline cellulose. 7. The pharmaceutical oral solid dosage form of any of Clauses 1-6, comprising, by weight, about 24% to about 26% microcrystalline cellulose. 8. The pharmaceutical oral solid dosage form of any of Clauses 1-7, comprising, by weight, about 1% to about 3% colloidal silicon dioxide.Docket No.230332PCT 9. The pharmaceutical oral solid dosage form of any of Clauses 1-8, comprising, by weight, about 1.2% to about 1.8% colloidal silicon dioxide. 10. The pharmaceutical oral solid dosage form of any of Clauses 1-9, comprising, by weight: at least one of phenobarbital and phenobarbital salt, wherein the total content of phenobarbital and phenobarbital salt is about 24% to about 30%; about 38% to about 47% lactose monohydrate; about 22.5% to about 27.5% microcrystalline cellulose; and about 1% to about 3% colloidal silicon dioxide. 11. The pharmaceutical oral solid dosage form of any of Clauses 1-10, further comprising sodium starch glycolate. 12. The pharmaceutical oral solid dosage form of any of Clauses 1-11, further comprising, by weight, about 1.5% to about 5% sodium starch glycolate. 13. The pharmaceutical oral solid dosage form of any of Clauses 1-12, further comprising, by weight, about 2.2% to about 3.4% sodium starch glycolate. 14. The pharmaceutical oral solid dosage form of any of Clauses 1-13, further comprising at least one lubricant selected from calcium stearate and magnesium stearate. 15. The pharmaceutical oral solid dosage form of Clause 14 comprising, by weight: at least one of phenobarbital and phenobarbital salt, wherein the total content of phenobarbital and phenobarbital salt is about 24% to about 30%; about 38% to about 47% lactose monohydrate; about 22.5% to about 27.5% microcrystalline cellulose; about 1.5% to about 5% sodium starch glycolate; about 1% to about 3% colloidal silicon dioxide; and about 0.5% to about 2.0% magnesium stearate. 16. The pharmaceutical oral solid dosage form of any of Clauses 1-15, provided that a total content of phenobarbital and phenobarbital salt in theDocket No.230332PCT pharmaceutical oral solid dosage form is at least 90%, at least 92%, at least 95%, or at least 97% of an original total content of phenobarbital and phenobarbital salt after the pharmaceutical oral solid dosage form has been stored for 12 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%. 17. The pharmaceutical oral solid dosage form of any of Clauses 1-15, provided that a total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form is at least 90%, at least 92%, at least 95%, or at least 97% of an original total content of phenobarbital and phenobarbital salt after the pharmaceutical oral solid dosage form has been stored for 18 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%. 18. The pharmaceutical oral solid dosage form of any of Clauses 1-15, provided that a total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form is at least 90%, at least 92%, at least 95%, or at least 97% of an original total content of phenobarbital and phenobarbital salt after the pharmaceutical oral solid dosage form has been stored for 36 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%. 19. The pharmaceutical oral solid dosage form of any of Clauses 1-15, provided that a total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form is at least 90%, at least 92%, at least 95%, or at least 97% of an original total content of phenobarbital and phenobarbital salt after the pharmaceutical oral solid dosage form has been stored for 48 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%. 20. The pharmaceutical oral solid dosage form of any of Clauses 1-15, provided that a total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form is at least 90%, at least 92%, at least 95%, or at least 97% an original total content of phenobarbital and phenobarbital salt after the pharmaceutical oral solid dosage form has been stored for 2 months at aDocket No.230332PCT temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%. 21. The pharmaceutical oral solid dosage form of any of Clauses 1-15, provided that a total content of phenobarbital and phenobarbital salt content in the pharmaceutical oral solid dosage form is at least 90%, at least 92%, at least 95%, or at least 97% an original total content of phenobarbital and phenobarbital salt after the pharmaceutical oral solid dosage form has been stored for 3 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%. 22. The pharmaceutical oral solid dosage form of any of Clauses 1-15, provided that a total content of phenobarbital and phenobarbital salt content in the pharmaceutical oral solid dosage form is at least 90%, at least 92%, at least 95%, or at least 97% an original total content of phenobarbital and phenobarbital salt after the pharmaceutical oral solid dosage form has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%. 23. The pharmaceutical oral solid dosage form of any of Clauses 1-15, provided that when a plurality of the pharmaceutical oral solid dosage forms are placed in a container sealed with a closure, each pharmaceutical oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 12 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%. 24. The pharmaceutical oral solid dosage form of any of Clauses 1-15, provided that when a plurality of the pharmaceutical oral solid dosage forms are placed in a container sealed with a closure, each pharmaceutical oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 18Docket No.230332PCT months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%. 25. The pharmaceutical oral solid dosage form of any of Clauses 1-15, provided that when a plurality of the pharmaceutical oral solid dosage forms are placed in a container sealed with a closure, each pharmaceutical oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 36 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%. 26. The pharmaceutical oral solid dosage form of any of Clauses 1-15, provided that when a plurality of the pharmaceutical oral solid dosage forms are placed in a container sealed with a closure, each pharmaceutical oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 48 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%. 27. The pharmaceutical oral solid dosage form of any of Clauses 1-15, provided that when a plurality of the pharmaceutical oral solid dosage forms are placed in a container sealed with a closure, each pharmaceutical oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%. 28. The pharmaceutical oral solid dosage form of any of Clauses 1-15, provided that when a plurality of the pharmaceutical oral solid dosage forms are placed in a container sealed with a closure, each pharmaceutical oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solidDocket No.230332PCT dosage form after the pharmaceutical oral solid dosage form has been stored for 3 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%. 29. The pharmaceutical oral solid dosage form of any of Clauses 1-15, provided that when a plurality of the pharmaceutical oral solid dosage forms are placed in a container sealed with a closure, each pharmaceutical oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%. 30. The pharmaceutical oral solid dosage form of any of Clauses 23-29, wherein the container comprises an internal volume of about 50 cm3to about 70 cm3. 31. The pharmaceutical oral solid dosage form of any of Clauses 23-29, wherein the container comprises an internal volume of about 110 cm3to about 130 cm3. 32. The pharmaceutical oral solid dosage form of any of Clauses 23-29, wherein the container comprises an internal volume of about 180 cm3to about 220 cm3. 33. The pharmaceutical oral solid dosage form of any of Clauses 23-29, wherein the container comprises an internal volume of about 360 cm3to about 440 cm3. 34. The pharmaceutical oral solid dosage form of any of Clauses 23-29, wherein the container comprises an internal volume of about 575 cm3to about 675 cm3. 35. The pharmaceutical oral solid dosage form of any of Clause 30 or 31, wherein about 90 to about 110 of the pharmaceutical oral solid dosage forms are disposed in the container.Docket No.230332PCT 36. The pharmaceutical oral solid dosage form of any of Clause 31-34, wherein about 900 to about 1100 of the pharmaceutical oral solid dosage forms are disposed in the container. 37. A packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form comprising, by weight, at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%; about 34% to about 51% lactose monohydrate, about 20% to about 30% microcrystalline cellulose, and about 1% to about 5% colloidal silicon dioxide; and a container closure system comprising a container and a sealing closure; provided that a plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure; and provided that each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 12 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%. 38. The packaged pharmaceutical oral solid dosage form product of Clause 37, wherein the pharmaceutical oral solid dosage form has a composition as recited in any of Clauses 2-15. 39. A packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form comprising, by weight, at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%, about 34% to about 51% lactose monohydrate, about 20% to about 30% microcrystalline cellulose, and about 1% to about 5% colloidal silicon dioxide; and a container closure system comprising a container and a sealing closure; provided that a plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure; andDocket No.230332PCT provided that each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 18 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%. 40. The packaged pharmaceutical oral solid dosage form product of Clause 39, wherein the pharmaceutical oral solid dosage form has a composition as recited in any of Clauses 2-15. 41. A packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form comprising, by weight, at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%, about 34% to about 51% lactose monohydrate, about 20% to about 30% microcrystalline cellulose, and about 1% to about 5% colloidal silicon dioxide; and a container closure system comprising a container and a sealing closure; provided that a plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure; and provided that each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 36 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%. 42. The packaged pharmaceutical oral solid dosage form product of Clause 41, wherein the pharmaceutical oral solid dosage form has a composition as recited in any of Clauses 2-15. 43. A packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form comprising, by weight,Docket No.230332PCT at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%, about 34% to about 51% lactose monohydrate, about 20% to about 30% microcrystalline cellulose, and about 1% to about 5% colloidal silicon dioxide; and a container closure system comprising a container and a sealing closure; provided that a plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure; and provided that each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 48 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%. 44. The packaged pharmaceutical oral solid dosage form product of Clause 43, wherein the pharmaceutical oral solid dosage form has a composition as recited in any of Clauses 2-15. 45. A packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form comprising, by weight, at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%, about 34% to about 51% lactose monohydrate, about 20% to about 30% microcrystalline cellulose, and about 1% to about 5% colloidal silicon dioxide; and a container closure system comprising a container and a sealing closure; provided that a plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure; and provided that each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 2Docket No.230332PCT months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%. 46. The packaged pharmaceutical oral solid dosage form product of Clause 45, wherein the pharmaceutical oral solid dosage form has a composition as recited in any of Clauses 2-15. 47. A packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form comprising, by weight, at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%, about 34% to about 51% lactose monohydrate, about 20% to about 30% microcrystalline cellulose, and about 1% to about 5% colloidal silicon dioxide; and a container closure system comprising a container and a sealing closure; provided that a plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure; and provided that each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 3 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%. 48. The packaged pharmaceutical oral solid dosage form product of Clause 47, wherein the pharmaceutical oral solid dosage form has a composition as recited in any of Clauses 2-15. 49. A packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form comprising, by weight, at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%, about 34% to about 51% lactose monohydrate, about 20% to about 30% microcrystalline cellulose, and about 1% to about 5% colloidal silicon dioxide; andDocket No.230332PCT a container closure system comprising a container and a sealing closure; provided that a plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure; and provided that each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%. 50. The packaged pharmaceutical oral solid dosage form product of Clause 49, wherein the pharmaceutical oral solid dosage form has a composition as recited in any of Clauses 2-15. 51. A method of treatment to address seizures in animals, the method comprising administering a pharmaceutical oral solid dosage form to an animal in need thereof, wherein the pharmaceutical oral solid dosage form comprises, by weight: at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%; about 34% to about 51% lactose monohydrate; about 20% to about 30% microcrystalline cellulose; and about 1% to about 5% colloidal silicon dioxide. 52. A method of treatment to address seizures in animals, the method comprising administering to an animal in need thereof the pharmaceutical oral solid dosage form of any of Clauses 1-36. 53. The method of any one of Clauses 51 or Clause 52, wherein the animal is a dog. 54. The method of any one of Clauses 51-53, wherein the animal has idiopathic epilepsy.

Claims

Docket No.230332PCT CLAIMS What is claimed is:

1. A pharmaceutical oral solid dosage form comprising, by weight: at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%; about 34% to about 51% lactose monohydrate; about 20% to about 30% microcrystalline cellulose; and about 1% to about 5% colloidal silicon dioxide.

2. The pharmaceutical oral solid dosage form of claim 1, wherein the total content of phenobarbital and phenobarbital salt is about 24% to about 30%.

3. The pharmaceutical oral solid dosage form of any of claim 1 or claim 2, wherein the total content of phenobarbital and phenobarbital salt is about 26% to about 28%.

4. The pharmaceutical oral solid dosage form of any of claims 1-3, comprising, by weight, about 38% to about 47% lactose monohydrate.

5. The pharmaceutical oral solid dosage form of any of claims 1-4, comprising, by weight, about 41% to about 45% lactose monohydrate.

6. The pharmaceutical oral solid dosage form of any of claims 1-5, comprising, by weight, about 22.5% to about 27.5% microcrystalline cellulose.

7. The pharmaceutical oral solid dosage form of any of claims 1-6, comprising, by weight, about 24% to about 26% microcrystalline cellulose.

8. The pharmaceutical oral solid dosage form of any of claims 1-7, comprising, by weight, about 1% to about 3% colloidal silicon dioxide.

9. The pharmaceutical oral solid dosage form of any of claims 1-8, comprising, by weight, about 1.2% to about 1.8% colloidal silicon dioxide.Docket No.230332PCT 10. The pharmaceutical oral solid dosage form of any of claims 1-9, comprising, by weight: at least one of phenobarbital and phenobarbital salt, wherein the total content of phenobarbital and phenobarbital salt is about 24% to about 30%; about 38% to about 47% lactose monohydrate; about 22.5% to about 27.5% microcrystalline cellulose; and about 1% to about 3% colloidal silicon dioxide.

11. The pharmaceutical oral solid dosage form of any of claims 1-10, further comprising sodium starch glycolate.

12. The pharmaceutical oral solid dosage form of any of claims 1-11, further comprising, by weight, about 1.5% to about 5% sodium starch glycolate.

13. The pharmaceutical oral solid dosage form of any of claims 1-12, further comprising, by weight, about 2.2% to about 3.4% sodium starch glycolate.

14. The pharmaceutical oral solid dosage form of any of claims 1-13, further comprising at least one lubricant selected from calcium stearate and magnesium stearate.

15. The pharmaceutical oral solid dosage form of claim 14 comprising, by weight: at least one of phenobarbital and phenobarbital salt, wherein the total content of phenobarbital and phenobarbital salt is about 24% to about 30%; about 38% to about 47% lactose monohydrate; about 22.5% to about 27.5% microcrystalline cellulose; about 1.5% to about 5% sodium starch glycolate; about 1% to about 3% colloidal silicon dioxide; and about 0.5% to about 2.0% magnesium stearate.

16. The pharmaceutical oral solid dosage form of any of claims 1-15, provided that a total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form is at least 90%, at least 92%, at least 95%, or at least 97% of an original total content of phenobarbital and phenobarbital salt after the pharmaceutical oral solid dosage form has been stored for 12 months at aDocket No.230332PCT temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%.

17. The pharmaceutical oral solid dosage form of any of claims 1-15, provided that a total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form is at least 90%, at least 92%, at least 95%, or at least 97% of an original total content of phenobarbital and phenobarbital salt after the pharmaceutical oral solid dosage form has been stored for 18 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%.

18. The pharmaceutical oral solid dosage form of any of claims 1-15, provided that a total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form is at least 90%, at least 92%, at least 95%, or at least 97% of an original total content of phenobarbital and phenobarbital salt after the pharmaceutical oral solid dosage form has been stored for 36 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%.

19. The pharmaceutical oral solid dosage form of any of claims 1-15, provided that a total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form is at least 90%, at least 92%, at least 95%, or at least 97% of an original total content of phenobarbital and phenobarbital salt after the pharmaceutical oral solid dosage form has been stored for 48 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%.

20. The pharmaceutical oral solid dosage form of any of claims 1-15, provided that a total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form is at least 90%, at least 92%, at least 95%, or at least 97% an original total content of phenobarbital and phenobarbital salt after the pharmaceutical oral solid dosage form has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%.Docket No.230332PCT 21. The pharmaceutical oral solid dosage form of any of claims 1-15, provided that a total content of phenobarbital and phenobarbital salt content in the pharmaceutical oral solid dosage form is at least 90%, at least 92%, at least 95%, or at least 97% an original total content of phenobarbital and phenobarbital salt after the pharmaceutical oral solid dosage form has been stored for 3 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%.

22. The pharmaceutical oral solid dosage form of any of claims 1-15, provided that a total content of phenobarbital and phenobarbital salt content in the pharmaceutical oral solid dosage form is at least 90%, at least 92%, at least 95%, or at least 97% an original total content of phenobarbital and phenobarbital salt after the pharmaceutical oral solid dosage form has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%.

23. The pharmaceutical oral solid dosage form of any of claims 1-15, provided that when a plurality of the pharmaceutical oral solid dosage forms are placed in a container sealed with a closure, each pharmaceutical oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 12 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%.

24. The pharmaceutical oral solid dosage form of any of claims 1-15, provided that when a plurality of the pharmaceutical oral solid dosage forms are placed in a container sealed with a closure, each pharmaceutical oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 18 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%.Docket No.230332PCT 25. The pharmaceutical oral solid dosage form of any of claims 1-15, provided that when a plurality of the pharmaceutical oral solid dosage forms are placed in a container sealed with a closure, each pharmaceutical oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 36 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%.

26. The pharmaceutical oral solid dosage form of any of claims 1-15, provided that when a plurality of the pharmaceutical oral solid dosage forms are placed in a container sealed with a closure, each pharmaceutical oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 48 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%.

27. The pharmaceutical oral solid dosage form of any of claims 1-15, provided that when a plurality of the pharmaceutical oral solid dosage forms are placed in a container sealed with a closure, each pharmaceutical oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%.

28. The pharmaceutical oral solid dosage form of any of claims 1-15, provided that when a plurality of the pharmaceutical oral solid dosage forms are placed in a container sealed with a closure, each pharmaceutical oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 3 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%.Docket No.230332PCT 29. The pharmaceutical oral solid dosage form of any of claims 1-15, provided that when a plurality of the pharmaceutical oral solid dosage forms are placed in a container sealed with a closure, each pharmaceutical oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%.

30. The pharmaceutical oral solid dosage form of any of claims 23-29, wherein the container comprises an internal volume of about 50 cm3to about 70 cm3.

31. The pharmaceutical oral solid dosage form of any of claims 23-29, wherein the container comprises an internal volume of about 110 cm3to about 130 cm3.

32. The pharmaceutical oral solid dosage form of any of claims 23-29, wherein the container comprises an internal volume of about 180 cm3to about 220 cm3.

33. The pharmaceutical oral solid dosage form of any of claims 23-29, wherein the container comprises an internal volume of about 360 cm3to about 440 cm3.

34. The pharmaceutical oral solid dosage form of any of claims 23-29, wherein the container comprises an internal volume of about 575 cm3to about 675 cm3.

35. The pharmaceutical oral solid dosage form of any of claim 30 or claim 31, wherein about 90 to about 110 of the pharmaceutical oral solid dosage forms are disposed in the container.

36. The pharmaceutical oral solid dosage form of any of claims 31-34, wherein about 900 to about 1100 of the pharmaceutical oral solid dosage forms are disposed in the container.Docket No.230332PCT 37. A packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form comprising, by weight, at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%; about 34% to about 51% lactose monohydrate, about 20% to about 30% microcrystalline cellulose, and about 1% to about 5% colloidal silicon dioxide; and a container closure system comprising a container and a sealing closure; provided that a plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure; and provided that each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 12 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%.

38. The packaged pharmaceutical oral solid dosage form product of claim 37, wherein the pharmaceutical oral solid dosage form has a composition as recited in any of claims 2-15.

39. A packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form comprising, by weight, at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%, about 34% to about 51% lactose monohydrate, about 20% to about 30% microcrystalline cellulose, and about 1% to about 5% colloidal silicon dioxide; and a container closure system comprising a container and a sealing closure; provided that a plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure; and provided that each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solidDocket No.230332PCT dosage form after the pharmaceutical oral solid dosage form has been stored for 18 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%.

40. The packaged pharmaceutical oral solid dosage form product of claim 39, wherein the pharmaceutical oral solid dosage form has a composition as recited in any of claims 2-15.

41. A packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form comprising, by weight, at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%, about 34% to about 51% lactose monohydrate, about 20% to about 30% microcrystalline cellulose, and about 1% to about 5% colloidal silicon dioxide; and a container closure system comprising a container and a sealing closure; provided that a plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure; and provided that each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 36 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%.

42. The packaged pharmaceutical oral solid dosage form product of claim 41, wherein the pharmaceutical oral solid dosage form has a composition as recited in any of claims 2-15.

43. A packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form comprising, by weight, at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%, about 34% to about 51% lactose monohydrate, about 20% to about 30% microcrystalline cellulose, andDocket No.230332PCT about 1% to about 5% colloidal silicon dioxide; and a container closure system comprising a container and a sealing closure; provided that a plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure; and provided that each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 48 months at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%.

44. The packaged pharmaceutical oral solid dosage form product of claim 43, wherein the pharmaceutical oral solid dosage form has a composition as recited in any of claims 2-15.

45. A packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form comprising, by weight, at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%, about 34% to about 51% lactose monohydrate, about 20% to about 30% microcrystalline cellulose, and about 1% to about 5% colloidal silicon dioxide; and a container closure system comprising a container and a sealing closure; provided that a plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure; and provided that each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 2 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%.

46. The packaged pharmaceutical oral solid dosage form product of claim 45, wherein the pharmaceutical oral solid dosage form has a composition as recited in any of claims 2-15.Docket No.230332PCT 47. A packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form comprising, by weight, at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%, about 34% to about 51% lactose monohydrate, about 20% to about 30% microcrystalline cellulose, and about 1% to about 5% colloidal silicon dioxide; and a container closure system comprising a container and a sealing closure; provided that a plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure; and provided that each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initial total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 3 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%.

48. The packaged pharmaceutical oral solid dosage form product of claim 47, wherein the pharmaceutical oral solid dosage form has a composition as recited in any of claims 2-15.

49. A packaged pharmaceutical oral solid dosage form product comprising: a pharmaceutical oral solid dosage form comprising, by weight, at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%, about 34% to about 51% lactose monohydrate, about 20% to about 30% microcrystalline cellulose, and about 1% to about 5% colloidal silicon dioxide; and a container closure system comprising a container and a sealing closure; provided that a plurality of the pharmaceutical oral solid dosage forms are enclosed in the container and sealed with the sealing closure; and provided that each pharmaceutical oral solid dosage form enclosed in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of an initialDocket No.230332PCT total content of phenobarbital and phenobarbital salt in the pharmaceutical oral solid dosage form after the pharmaceutical oral solid dosage form has been stored for 6 months at a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%.

50. The packaged pharmaceutical oral solid dosage form product of claim 49, wherein the pharmaceutical oral solid dosage form has a composition as recited in any of claims 2-15.

51. A method of treatment to address seizures in animals, the method comprising administering a pharmaceutical oral solid dosage form to an animal in need thereof, wherein the pharmaceutical oral solid dosage form comprises, by weight: at least one of phenobarbital and phenobarbital salt, wherein a total content of phenobarbital and phenobarbital salt is about 21% to about 33%; about 34% to about 51% lactose monohydrate; about 20% to about 30% microcrystalline cellulose; and about 1% to about 5% colloidal silicon dioxide.

52. A method of treatment to address seizures in animals, the method comprising administering to an animal in need thereof the pharmaceutical oral solid dosage form of any of claims 1-36.

53. The method of any one of claim 51 and claim 52, wherein the animal is a dog.

54. The method of any one of claims 51-53, wherein the animal has idiopathic epilepsy.

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