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

Abstract

Disclosed herein are pharmaceutical oral solid dosage forms comprising at least one of phenobarbital and a phenobarbital salt, and methods of making and using the pharmaceutical oral solid dosage forms.

Description

Technical Field

[0001] The published text relates to oral solid dosage forms of pharmaceuticals including at least one of phenobarbital and phenobarbital salts, and to methods of manufacturing and using the oral solid dosage forms. Background Technology

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

[0003] There are many causes of seizures. Idiopathic epilepsy is the most common cause of seizures in dogs; it is a genetic disorder, but its exact cause is unknown. Other causes include liver disease, kidney failure, brain tumors, brain trauma, and toxins. Seizures often occur when there are changes in brain activity, such as during excitement or eating, or when the dog is falling asleep or waking up. Affected dogs may appear completely normal between seizures.

[0004] Phenobarbital is a classic barbiturate drug with sedative, hypnotic, and antiepileptic properties. It is a white or nearly white crystalline powder or colorless crystals, with the empirical formula C1. 12 H 12 N₂O₃ has a molecular weight of 232.24. It is slightly soluble in water, readily soluble in alcohol, and soluble in solutions of potassium hydroxide and sodium hydroxide. It forms water-soluble compounds with alkali metal hydroxides and carbonates, as well as with ammonia.

[0005] Phenobarbital is used in veterinary medicine as a treatment for seizure control in dogs. Despite its long and widespread use, no products are approved for veterinary or human use. For dogs to receive the desired amount of phenobarbital and / or phenobarbital salts in the treatment of idiopathic epilepsy, it is important that the solid dosage form comprising phenobarbital and / or phenobarbital salts is adequately stable, such that it retains the desired minimum amount of the active pharmaceutical compound after the dosage form has been stored for a period of time.

[0006] Therefore, there is a need for an oral solid dosage form of medicine that includes at least one active ingredient selected from phenobarbital and phenobarbital salts and exhibits favorable stability and improved shelf life. Summary of the Invention

[0007] It should be understood that the invention disclosed and described in this specification is not limited to the embodiments described in the content of this invention.

[0008] According to a non-limiting aspect of the published text, there is a pharmaceutical oral solid dosage form comprising, by weight percentage: at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%; from about 34% to about 51% lactose monohydrate; from about 20% to about 30% microcrystalline cellulose; and from about 1% to about 5% colloidal silica. In various non-limiting embodiments, the pharmaceutical oral solid dosage form is stable such that, for example, 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%, the total content of phenobarbital and phenobarbital salts in the pharmaceutical oral solid dosage form is at least 90%, at least 92%, at least 95%, or at least 97% of the original total content of phenobarbital and phenobarbital salts.

[0009] Another non-limiting aspect of the published text relates to an oral solid dosage form of a drug, comprising, by weight percentage: at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 24% to about 30%; from about 38% to about 47% lactose monohydrate; from about 22.5% to about 27.5% microcrystalline cellulose; from about 1.5% to about 5% sodium glycolate starch; from about 1% to about 3% colloidal silica; and from about 0.5% to about 2.0% magnesium stearate. In various non-limiting embodiments, the oral solid dosage form of the drug is stable such that, for example, after the oral solid dosage form of the drug 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%, the total content of phenobarbital and phenobarbital salts in the oral solid dosage form of the drug is at least 90%, at least 92%, at least 95%, or at least 97% of the original total content of phenobarbital and phenobarbital salts.

[0010] An additional non-limiting embodiment of the disclosed text relates to a packaged oral solid dosage form product comprising: an oral solid dosage form; and a container closure system comprising a container and a sealing closure. The oral solid dosage form comprises, by weight percentage: at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%; from about 34% to about 51% lactose monohydrate; from about 20% to about 30% microcrystalline cellulose; and from about 1% to about 5% colloidal silica. Multiple oral solid dosage forms are encapsulated in a container and sealed using the sealing closure, and after the oral solid dosage forms have 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%, each oral solid dosage form encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salts in the oral solid dosage form.

[0011] An additional non-limiting embodiment of the disclosed text relates to a packaged oral solid dosage form product comprising: an oral solid dosage form; and a container closure system comprising a container and a sealing closure. The oral solid dosage form comprises, by weight percentage: at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%; from about 34% to about 51% lactose monohydrate; from about 20% to about 30% microcrystalline cellulose; and from about 1% to about 5% colloidal silica. Multiple oral solid dosage forms are encapsulated in a container and sealed using the sealing closure, and after the oral solid dosage forms have 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%, each oral solid dosage form encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salts in the oral solid dosage form.

[0012] The additional non-limiting aspect of the published text relates to a packaged oral solid dosage form product comprising: an oral solid dosage form; and a container closure system comprising a container and a sealing closure. The oral solid dosage form comprises, by weight percentage: at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%; from about 34% to about 51% lactose monohydrate; from about 20% to about 30% microcrystalline cellulose; and from about 1% to about 5% colloidal silica. After multiple oral solid dosage forms are encapsulated in a container and sealed using the sealing closure, each oral solid dosage form encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salts in the oral solid dosage form, following storage of the oral solid dosage forms at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65% for 36 months.

[0013] The additional non-limiting aspect of the published text relates to a packaged oral solid dosage form product comprising: an oral solid dosage form; and a container closure system comprising a container and a sealing closure. The oral solid dosage form comprises, by weight percentage: at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%; from about 34% to about 51% lactose monohydrate; from about 20% to about 30% microcrystalline cellulose; and from about 1% to about 5% colloidal silica. Multiple oral solid dosage forms are encapsulated in a container and sealed using a sealing closure, and after the oral solid dosage forms have 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%, each oral solid dosage form encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salts in the oral solid dosage form.

[0014] Another non-limiting aspect of the published text relates to a packaged oral solid dosage form product comprising: an oral solid dosage form; and a container closure system comprising a container and a sealing closure. The oral solid dosage form comprises, by weight percentage: at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%; from about 34% to about 51% lactose monohydrate; from about 20% to about 30% microcrystalline cellulose; and from about 1% to about 5% colloidal silica. Multiple oral solid dosage forms are encapsulated in a container and sealed using the sealing closure, and after the oral solid dosage forms have 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%, each oral solid dosage form encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salts in the oral solid dosage form.

[0015] Another non-limiting aspect of the published text relates to a packaged oral solid dosage form product comprising: an oral solid dosage form; and a container closure system comprising a container and a sealing closure. The oral solid dosage form comprises, by weight percentage: at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%; from about 34% to about 51% lactose monohydrate; from about 20% to about 30% microcrystalline cellulose; and from about 1% to about 5% colloidal silica. Multiple oral solid dosage forms are encapsulated in a container and sealed using the sealing closure, and after the oral solid dosage forms have 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%, each oral solid dosage form encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salts in the oral solid dosage form.

[0016] Another non-limiting aspect of the published text relates to a packaged oral solid dosage form product comprising: an oral solid dosage form; and a container closure system comprising a container and a sealing closure. The oral solid dosage form comprises, by weight percentage: at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%; from about 34% to about 51% lactose monohydrate; from about 20% to about 30% microcrystalline cellulose; and from about 1% to about 5% colloidal silica. Multiple oral solid dosage forms are encapsulated in a container and sealed using a sealing closure, and after the oral solid dosage forms have 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%, each oral solid dosage form encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salts in the oral solid dosage form.

[0017] The additional non-limiting aspect of the published text relates to a treatment method for managing animal seizures, the method comprising administering an oral solid dosage form of a drug according to the published text to the animal in need. Attached Figure Description

[0018] By referring to the accompanying drawings, one can better understand the various features and characteristics of the non-limiting and non-exhaustive embodiments disclosed and described in this specification, wherein:

[0019] Figure 1A and Figure 1B These are, as described in this article, 60cm containers for containing oral solid dosage forms. 3 Side and cross-sectional views of an embodiment of a (2.0 oz) internal volume white high-density polyethylene (“HDPE”) bottle.

[0020] Figure 1C yes Figure 1A Side view of detail "A".

[0021] Figure 2A and Figure 2B These are, as described in this article, 120cm containers for containing oral solid dosage forms. 3 Side and cross-sectional views of an embodiment of a (4.0 oz) internal volume white high-density polyethylene (“HDPE”) bottle.

[0022] Figure 2C yes Figure 2A Side view of detail "A".

[0023] Figure 3A and Figure 3B It is possible to be with Figure 1A , Figure 1B and Figure 1C The container shown in the image and its relation to Figure 2A , Figure 2B and Figure 2C The diagram shows an embodiment of a container closure used with containers, wherein... Figure 3A This is a top view of the exterior of a threaded, ribbed closure cap. Figure 3B yes Figure 3A The image shows a side sectional view of the lid.

[0024] Figure 4A and Figure 4B These are, as described in this article, 200cm containers for containing oral solid dosage forms. 3 Side and cross-sectional views of an embodiment of a (6.75 oz) internal volume white high-density polyethylene (“HDPE”) bottle.

[0025] Figure 4C yes Figure 4A Side view of detail "A".

[0026] Figure 5A and Figure 5B It is possible to be with Figure 2A , Figure 2B and Figure 2C The container shown in the image and its relation to Figure 4A , Figure 4B and Figure 4C The diagram shows an embodiment of a container closure used with containers, wherein... Figure 5A This is a top view of the exterior of a threaded, ribbed closure cap. Figure 5B yes Figure 5A The image shows a side sectional view of the lid.

[0027] Figure 6A and Figure 6BThese are, as described in this article, 400cm³ for containing oral solid dosage forms. 3 Side and cross-sectional views of an embodiment of a (13.5 oz) internal volume white high-density polyethylene (“HDPE”) bottle.

[0028] Figure 6C yes Figure 6A Side view of detail "A".

[0029] Figure 7A and Figure 7B These are, as described in this article, 625 cm³ for containing oral solid dosage forms. 3 Side and cross-sectional views of an embodiment of a (21.1 oz) internal volume white high-density polyethylene (“HDPE”) bottle.

[0030] Figure 7C yes Figure 7A Side view of detail "A".

[0031] Figures 8A to 8C It is possible to be with Figure 6A , Figure 6B and Figure 6C The container shown in the image and its relation to Figure 7A , Figure 7B and Figure 7C The diagram shows an embodiment of a container closure used with containers, wherein... Figure 8A This is an external front view of a threaded closure cap with ridges. Figure 8B This is a top view of the exterior of a threaded, ribbed closure cap. Figure 8C yes Figure 8B The image shows a side sectional view of the lid.

[0032] Dimensions not in parentheses shown in Figures 1 through 8 are in inches. Dimensions in parentheses shown in Figures 1 through 8 are in millimeters.

[0033] The foregoing details, as well as others, will be understood when considering the following detailed description of various non-restrictive and non-exhaustive embodiments based on the published text. Detailed Implementation

[0034] Various embodiments are described and illustrated in this specification to provide a comprehensive understanding of the disclosed compositions, dosage forms, and methods. It should be understood that the various embodiments described and illustrated in this specification are non-limiting and non-exhaustive. Therefore, the invention is not limited to the description of the various non-limiting and non-exhaustive embodiments disclosed in this specification. Rather, the invention is defined solely by the claims. Specific features and characteristics shown and / or described in conjunction with the various embodiments may be combined with features and characteristics of other embodiments. Such modifications and variations are intended to be included within the scope of this specification. Therefore, the claims may be modified to recite any feature or characteristic explicitly or inherently described in this specification or otherwise explicitly or inherently supported by this specification. Furthermore, the applicant reserves the right to modify the claims to explicitly waive any feature or characteristic that may be present in the prior art. The various embodiments disclosed and described in this specification may include, consist of, or substantially consist of features and characteristics as described in different aspects herein.

[0035] Unless otherwise stated, all percentages provided herein are weight percentages based on the total weight of the respective composition, dosage form, mixture, etc.

[0036] Any numerical range described in this specification is intended to include all subranges with the same numerical precision contained within the described range. For example, the range “1.0 to 10.0” is intended to include all subranges between (and including) the described minimum value of 1.0 and the described maximum value of 10.0, i.e., a minimum value equal to or greater than 1.0 and a maximum value equal to or less than 10.0, for example, 2.4 to 7.6. Any maximum numerical limit described in this specification is intended to include all lower numerical limits contained therein, and any minimum numerical limit described in this specification is intended to include all higher numerical limits contained therein. The applicant reserves the right to amend this specification (including the claims) to expressly describe any subranges contained within the range expressly described herein.

[0037] As is generally used herein, the term “about” refers to the acceptable degree of error for the measured quantity, taking into account 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 in this document and are intended to refer to, as appropriate, the recipient of a method implemented according to a published text or another method.

[0039] As used herein, the terms “stability” and “stable” mean that, after the oral solid dosage form of the drug has been stored under the indicated conditions for a period of time, each oral solid dosage form retains at least 90%, at least 95%, at least 97%, at least 99%, or at least 100% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug.

[0040] This document discloses storage-stable oral solid dosage forms of pharmaceuticals comprising phenobarbital and / or phenobarbital salts as active ingredients. In specific embodiments thereof, the oral solid dosage forms (e.g., tablets) comprise phenobarbital and / or phenobarbital salts (i.e., at least one of phenobarbital and phenobarbital salts), lactose monohydrate, microcrystalline cellulose, and colloidal silica. The inventors have observed that specific embodiments of the oral solid dosage forms of pharmaceuticals according to the disclosure exhibit unexpectedly favorable stability of the active pharmaceutical ingredient.

[0041] In certain non-limiting embodiments, the oral solid dosage form of the present invention may include phenobarbital (as shown below) as an active pharmaceutical ingredient.

[0042]

[0043] In certain other non-limiting embodiments, the oral solid dosage form of the present invention may include a salt of phenobarbital as the active pharmaceutical ingredient. One such salt is shown below: sodium phenobarbital.

[0044]

[0045] It is further conceivable that, in other non-limiting embodiments, the oral solid dosage form according to the disclosure may include both phenobarbital and phenobarbital salts. Therefore, although the following description may sometimes refer to one or the other of phenobarbital and phenobarbital salts, it should be understood that the oral solid dosage form according to the disclosure may include phenobarbital, phenobarbital salts, or a combination of both.

[0046] In a particular non-limiting embodiment, phenobarbital and / or phenobarbital salts are present in the oral solid dosage form according to the disclosed text, and the total concentration of phenobarbital and phenobarbital salts in the oral solid dosage form is 21% to 33%, 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 weight percentages being based on the total weight of the oral solid dosage form. In various embodiments, phenobarbital and / or phenobarbital salts are present in the oral solid dosage form according to the disclosed text, and the total concentration of phenobarbital and phenobarbital salts in the oral solid dosage form 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% by weight percentage based on the total weight of the oral solid dosage form.

[0047] In specific non-limiting embodiments, depending on the desired strength of a particular oral solid dosage form, the total mass of phenobarbital and phenobarbital salts included in the oral solid dosage form, according to the disclosed text, can range from about 12 mg to about 20 mg, about 13 mg to about 20 mg, about 14 mg to about 20 mg, about 15 mg to about 20 mg, about 12 mg to about 19 mg, about 12 mg to about 18 mg, about 12 mg to about 17 mg, about 24 mg to about 40 mg, about 24 mg to about 38 mg, about 24 mg to about 36 mg, about 24 mg to about 34 mg, about 28 mg to about 40 mg, About 30 mg to about 40 mg, about 28 mg to about 34 mg, about 49 mg to about 81 mg, about 49 mg to about 78 mg, about 49 mg to about 72 mg, about 49 mg to about 68 mg, about 52 mg to about 78 mg, about 56 mg to about 74 mg, about 60 mg to about 68 mg, about 73 mg to about 122 mg, about 73 mg to about 114 mg, about 73 mg to about 106 mg, about 80 mg to about 116 mg, about 86 mg to about 110 mg, about 90 mg to about 102 mg, about 94 mg to about 100 mg, or about 96 mg to about 162 mg.

[0048] Various non-limiting embodiments of the oral solid dosage form of a drug according to the disclosed text may include one or more diluents. The diluent may be included as a filler in the oral solid dosage form of the drug (e.g., tablets) to increase the dosage form weight and improve content uniformity. Non-limiting examples of suitable diluents that may be used in the oral solid dosage forms of the drug disclosed herein include at least one of the following: 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)), sugars from confectionery (including corn starch), croscarmellose sodium, dicalcium phosphate, inulin, carbohydrates (e.g., arabinose, sucrose, dextrose, fructose, maltose, lactose, lactose monohydrate, trehalose, isomaltitol, starch, monosaccharides, disaccharides, polysaccharides and sugar alcohols (e.g., sorbitol, mannitol, erythritol, xylitol, lactitol)), derivatives of the foregoing, and any combination thereof.

[0049] In certain non-limiting embodiments, the diluent may be present in the oral solid dosage form of the drug according to the disclosed text at a concentration of about 20% to about 30%, 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 at a concentration of about 34% to about 51%, 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 weight percentages are based on the total weight of the oral solid dosage form of the drug. In other embodiments, the diluent may be present in the oral solid dosage form of the drug according to the disclosed text at 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 weight percentages based on the total weight of the oral solid dosage form of the drug.

[0050] In a specific non-limiting embodiment according to the published text, the amount of diluent included in the oral solid dosage form of the drug may range from about 12 mg to about 99 mg, such as about 12 mg to about 18 mg, about 24 mg to about 36 mg, about 48 mg to about 72 mg, about 81 mg to about 99 mg, about 84 mg to about 96 mg, or about 86 mg to about 94 mg, or the range may be from about 20 mg to about 170 mg, such as about 20 mg to about 30 mg, about 22 mg to about 28 mg, about 40 mg to about 60 mg, about 46 mg to about 54 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 135 mg to about 170 mg, about 140 mg to about 165 mg, or about 145 mg to about 160 mg.

[0051] In certain non-limiting embodiments, microcrystalline cellulose (MCC) may be present in the oral solid dosage form of the drug according to the disclosure at a concentration of about 20% to about 30%, 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 weight percentages based on the total weight of the oral solid dosage form of the drug. In other embodiments, MCC may be present in the oral solid dosage form of the drug according to the disclosure at 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 weight percentages based on the total weight of the oral solid dosage form of the drug.

[0052] In certain non-limiting embodiments, the amount of MCC included in the oral solid dosage form of the drug can range from about 12 mg to about 99 mg, such as about 12 mg to about 18 mg, about 24 mg to about 36 mg, about 48 mg to about 72 mg, about 81 mg to about 99 mg, about 84 mg to about 96 mg, or about 86 mg to about 94 mg.

[0053] In a specific non-limiting embodiment, lactose monohydrate may be present in the oral solid dosage form of the drug according to the disclosed text at a concentration of about 34% to about 51%, 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 weight percentages being based on the total weight of the oral solid dosage form of the drug. In other embodiments, the MCC may be present in the oral solid dosage form of the drug according to the published text at a concentration of 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 weight percentages based on the total weight of the oral solid dosage form of the drug.

[0054] In certain non-limiting embodiments, the amount of lactose monohydrate included in the oral solid dosage form of the drug can range from about 20 mg to about 170 mg, such as about 20 mg to about 30 mg, about 22 mg to about 28 mg, about 40 mg to about 60 mg, about 46 mg to about 54 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 135 mg to about 170 mg, about 140 mg to about 165 mg, or about 145 mg to about 160 mg.

[0055] Various non-limiting embodiments of the oral solid dosage form of the drug according to the disclosed text include one or more lubricants. Lubricants may be included in the oral solid dosage form of the drug, for example, to improve powder processing properties during the manufacture of the drug solid dosage form. Non-limiting examples of suitable lubricants that may be used in the oral solid dosage form of the drug according to the disclosed text include sodium stearoyl fumarate, polyethylene glycol, mineral oil, medium-chain triglycerides, sodium stearoyl sulfate, cocoa butter, sodium benzoate, stearic acid (and its derivatives or esters, such as sodium stearate, magnesium stearate, calcium stearate), and any combination thereof.

[0056] The concentration of lubricant in the oral solid dosage form of the drug, according to a specific non-limiting embodiment of the disclosed text, may range from about 0.5% to about 2%, about 0.75% to about 2%, about 0.75% to about 1.75%, about 0.75% to about 1.5%, about 0.5% to about 1.75%, about 0.5% to about 1.5%, or about 0.75% to about 1.25%, all weight percentages being based on the total weight of the oral solid dosage form.

[0057] In certain non-limiting embodiments, the amount of lubricant included in the oral solid dosage form of the drug can range from about 0.5 mg to about 5 mg, such as about 0.5 mg to about 0.7 mg, about 0.5 mg to about 0.65 mg, about 0.55 mg to about 0.7 mg, about 0.55 mg to about 0.65 mg, about 1.0 mg to about 1.4 mg, about 1.1 mg to about 1.4 mg, about 1.0 mg to about 1.3 mg, about 1.1 mg to about 1.3 mg, or about 1.15 mg to about 1.25 mg. mg, about 2.0 mg to about 2.6 mg, about 2.0 mg to about 2.5 mg, about 2.1 mg to about 2.6 mg, about 2.2 mg to about 2.6 mg, about 2.2 mg to about 2.5 mg, about 2.3 mg to about 2.5 mg, about 3.2 mg to about 5 mg, about 3.4 mg to about 4.8 mg, about 3.2 mg to about 4.6 mg, about 3.2 mg to about 4.4 mg, about 3.2 mg to about 4 mg, about 3.2 mg to about 3.8 mg, or about 3.4 mg to about 3.8 mg.

[0058] Various non-limiting embodiments of the oral solid dosage form of the drug according to the disclosed text may include one or more flow aids. Flow aids may be included to enhance the flowability of the powder components during dosage form production by reducing interparticle friction, particle surface charge, and / or particle cohesion. Non-limiting examples of suitable flow aids that may be used in the oral solid dosage form according to the disclosed text include talc, silica, colloidal silica, and any combination thereof.

[0059] The concentration of the glidant in the oral solid dosage form of the drug according to a specific non-limiting embodiment of the published text may range from about 1% to about 5%, about 1% to about 4.5%, about 1% to about 4%, about 1% to about 3.5%, about 1% to about 3.25%, about 1% to about 3%, about 1.25% to about 3%, about 1% to about 2.75%, about 1% to about 2.5%, about 1% to about 2.25%, about 1% to about 2%, about 1% to about 1.75%, about 1.25% to about 2%, about 1.2% to about 1.8%, all weight percentages are based on the total weight of the oral solid dosage form of the drug.

[0060] In certain non-limiting embodiments, the amount of the glidant included in the oral solid dosage form of the drug according to the disclosed text can range from about 0.5 mg to about 6 mg, such as about 0.5 mg to about 1.5 mg, about 0.7 mg to about 1.5 mg, about 0.7 mg to about 1.3 mg, about 0.7 mg to about 1.1 mg, about 1.0 mg to about 3.0 mg, about 1.4 mg to about 3.0 mg, about 1.4 mg to about 2.6 mg, or about 1.4 mg to about 2.4 mg. g, about 1.0 mg to about 2.4 mg, about 2.5 mg to about 4.5 mg, about 2.8 mg to about 4.5 mg, about 2.5 mg to about 4.0 mg, about 2.8 mg to about 3.8 mg, about 3.2 mg to about 3.8 mg, about 4.0 mg to about 6.0 mg, about 4.4 mg to about 6.0 mg, about 4.8 mg to about 6.0 mg, about 5.0 mg to about 6.0 mg, about 5.2 mg to about 6.0 mg, or about 5.2 mg to about 5.8 mg.

[0061] Various non-limiting embodiments of the oral solid dosage form of a drug according to the published text may include one or more disintegrants. Disintegrants may be included in the oral solid dosage form of a drug, for example, to facilitate disintegration after oral administration. Non-limiting examples of suitable disintegrants that may be used in the oral solid dosage form of a drug according to the published text include sodium glycolate starch and / or sodium croscarmellose.

[0062] The concentration of disintegrant in a drug oral solid dosage form according to a specific non-limiting embodiment of the published text may range from about 1.5% to about 5%, about 1.5% to about 4.5%, about 1.5% to about 4%, about 1.5% to about 3.5%, about 1.5% to about 3.25%, about 1.5% to about 3%, about 2% to about 3.5%, about 2.25% to about 3.5%, about 2.5% to about 3.5%, or about 2.2% to about 3.4%, all weight percentages being based on the total weight of the drug oral solid dosage form.

[0063] In certain non-limiting embodiments, the amount of disintegrant included in the oral solid dosage form of the drug according to the disclosed text can range from about 1 mg to about 12 mg, such as about 1.0 mg to about 2.0 mg, about 1.25 mg to about 2.0 mg, about 1.5 mg to about 2.0 mg, about 2.5 mg to about 4.0 mg, about 2.75 mg to about 3.75 mg, about 3.0 mg to about 3.75 mg, about 3.25 mg to about 3.75 mg, about 5.0 mg to about 7.5 mg, about 5.5 mg to about 7.5 mg, about 6.0 mg to about 7.5 mg, about 5.75 mg to about 7.0 mg, about 6.0 mg to about 7.0 mg, about 6.5 mg to about 7.0 mg, about 9.0 mg to about 11.0 mg, about 9.5 mg to about 11.0 mg, about 9.5 mg to about 10.5 mg, or about 9.0 mg to about 10.5 mg.

[0064] Optionally, various non-limiting embodiments of the oral solid dosage form of the drug according to the disclosed text may include one or more colorants. Examples of colorants that may be used in the oral dosage form according to the disclosed text include, but are not limited to, one or more of FD&C Blue #1 aluminum lake pigment (11-13%), D&C Yellow #10 aluminum lake pigment (14-18%), and FD&C Red #40 aluminum lake pigment (14-16%).

[0065] Optionally, various non-limiting embodiments of the oral solid dosage form of the drug according to the disclosed text may also include one or more coatings. Coatings may be included on the oral solid dosage form of the drug, for example, to mask taste, facilitate swallowing, and / or protect the active pharmaceutical ingredient. Non-limiting examples of suitable coatings that may be applied to various non-limiting embodiments of the oral solid dosage form of the drug according to the disclosed text include OPADRY. ® white coating and OPADRY ® II 85F19316clear (transparent) coating (available from Colorcon, Inc. (West Point, PA USA)).

[0066] In various non-limiting embodiments, the oral solid dosage form of the drug according to the published text may be provided as tablets, capsules, powders, lozenges or other suitable solid dosage forms.

[0067] In specific embodiments according to the published text, the oral solid dosage form of the drug comprises at least one of phenobarbital and phenobarbital salts (i.e., phenobarbital and / or phenobarbital salts), lactose monohydrate, microcrystalline cellulose, and colloidal silica. In various embodiments, the oral solid dosage form of the drug is prepared by a method including a dry blending process. In various embodiments, when the dosage form is stored under one or more of the following storage conditions, the oral solid dosage form of the drug retains at least 90% of the original total content of phenobarbital and phenobarbital salts in the solid dosage form: for 48 months under standard test conditions (25°C ± 2°C and 60% ± 5% relative humidity); and for 6 months under accelerated test conditions (40°C ± 2°C and 75% ± 5% relative humidity).

[0068] In specific embodiments according to the published text, the oral solid dosage form of the drug comprises at least one of phenobarbital and phenobarbital salts, lactose monohydrate, microcrystalline cellulose, and colloidal silica. In various embodiments, the oral solid dosage form of the drug is prepared by a method including a dry blending process. In various embodiments, the oral solid dosage form of the drug retains at least 95% of the original total content of phenobarbital and phenobarbital salts in the solid dosage form when stored under one or more of the following storage conditions: for 48 months under standard test conditions (25°C ± 2°C and 60% ± 5% relative humidity); and for 6 months under accelerated test conditions (40°C ± 2°C and 75% ± 5% relative humidity).

[0069] In specific embodiments according to the published text, the oral solid dosage form of the drug comprises at least one of phenobarbital and phenobarbital salts, lactose monohydrate, microcrystalline cellulose, and colloidal silica. In various embodiments, the oral solid dosage form of the drug is prepared by a method including a dry blending process. In various embodiments, the oral solid dosage form of the drug retains at least 97% of the original total content of phenobarbital and phenobarbital salts in the solid dosage form when stored under one or more of the following storage conditions: for 48 months under standard test conditions (25°C ± 2°C and 60% ± 5% relative humidity); and for 6 months under accelerated test conditions (40°C ± 2°C and 75% ± 5% relative humidity).

[0070] In specific embodiments according to the published text, the oral solid dosage form of the drug comprises at least one of phenobarbital and phenobarbital salts, lactose monohydrate, microcrystalline cellulose, and colloidal silica. In various embodiments, the oral solid dosage form of the drug is prepared by a method including a dry blending process. In various embodiments, the oral solid dosage form of the drug retains at least 99% of the original total content of phenobarbital and phenobarbital salts in the solid dosage form when stored under one or more of the following storage conditions: for 48 months under standard test conditions (25°C ± 2°C and 60% ± 5% relative humidity); and for 6 months under accelerated test conditions (40°C ± 2°C and 75% ± 5% relative humidity).

[0071] In various embodiments, oral solid dosage forms of pharmaceuticals according to the disclosure can be prepared by a dry blending process that includes providing a homogeneous blend of the components. The dry homogeneous blending of the components may include techniques known in the art, such as one or more of blending, mixing, sieving, co-grinding, milling, granulation, and high-intensity granulation.

[0072] In a specific, non-limiting embodiment according to the disclosed text, a pre-packaged pharmaceutical product is provided, comprising an oral solid dosage form according to the disclosed text, the oral solid dosage form being contained in a container closure system including a container and a sealing closure. In a specific, non-limiting embodiment according to the disclosed text, the container has approximately 50 cm². 3 Approximately 70cm 3 The internal volume includes approximately 90 to approximately 110 oral solid dosage forms according to the disclosed text, and optionally includes at least one silica gel desiccant container, each containing, for example, approximately 2 grams of desiccant. In various embodiments, the container closure system may also include at least one oxygen absorber containing, for example, approximately 2 grams of oxygen-absorbing material. In a specific non-limiting embodiment according to the disclosed text, the pre-packaged pharmaceutical product according to the disclosed text includes a container closure system wherein the container has approximately 50 cm³. 3 Approximately 70cm 3 The internal volume, and contains approximately 90 to approximately 110 oral solid dosage forms according to the published text and at least one oxygen absorber canister or other container type (including, for example, approximately 2 grams of oxygen absorbent material).

[0073] In a specific, non-limiting embodiment according to the disclosed text, a pre-packaged pharmaceutical product is provided, comprising an oral solid dosage form according to the disclosed text, the oral solid dosage form being contained in a container closure system including a container and a sealing closure. In a specific, non-limiting embodiment according to the disclosed text, the container has approximately 110 cm². 3 Approximately 130cm 3The internal volume includes approximately 90 to approximately 110 oral solid dosage forms according to the disclosed text, and optionally includes at least one silica gel desiccant container, each containing, for example, approximately 2 grams of desiccant. In various embodiments, the container closure system may also include at least one oxygen absorber container or other container type containing, for example, approximately 2 grams of oxygen-absorbing material. In a specific non-limiting embodiment according to the disclosed text, the pre-packaged pharmaceutical product according to the disclosed text includes a container closure system wherein the container has an internal volume of approximately 110 cm³. 3 Approximately 130cm 3 The internal volume, and contains approximately 90 to approximately 110 oral solid dosage forms according to the published text and at least one oxygen absorber canister or other container type (including, for example, approximately 2 grams of oxygen absorbent material).

[0074] In a specific, non-limiting embodiment according to the disclosed text, a pre-packaged pharmaceutical product is provided, comprising an oral solid dosage form according to the disclosed text, the oral solid dosage form being contained in a container closure system including a container and a sealing closure. In a specific, non-limiting embodiment according to the disclosed text, the container has approximately 110 cm². 3 Approximately 130cm 3 The internal volume includes approximately 900 to 1100 oral solid dosage forms according to the disclosed text, and optionally includes at least one silica gel desiccant container, each containing, for example, about 2 grams of desiccant. In various embodiments, the container closure system may also include at least one oxygen absorber container or other container type containing, for example, about 2 grams of oxygen-absorbing material. In a specific non-limiting embodiment according to the disclosed text, the pre-packaged pharmaceutical product according to the disclosed text includes a container closure system wherein the container has an internal volume of approximately 110 cm³. 3 Approximately 130cm 3 The internal volume, and therein contain approximately 900 to approximately 1100 oral solid dosage forms according to the published text and at least one oxygen absorber canister or other container type (including, for example, approximately 2 grams of oxygen absorbent material).

[0075] In a specific, non-limiting embodiment according to the disclosed text, a pre-packaged pharmaceutical product is provided, comprising an oral solid dosage form according to the disclosed text, the oral solid dosage form being contained in a container closure system including a container and a sealing closure. In a specific, non-limiting embodiment according to the disclosed text, the container has approximately 180 cm². 3 Approximately 220cm 3The internal volume includes approximately 900 to approximately 1100 oral solid dosage forms according to the disclosed text, and optionally includes at least one silica gel desiccant container, each containing, for example, approximately 2 grams of desiccant. In various embodiments, the container closure system may also include at least one oxygen absorber containing, for example, approximately 2 grams of oxygen-absorbing material. In a specific non-limiting embodiment according to the disclosed text, the pre-packaged pharmaceutical product according to the disclosed text includes a container closure system wherein the container has approximately 180 cm³. 3 Approximately 220cm 3 The internal volume, and therein contain approximately 900 to approximately 1100 oral solid dosage forms according to the published text and at least one oxygen absorber canister or other container type (including, for example, approximately 2 grams of oxygen absorbent material).

[0076] In a specific, non-limiting embodiment according to the disclosed text, a pre-packaged pharmaceutical product is provided, comprising an oral solid dosage form according to the disclosed text, the oral solid dosage form being contained in a container closure system including a container and a sealing closure. In a specific, non-limiting embodiment according to the disclosed text, the container has approximately 360 cm³. 3 Approximately 440cm 3 The internal volume includes approximately 900 to approximately 1100 oral solid dosage forms according to the disclosed text, and optionally includes at least one silica gel desiccant container, each containing, for example, approximately 2 grams of desiccant. In various embodiments, the container closure system may also include at least one oxygen absorber container or other container type containing, for example, approximately 2 grams of oxygen-absorbing material. In a specific non-limiting embodiment according to the disclosed text, the pre-packaged pharmaceutical product according to the disclosed text includes a container closure system wherein the container has an internal volume of approximately 360 cm³. 3 Approximately 440cm 3 The internal volume, and therein contain approximately 900 to approximately 1100 oral solid dosage forms according to the published text and at least one oxygen absorber canister or other container type (including, for example, approximately 2 grams of oxygen absorbent material).

[0077] In a specific, non-limiting embodiment according to the disclosed text, a pre-packaged pharmaceutical product is provided, comprising an oral solid dosage form according to the disclosed text, the oral solid dosage form being contained in a container closure system including a container and a sealing closure. In a specific, non-limiting embodiment according to the disclosed text, the container has approximately 575 cm³. 3 Approximately 675cm 3The internal volume includes approximately 900 to approximately 1100 oral solid dosage forms according to the disclosed text, and optionally includes at least one silica gel desiccant container, each containing, for example, approximately 2 grams of desiccant. In various embodiments, the container closure system may also include at least one oxygen absorber containing, for example, approximately 2 grams of oxygen-absorbing material. In a specific non-limiting embodiment according to the disclosed text, the pre-packaged pharmaceutical product according to the disclosed text includes a container closure system wherein the container has approximately 575 cm³. 3 Approximately 675cm 3 The internal volume, and therein contain approximately 900 to approximately 1100 oral solid dosage forms according to the published text and at least one oxygen absorber canister or other container type (including, for example, approximately 2 grams of oxygen absorbent material).

[0078] The container of a container closure system for a prepackaged pharmaceutical product according to a specific non-limiting embodiment of the disclosed text may include at least one of glass, plastic, or other suitable polymer materials. For example, in a specific embodiment, the container of a container closure system for a prepackaged pharmaceutical product according to a specific non-limiting embodiment of the disclosed text may include polypropylene or high-density polyethylene. In a specific embodiment of a prepackaged pharmaceutical product according to the disclosed text, an oral solid dosage form of the drug may be stored in the container of the container closure system, and the container has been purged with an inert gas to displace at least a portion of the ambient oxygen within the container before sealing it with a closure element. In a specific embodiment of the disclosed text, the inert gas used to purge the container may include nitrogen, argon, a mixture of nitrogen and argon, or another inert gas or a mixture of inert gases. In a specific embodiment of a prepackaged pharmaceutical product according to the disclosed text, an oral solid dosage form of the drug may be stored in the container of the container closure system, and the container has not been purged with an inert gas before sealing it with a closure element. In a specific embodiment of the disclosed text, at least a portion of the air space within the container may be filled with pill packaging material, such as rayon or cotton, before sealing the container with a closure element.

[0079] One aspect of the disclosed text relates to a treatment method for managing the occurrence of seizures in animals caused by idiopathic epilepsy or other etiologies. According to one method, an oral solid dosage form of a drug according to the disclosed text is administered to an animal in need, such that the animal receives a total of about 15 mg to about 100 mg of phenobarbital and / or phenobarbital salts per dose. In a specific embodiment according to the disclosed text, the animal is a canine. In other specific embodiments according to the disclosed text, the animal suffers from idiopathic epilepsy.

[0080] According to a specific non-limiting embodiment, an oral solid dosage form according to the disclosed text can be prepared using a dry layering / mixing process that typically includes the following steps: first, a diluent (e.g., AVICEL) is added... ® PH-102 MCC powder was sieved through a #30 mesh sieve, and then a dry-process layered blend was prepared by mixing the diluent in a V-type mixer to form the first layer in the V-type mixer. Next, the remaining diluent (e.g., AVICEL) was used to further refine the blend. ® A sieved blend is prepared by sieving together PH-102 MCC powder, a second diluent (e.g., lactose monohydrate), at least one of phenobarbital and phenobarbital salts, a gliding agent (e.g., colloidal silica), and a disintegrant (e.g., sodium glycolate starch) to form a sieved blend. The sieved blend is deposited on a first layer to form a second layer in a V-type mixer. Next, a third layer is formed on the second layer by sieving a lubricant (e.g., magnesium stearate) through a #30 sieve and depositing it on the second layer in the V-type mixer. The dry-layered arrangement comprising the first, second, and third layers of powdered material is then uniformly mixed in the V-type mixer to provide a homogeneous powder mixture. A predetermined amount of the dry mixture is compressed to form tablets of a desired quality, each tablet comprising a desired amount of at least one of phenobarbital and phenobarbital salts. Alternatively, a predetermined amount of the dry oral solid dosage mixture can be arranged in a capsule (e.g., a hard gelatin capsule) or used to prepare other suitable oral solid dosage forms.

[0081] The inventors have observed that various embodiments of oral solid dosage forms of pharmaceuticals comprising at least one of phenobarbital and phenobarbital salts, according to the disclosed text, exhibit advantageous stability.

[0082] For example, the inventors observed that, under standard test conditions including a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, after storage for 12 months, 18 months, 36 months, or 48 months, at least 90% of the original total content of phenobarbital and phenobarbital salts was retained according to specific non-limiting embodiments of the oral solid dosage form of the disclosed text. The inventors also observed that, under accelerated test conditions including a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, after storage for two months, three months, or six months, at least 90% of the original total content of phenobarbital and phenobarbital salts was retained according to specific embodiments of the oral solid dosage form of the disclosed text.

[0083] Furthermore, the inventors observed that, under standard test conditions including a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, after storage for 12 months, 18 months, 36 months, or 48 months, at least 92% of the original total content of phenobarbital and phenobarbital salts was retained according to specific non-limiting embodiments of the oral solid dosage form of the disclosed text. The inventors also observed that, under accelerated test conditions including a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, after storage for two months, three months, or six months, at least 92% of the original total content of phenobarbital and phenobarbital salts was retained according to specific embodiments of the oral solid dosage form of the disclosed text.

[0084] Furthermore, the inventors observed that, under standard test conditions including a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, after storage for 12 months, 18 months, 36 months, or 48 months, at least 95% of the original total content of phenobarbital and phenobarbital salts was retained according to specific non-limiting embodiments of the oral solid dosage form of the disclosed text. The inventors also observed that, under accelerated test conditions including a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, after storage for two months, three months, or six months, at least 95% of the original total content of phenobarbital and phenobarbital salts was retained according to specific embodiments of the oral solid dosage form of the disclosed text.

[0085] Furthermore, the inventors observed that, under standard test conditions including a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, after storage for 12 months, 18 months, 36 months, or 48 months, at least 97% of the original total content of phenobarbital and phenobarbital salts was retained according to specific non-limiting embodiments of the oral solid dosage form of the disclosed text. The inventors also observed that, under accelerated test conditions including a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, after storage for two months, three months, or six months, at least 97% of the original total content of phenobarbital and phenobarbital salts was retained according to specific embodiments of the oral solid dosage form of the disclosed text.

[0086] Furthermore, the inventors observed that, under standard test conditions including a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65%, after storage for 12 months, 18 months, 36 months, or 48 months, at least 99% of the original total content of phenobarbital and phenobarbital salts was retained according to specific non-limiting embodiments of the oral solid dosage form of the disclosed text. The inventors also observed that, under accelerated test conditions including a temperature of about 38°C to about 42°C and a relative humidity of about 70% to about 80%, after storage for two months, three months, or six months, at least 99% of the original total content of phenobarbital and phenobarbital salts was retained according to specific embodiments of the oral solid dosage form of the disclosed text.

[0087] The following are non-limiting examples of oral dosage forms of drugs including at least one of phenobarbital and phenobarbital salts, and methods for manufacturing oral dosage forms of drugs including at least one of phenobarbital and phenobarbital salts, all based on the published text.

[0088] Example

[0089] Example 1

[0090] This embodiment describes a non-limiting implementation of a dry layering / mixing and tableting process, which can be used to manufacture oral solid dosage forms of pharmaceuticals according to the disclosed text.

[0091] Apply the desired total amount of powdered diluent (e.g., AVICEL). ®Half of the PH-102 MCC powder was sieved through a #30 mesh sieve, and the sieved material was mixed at 20 RPM for 1 minute in a first V-type mixer. The sieved and mixed portion of the diluent powder formed the first powder layer in the first V-type mixer. Next, the remaining portion of the powdered diluent was added to a container containing a certain amount of additional gliding agent (e.g., lactose monohydrate), phenobarbital, powdered gliding agent (e.g., colloidal silica), and powdered disintegrant (e.g., sodium glycolate starch), and the resulting powder blend was sieved through a #30 mesh sieve into a high-density polyethylene (HDPE) bag to prepare a sieved blend. Then, the sieved blend of diluent powder, phenobarbital, gliding agent powder, and disintegrant powder from the HDPE bag was mixed at 20 RPM for 10 minutes in a second V-type mixer. A sieved and mixed mixture of diluent powder, phenobarbital, glidant powder, and disintegrant powder forms a second layer on top of the first layer in a first V-type mixer. Next, a measured amount of lubricant (e.g., magnesium stearate) is sieved through a #30 mesh sieve and mixed at 20 RPM for 2 minutes in a third V-type mixer. A sieved and mixed portion of the lubricant material is then arranged on top of the second layer in the first V-type mixer to form a third layer. The layered arrangement is then mixed in the first V-type mixer until they are uniformly combined to form the final powder blend.

[0092] Cradle discharge is used to remove multiple small batches of the final powder blend from the V-type mixer in a short time to prevent component segregation. PROTAB is used. TM A 300 tablet press (available from ProTab Laboratories (Foothill Ranch, CAUSA)) compresses the measured portion of the final powder blend removed from the V-type blender into 15.0 mg, 16.2 mg, 30 mg, 32.4 mg, 60 mg, 64.8 mg, 97.2 mg, and 100 mg tablets with a hardness ranging from 1.9 Kp to 11.0 Kp. The tablets are then packaged in containers approximately 60 cm² in size. 3 Approximately 120cm 3 Approximately 200cm 3 Approximately 400cm 3 or approximately 625cm 3 The internal volume is contained in a high-density polyethylene (HDPE) container (i.e., a bottle).

[0093] Arrange approximately 90 to 110 tablets in a 60cm space. 3 HDPE container (as shown in the picture) Figure 1A , Figure 1B and Figure 1C (as shown). Use a sealing closure (in) Figure 3A and Figure 3B (Depicted in the middle) Sealed 60cm3 Containers that provide packaged oral solid dosage form products for pharmaceuticals.

[0094] Arrange approximately 90 to 110 tablets at a height of 120 cm. 3 HDPE containers (such as) Figure 2A , Figure 2B and Figure 2C (as shown). Use a sealing closure (in) Figure 3A and Figure 3B (Depicted in the middle) Sealed 120cm 3 Containers that provide packaged oral solid dosage form products for pharmaceuticals.

[0095] Arrange approximately 900 to 1100 tablets at a depth of 120 cm. 3 HDPE container (as shown in the picture) Figure 2A , Figure 2B and Figure 2C (as shown). Use a sealing closure (in) Figure 5A and Figure 5B (Depicted in the middle) Sealed 120cm 3 Containers that provide packaged oral solid dosage form products for pharmaceuticals.

[0096] Arrange approximately 900 to 1100 tablets in a 200cm space. 3 HDPE containers (such as) Figure 4A , Figure 4B and Figure 4C (as shown). Use a sealing closure (in) Figure 5A and Figure 5B (Depicted in the middle) Sealed 200cm 3 Containers that provide packaged oral solid dosage form products for pharmaceuticals.

[0097] Arrange approximately 900 to 1100 tablets in a 400cm space. 3 HDPE container (as shown in the picture) Figure 6A , Figure 6B and Figure 6C (as shown). Use a sealing closure (in) Figure 8A , Figure 8B and Figure 8C (Depicted in the middle) Sealed 400cm 3 Containers that provide packaged oral solid dosage form products for pharmaceuticals.

[0098] Arrange approximately 900 to approximately 1100 tablets in a 625cm space. 3 HDPE containers (such as) Figure 7A , Figure 7B and Figure 7C (as shown). Use a sealing closure (in) Figure 8A , Figure 8B and Figure 8C(Depicted in the middle) Sealed 625cm 3 Containers that provide packaged oral solid dosage form products for pharmaceuticals.

[0099] Example 2

[0100] Oral solid dosage forms of the medicine were prepared by compressing portions of several homogeneous mixtures manufactured using the method generally described in Example 1. Each of these tablets comprises phenobarbital, microcrystalline cellulose (MCC) powder, lactose monohydrate, colloidal silica, sodium glycolate starch, 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 of phenobarbital per tablet. The amount of phenobarbital in the dosage form is referred to as the “strength” of the individual tablet. All tablets listed in Table 1 with a specific strength comprise the same ingredients at the same weight percentage concentration.

[0101] Table 1 Tablet composition

[0102]

[0103] Example 3

[0104] A study was conducted to evaluate the stability of the implementation scheme for the oral solid dosage form based on the published text.

[0105] Tablets comprising 16.2 mg of phenobarbital were prepared by compressing portions of several homogeneous mixtures manufactured using the method generally described in Example 1. Each of these mixtures comprised phenobarbital, microcrystalline cellulose (MCC), lactose monohydrate, colloidal silica, sodium glycolate starch, 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 a single tablet containing 16.2 mg of phenobarbital per tablet produced in batches S54100118C and S54100118D.

[0106] Table 2 Composition of tablets in batches S54100118C and S54100118D

[0107]

[0108] To conduct stability studies, tablets from batch S54100118C were arranged in a container closure system, which included a container and a sealing closure. The container consisted of approximately 60 cm³ of... 3The internal volume (including 90 to 110 tablets) was used. For stability studies, tablets from batch S54100118D were arranged in a container closure system comprising a container and a sealing closure. The container comprised approximately 120 cm² of internal volume. 3 Internal volume (including 900 to 1100 tablets).

[0109] Two studies were conducted to evaluate the stability of phenobarbital in tablets manufactured in batches S54100118C and S54100118D. The stability studies involved the following test periods and conditions:

[0110] • Store for up to 48 months under standard testing conditions (25℃±2℃ and 60%±5% relative humidity).

[0111] • Store for up to 6 months under accelerated testing conditions (40℃±2℃ and 75%±5% relative humidity).

[0112] A 48-month standard test condition stability study was conducted on tablets of batches S54100118C and S54100118D contained in a container-closed system to determine the physical or chemical degradation rate of phenobarbital contained in the tablets when stored under standard environmental conditions.

[0113] During stability studies, the sealed container system containing tablets (each tablet containing approximately 16.2 mg of phenobarbital) prepared as described above was placed upright in a calibrated environmental chamber and maintained in an upright position. Sealed containers containing 90 to 110 or 900 to 1100 tablets were maintained uninterruptedly at 25°C ± 2°C and 60% ± 5% relative humidity for 12, 18, 36, or 48 months (except for the addition or withdrawal of test samples). At specified time points, the tablets were removed from storage conditions, and their phenobarbital content was determined using high-performance liquid chromatography (HPLC).

[0114] Considering the phenobarbital content, the shelf life of tablets in batches S54100118C and S54100118D is estimated to be at least 48 months when stored under standard testing conditions. Table 3 provides the 48-month stability test results for tablets in batches S54100118C and S54100118D. The stability test results indicate that the tablets stored under standard testing conditions for 48 months retained more than 98% of the original phenobarbital content.

[0115] During stability testing, accelerated-condition stability samples were placed upright in an environmental chamber and maintained in an upright position. As discussed, each tablet was arranged in a sealed container containing 90 to 110 or 900 to 1100 tablets from batches S54100118C and S54100118D, each tablet containing approximately 16.2 mg of phenobarbital. The sealed containers were maintained uninterruptedly at 40°C ± 2°C and 75% ± 5% relative humidity for two, three, or six months (except for the addition or withdrawal of test samples). At specified time points, the tablets were removed from storage conditions, and their phenobarbital content was determined using high-performance liquid chromatography (HPLC).

[0116] Considering the phenobarbital content, the shelf life of tablets in batches S54100118C and S54100118D is estimated to be at least 6 months when stored under accelerated testing conditions. Table 3 provides the 6-month stability test results for tablets in batches S54100118C and S54100118D under accelerated testing conditions. The stability test results show that the tablets stored for 6 months under accelerated testing conditions retained more than 99% of the original phenobarbital content.

[0117] Table 3 reports stability data for oral solid dosage form samples (lots S54100118C and S54100118D) under standard and accelerated conditions. Table 3 identifies the bottle size used to store each test sample. The percentages of determination listed in Table 3 are based on the expected (“label claim” content (16.2 mg of phenobarbital) per tablet of lots S54100118C and S54100118D.

[0118] Table 3 Stability test results of tablets from batches S54100118C and S54100118D

[0119]

[0120] Referring to the results shown in Table 3, the inventors surprisingly observed that when stored for 48 months under standard test conditions of 25°C ± 2°C and 60% ± 5% relative humidity, the oral solid dosage forms produced in batches S54100118C and S54100118D retained more than approximately 98% of the original phenobarbital content. Even when the tablets were stored for 6 months under accelerated conditions (40°C ± 2°C and 75% ± 5% relative humidity), the tablets produced in batches S54100118C and S54100118D retained more than 99% of the original phenobarbital content (the reduction in phenobarbital content in the tablets was less than one percent).

[0121] Example 4

[0122] Additional studies were conducted to assess the stability of oral solid dosage forms, including phenobarbital, based on the published text.

[0123] Tablets comprising 32.4 mg of phenobarbital were prepared by compressing portions of several homogeneous mixtures manufactured using the method generally described in Example 1. Each of these mixtures comprised phenobarbital, microcrystalline cellulose (MCC), lactose monohydrate, colloidal silica, sodium glycolate starch, and magnesium stearate. MCC is AVICEL ® PH-102MCC powder. Table 4 below provides the mass and weight / weight concentration of the ingredients in a single tablet containing 32.4 mg of phenobarbital per tablet produced in batches S54200119A and S54200119C.

[0124] Table 4 Composition of tablets in batches S54200119A and S54200119C

[0125]

[0126] To conduct stability studies, tablets from batch S54200119A were arranged in a container closure system, which includes a container and a sealing closure. The container comprises approximately 60 cm² of... 3 The internal volume includes 90 to 110 tablets. For stability studies, tablets from batch S54200119C were arranged in a container closure system comprising a container and a sealing closure element. The container comprises approximately 200 cm² of internal volume. 3 Internal volume (including 900 to 1100 tablets).

[0127] Two studies were conducted to evaluate the stability of phenobarbital in tablets manufactured in batches S54200119A and S54200119C. The stability studies involved the following test periods and conditions:

[0128] • Store for up to 48 months under standard testing conditions (25℃±2℃ and 60%±5% relative humidity).

[0129] • Store for up to 6 months under accelerated testing conditions (40℃±2℃ and 75%±5% relative humidity).

[0130] A 48-month standard test condition stability study was conducted on tablets of batches S54200119A and S54200119C contained in a container-closed system to determine the physical or chemical degradation rate of phenobarbital contained in the tablets when stored under standard environmental conditions.

[0131] During stability studies, the sealed container system containing tablets (each tablet containing approximately 32.4 mg of phenobarbital) prepared as described above was placed upright in a calibrated environmental chamber and maintained in an upright position. The sealed containers, containing 90 to 110 or 900 to 1100 tablets, were maintained uninterruptedly at 25°C ± 2°C and 60% ± 5% relative humidity for 12, 18, 36, or 48 months (except for the addition or withdrawal of test samples). At specified time points, the tablets were removed from the storage conditions, and their phenobarbital content was determined using high-performance liquid chromatography (HPLC).

[0132] Considering the phenobarbital content, the shelf life of tablets in batches S54200119A and S54200119C is estimated to be at least 48 months when stored under standard testing conditions. Table 5 provides the 48-month stability test results for tablets in batches S54200119A and S54200119C. The stability test results indicate that the tablets stored under standard testing conditions for 48 months retained 100% of the original phenobarbital content.

[0133] During stability testing, accelerated-condition stability samples were placed upright in an environmental chamber and maintained in an upright position. As discussed, each tablet was arranged in a sealed container containing 90 to 110 or 900 to 1100 tablets from batches S54200119A and S54200119C, each tablet containing approximately 32.4 mg of phenobarbital. The sealed containers were maintained uninterruptedly at 40°C ± 2°C and 75% ± 5% relative humidity for two, three, or six months (except for the addition or withdrawal of test samples). At specified time points, the tablets were removed from storage conditions, and their phenobarbital content was determined using high-performance liquid chromatography (HPLC).

[0134] Considering the phenobarbital content, the shelf life of tablets in batches S54200119A and S54200119C is estimated to be at least 6 months when stored under accelerated testing conditions. Table 5 provides the 6-month stability test results for tablets in batches S54200119A and S54200119C under accelerated testing conditions. The stability test results indicate that the tablets stored for 6 months under accelerated testing conditions retained 100% of the original phenobarbital content.

[0135] Table 5 reports stability data for oral solid dosage form samples (lots S54200119A and S54200119C) under standard and accelerated conditions. Table 5 identifies the bottle size used to store each test sample. The percentages of determination listed in Table 5 are based on the expected (“label claim” content (32.4 mg of phenobarbital) per tablet of lots S54200119A and S54200119C.

[0136] Table 5 Stability test results of tablets from batches S54200119A and S54200119C

[0137]

[0138] Referring to the results shown in Table 5, the inventors surprisingly observed that when stored for 48 months under standard test conditions of 25°C ± 2°C and 60% ± 5% relative humidity, the oral solid dosage forms produced in batches S54200119A and S54200119C retained approximately 100% of the original phenobarbital content. Even when the tablets were stored for 6 months under accelerated conditions (40°C ± 2°C and 75% ± 5% relative humidity), the tablets produced in batches S54200119A and S54200119C retained approximately 100% of the original phenobarbital content.

[0139] Example 5

[0140] A study was conducted to evaluate the stability of the implementation scheme for the oral solid dosage form based on the published text.

[0141] Tablets comprising 64.8 mg of phenobarbital were prepared by compressing portions of several homogeneous mixtures manufactured using the method generally described in Example 1. Each of these mixtures comprised phenobarbital, microcrystalline cellulose (MCC), lactose monohydrate, colloidal silica, sodium glycolate starch, and magnesium stearate. MCC is AVICEL ® PH-102MCC powder. Table 6 below provides the mass and weight / weight concentration of the ingredients in a single tablet containing 64.8 mg of phenobarbital per tablet produced in batches S54300119A and S54300119B.

[0142] Table 6 Composition of tablets in batches S54300119A and S54300119B

[0143]

[0144] To conduct stability studies, tablets from batch S54300119A were arranged in a container closure system, which includes a container and a sealing closure. The container comprises approximately 120 cm³. 3 The internal volume includes 90 to 110 tablets. For stability studies, tablets from batch S54300119B were arranged in a container closure system comprising a container and a sealing closure element. The container comprises approximately 400 cm³ of internal volume. 3 Internal volume (including 900 to 1100 tablets).

[0145] Two studies were conducted to evaluate the stability of phenobarbital in tablets manufactured in batches S54300119A and S54300119B. The stability studies involved the following test periods and conditions:

[0146] • Store for up to 48 months under standard testing conditions (25℃±2℃ and 60%±5% relative humidity).

[0147] • Store for up to 6 months under accelerated testing conditions (40℃±2℃ and 75%±5% relative humidity).

[0148] A 48-month standard test condition stability study was conducted on tablets of batches S54300119A and S54300119B contained in a container-sealed system to determine the physical or chemical degradation rate of phenobarbital contained in the tablets when stored under standard environmental conditions.

[0149] During stability studies, the sealed container system containing tablets (each tablet containing approximately 64.8 mg of phenobarbital) prepared as described above was placed upright in a calibrated environmental chamber and maintained in an upright position. Sealed containers containing 90 to 110 or 900 to 1100 tablets were maintained uninterruptedly at 25°C ± 2°C and 60% ± 5% relative humidity for 12, 18, 36, or 48 months (except for the addition or withdrawal of test samples). At specified time points, the tablets were removed from storage conditions, and their phenobarbital content was determined using high-performance liquid chromatography (HPLC).

[0150] Considering the phenobarbital content, the shelf life of tablets in batches S54300119A and S54300119B is estimated to be at least 48 months when stored under standard testing conditions. Table 7 provides the 48-month stability test results for tablets in batches S54300119A and S54300119B. The stability test results indicate that the tablets stored under standard testing conditions for 48 months retained more than 99% of the original phenobarbital content.

[0151] During stability testing, accelerated-condition stability samples were placed upright in an environmental chamber and maintained in an upright position. As discussed, each tablet was arranged in a sealed container containing 90 to 110 or 900 to 1100 tablets from batches S54300119A and S54300119B, each tablet containing approximately 64.8 mg of phenobarbital. The sealed containers were maintained uninterruptedly at 40°C ± 2°C and 75% ± 5% relative humidity for two, three, or six months (except for the addition or withdrawal of test samples). At specified time points, the tablets were removed from storage conditions, and their phenobarbital content was determined using high-performance liquid chromatography (HPLC).

[0152] Considering the phenobarbital content, the shelf life of tablets in batches S54300119A and S54300119B is estimated to be at least 6 months when stored under accelerated testing conditions. Table 7 provides the 6-month stability test results for tablets in batches S54300119A and S54300119B under accelerated testing conditions. The stability test results show that the tablets stored for 6 months under accelerated testing conditions retained more than 99% of the original phenobarbital content.

[0153] Table 7 reports stability data for oral solid dosage form samples (lots S54300119A and S54300119B) under standard and accelerated conditions. Table 7 identifies the bottle size used to store each test sample. The percentages of determination listed in Table 7 are based on the expected (“label claim” content (64.8 mg of phenobarbital) per tablet of lots S54300119A and S54300119B.

[0154] Table 7 Stability test results of tablets from batches S54300119A and S54300119B

[0155]

[0156] Referring to the results shown in Table 7, the inventors surprisingly observed that when stored for 48 months under standard test conditions of 25°C ± 2°C and 60% ± 5% relative humidity, the oral solid dosage forms produced in batches S54300119A and S54300119B retained more than 99% of the original phenobarbital content. Even when the tablets were stored for 6 months under accelerated conditions (40°C ± 2°C and 75% ± 5% relative humidity), the tablets produced in batches S54300119A and S54300119B retained more than 99% of the original phenobarbital content.

[0157] Example 6

[0158] A study was conducted to evaluate the stability of the implementation scheme for the oral solid dosage form based on the published text.

[0159] Tablets comprising 97.2 mg of phenobarbital were prepared by compressing portions of several homogeneous mixtures manufactured using the method generally described in Example 1. Each of these mixtures comprised phenobarbital, microcrystalline cellulose (MCC), lactose monohydrate, colloidal silica, sodium glycolate starch, and magnesium stearate. MCC is AVICEL ® PH-102MCC powder. Table 8 below provides the mass and weight / weight concentration of the ingredients in a single tablet containing 97.2 mg of phenobarbital per tablet produced in batches S54400119A and S54400119B.

[0160] Table 8 Composition of tablets in batches S54400119A and S54400119B

[0161]

[0162] To conduct stability studies, tablets from batch S54400119A were arranged in a container closure system, which includes a container and a sealing closure. The container comprises approximately 120 cm³. 3 The internal volume (including 90 to 110 tablets) was used. For stability studies, tablets from batch S54400119B were arranged in a container closure system comprising a container and a sealing closure. The container comprised approximately 625 cm³ of internal volume. 3 Internal volume (including 900 to 1100 tablets).

[0163] Two studies were conducted to evaluate the stability of phenobarbital in tablets manufactured in batches S54400119A and S54400119B. The stability studies involved the following test periods and conditions:

[0164] • Store for up to 48 months under standard testing conditions (25℃±2℃ and 60%±5% relative humidity).

[0165] • Store for up to 6 months under accelerated testing conditions (40℃±2℃ and 75%±5% relative humidity).

[0166] A 48-month standard test condition stability study was conducted on tablets of batches S54400119A and S54400119B contained in a container-sealed system to determine the physical or chemical degradation rate of phenobarbital contained in the tablets when stored under standard environmental conditions.

[0167] During stability studies, the sealed container system containing tablets (each tablet containing approximately 97.2 mg of phenobarbital) prepared as described above was placed upright in a calibrated environmental chamber and maintained in an upright position. Sealed containers containing 90 to 110 or 900 to 1100 tablets were maintained uninterruptedly at 25°C ± 2°C and 60% ± 5% relative humidity for 12, 18, 36, or 48 months (except for the addition or withdrawal of test samples). At specified time points, the tablets were removed from storage conditions, and their phenobarbital content was determined using high-performance liquid chromatography (HPLC).

[0168] Considering the phenobarbital content, the shelf life of tablets in batches S54400119A and S54400119B is estimated to be at least 48 months when stored under standard testing conditions. Table 9 provides the 48-month stability test results for tablets in batches S54400119A and S54400119B. The stability test results indicate that the tablets stored under standard testing conditions for 48 months retained 100% of the original phenobarbital content.

[0169] During stability testing, accelerated-condition stability samples were placed upright in an environmental chamber and maintained in an upright position. As discussed, each tablet was arranged in a sealed container containing 90 to 110 or 900 to 1100 tablets from batches S54400119A and S54400119B, each tablet containing approximately 97.2 mg of phenobarbital. The sealed containers were maintained uninterruptedly at 40°C ± 2°C and 75% ± 5% relative humidity for two, three, or six months (except for the addition or withdrawal of test samples). At specified time points, the tablets were removed from storage conditions, and their phenobarbital content was determined using high-performance liquid chromatography (HPLC).

[0170] Considering the phenobarbital content, the shelf life of tablets in batches S54400119A and S54400119B is estimated to be at least 6 months when stored under accelerated testing conditions. Table 9 provides the 6-month stability test results for tablets in batches S54400119A and S54400119B under accelerated testing conditions. The stability test results indicate that the tablets stored for 6 months under accelerated testing conditions retained 100% of the original phenobarbital content.

[0171] Table 9 reports stability data for oral solid dosage form samples (lots S54400119A and S54400119B) tested under standard and accelerated conditions. Table 9 identifies the bottle size used to store each test sample. The percentages of determination listed in Table 9 are based on the expected (“label claim” content (97.2 mg of phenobarbital) per tablet of lots S54400119A and S54400119B.

[0172] Table 9 Stability test results of tablets from batches S54400119A and S54400119B

[0173]

[0174] Referring to the results shown in Table 9, the inventors surprisingly observed that when stored for 48 months under standard test conditions of 25°C ± 2°C and 60% ± 5% relative humidity, the oral solid dosage forms produced in batches S54400119A and S54400119B retained 100% of the original phenobarbital content. Even when the tablets were stored for 6 months under accelerated conditions (40°C ± 2°C and 75% ± 5% relative humidity), the tablets produced in batches S54400119A and S54400119B retained 100% of the original phenobarbital content.

[0175] The following numbered clauses relate to various non-limiting embodiments of the invention based on the published text:

[0176] 1. An oral solid dosage form of a drug, comprising, by weight:

[0177] At least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%;

[0178] Lactose monohydrate comprises approximately 34% to approximately 51%;

[0179] Approximately 20% to 30% microcrystalline cellulose; and

[0180] Colloidal silica, approximately 1% to approximately 5%.

[0181] 2. The oral solid dosage form of the drug according to Clause 1, wherein the total content of phenobarbital and phenobarbital salt is about 24% to about 30%.

[0182] 3. An oral solid dosage form of the drug according to either Clause 1 or Clause 2, wherein the total content of phenobarbital and phenobarbital salt is about 26% to about 28%.

[0183] 4. Oral solid dosage forms of medicines according to any one of clauses 1 to 3, comprising about 38% to about 47% by weight of lactose monohydrate.

[0184] 5. Oral solid dosage forms of medicines according to any one of clauses 1 to 4, comprising about 41% to about 45% by weight of lactose monohydrate.

[0185] 6. An oral solid dosage form of a drug according to any one of Clauses 1 to 5, comprising about 22.5% to about 27.5% by weight of microcrystalline cellulose.

[0186] 7. An oral solid dosage form of a drug according to any one of Clauses 1 to 6, comprising about 24% to about 26% by weight of microcrystalline cellulose.

[0187] 8. Oral solid dosage forms of medicines according to any one of clauses 1 to 7, comprising about 1% to about 3% by weight of colloidal silica.

[0188] 9. An oral solid dosage form of a drug according to any one of Clauses 1 to 8, comprising about 1.2% to about 1.8% by weight of colloidal silica.

[0189] 10. An oral solid dosage form of a drug according to any one of clauses 1 to 9, comprising, by weight:

[0190] The ingredient is at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 24% to about 30%.

[0191] Lactose monohydrate comprises approximately 38% to approximately 47%;

[0192] Microcrystalline cellulose, approximately 22.5% to approximately 27.5%; and

[0193] Colloidal silica, approximately 1% to approximately 3%.

[0194] 11. Oral solid dosage forms of drugs according to any one of clauses 1 to 10 also include sodium glycolate starch.

[0195] 12. The oral solid dosage form of the drug according to any one of clauses 1 to 11 also includes about 1.5% to about 5% by weight of sodium glycolate starch.

[0196] 13. The oral solid dosage form of the drug according to any one of clauses 1 to 12 also includes about 2.2% to about 3.4% by weight of sodium glycolate starch.

[0197] 14. The oral solid dosage form of the drug according to any one of clauses 1 to 13 further includes at least one lubricant selected from calcium stearate and magnesium stearate.

[0198] 15. According to Clause 14, oral solid dosage forms of medicines comprise, by weight:

[0199] The ingredient is at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 24% to about 30%.

[0200] Lactose monohydrate comprises approximately 38% to approximately 47%;

[0201] Microcrystalline cellulose, approximately 22.5% to approximately 27.5%;

[0202] Sodium glycolate starch, approximately 1.5% to approximately 5%;

[0203] Colloidal silica of approximately 1% to approximately 3%; and

[0204] Magnesium stearate, approximately 0.5% to approximately 2.0%.

[0205] 16. An oral solid dosage form of a drug according to any one of Clauses 1 to 15, wherein after the oral solid dosage form of the drug 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%, the total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug is at least 90%, at least 92%, at least 95%, or at least 97% of the original total content of phenobarbital and phenobarbital salt.

[0206] 17. An oral solid dosage form of a drug according to any one of Clauses 1 to 15, wherein after the oral solid dosage form of the drug 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%, the total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug is at least 90%, at least 92%, at least 95%, or at least 97% of the original total content of phenobarbital and phenobarbital salt.

[0207] 18. An oral solid dosage form of a drug according to any one of Clauses 1 to 15, wherein after the oral solid dosage form of the drug 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%, the total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug is at least 90%, at least 92%, at least 95%, or at least 97% of the original total content of phenobarbital and phenobarbital salt.

[0208] 19. An oral solid dosage form of a drug according to any one of Clauses 1 to 15, wherein after the oral solid dosage form of the drug 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%, the total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug is at least 90%, at least 92%, at least 95%, or at least 97% of the original total content of phenobarbital and phenobarbital salt.

[0209] 20. An oral solid dosage form of a drug according to any one of Clauses 1 to 15, wherein after the oral solid dosage form of the drug 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%, the total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug is at least 90%, at least 92%, at least 95%, or at least 97% of the original total content of phenobarbital and phenobarbital salt.

[0210] 21. An oral solid dosage form of a drug according to any one of Clauses 1 to 15, wherein after the oral solid dosage form of the drug 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%, the total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug is at least 90%, at least 92%, at least 95%, or at least 97% of the original total content of phenobarbital and phenobarbital salt.

[0211] 22. An oral solid dosage form of a drug according to any one of Clauses 1 to 15, wherein after the oral solid dosage form of the drug 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%, the total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug is at least 90%, at least 92%, at least 95%, or at least 97% of the original total content of phenobarbital and phenobarbital salt.

[0212] 23. An oral solid dosage form of a drug according to any one of Clauses 1 to 15, wherein when multiple oral solid dosage forms are placed in a container sealed with a closure, after the oral solid dosage forms have 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%, each oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form.

[0213] 24. An oral solid dosage form of a drug according to any one of Clauses 1 to 15, wherein when multiple oral solid dosage forms are placed in a sealed container using a closure, after the oral solid dosage forms have 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%, each oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form.

[0214] 25. An oral solid dosage form of a drug according to any one of Clauses 1 to 15, wherein when multiple oral solid dosage forms are placed in a container sealed with a closure, after the oral solid dosage forms have been stored at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65% for 36 months, each oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form.

[0215] 26. An oral solid dosage form of a drug according to any one of Clauses 1 to 15, wherein when multiple oral solid dosage forms are placed in a container sealed with a closure, after the oral solid dosage forms have been stored at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65% for 48 months, each oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form.

[0216] 27. An oral solid dosage form of a drug according to any one of Clauses 1 to 15, wherein when multiple oral solid dosage forms are placed in a sealed container using a closure, after the oral solid dosage forms have 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%, each oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form.

[0217] 28. An oral solid dosage form of a drug according to any one of Clauses 1 to 15, wherein when multiple oral solid dosage forms are placed in a sealed container using a closure, after the oral solid dosage forms have 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%, each oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form.

[0218] 29. An oral solid dosage form of a drug according to any one of Clauses 1 to 15, wherein when multiple oral solid dosage forms are placed in a sealed container using a closure, after the oral solid dosage forms have 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%, each oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form.

[0219] 30. An oral solid dosage form of medicine according to any one of clauses 23 to 29, wherein the container comprises approximately 50 cm³. 3 Approximately 70cm 3 The internal volume.

[0220] 31. An oral solid dosage form of medicine according to any one of clauses 23 to 29, wherein the container comprises approximately 110 cm³. 3 Approximately 130cm 3 The internal volume.

[0221] 32. An oral solid dosage form of medicine according to any one of clauses 23 to 29, wherein the container comprises approximately 180 cm³. 3 Approximately 220cm 3 The internal volume.

[0222] 33. An oral solid dosage form of medicine according to any one of clauses 23 to 29, wherein the container comprises approximately 360 cm³. 3 Approximately 440cm 3 The internal volume.

[0223] 34. An oral solid dosage form of medicine according to any one of clauses 23 to 29, wherein the container comprises approximately 575 cm³. 3 Approximately 675cm 3 The internal volume.

[0224] 35. An oral solid dosage form of a drug according to any one of clauses 30 or 31, wherein about 90 to about 110 oral solid dosage forms of the drug are arranged in a container.

[0225] 36. An oral solid dosage form of a drug according to any one of clauses 31 to 34, wherein about 900 to about 1,100 oral solid dosage forms of a drug are arranged in a container.

[0226] 37. A packaged oral solid dosage form of medicine, comprising:

[0227] Oral solid dosage forms of medicines, by weight, include:

[0228] At least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%;

[0229] Lactose monohydrate, approximately 34% to approximately 51%,

[0230] Approximately 20% to 30% microcrystalline cellulose, and

[0231] Colloidal silica of approximately 1% to approximately 5%; and

[0232] A container closure system, comprising a container and a sealing closure;

[0233] This involves encapsulating multiple oral solid dosage forms of drugs in a container and sealing it with a sealing closure; and

[0234] Wherein, after the oral solid dosage form of the drug 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%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug.

[0235] 38. A packaged oral solid dosage form of medicine pursuant to Clause 37, wherein the oral solid dosage form of medicine has the composition pursuant to any one of Clauses 2 to 15.

[0236] 39. A packaged oral solid dosage form of medicine, comprising:

[0237] Oral solid dosage forms of medicines, by weight, include:

[0238] The substance contains at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%.

[0239] Lactose monohydrate, approximately 34% to approximately 51%,

[0240] Approximately 20% to 30% microcrystalline cellulose, and

[0241] Colloidal silica of approximately 1% to approximately 5%; and

[0242] A container closure system, comprising a container and a sealing closure;

[0243] This involves encapsulating multiple oral solid dosage forms of drugs in a container and sealing it with a sealing closure; and

[0244] Wherein, after the oral solid dosage form of the drug 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%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug.

[0245] 40. Packaged oral solid dosage form of medicine under Clause 39, wherein the oral solid dosage form of medicine has the composition according to any one of Clauses 2 to 15.

[0246] 41. A packaged oral solid dosage form of medicine, comprising:

[0247] Oral solid dosage forms of medicines, by weight, include:

[0248] The substance contains at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%.

[0249] Lactose monohydrate, approximately 34% to approximately 51%,

[0250] Approximately 20% to 30% microcrystalline cellulose, and

[0251] Colloidal silica of approximately 1% to approximately 5%; and

[0252] A container closure system, comprising a container and a sealing closure;

[0253] This involves encapsulating multiple oral solid dosage forms of drugs in a container and sealing it with a sealing closure; and

[0254] Wherein, after the oral solid dosage form of the drug 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%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug.

[0255] 42. A packaged oral solid dosage form of medicine pursuant to Clause 41, wherein the oral solid dosage form of medicine has the composition pursuant to any one of Clauses 2 to 15.

[0256] 43. A packaged oral solid dosage form of medicine, comprising:

[0257] Oral solid dosage forms of medicines, by weight, include:

[0258] The substance contains at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%.

[0259] Lactose monohydrate, approximately 34% to approximately 51%,

[0260] Approximately 20% to 30% microcrystalline cellulose, and

[0261] Colloidal silica of approximately 1% to approximately 5%; and

[0262] A container closure system, comprising a container and a sealing closure;

[0263] This involves encapsulating multiple oral solid dosage forms of drugs in a container and sealing it with a sealing closure; and

[0264] Wherein, after the oral solid dosage form of the drug 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%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug.

[0265] 44. Packaged oral solid dosage form products of medicines in accordance with Clause 43, wherein the oral solid dosage form of medicine has the composition in accordance with any one of Clauses 2 to 15.

[0266] 45. A packaged oral solid dosage form of medicine, comprising:

[0267] Oral solid dosage forms of medicines, by weight, include:

[0268] The substance contains at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%.

[0269] Lactose monohydrate, approximately 34% to approximately 51%,

[0270] Approximately 20% to 30% microcrystalline cellulose, and

[0271] Colloidal silica of approximately 1% to approximately 5%; and

[0272] A container closure system, comprising a container and a sealing closure;

[0273] This involves encapsulating multiple oral solid dosage forms of drugs in a container and sealing it with a sealing closure; and

[0274] Wherein, after the oral solid dosage form of the drug 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%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug.

[0275] 46. ​​A packaged oral solid dosage form of medicine pursuant to Clause 45, wherein the oral solid dosage form of medicine has the composition pursuant to any one of Clauses 2 to 15.

[0276] 47. A packaged oral solid dosage form of medicine, comprising:

[0277] Oral solid dosage forms of medicines, by weight, include:

[0278] The substance contains at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%.

[0279] Lactose monohydrate, approximately 34% to approximately 51%,

[0280] Approximately 20% to 30% microcrystalline cellulose, and

[0281] Colloidal silica of approximately 1% to approximately 5%; and

[0282] A container closure system, comprising a container and a sealing closure;

[0283] This involves encapsulating multiple oral solid dosage forms of drugs in a container and sealing it with a sealing closure; and

[0284] Wherein, after the oral solid dosage form of the drug 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%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug.

[0285] 48. A packaged oral solid dosage form of medicine pursuant to Clause 47, wherein the oral solid dosage form of medicine has the composition pursuant to any one of Clauses 2 to 15.

[0286] 49. A packaged oral solid dosage form of medicine, comprising:

[0287] Oral solid dosage forms of medicines, by weight, include:

[0288] The substance contains at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%.

[0289] Lactose monohydrate, approximately 34% to approximately 51%,

[0290] Approximately 20% to 30% microcrystalline cellulose, and

[0291] Colloidal silica of approximately 1% to approximately 5%; and

[0292] A container closure system, comprising a container and a sealing closure;

[0293] This involves encapsulating multiple oral solid dosage forms of drugs in a container and sealing it with a sealing closure; and

[0294] Wherein, after the oral solid dosage form of the drug 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%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug.

[0295] 50. A packaged oral solid dosage form of medicine pursuant to Clause 49, wherein the oral solid dosage form of medicine has the composition pursuant to any one of Clauses 2 to 15.

[0296] 51. A treatment method for treating animal seizures, the method comprising administering an oral solid dosage form of a drug to the animal in need, wherein the oral solid dosage form of the drug comprises, by weight:

[0297] At least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%;

[0298] Lactose monohydrate comprises approximately 34% to approximately 51%;

[0299] Approximately 20% to 30% microcrystalline cellulose; and

[0300] Colloidal silica, approximately 1% to approximately 5%.

[0301] 52. A treatment for treating seizures in animals, comprising administering to an animal in need an oral solid dosage form of a drug according to any one of clauses 1 to 36.

[0302] 53. The method according to either clause 51 or clause 52, wherein the animal is a canine.

[0303] 54. The method according to any one of clauses 51 to 53, wherein the animal suffers from idiopathic epilepsy.

Claims

1. An oral solid dosage form of a drug, comprising, by weight: At least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%; Lactose monohydrate comprises approximately 34% to approximately 51%; Approximately 20% to 30% microcrystalline cellulose; and Colloidal silica, approximately 1% to approximately 5%.

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

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

4. The oral solid dosage form of the drug according to any one of claims 1 to 3, comprising about 38% to about 47% by weight of lactose monohydrate.

5. The oral solid dosage form of the drug according to any one of claims 1 to 4, comprising about 41% to about 45% by weight of lactose monohydrate.

6. The oral solid dosage form of the drug according to any one of claims 1 to 5, comprising about 22.5% to about 27.5% by weight of microcrystalline cellulose.

7. The oral solid dosage form of the drug according to any one of claims 1 to 6, comprising about 24% to about 26% by weight of microcrystalline cellulose.

8. The oral solid dosage form of the drug according to any one of claims 1 to 7, comprising about 1% to about 3% by weight of colloidal silica.

9. The oral solid dosage form of the drug according to any one of claims 1 to 8, comprising about 1.2% to about 1.8% colloidal silica by weight.

10. The oral solid dosage form of a drug according to any one of claims 1 to 9, comprising, by weight: At least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 24% to about 30%; Lactose monohydrate comprises approximately 38% to approximately 47%; Microcrystalline cellulose, approximately 22.5% to approximately 27.5%; and Colloidal silica, approximately 1% to approximately 3%.

11. The oral solid dosage form of the drug according to any one of claims 1 to 10 further comprises sodium glycolate starch.

12. The oral solid dosage form of the drug according to any one of claims 1 to 11 further comprises about 1.5% to about 5% by weight of sodium glycolate starch.

13. The oral solid dosage form of the drug according to any one of claims 1 to 12 further comprises about 2.2% to about 3.4% by weight of sodium glycolate starch.

14. The oral solid dosage form of the drug according to any one of claims 1 to 13 further comprises at least one lubricant selected from calcium stearate and magnesium stearate.

15. The oral solid dosage form of the drug according to claim 14, comprising, by weight: At least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 24% to about 30%; Lactose monohydrate comprises approximately 38% to approximately 47%; Microcrystalline cellulose, approximately 22.5% to approximately 27.5%; Sodium glycolate starch, approximately 1.5% to approximately 5%; Colloidal silica of approximately 1% to approximately 3%; and Magnesium stearate, approximately 0.5% to approximately 2.0%.

16. The oral solid dosage form of a drug according to any one of claims 1 to 15, wherein after the oral solid dosage form of the drug 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%, the total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug is at least 90%, at least 92%, at least 95%, or at least 97% of the original total content of phenobarbital and phenobarbital salt.

17. The oral solid dosage form of a drug according to any one of claims 1 to 15, wherein after the oral solid dosage form of the drug 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%, the total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug is at least 90%, at least 92%, at least 95%, or at least 97% of the original total content of phenobarbital and phenobarbital salt.

18. The oral solid dosage form of a drug according to any one of claims 1 to 15, wherein after the oral solid dosage form of the drug 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%, the total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug is at least 90%, at least 92%, at least 95%, or at least 97% of the original total content of phenobarbital and phenobarbital salt.

19. The oral solid dosage form of a drug according to any one of claims 1 to 15, wherein after the oral solid dosage form of the drug 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%, the total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug is at least 90%, at least 92%, at least 95%, or at least 97% of the original total content of phenobarbital and phenobarbital salt.

20. The oral solid dosage form of a drug according to any one of claims 1 to 15, wherein after the oral solid dosage form of the drug 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%, the total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug is at least 90%, at least 92%, at least 95%, or at least 97% of the original total content of phenobarbital and phenobarbital salt.

21. The oral solid dosage form of a drug according to any one of claims 1 to 15, wherein after the oral solid dosage form of the drug 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%, the total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug is at least 90%, at least 92%, at least 95%, or at least 97% of the original total content of phenobarbital and phenobarbital salt.

22. The oral solid dosage form of a drug according to any one of claims 1 to 15, wherein after the oral solid dosage form of the drug 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%, the total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug is at least 90%, at least 92%, at least 95%, or at least 97% of the original total content of phenobarbital and phenobarbital salt.

23. The oral solid dosage form of a drug according to any one of claims 1 to 15, wherein when a plurality of the oral solid dosage forms are placed in a container sealed with a closure, after the oral solid dosage forms have 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%, each oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form.

24. The oral solid dosage form of a drug according to any one of claims 1 to 15, wherein when a plurality of the oral solid dosage forms are placed in a container sealed with a closure, after the oral solid dosage forms have 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%, each oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form.

25. The oral solid dosage form of a drug according to any one of claims 1 to 15, wherein when a plurality of the oral solid dosage forms are placed in a container sealed with a closure, after the oral solid dosage forms have been stored at a temperature of about 23°C to about 27°C and a relative humidity of about 55% to about 65% for 36 months, each oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form.

26. The oral solid dosage form of a drug according to any one of claims 1 to 15, wherein when a plurality of the oral solid dosage forms are placed in a container sealed with a closure, after the oral solid dosage forms have 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%, each oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form.

27. The oral solid dosage form of a drug according to any one of claims 1 to 15, wherein when a plurality of the oral solid dosage forms are placed in a container sealed with a closure, after the oral solid dosage forms have 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%, each oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form.

28. The oral solid dosage form of a drug according to any one of claims 1 to 15, wherein when a plurality of the oral solid dosage forms are placed in a container sealed with a closure, after the oral solid dosage forms have 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%, each oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form.

29. The oral solid dosage form of a drug according to any one of claims 1 to 15, wherein when a plurality of the oral solid dosage forms are placed in a container sealed with a closure, after the oral solid dosage forms have 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%, each oral solid dosage form retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form.

30. The oral solid dosage form of a drug according to any one of claims 23 to 29, wherein the container comprises about 50 cm³. 3 Approximately 70cm 3 The internal volume.

31. The oral solid dosage form of a drug according to any one of claims 23 to 29, wherein the container comprises about 110 cm³. 3 Approximately 130cm 3 The internal volume.

32. The oral solid dosage form of a drug according to any one of claims 23 to 29, wherein the container comprises about 180 cm³. 3 Approximately 220cm 3 The internal volume.

33. The oral solid dosage form of a drug according to any one of claims 23 to 29, wherein the container comprises approximately 360 cm³. 3 Approximately 440cm 3 The internal volume.

34. The oral solid dosage form of a drug according to any one of claims 23 to 29, wherein the container comprises approximately 575 cm³. 3 Approximately 675cm 3 The internal volume.

35. The oral solid dosage form of a drug according to claim 30 or 31, wherein about 90 to about 110 of the oral solid dosage forms of the drug are arranged in the container.

36. The oral solid dosage form of a drug according to any one of claims 31 to 34, wherein about 900 to about 1,100 of the oral solid dosage forms of the drug are arranged in the container.

37. A packaged oral solid dosage form of medicine, comprising: Oral solid dosage forms of medicines, wherein the oral solid dosage forms of medicines comprise, by weight: At least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%; Lactose monohydrate, approximately 34% to approximately 51%, Approximately 20% to 30% microcrystalline cellulose, and Colloidal silica of approximately 1% to approximately 5%; and A container closure system, comprising a container and a sealing closure; The plurality of said oral solid dosage forms of the drug are encapsulated in the container and sealed using the said sealing closure; and Wherein, after the oral solid dosage form of the drug 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%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug.

38. The packaged oral solid dosage form of a drug according to claim 37, wherein the oral solid dosage form of the drug has the composition of any one of claims 2 to 15.

39. A packaged oral solid dosage form of medicine, comprising: Oral solid dosage forms of medicines, wherein the oral solid dosage forms of medicines comprise, by weight: The substance contains at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%. Lactose monohydrate, approximately 34% to approximately 51%, Approximately 20% to 30% microcrystalline cellulose, and Colloidal silica of approximately 1% to approximately 5%; and A container closure system, comprising a container and a sealing closure; The plurality of said oral solid dosage forms of the drug are encapsulated in the container and sealed using the said sealing closure; and Wherein, after the oral solid dosage form of the drug 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%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug.

40. The packaged oral solid dosage form of a drug according to claim 39, wherein the oral solid dosage form of the drug has the composition of any one of claims 2 to 15.

41. A packaged oral solid dosage form of medicine, comprising: Oral solid dosage forms of medicines, wherein the oral solid dosage forms of medicines comprise, by weight: The substance contains at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%. Lactose monohydrate, approximately 34% to approximately 51%, Approximately 20% to 30% microcrystalline cellulose, and Colloidal silica of approximately 1% to approximately 5%; and A container closure system, comprising a container and a sealing closure; The plurality of said oral solid dosage forms of the drug are encapsulated in the container and sealed using the said sealing closure; and Wherein, after the oral solid dosage form of the drug 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%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug.

42. The packaged oral solid dosage form of a drug according to claim 41, wherein the oral solid dosage form of the drug has the composition of any one of claims 2 to 15.

43. A packaged oral solid dosage form of medicine, comprising: Oral solid dosage forms of medicines, wherein the oral solid dosage forms of medicines comprise, by weight: The substance contains at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%. Lactose monohydrate, approximately 34% to approximately 51%, Approximately 20% to 30% microcrystalline cellulose, and Colloidal silica of approximately 1% to approximately 5%; and A container closure system, comprising a container and a sealing closure; The plurality of said oral solid dosage forms of the drug are encapsulated in the container and sealed using the said sealing closure; and Wherein, after the oral solid dosage form of the drug 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%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug.

44. The packaged oral solid dosage form of a drug according to claim 43, wherein the oral solid dosage form of the drug has the composition of any one of claims 2 to 15.

45. A packaged oral solid dosage form of medicine, comprising: Oral solid dosage forms of medicines, wherein the oral solid dosage forms of medicines comprise, by weight: The substance contains at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%. Lactose monohydrate, approximately 34% to approximately 51%, Approximately 20% to 30% microcrystalline cellulose, and Colloidal silica of approximately 1% to approximately 5%; and A container closure system, comprising a container and a sealing closure; The plurality of said oral solid dosage forms of the drug are encapsulated in the container and sealed using the said sealing closure; and Wherein, after the oral solid dosage form of the drug 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%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug.

46. ​​The packaged oral solid dosage form of a drug according to claim 45, wherein the oral solid dosage form of the drug has the composition of any one of claims 2 to 15.

47. A packaged oral solid dosage form of medicine, comprising: Oral solid dosage forms of medicines, wherein the oral solid dosage forms of medicines comprise, by weight: The substance contains at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%. Lactose monohydrate, approximately 34% to approximately 51%, Approximately 20% to 30% microcrystalline cellulose, and Colloidal silica of approximately 1% to approximately 5%; and A container closure system, comprising a container and a sealing closure; The plurality of said oral solid dosage forms of the drug are encapsulated in the container and sealed using the said sealing closure; and Wherein, after the oral solid dosage form of the drug 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%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug.

48. The packaged oral solid dosage form of a drug according to claim 47, wherein the oral solid dosage form of the drug has the composition of any one of claims 2 to 15.

49. A packaged oral solid dosage form of medicine, comprising: Oral solid dosage forms of medicines, wherein the oral solid dosage forms of medicines comprise, by weight: The substance contains at least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%. Lactose monohydrate, approximately 34% to approximately 51%, Approximately 20% to 30% microcrystalline cellulose, and Colloidal silica of approximately 1% to approximately 5%; and A container closure system, comprising a container and a sealing closure; The plurality of said oral solid dosage forms of the drug are encapsulated in the container and sealed using the said sealing closure; and Wherein, after the oral solid dosage form of the drug 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%, each oral solid dosage form of the drug encapsulated in the container retains at least 90%, at least 92%, at least 95%, or at least 97% of the initial total content of phenobarbital and phenobarbital salt in the oral solid dosage form of the drug.

50. The packaged oral solid dosage form of a pharmaceutical product according to claim 49, wherein the oral solid dosage form of the pharmaceutical product has the composition of any one of claims 2 to 15.

51. A treatment method for treating animal seizures, the method comprising administering an oral solid dosage form of a drug to an animal in need, wherein the oral solid dosage form comprises, by weight: At least one of phenobarbital and phenobarbital salts, wherein the total content of phenobarbital and phenobarbital salts is from about 21% to about 33%; Lactose monohydrate comprises approximately 34% to approximately 51%; Approximately 20% to 30% microcrystalline cellulose; and Colloidal silica, approximately 1% to approximately 5%.

52. A treatment method for treating animal seizures, the method comprising administering to an animal in need an oral solid dosage form of any one of claims 1 to 36.

53. The method according to claim 51 or 52, wherein the animal is a canine.

54. The method according to any one of claims 51 to 53, wherein the animal suffers from idiopathic epilepsy.

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