Suppository capsule

Abstract

A suppository is disclosed that includes a suppository base. The suppository may have a length relative to a horizontal axis that is greater than its width relative to a vertical axis. The suppository may have a proximal end and a distal end along the horizontal axis. The proximal end may be adapted for insertion into a body cavity. The distal end may have at least one recess, for example, adapted to be gripped during manual insertion of the suppository into a body cavity.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 928,679, filed October 31, 2019, which is incorporated herein by reference in its entirety.

[0002] The present invention relates to suppository capsules, particularly softgel suppository capsules, methods for their preparation, and methods for their use. [Background technology]

[0003] Suppositories are commonly shaped, such as bullets, tampons, ovals, ovals, teardrops, and torpedoes. Regardless of their shape, suppositories can be difficult to handle and / or administer. With some shapes, the direction in which the suppository should be inserted may be unclear. In some cases, certain shapes may easily fall out of the patient's hand, making handling and / or administration difficult. These challenges may be partially resolved by providing instructions on handling and / or administration. Nevertheless, producing user-friendly suppositories with regard to handling and / or administration methods could benefit the existing suppository market. Summary of the Invention

[0004] The present disclosure may be directed to a suppository comprising a suppository base. The suppository may have a length measured along a horizontal axis that is greater than a diameter measured along a vertical axis. The suppository may have a proximal end and a distal end along the horizontal axis. The proximal end of the suppository may be adapted for insertion into a body cavity of a subject. The distal end of the suppository may have at least one recess.

[0005] The suppository may be a softgel suppository capsule having at least one "easy grip" depression to facilitate handling and / or administration of the suppository. The depression suppository shapes described herein may be implemented in any suppository shape, including, but not limited to, a depression bullet, a depression oval, a depression oval, a depression teardrop, or a depression torpedo. The at least one depression may be, but is not limited to, flat, concave, or perforated.

[0006] The suppositories described herein may contain an active agent. In some embodiments, the suppository may have a core and shell structure, and the active agent may be present only in the core, only in the shell, or in both the core and the shell. In certain embodiments, the active agent may be dispersed throughout the suppository. In certain embodiments, the active agent may not be dispersed in at least a portion of the suppository (e.g., at least the distal portion of the suppository).

[0007] Certain embodiments of the present disclosure may be directed to a method for preparing any of the recessed suppository capsules described herein. The method may include encapsulating (e.g., via rotary die stamping) a liquid core containing a suppository base into a shell (e.g., a gelatin shell). The method may also include immersing a solid core containing a suppository base into a liquid shell composition (e.g., a gelatin shell composition).

[0008] Certain embodiments of the present disclosure may be directed to methods of treating diseases or conditions such as, but not limited to, pain, migraine, inflammation, fungal infection, bacterial infection, viral infection, vaginal pain, menopause, vulvar and vaginal atrophy, cancer, nausea, vomiting, or a combination thereof. The method may include inserting any of the recessed suppositories described herein into a body cavity such as, but not limited to, the rectum, vagina, or urethra.

[0009] The above and other features of the present disclosure, its nature and various advantages will become more apparent from a consideration of the following detailed description taken in conjunction with the accompanying drawings. [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 is a perspective view of a suppository capsule according to a first embodiment. [Figure 2] FIG. 1 is a top plan view of the first embodiment. [Figure 3] FIG. 2 is a bottom plan view of the first embodiment. [Figure 4] FIG. 2 is a left side view of the first embodiment. [Figure 5] FIG. 2 is a right side view of the first embodiment. [Figure 6] FIG. 1 is a rear view of the distal end of the first embodiment. [Figure 7] FIG. 1 is a front view of the proximal end of the first embodiment. [Figure 8] FIG. 10 is a perspective view of a suppository capsule according to a second embodiment. [Figure 9] FIG. 10 is a top plan view of the second embodiment. [Figure 10] FIG. 10 is a bottom plan view of the second embodiment. [Figure 11] FIG. 10 is a left side view of the second embodiment. [Figure 12] FIG. 10 is a right side view of the second embodiment. [Figure 13] FIG. 10 is a rear view of the distal end of the second embodiment. [Figure 14] FIG. 10 is a front view of the proximal end of the second embodiment. [Figure 15] FIG. 10 is a perspective view of a suppository capsule according to a third embodiment. [Figure 16] FIG. 10 is a top plan view of the third embodiment. [Figure 17] FIG. 10 is a bottom plan view of the third embodiment. [Figure 18] FIG. 10 is a left side view of the third embodiment. [Figure 19] FIG. 10 is a right side view of the third embodiment. [Figure 20] FIG. 10 is a rear view of the distal end of the third embodiment. [Figure 21] FIG. 10 is a front view of the proximal end of the third embodiment. [Figure 22]FIG. 10 is a perspective view of a suppository capsule according to a fourth embodiment. [Figure 23] FIG. 10 is a top plan view of the fourth embodiment. [Figure 24] FIG. 10 is a bottom plan view of the fourth embodiment. [Figure 25] FIG. 10 is a left side view of the fourth embodiment. [Figure 26] FIG. 10 is a right side view of the fourth embodiment. [Figure 27] FIG. 10 is a rear view of the distal end of the fourth embodiment. [Figure 28] FIG. 10 is a front view of the proximal end of the fourth embodiment. [Figure 29] FIG. 10 is a perspective view of a suppository capsule according to a fifth embodiment. [Figure 30] FIG. 10 is a top plan view of the fifth embodiment. [Figure 31] FIG. 10 is a bottom plan view of the fifth embodiment. [Figure 32] FIG. 10 is a left side view of the fifth embodiment. [Figure 33] FIG. 10 is a right side view of the fifth embodiment. [Figure 34] FIG. 10 is a rear view of the distal end of the fifth embodiment. [Figure 35] FIG. 10 is a front view of the proximal end of the fifth embodiment.

[0011] definition As used herein, "active agent," "pharmaceutical active ingredient," refers to any substance intended to produce a therapeutic, prophylactic, or other intended effect and used in the diagnosis, cure, mitigation, treatment, or prevention of a condition, whether or not approved for that purpose by a governmental agency. These terms, with respect to a particular agent, include all pharmaceutically active agents, all pharmaceutically acceptable salts, stereoisomers, crystalline forms, co-crystals, ethers, esters, hydrates, solvates, and mixtures thereof, in which the form is pharmaceutically active.

[0012] The terms "treatment of" and "treating" include administering an active agent with the intent of reducing the severity of or preventing a condition.

[0013] The terms "prevention of" and "preventing" include avoiding the onset of a condition.

[0014] The term "condition" or "conditions" refers to those medical conditions that can be treated, alleviated, or prevented by administering an effective amount of an active agent to a subject. Exemplary non-limiting conditions that can benefit from the suppository capsules described herein can include, but are not limited to, pain, migraine, inflammation, fungal infection, bacterial infection, viral infection, vaginal pain, menopausal symptoms, vulvar and vaginal atrophy, cancer, nausea, or vomiting.

[0015] The suppository capsules of the present disclosure may contain various active agents and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc.; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate, etc.; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; amino acid salts such as alginate, aspartate, glutamate, etc., and metal salts such as sodium salt, potassium salt, cesium salt, etc.; alkaline earth metal salts such as calcium salt, magnesium salt, etc.; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.

[0016] An "effective amount" or "therapeutically effective amount" refers to the amount of an active agent in a pharmaceutical composition (e.g., a suppository capsule) sufficient to produce a beneficial or desired effect at a level readily detectable by methods commonly used to detect that effect. In some embodiments, such an effect results in at least a 10% change from basal levels when the active agent is not administered. In other embodiments, the change is at least 20%, 50%, 80%, or even higher from basal levels. As discussed below, the effective amount of an active agent may vary from subject to subject, depending on the age, the subject's general condition, the severity of the condition being treated, the particular active agent being administered, and the like. An appropriate "effective" amount in a particular case can be determined by one of ordinary skill in the art by reference to relevant texts and literature and / or by routine experimentation.

[0017] As used herein, "shell" or "shell composition" refers to the component of a softgel suppository capsule that encapsulates the suppository base.

[0018] As used herein, "suppository base" refers to a pharmaceutically acceptable substance suitable for use as a suppository delivery system.

[0019] As used herein, "patient" refers to a subject, particularly a human (but can include non-humans), who is exhibiting the clinical manifestation of a particular symptom or symptoms indicating the need for treatment, is being treated prophylactically for a condition, or has been diagnosed with a condition to be treated.

[0020] The term "subject" encompasses the definition of the term "patient" and does not exclude otherwise healthy individuals.

[0021] The terms "suppository," "suppository capsule," and "dosage form" may all be used interchangeably throughout this specification.

[0022] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to an "active agent" includes a single active agent and mixtures of two or more different active agents, reference to a "state" includes a single state and mixtures of two or more different states, etc.

[0023] As used herein, the term "about" in connection with a measurand refers to the normal variation in that measurand that would be expected when one of ordinary skill in the art makes the measurement and exercises a level of care commensurate with the purpose of the measurement and the precision of the measurement device. In certain embodiments, the term "about" includes the recited number ±10%, such that "about 10" would include 9 to 11.

[0024] The term "at least about," in reference to a measurand, refers to normal variations in the measurand that would be expected when one of ordinary skill in the art makes a measurement and exercises a level of care commensurate with the purpose of the measurement and the precision of the measurement device, and any amount greater than that. In certain embodiments, the term "at least about" includes the recited number minus 10%, and any amount greater, such that "at least about 10" would include 9 and greater than 9. The term can also be expressed as "about 10 or greater." Similarly, the term "less than about" includes the recited number plus 10%, and any amount less, such that "less than about 10" would include 11 and less than 11. The term can also be expressed as "about 10 or less."

[0025] Unless otherwise indicated herein, the recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, with each separate value being incorporated herein as if it were individually recited herein. Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order.

[0026] The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to clarify certain materials and methods and does not pose a limitation on scope. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosed materials and methods. DETAILED DESCRIPTION OF THE INVENTION

[0027] The present disclosure may be directed to suppository dosage forms designed with at least one indentation that allows for grasping and / or administering the dosage form with one or two fingers. The indentation may also aid in administering the dosage form, for example, by providing clear direction for inserting the suppository. The indentation may be ergonomically designed to allow for comfortable grasping and efficient insertion of the suppository. The indentation may also be shaped to prevent the suppository from slipping or slipping out of the body cavity.

[0028] The depression can be applied to existing suppository shapes (e.g., bullet, tampon, oval, egg, teardrop, torpedo, etc.) by modifying a portion (e.g., one end) of the dosage form's shape. In some embodiments, the gripping portion of the suppository capsule described herein may have at least a portion of the active agent present therein. In other embodiments, the gripping portion of the suppository capsule described herein may not include an active agent.

[0029] An exemplary recessed suppository capsule is described in detail below with reference to the figures.

[0030] FIG. 1 shows a perspective view of a suppository capsule according to a first embodiment. FIG. 2 shows a top plan view of a suppository according to the embodiment of FIG. 1. FIG. 3 shows a bottom plan view of a suppository according to the embodiment of FIG. 1. FIG. 4 shows a left side view of the embodiment of FIG. 1. FIG. 5 shows a right side view of the embodiment of FIG. 1. As shown in FIGS. 1-5, the suppository capsule 100 may have a concave bullet shape, such that the proximal end 160 has a conventional bullet shape and the distal end 170 has at least one concave. It should be understood that the bullet shape depicted in FIGS. 1-5 (the cylindrical portion of the suppository's proximal end 160 terminating in a dome or cone) is merely exemplary and non-limiting. For example, the dome- or cone-shaped ending may be more rounded or pointed than depicted in the embodiment. The cylindrical portion of the bullet-shaped proximal end may be a cylinder with a constant diameter throughout the length of the cylinder, as shown in FIGS. 1-5. Alternatively, the diameter or width of the cylinder may widen or narrow throughout the length of the suppository (as shown in the indented teardrop embodiment described hereinbelow, or as shown in the indented oval embodiment described hereinbelow).

[0031] In embodiments, the insertion direction of the suppositories described herein into a body cavity can be easily ascertained due to the distinct shapes of the proximal and distal ends of the suppository: the proximal end (e.g., 160), which has a traditional suppository shape, is designed to be inserted into the body cavity first, and the distal end (e.g., 170) is designed to be grasped for manual insertion into the body cavity.

[0032] As shown in FIGS. 4 and 5, the suppository capsule 100 can have a length 110 measured along a horizontal axis X and a width 120 measured along a vertical axis Y. The horizontal axis X and the vertical axis Y are shown in FIGS. 4 and 5. In the embodiment shown in FIGS. 4 and 5, the width 120 also corresponds to the diameter of the suppository capsule at the cylindrical portion of the bullet-shaped end of the suppository capsule. The length (e.g., 110) of the suppository is defined as the longest portion of the suppository measured along its horizontal axis X. The width (e.g., 120) of the suppository is defined as the widest portion of the suppository measured along its vertical axis Y. For the first embodiment, the width of the suppository is shown as the numeral 120 in FIGS. 4 and 5. In the first embodiment, the width 120 of the suppository also corresponds to the diameter of the cylindrical portion of the bullet-shaped proximal end.

[0033] The length of a suppository capsule, measured along its horizontal axis X, may vary at different positions along the vertical axis Y, depending on the shape of the suppository capsule. In certain embodiments, the center of the suppository along the vertical Y axis is the longest horizontal portion or dimension of the suppository. Thus, in certain embodiments, the length of the suppository is the length of the center of the suppository along the vertical Y axis. In certain embodiments, the horizontal length of the suppository tapers (or shortens) as it moves away from the center of the suppository along the vertical Y axis toward the edges of the suppository. For example, Figures 1-5 depict a concave, bullet-shaped suppository capsule according to a first embodiment. In such an embodiment, the horizontal length of the suppository capsule may be shortest at edges 130 and 140 (the edges of the suppository capsule along the vertical axis Y when viewed from the left side view shown in Figure 4 and the right side view shown in Figure 5) and gradually increase until the longest horizontal length 110 reaches the center of the suppository capsule 150 (the center of the suppository capsule along the vertical axis Y as shown in Figures 4 and 5).

[0034] In certain embodiments, the horizontal length 110 of the suppository capsule can range from about 10 mm to about 50 mm, from about 12 mm to about 45 mm, from about 15 mm to about 40 mm, or from about 20 mm to about 35 mm. These dimensions are merely exemplary and should not be construed as limiting.

[0035] The width of the suppository, measured along its vertical axis Y, may also vary at different locations along the horizontal axis X, depending on the shape of the suppository capsule. For example, the suppository of the first embodiment may have one width at the proximal end 160 of the suppository and another width at the distal end 170 of the suppository. The suppository capsule may have a proximal end 160 at one end of the horizontal axis X and a distal end 170 at the opposite end of the horizontal axis X. The proximal end 160 may be adapted for insertion into a body cavity. For example, the proximal end 160 may have a conventional suppository shape, such as, but not limited to, a bullet, oval, egg, teardrop, torpedo, etc. The distal end 170 may have at least one recess 180 that may be adapted to grip the suppository capsule for easy handling and / or administration.

[0036] In embodiments, the suppository capsule length 110 is comprised of the length of the portion of the suppository having a conventional suppository shape (i.e., the length of the bullet shape) plus the length of the portion of the suppository having a depression. The length of the portion of the suppository having a conventional suppository shape is shown in Figures 4 and 5 as length 112. The length of the portion of the suppository having at least one depression is shown in Figures 4 and 5 as length 115. Lengths 112 and 115 may be combined to form length 110. Length 112 (i.e., the length of the conventional suppository shape portion) and length 115 (the length of the portion with the depression) may be separated by a boundary line 190.

[0037] In certain embodiments, the ratio of length 112 to length 115 can be in the range of about 10:1 to about 1:10, about 8:1 to about 1:8, about 5:1 to about 1:5, about 3:1 to about 1:3, about 2:1 to about 1:2, about 10:1 to about 1:1, about 8:1 to about 1:1, about 5:1 to about 1:1, about 3:1 to about 1:1, about 2:1 to about 1:1, about 1:1 to about 1:2, about 1:1 to about 1:3, about 1:1 to about 1:5, about 1:1 to about 1:8, or about 1:1 to about 1:10. These dimensions are merely exemplary and should not be construed as limiting.

[0038] In some embodiments, the dividing line 190 between the proximal end 160 and the distal end 170 may be the widest part of the suppository to minimize the possibility of the suppository being expelled from the body cavity. In some embodiments, the widest part of the suppository may be along the length 112 (i.e., on the portion of the suppository that has a traditional suppository shape). In some embodiments, the widest part of the suppository may be along the length 115 (i.e., on the portion of the suppository that has at least one depression).

[0039] The width of the suppository capsule (e.g., 120) can range from about 1 mm to about 30 mm, from about 2 mm to about 25 mm, from about 3 mm to about 20 mm, or from about 4 mm to about 15 mm. These dimensions are merely exemplary and should not be construed as limiting.

[0040] In certain embodiments, the at least one depression may be flat. In other embodiments, the at least one depression may be concave (i.e., curved inward) so as to be ergonomically adapted for gripping by at least one finger. In still other embodiments, the at least one depression may be perforated and may optionally have a hole (e.g., a donut hole). In certain embodiments, the at least one depression may be adapted to be gripped by two fingers or by a device for easy gripping and insertion into a body cavity.

[0041] In one embodiment, distal end 170 may have two recesses 180A and 180B, as shown in the rear view (FIG. 6) of the suppository capsule according to the embodiment of FIGS. 1-5. In such an embodiment, each of the two recesses may be on opposite sides of the distal end. The shortest distance between the boundaries of the two recesses may be designated by numeral 610 in FIG. 6 and may range from 0 mm to about 30 mm, from about 1 mm to about 25 mm, from about 2 mm to about 20 mm, from about 3 mm to about 15 mm, or any number of ranges therebetween. These dimensions are merely exemplary and should not be construed as limiting.

[0042] In other embodiments, the distal end of the suppository may have one depression, three depressions, four depressions, five depressions, etc. In certain embodiments, when two or more depressions are present, the depressions may be evenly spaced around the circumference of the distal end of the suppository. In certain embodiments, when two or more depressions are present, the depressions may not be evenly spaced around the circumference of the distal end of the suppository.

[0043] Figure 6 is a rear view of the distal end 170 of a first embodiment of a suppository capsule according to Figures 1-5. Two depressions 180A and 180B on opposite sides with a minimum distance 610 between their distal end boundaries are shown in Figure 6. Figure 7 is a front view of the proximal end 160 of the first embodiment, depicting a front view of a bullet-shaped suppository with concentric circles to illustrate the dome shape associated with the bullet-shaped proximal end.

[0044] Figure 8 is a perspective view of suppository capsule 800 having a concave teardrop shape according to a second embodiment. Figure 15 is a perspective view of suppository capsule 1500 having a concave teardrop shape according to a third embodiment. Figure 22 is a perspective view of suppository capsule 2200 having a concave teardrop shape according to a fourth embodiment. Suppository capsules 800, 1500, and 2200 can each have a length measured along horizontal axis X and a width measured along vertical axis Y. The lengths of suppositories 800, 1500, and 2200, defined as the longest horizontal dimension of the suppository, are shown as lengths 810 (Figures 11-12), 1510 (Figures 18-19), and 2210 (Figures 25-26), respectively. The widths 800, 1500, and 2200 of the suppositories, defined as the widest dimension of the suppository measured along its vertical axis Y, are shown as width 820 (Figures 11-12), width 1520 (Figures 18-19), and width 2220 (Figures 25-26), respectively.

[0045] The dimensions of the suppository capsule may vary depending on the shape of the suppository capsule. For example, Figures 8-12, 15-19, and 22-26 depict various embodiments of a concave, teardrop-shaped suppository capsule. These suppositories may have a pointed, elongated proximal end 860 (Figures 8-12), 1560 (Figures 15-19), and 2260 (Figures 22-26) that gradually increases in width from the proximal end toward the distal end 870 (Figures 8-12), 1570 (Figures 15-19), and 2270 (Figures 22-26) until the widest respective widths 820, 1520, and 2220 are reached. The proximal end 860, 1560, 2260 may be adapted for insertion into a body cavity, while the distal end 870, 1570, 2270 may have at least one recess 880 (FIG. 8), 1580 (FIG. 15), 2280 (FIG. 22) that may be adapted to grip any suppository capsule for easy handling and / or administration.

[0046] The length of the suppository capsule 810, 1510, 2210 can range from about 10 mm to about 50 mm, from about 12 mm to about 45 mm, from about 15 mm to about 40 mm, or from about 20 mm to about 35 mm. These dimensions are merely illustrative and should not be construed as limiting.

[0047] In embodiments, the lengths 810, 1510, and 2210 of the suppository capsules in Figures 8-12, 15-19, and 22-26 are respectively the length of the portion of the suppository having a conventional suppository shape (i.e., the teardrop-shaped length) plus the length of the portion of the suppository having a depression. The lengths of the portion of the suppository having a teardrop-shaped suppository shape are shown as length 812 (Figures 11-12), length 1512 (Figures 18-19), and length 2215 (Figures 25-26). The lengths of the portion of the suppository having at least one depression are shown as length 815 (Figures 11-12), length 1515 (Figures 18-19), and length 2215 (Figures 25-26). Lengths 812 and 815 can be combined to form length 810. Lengths 1512 and 1515 can be combined to form length 1510. Length 2212 and length 2215 may be combined to form length 2210. Each of lengths 812, 1512, and 2212 (i.e., the lengths of the conventional suppository-shaped portions) and each of lengths 815, 1515, and 2215 (the lengths of the recessed portions) may be separated by corresponding boundary lines 890, 1590, and 2290.

[0048] The ratio of length 812 to length 815 (or the ratio of length 1512 to 1515, or the ratio of length 2212 to 2215) can be in the range of about 10:1 to about 1:10, about 8:1 to about 1:8, about 5:1 to about 1:5, about 3:1 to about 1:3, about 2:1 to about 1:2, about 10:1 to about 1:1, about 8:1 to about 1:1, about 5:1 to about 1:1, about 3:1 to about 1:1, about 2:1 to about 1:1, about 1:1 to about 1:2, about 1:1 to about 1:3, about 1:1 to about 1:5, about 1:1 to about 1:8, or about 1:1 to about 1:10. These dimensions are merely exemplary and should not be construed as limiting.

[0049] In some embodiments, boundary lines 890, 1590, and 2290 may be at the widest part of the suppository to minimize the possibility of the suppository being expelled from the body cavity. In some embodiments, the widest part of the suppository may be along length 812, 1512, or 2212 (i.e., on the portion of the suppository having a traditional suppository shape). In some embodiments, the widest part of the suppository may be along length 815, 1515, or 2215 (i.e., on the portion of the suppository having at least one depression).

[0050] The width 820, 1520, 2220 of the suppository capsule can range from about 1 mm to about 30 mm, from about 2 mm to about 25 mm, from about 3 mm to about 20 mm, or from about 4 mm to about 15 mm. These dimensions are merely exemplary and should not be construed as limiting.

[0051] In certain embodiments, at least one cavity in a concave teardrop-shaped suppository may be flat. In other embodiments, at least one cavity in a concave teardrop-shaped suppository may be concave (i.e., curved inward) so as to be ergonomically adapted for gripping by at least one finger. In still other embodiments, at least one cavity in a concave teardrop-shaped suppository may be perforated, optionally having a hole (e.g., a donut hole). In certain embodiments, at least one cavity may be adapted to be held by two fingers or by a device for easy gripping and insertion into a body cavity.

[0052] In one embodiment, distal end 870 may have two indentations 880A and 880B in Figures 11, 12, and 13. Similarly, distal end 1570 may have two indentations 1580A and 1580B in Figures 18, 19, and 20. Similarly, distal end 2270 may have two indentations 2280A and 2280B in Figures 25, 26, and 27. In such an embodiment, each of the two indentations may be on opposite sides of the distal end. The shortest distance between the boundaries of two indentations may be designated by the numeral 861 (Figures 11, 12, and 13), 1561 (Figures 18, 19, and 20), or 2261 (Figures 25, 26, and 27). The 861, 1561, or 2261 may range from 0 mm to about 30 mm, from about 1 mm to about 25 mm, from about 2 mm to about 20 mm, from about 3 mm to about 15 mm, or any number in between. These dimensions are merely examples and should not be construed as limiting.

[0053] In other embodiments, the distal end of a dimpled teardrop-shaped suppository may have one dimple, three dimples, four dimples, five dimples, etc. In certain embodiments, when two or more dimples are present, the dimples may be evenly spaced around the circumference of the distal end of the suppository. In certain embodiments, when two or more dimples are present, the dimples may not be evenly spaced around the circumference of the distal end of the suppository.

[0054] Figure 9 is a top plan view of the second embodiment. Figure 10 is a bottom plan view of the second embodiment. Figure 16 is a top plan view of the third embodiment. Figure 17 is a bottom plan view of the third embodiment. Figure 23 is a top plan view of the fourth embodiment. Figure 24 is a bottom plan view of the fourth embodiment.

[0055] As shown in Figures 9, 10, 16, 17, 23, and 24, the suppositories can have various indented teardrop shapes, such as those shown at proximal end 860 (Figures 9, 10), 1560 (Figures 16, 17), or 2260 (Figures 23, 24). As shown in Figures 9, 10, 16, 17, 23, and 24, the suppositories can also have indentations of various shapes, such as those shown at distal end 870 (Figures 9, 10), 1570 (Figures 16, 17), or 2270 (Figures 23, 24). The illustrated shapes of the proximal and distal ends should not be construed as limiting. Many suppository shapes can be achieved depending on the strength of the shell composition (e.g., the strength of the gelatin shell composition).

[0056] Figure 11 is a left side view of the second embodiment. Figure 12 is a right side view of the second embodiment. Figure 18 is a left side view of the third embodiment. Figure 19 is a right side view of the third embodiment. Figure 25 is a left side view of the fourth embodiment. Figure 26 is a right side view of the fourth embodiment. Figures 11, 12, 18, 19, 25, and 26 show various possible concave teardrop shapes of suppositories from different angles.

[0057] Figure 13 is a rear view of the distal end 870 of the second embodiment. Two indentations 880A and 880B on opposite sides with a minimum distance 861 between their distal end boundaries are shown in Figure 13. Figure 14 is a front view of the proximal end 860 of the second embodiment, depicting a front view of a teardrop-shaped suppository.

[0058] Figure 20 is a rear view of the distal end 1570 of the third embodiment. Two depressions 1580A and 1580B on opposite sides with a minimum distance 1561 between their distal end boundaries are shown in Figure 20. Figure 21 is a front view of the proximal end 1560 of the third embodiment, depicting a front view of a teardrop-shaped suppository.

[0059] Figure 27 is a rear view of the distal end 2270 of the fourth embodiment. Two indentations 2280A and 2280B on opposite sides having a minimum distance 2261 between their distal end boundaries are shown in Figure 27. Figure 28 is a front view of the proximal end 2260 of the fourth embodiment, depicting a front view of a teardrop-shaped suppository.

[0060] 29 is a perspective view of a suppository capsule 2900 having a concave oval shape according to a fifth embodiment. The suppository capsule 2900 may have a length measured along a horizontal axis X and a width measured along a vertical axis Y. The length of the suppository 2900, defined as the suppository's longest horizontal dimension and measured along its horizontal axis X, is represented as length 2910. The widest dimension of the suppository 2900, measured along its vertical axis Y, is represented as width 2920.

[0061] The dimensions of the suppository capsule can vary depending on the shape of the suppository capsule. For example, Figure 29 depicts an oval-shaped suppository capsule with a recess, according to an embodiment. The proximal end 2960 can be adapted for insertion into a body cavity, while the distal end 2970 can have at least one recess 2980 that can be adapted for gripping the suppository capsule for easy handling and / or administration.

[0062] The length 2910 of the suppository capsule can range from about 10 mm to about 50 mm, from about 12 mm to about 45 mm, from about 15 mm to about 40 mm, and from about 20 mm to about 35 mm. These dimensions are merely exemplary and should not be construed as limiting.

[0063] In embodiments, suppository capsule length 2910 is comprised of the length of the portion of the suppository having a conventional suppository shape (i.e., the length of the oval shape) plus the length of the portion of the suppository having a depression. The length of the portion of the suppository having an oval suppository shape is represented as length 2912. The length of the portion of the suppository having at least one depression is represented as length 2915. Length 2912 and length 2915 may together equal length 2910. Length 2912 (i.e., the length of the conventional suppository shape) and length 2915 (the length of the portion with the depression) may be separated by boundary line 2990.

[0064] The ratio of length 2912 to length 2915 can be in the range of about 10:1 to about 1:10, about 8:1 to about 1:8, about 5:1 to about 1:5, about 3:1 to about 1:3, about 2:1 to about 1:2, about 10:1 to about 1:1, about 8:1 to about 1:1, about 5:1 to about 1:1, about 3:1 to about 1:1, about 2:1 to about 1:1, about 1:1 to about 1:2, about 1:1 to about 1:3, about 1:1 to about 1:5, about 1:1 to about 1:8, or about 1:1 to about 1:10. These dimensions are merely exemplary and should not be construed as limiting.

[0065] In some embodiments, boundary line 2990 may be at the widest part of the suppository to minimize the possibility of the suppository being expelled from the body cavity. In some embodiments, the widest part of the suppository may be along length 2912 (i.e., on the portion of the suppository that has a traditional suppository shape). In some embodiments, the widest part of the suppository may be along length 2915 (i.e., on the portion of the suppository that has at least one depression).

[0066] For example, in FIG. 29, which depicts a concave, oval-shaped suppository according to the fifth embodiment, the widest part of the suppository is along the oval (i.e., along length 2912), which may minimize the possibility of the suppository being expelled from the body cavity.

[0067] The diameter 2920 of the suppository capsule can range from about 1 mm to about 30 mm, about 2 mm to about 25 mm, about 3 mm to about 20 mm, or about 4 mm to about 15 mm. These dimensions are merely exemplary and should not be construed as limiting.

[0068] In certain embodiments, at least one depression in a concave oval suppository may be flat. In other embodiments, at least one depression in a concave oval suppository may be concave (i.e., curved inward) so as to be ergonomically adapted for gripping by at least one finger. In still other embodiments, at least one depression in a concave oval suppository may be perforated, optionally having a hole (e.g., a donut hole). In certain embodiments, at least one depression may be adapted to be held by two fingers or by a device for easy gripping and insertion into a body cavity.

[0069] In one embodiment, distal end 2970 may have two indentations 2980A and 2980B in Figures 32, 33, and 34. In such an embodiment, each of the two indentations may be on opposite sides of the distal end. The shortest distance between the boundaries of the two indentations may be designated by numeral 2961. Distance 2961 may range from 0 mm to about 30 mm, from about 1 mm to about 25 mm, from about 2 mm to about 20 mm, from about 3 mm to about 15 mm, or any number of ranges therebetween. These dimensions are merely exemplary and should not be construed as limiting.

[0070] In other embodiments, the distal end of a dimpled teardrop-shaped suppository may have one dimple, three dimples, four dimples, five dimples, etc. In certain embodiments, when two or more dimples are present, the dimples may be evenly spaced around the circumference of the distal end of the suppository. In certain embodiments, when two or more dimples are present, the dimples may not be evenly spaced around the circumference of the distal end of the suppository.

[0071] Figure 30 is a top plan view of the fifth embodiment. Figure 31 is a bottom plan view of the fifth embodiment. As shown in Figures 30 and 31, the suppository can have an indented oval shape, such that the proximal end 2960 has an oval shape and the distal end 2970 has at least one indentation.

[0072] Figure 32 is a left side view of the fifth embodiment. Figure 33 is a right side view of the fifth embodiment. Figures 32 and 33 also show the concave oval shape of the suppository from different angles.

[0073] Figure 34 is a rear view of the distal end 2970 of the fifth embodiment. Two indentations 2980A and 2980B on opposite sides having a minimum distance 2961 between their distal end boundaries are shown in Figure 34. Figure 35 is a front view of the proximal end 2960 of the fifth embodiment, depicting a front view of an oval-shaped suppository.

[0074] While the suppository shapes depicted in the figures are a concave bullet, three various concave teardrop shapes, and a concave oval, other concave suppository capsule shapes are also encompassed herein. For example, the present disclosure may encompass shapes such as, but not limited to, a concave bullet, a concave tampon, a concave oval (e.g., a concave oval or a concave round oval), a concave oval, a concave teardrop, a concave torpedo, etc.

[0075] The suppository capsule may contain a suppository base that may be sufficiently sturdy to allow for the construction of the recessed suppository shapes described herein. The suppository base may include, but is not limited to, one or more of cocoa butter, lauric fat, beef tallow, hard fat, theobroma oil, glycerides of fatty acids, glycerol-gelatin bases, or combinations thereof. The suppository base may be in liquid or solid form. In one embodiment, the suppository base may be in solid form at ambient temperature outside the body and have a melting point at body core temperature (e.g., about 30°C to about 45°C, about 33°C to about 42°C, about 35°C to about 40°C, or about 37°C) so that it can melt to a liquid form upon insertion of the suppository into a body cavity.

[0076] A suppository may encapsulate a suppository base (e.g., in a core and shell configuration). The suppository base may contain an active agent. In certain embodiments, the active agent may be dispersed entirely throughout the suppository base. In other embodiments, the active agent may be dispersed in a specific portion of the suppository base, or may not be dispersed entirely throughout the suppository base. For example, in some embodiments, the active agent may not be dispersed entirely throughout the suppository base in at least a portion of the distal end of the suppository capsule, such as in the area of ​​at least one depression for easy gripping of the suppository.

[0077] Core and Shell Formulation In certain embodiments, the suppository capsule may have a core and shell structure, and the active agent may be contained only in the core, only in the shell, or in both the core and the shell. In one embodiment, the active agent may be contained only in the core. In one embodiment, the active agent may be contained only in the shell. In one embodiment, the active agent may be contained in both the core and the shell. Regardless of where the active agent is contained (core, shell, or both), the active agent may be dispersed throughout or may not be dispersed in at least a portion (e.g., distal portions of the core, shell, or both).

[0078] In one embodiment, the distal portion of the suppository may be free of active agent, such that at least one depression may be flat and form a flat "gripping area." In other embodiments, the active agent may be dispersed throughout the suppository (including at least one depression at the distal end of the suppository), such that at least one depression may form a concave "gripping area." These embodiments are merely exemplary, as the shape of any "gripping area" or depression may be designed to accommodate active agent dispersed throughout the suppository or dispersed only in a portion of the suppository (e.g., when the distal end of the suppository does not contain active agent).

[0079] In certain embodiments, the shell may be sturdy enough to allow for at least one depression in the distal portion of the suppository (for "easy grip") and a conventional suppository shape in the proximal portion of the suppository. In some embodiments, the core (or suppository base) may be sturdy enough to allow for at least one depression in the distal portion of the suppository (for "easy grip") and a conventional suppository shape in the proximal portion of the suppository. In some embodiments, the shell may comprise at least one of, but not limited to, gelatin, starch, modified starch, carrageenan, alginate, biodegradable polymer, or a combination thereof.

[0080] In certain embodiments, the shell composition comprises gelatin. The gelatin may include, but is not limited to, Type A gelatin, Type B gelatin, or a mixture thereof. The gelatin may include, but is not limited to, fish gelatin, hide gelatin, bone gelatin, or a mixture thereof. The gelatin may be present in the shell in an amount ranging from about 40% w / w to about 80% w / w, from about 45% w / w to about 75% w / w, or from about 50% w / w to about 70% w / w, based on the total weight of the shell composition.

[0081] In certain embodiments, the shell composition comprises carrageenan. The carrageenan in the shell composition can be κ-carrageenan, ι-carrageenan, λ-carrageenan, and mixtures thereof. According to one embodiment, the carrageenan is κ-carrageenan. According to another embodiment, the carrageenan is ι-carrageenan. In one embodiment, the amount of carrageenan in the shell composition is about 2% w / w to about 10% w / w, about 2% w / w to about 8% w / w, or about 2% w / w to about 5% w / w, based on the total weight of the shell composition.

[0082] In certain embodiments, the shell composition comprises a biodegradable polymer, which may include, but is not limited to, polylactic acid (PLA), poly(ε-caprolactone) (PCL), poly(lactide-co-glycolic acid) (PLGA), or a combination thereof.

[0083] In certain embodiments, the shell may include a plasticizer, such as, but not limited to, glycerol, sorbitol, or a mixture thereof. Other suitable plasticizers may include, but are not limited to, sugar alcohol plasticizers, such as isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or polyol plasticizers, such as diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycols up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamine; and mixtures thereof. Other exemplary plasticizers may include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyls, ester-based plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single-block polymers, citrate ester-based plasticizers, and triacetin. Such plasticizers may include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate, and allyl glycolate, and mixtures thereof. The plasticizer may be present in the shell in an amount ranging from about 15% w / w to about 40% w / w, from about 20% w / w to about 35% w / w, or from about 25% w / w to about 30% w / w, based on the total weight of the shell composition.

[0084] In one embodiment, the suppository may have a core and shell structure, with the core comprising a suppository base. In certain embodiments, the core may be solid at ambient temperature and melt at body temperature (e.g., about 30°C to about 45°C, about 33°C to about 42°C, about 35°C to about 40°C, or about 37°C). In other embodiments, the core may be liquid at ambient temperature.

[0085] activator Suitable active agents that may be contained in the suppository capsules described herein may include, but are not limited to, analgesics, anti-migraine agents, anti-inflammatory agents, anti-fungals, antibiotics, anti-virals, hormones, chemotherapeutic agents, anti-nausea agents, anti-emetic agents, or combinations thereof.

[0086] Exemplary analgesic active agents may include, but are not limited to, acetaminophen and opioids. Exemplary opioids include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromamide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, heroin, hydrocodone, hydromorphone, hydrochloride, thiambutane ... These may include cypetidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretam, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propeptadine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, and combinations thereof.

[0087] Exemplary anti-migraine active agents may include, but are not limited to, ergotamine, dihydroergotamine, ergostine, butalbital, phenobarbital, sumatriptan, naratriptan, razatriptan, zolmitriptan, almotriptan, eletriptan, valproic acid, gabapentin, topiramate, divalproex, pharmaceutically acceptable salts thereof, or mixtures thereof.

[0088] Exemplary anti-inflammatory active agents may include, but are not limited to, ibuprofen, fenoprofen, naproxen, sulindac, diclofenac, piroxicam, ketoprofen, diflunisal, nabumetone, etodolac, oxaprozin, indomethacin, pharmaceutically acceptable salts thereof, or mixtures thereof.

[0089] Exemplary antifungal agents include, but are not limited to, abafungin, albaconazole, amorolfine, amphotericin b, anidulafungin, bifonazole, butenafine, butoconazole, candicidin, caspofungin, ciclopirox, clotrimazole, econazole, fenticonazole, filipin, fluconazole, flucytosine, griseofulvin, haloprogin, hamycin, isavuconazole, isoconazole, itraconazole, ketoconazole, The active ingredient may include nazole, micafungin, miconazole, naftifine, natamycin, nystatin, omoconazole, oxiconazole, poligodial, posaconazole, ravuconazole, rimocidin, sertaconazole, sulconazole, terbinafine, terconazole, tioconazole, tolnaftate, undecylenic acid, voriconazole, pharmaceutically acceptable salts thereof or mixtures thereof.

[0090] Exemplary antibiotic agents may include, but are not limited to, mitomycin, ciprofloxacin, norfloxacin, ofloxacin, methanamine, nitrofurantoin, ampicillin, amoxicillin, nafcillin, trimethoprim, the sulfa drug trimethoprim-sulfamethoxazole, erythromycin, doxycycline, metronidazole, tetracycline, kanamycin, penicillin, cephalosporins, aminoglycosides, pharmaceutically acceptable salts thereof, or mixtures thereof.

[0091] Exemplary antiviral active agents include, but are not limited to, abacavir, acyclovir, adefovir, amprenavir, atazanavir, cidofovir, darunavir, delavirdine, didavines, didanosine, docosanol, efavirenz, elbitegra, emtricitabine, entravirin, famciclovir, foscarnet, fomivirsen, ganciclovir, indiflunisone, fluticasone, fluoxetine ... navir, idoxuridine, lamivudine, nelfinavir, nevirapine, penciclovir, raltegravir, rilpivirine, rilupavirin, ritonavir, saquinavir, stavudine, tenofovir, trifluridine, valacyclovir, valganciclovir, vidarabine, ibacitabine, tipranavir, zalcitabine, zidovudine, pharmaceutically acceptable salts thereof, and mixtures thereof.

[0092] Exemplary hormonally active agents may include, but are not limited to, estradiol and pharmaceutically acceptable salts thereof. Additional hormonally active agents may include, but are not limited to, progesterone and pharmaceutically acceptable salts thereof.

[0093] Exemplary anti-nausea active agents may include, but are not limited to, metoclopramide, prochlorperazine, domperidone, ondansetron, tropisetron, dolasetron, nabilone, dronabinol, levonantradol, aprepitant, cyclizine, promethazine, pharmaceutically acceptable salts thereof, and mixtures thereof.

[0094] Exemplary antiemetic active agents may include, but are not limited to, chlorpromazine, dimenhydrinate, dolasetron, dronabinol, granisetron, meclizine, metocloproamide, ondansetron, perphenazine, prochlorperazine, promethazine, scopolamine, thiethylperazine, trimethobenzamide, pharmaceutically acceptable salts thereof, and mixtures thereof.

[0095] excipients In some embodiments, the suppositories described herein may further comprise a pharmaceutically acceptable excipient or carrier. The term "pharmaceutically acceptable excipient or carrier" refers to any inactive ingredient in a composition that may, for example, stabilize an active ingredient. Pharmaceutically acceptable excipients may include, but are not limited to, carbohydrates (such as glucose, sucrose, or dextran), antioxidants (such as d-α-tocopherol, ascorbic acid, or glutathione), chelating agents, low molecular weight proteins, high molecular weight polymers, gel-forming agents, or other stabilizers and additives. Other examples of pharmaceutically acceptable carriers include wetting agents (e.g., lecithin), emulsifiers, surfactants and / or dispersing agents (e.g., polysorbate 80), alkalinity agents, coloring agents, synthetic dyes, fillers, diluents, mineral oxides, or preservatives, which are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid. Examples of carriers, stabilizers or adjuvants can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17th ed. (1985).

[0096] Suitable antioxidants may include, but are not limited to, sterically hindered phenols, arylamines, thioureas, thiocarbamates, phosphites, thioether esters, and combinations of the foregoing. Other suitable examples of antioxidants include alkylated monophenols, such as, but not limited to, 2,6-di-tert-butyl-4-methylphenol, 2-tert-butyl-4,6-di-methylphenol, 2,6-di-tert-butyl-4-ethylphenol, 2,6-di-tert-butyl-4-n-butylphenol, 2,6-di-tert-butyl-4-isobutylphenol, 2,6-dicyclopentyl-4-methylphenol, 2-(α-methylcyclohexyl) ... nonylphenols having linear or branched side chains, such as 2,6-di-nonyl-4-methylphenol, 2,4-dimethyl-6-(1'-methylundec-1'-yl)phenol, 2,4-dimethyl-6-(1'-methylheptadec-1'-yl)phenol, 2,4- Dimethyl-6-(1'-methyltridec-1-yl)phenol and mixtures thereof, alkylthiomethylphenols, such as, but not limited to, 2,4-dioctylthiomethyl-6-tert-butylphenol, 2,4-dioctylthiomethyl-6-methylphenol, 2,4-dioctylthiomethyl-6-ethylphenol, 2,6-di-dodecylthiomethyl-4-nonylphenol, hydroquinone and alkylated hydroquinones, such as, but not limited to, However, 2,6-di-tert-butyl-4-methoxyphenol, 2,5-di-tert-butylhydroquinone, 2,5-di-tert-amylhydroquinone, 2,6-diphenyl-4-octadecyloxyphenol, 2,6-di-tert-butylhydroquinone, 2,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyphenyl stearate, bis(3,5-di-tert-butyl-4-hydroxyphenyl) adipate, tocopherols, such as, but not limited to, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol and mixtures thereof (vitamin E), hydroxylated thiodiphenyl ethers, such as, but not limited to, 2,2'-thiobis(6-tert-butyl-4-methylphenol), 2,2'-thiobis(4-octylphenol), 4,4'-thiobis(6-tert-butyl-3-methylphenol), 4,4'-thiobis(6- tert-butyl-2-methylphenol), 4,4'-thiobis(3,6-di-sec-amylphenol), 4,4'-bis(2,6-dimethyl-4-hydroxyphenyl)-disulfide, alkylidene bisphenols, such as, but not limited to, 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 2,2'-methylenebis(6-tert-butyl-4-ethylphenol), 2,2'-methylenebis[4-methyl-6-(α-methylcyclohexyl)-phenol], 2,2'-methylenebis(4-methyl-6 -cyclohexylphenol), 2,2'-methylenebis(6-nonyl-4-methylphenol), 2,2'-methylenebis(4,6-di-tert-butylphenol), 2,2'-ethylidenebis(4,6-di-tert-butylphenol), 2,2'-ethylidenebis(6-tert-butyl-4-isobutylphenol), 2,2'-methylenebis[6-(α-methylbenzyl)-4-nonylphenol], 2,2'-methylenebis[6-(α,α-dimethylbenzyl)-4-nonylphenol], 4,4'-methylenebis(2,6-di-t tert-butylphenol), 4,4'-methylenebis(6-tert-butyl-2-methylphenol), 1,1-bis(5-tert-butyl-4-hydroxy-2-methylphenyl)butane, 2,6-bis(3-tert-butyl-5-methyl-2-hydroxybenzyl)-4-methylphenol, 1,1,3-tris(5-tert-butyl-4-hydroxy-2-methylphenyl)butane, 1,1-bis(5-tert-butyl-4-hydroxy-2-methylphenyl)-3-n-dodecylmercaptobutane, ethylene glycol bis[3,3-bis(3'-tert-butyl-4'-hydroxyphenyl)butyrate], bis(3-tert-butyl-4-hydroxy-5-methyl-phenyl)dicyclopentadiene, bis[2-(3'-tert-butyl-2'-hydroxy-5'-methylbenzyl)-6-tert-butyl-4-methylphenyl]terephthalate, 1,1-bis-(3,5-dimethyl-2-hydroxyphenyl)butane, 2,2-bis(3,5-di-tert-butyl-4-hydroxyphenyl)propane, 2,2-bis(5-tert-butyl-4-hydroxyphenyl)propane -2-methylphenyl)-4-n-dodecylmercaptobutane, 1,5,5-tetra-(5-tert-butyl-4-hydroxy-2-methylphenyl)pentane, O-, N- and S-benzyl compounds, such as, but not limited to, 3,5,3',5'-tetra-tert-butyl-4,4'-dihydroxydibenzyl ether, octadecyl-4-hydroxy-3,5-dimethylbenzyl mercaptoacetate, tridecyl-4-hydroxy-3,5-di-tert-butylbenzyl mercaptoacetate, tris(3,5-di-tert -butyl-4-hydroxybenzyl)amine, bis(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)dithioterephthalate, bis(3,5-di-tert-butyl-4-hydroxybenzyl)sulfide, isooctyl-3,5-di-tert-butyl-4-hydroxybenzyl mercaptoacetate, hydroxybenzylated malonates, such as, but not limited to, dioctadecyl-2,2-bis(3,5-di-tert-butyl-2-hydroxybenzyl)malonate, di-octadecyl-2-(3-tert- butyl-4-hydroxy-5-methylbenzyl)malonate, didodecylmercaptoethyl-2,2-bis(3,5-di-tert-butyl-4-hydroxybenzyl)malonate, bis[4-(1,1,3,3-tetramethylbutyl)phenyl]-2,2-bis(3,5-di-tert-butyl-4-hydroxybenzyl)malonate, aromatic hydroxybenzyl compounds, such as, but not limited to, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)-2,4,6-trimethylbenzene, 1,4-bis(3,5-di-tert-butyl-4-hydroxybenzyl)-2,3,5,6-tetramethylbenzene, 2,4,6-tris(3,5-di-tert-butyl-4-hydroxybenzyl)phenol, triazine compounds, such as, but not limited to, 2,4-bis(octylmercapto)-6-(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2-octylmercapto-4,6-bis ... Octylmercapto-4,6-bis(3,5-di-tert-butyl-4-hydroxyphenoxy)-1,3,5-triazine, 2,4,6-tris-(3,5-di-tert-butyl-4-hydroxyphenoxy)-1,2,3-triazine, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)isocyanurate, 1,3,5-tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)isocyanurate, 2,4,6-tris-(3,5-di-tert-butyl-4-hydroxy 1,3,5-tris(3,5-di-tert-butyl-4-hydroxyphenylethyl)-1,3,5-triazine, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxy-phenylpropionyl)-hexahydro-1,3,5-triazine, 1,3,5-tris(3,5-dicyclohexyl-4-hydroxybenzyl)iso-cyanurate, benzyl phosphonates, such as, but not limited to, dimethyl-2,5-di-tert-butyl-4-hydroxybenzylphosphonate, diethyl-3,5-di-tert-butyl-4-hydroxybenzylphosphonate, di octadecyl-3,5-di-tert-butyl-4-hydroxybenzylphosphonate, dioctadecyl-5-tert-butyl-4-hydroxy-3-methylbenzylphosphonate, calcium salt of the monoethyl ester of 3,5-di-tert-butyl-4-hydroxybenzylphosphonic acid, acylaminophenols, such as, but not limited to, 4-hydroxylauranilide, 4-hydroxystearanilide, octyl N-(3,5-di-tert-butyl-4-hydroxyphenyl)carbamate, β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid with monohydric or polyhydric alcohols, such as methanol, ethanol, n-octanol, i-octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N'-bis( hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, esters of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane, esters of β-(5-tert-butyl-4-hydroxy-3-methylphenyl)propionic acid with mono- or polyhydric alcohols, such as methanol, ethanol, n-octanol, i-octanol, octadecanol, 1,6-hexanediol, 1 ,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N'-bis-(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2. 2]octane, esters of 3,9-bis[2-{3-(3-tert-butyl-4-hydroxy-5-methylphenyl)propionyloxy}-1,1-dimethylethyl]-2,4,8,10-tetraoxaspiro[5.5]-undecane, esters of 6-(3,5-dicyclohexyl-4-hydroxyphenyl)propionic acid with monohydric or polyhydric alcohols, such as methanol, ethanol, octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N'-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, esters of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane, esters of 3,5-di-tert-butyl-4-hydroxyphenylacetic acid with mono- or polyhydric alcohols, such as methanol, ethanol, octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, ethanol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N'-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, esters with 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane, 6-(3,5-di-tert-butyl-4-hydroxybenzoyl)benzoate, amides of N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)hexamethylenediamide, N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)trimethylenediamide, N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)hydrazide, N,N'-bis[2-(3-[3,5-di-tert-butyl-4-hydroxyphenyl]propionyloxy)ethyl]oxamide ( Naugard® XL-1 (Uniroyal), ascorbic acid (vitamin C), amine antioxidants, such as, but not limited to, N,N'-di-isopropyl-p-phenylenediamine, N,N'-di-sec-butyl-p-phenylenediamine, N,N'-bis(1,4-dimethylpentyl)-p-phenylenediamine, N,N'-bis(1-ethyl-3-methylpentyl)-p-phenylenediamine, N,N'-bis(1-methylheptyl)-p-phenylenediamine, N,N'-dicyclohexyl ... xyl-p-phenylenediamine, N,N'-diphenyl-p-phenylenediamine, N,N'-bis(2-naphthyl)-p-phenylenediamine, N-isopropyl-N'-phenyl-p-phenylenediamine, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine, N-(1-methylheptyl)-N'-phenyl-p-phenylenediamine, N-cyclohexyl-N'-phenyl-p-phenylenediamine, 4-(p-toluenesulfamoyl)diphenylamine, N,N'-dimethyl-N,N'-di-sec-butyl-p-phenylenediamine, diphenylamine, N-allyldiphenylamine, 4-isopropoxydiphenylamine, N-phenyl-1-naphthylamine, N-(4-tert-octylphenyl)-1-naphthylamine, N-phenyl-2-naphthylamine, octylated diphenylamines, such as, but not limited to, p,p'-di-tert-octyldiphenylamine, 4-n-butylaminophenol, 4-butyrylaminophenol, 4-nonanoylaminophenol, Aminophenol, 4-dodecanoylaminophenol, 4-octadecanoylaminophenol, bis(4-methoxyphenyl)amine, 2,6-di-tert-butyl-4-dimethylaminomethylphenol, 2,4'-diaminodiphenylmethane, 4,4'-diaminodiphenylmethane, N,N,N',N'-tetramethyl-4,4'-diaminodiphenylmethane, 1,2-bis[(2-methylphenyl)amino]ethane, 1,2-bis(phenylamino)propane, (o-tolyl)biguanide , bis[4-(1',3'-dimethylbutyl)phenyl]amine, tert-octylated N-phenyl-1-naphthylamine, mixture of mono- and di-alkylated tert-butyl / tert-octyldiphenylamines, mixture of mono- and di-alkylated nonyldiphenylamines, mixture of mono- and di-alkylated dodecyldiphenylamines, mixture of mono- and di-alkylated isopropyl / isohexyldiphenylamines, mixture of mono- and di-alkylated The alkylated tert-butylphenylamines include, but are not limited to, mixtures of mono- and di-alkylated tert-butyl / tert-octylphenothiazines, 2,3-dihydro-3,3-dimethyl-4H-1,4-benzothiazine, phenothiazine, mixtures of mono- and di-alkylated tert-butyl / tert-octylphenothiazines, mixtures of mono- and di-alkylated tert-octyl-phenothiazines, N-allylphenothiazine, N,N,N',N'-tetraphenyl-1,4-diaminobut-2-ene, and combinations of the foregoing.

[0097] Suitable alkaline agents may include, but are not limited to, magnesium oxide, ammonium hydroxide, sodium hydroxide, sodium carbonate, sodium citrate, trisodium phosphate and / or disodium phosphate.

[0098] Suitable colorants may include, but are not limited to, colors such as white, black, yellow, blue, green, pink, red, orange, violet, indigo, and brown, etc. In certain embodiments, the color of the dosage form may indicate the contents (e.g., one or more active agents) contained therein.

[0099] Suitable lubricants / release agents may include, but are not limited to, fatty acids and their salts, fatty alcohols, fatty esters, fatty amines, fatty amine acetates, and fatty amides. Other suitable lubricants may include, but are not limited to, glyceryl behenate (Compritol™ 888), metallic stearates (e.g., magnesium stearate, calcium stearate, and sodium stearate), stearic acid, hydrogenated vegetable oils (e.g., Sterotex™), talc, waxes such as beeswax and carnauba wax, silica, fumed silica, colloidal silica, calcium stearate, long chain fatty alcohols, boric acid, sodium benzoate and sodium acetate, sodium chloride, DL-leucine, polyethylene glycol (e.g., Carbowax™ 4000 and Carbowax™ 6000), sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, sodium stearyl fumarate (Pruv®), magnesium lauryl sulfate, stearic acid, stearyl alcohol, mineral oil, paraffin, microcrystalline cellulose, glycerin, propylene glycol, and combinations thereof.

[0100] Suitable bulking agents / antiblocking agents / de-tackifying agents may include, but are not limited to, starch, modified starch, cross-linked polyvinylpyrrolidone, cross-linked cellulose, microcrystalline cellulose, silica, metal oxides, calcium carbonate, talc, and mica.

[0101] Suitable diluents include, but are not limited to, lactose USP, lactose USP (anhydrous), lactose USP (spray dried), starch USP, directly compressible starch, mannitol USP, sorbitol, dextrose monohydrate, microcrystalline cellulose NF, dibasic calcium phosphate dihydrate NF, sucrose-based diluents, powdered sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate NF, calcium lactate trihydrate granular NF, dextrate NF (e.g., Emdex™), dextrose (e.g., Cerelose™), inositol, hydrolyzed cereal solids such as Maltrons™ and Mor-Rex™, amylose, powdered cellulose (e.g., Elcema™), calcium carbonate, glycine, bentonite, polyvinylpyrrolidone, and the like.

[0102] Exemplary oils and fats may include, but are not limited to, almond oil, argan oil, avocado oil, canola oil, cashew oil, castor oil, cocoa butter, palm oil, rapeseed oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, flaxseed oil, macadamia oil, mango butter, manila oil, mongogo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, walnut oil, and watermelon seed oil. Other oils and fats that may be included in the filling of the PVA shell include, but are not limited to, fish oil (omega-3), krill oil, animal or vegetable fats such as their hydrogenated forms, monoglycerides, diglycerides, and triglycerides containing C12-, C14-, C16-, C18-, C20-, and C22-fatty acids.

[0103] Exemplary pH adjusters may include, but are not limited to, hydrochloric acid, potassium hydroxide, sodium hydroxide, ammonium hydroxide, sulfuric acid, phosphoric acid, and nitric acid.

[0104] Other exemplary excipients include, but are not limited to, vegetable proteins such as sunflower protein, soy protein, cottonseed protein, peanut protein, grape seed protein, whey protein, whey protein isolate, blood protein, egg protein, acrylated proteins, water-soluble polysaccharides such as alginates, carrageenan, guar gum, agar, xanthan gum, gellan gum, gum arabic and similar gums (gum ghatti, gum karaya, gum tragacanth), pectin, water-soluble derivatives of cellulose: alkylcellulose, hydroxyalkylcellulose, and hydroxyalkylalkylcellulose, such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropyl ... butylmethylcellulose, cellulose esters and hydroxyalkylcellulose esters, such as cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose (HPMC); carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters, such as carboxymethylcellulose and their alkali metal salts; water-soluble synthetic polymers, such as polyacrylic acid, polyacrylamide, and polyacrylic acid esters, polymethacrylic acid, polymethacrylamide, and polymethacrylic acid esters, polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate phthalate (PVAP), polyvinylpyrrolidone (PVP), PVY / vinyl acetate copolymer, and polycrotonic acid; also suitable are phthalated gelatin, gelatin succinate. succinate), cross-linked gelatin, shellac, water-soluble chemical derivatives of starch, e.g., cationically modified acrylates and methacrylates (optionally quaternized) having tertiary or quaternary amino groups such as diethylaminoethyl groups; and other similar polymers; inorganic fillers such as oxides of magnesium, aluminum, silicon, titanium, etc.

[0105] Other pharmaceutically acceptable excipients may include, but are not limited to, hydrophobic substances, such as, for example, digestible long-chain (C8-C50, particularly C12-C40) substituted or unsubstituted hydrocarbons, including, but not limited to, natural or synthetic waxes (e.g., beeswax, glycowax, castor wax, and carnauba wax), fatty alcohols (e.g., lauryl, myristyl, stearyl, cetyl, or preferably cetostearyl alcohol), fatty acids, such as, but not limited to, monodiglycerides, medium-chain triglycerides, fatty acid esters, fatty acid glycerides (monoglycerides, diglycerides, and triglycerides) of medium-chain fatty acids (e.g., caprylic acid, capric acid, caproic acid, lauric acid, oleic acid, linoleic acid), hydrogenated fats, hydrocarbons, conventional waxes, stearic acid, stearyl alcohol, and hydrophobic and hydrophilic substances with a hydrocarbon backbone.

[0106] Additional pharmaceutically acceptable excipients may further include polyvinyl alcohol, polyvinylpyrrolidone, polyalkylene oxides, polyacrylic acid, cellulose, cellulose ethers, cellulose esters, cellulose amides, polyvinyl acetate, polycarboxylic acids and salts, acetic acid, caprylic acid, oleic acid, polyamino acids or peptides, polyamides, polyacrylamides, maleic / acrylic acid copolymers, polysaccharides such as starch and gelatin, natural gums such as xanthan, and carrageenan. For example, the polymer can be selected from polyacrylates and water-soluble acrylate copolymers, methylcellulose, sodium carboxymethylcellulose, dextrin, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, maltodextrin, polymethacrylates, and combinations thereof, or can be selected from polyvinyl alcohol, polyvinyl alcohol copolymers and hydroxypropylmethylcellulose (HPMC), methacrylic acid / methyl methacrylate, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl acrylate / methyl methacrylate copolymer, shellac, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose trimellitate, cellulose acetate phthalate, polyvinyl acetate phthalate, PEG-35 castor oil, caprylocaproyl polyoxyl-8 glyceride, glyceryl distearate, and combinations thereof.

[0107] Suitable high HLB surfactants may include, but are not limited to, polysorbate 80-polyoxyethylene (20) sorbitan monooleate, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, caprylocaproyl macrogolglyceride, and combinations thereof.

[0108] Exemplary fillers may be selected from the group consisting of, but not limited to, lactose, microcrystalline cellulose, and combinations thereof.

[0109] In some embodiments, the excipients may be present in the suppository, individually or cumulatively, at a concentration of about 90 w / w% or less, about 80 w / w% or less, about 70 w / w% or less, about 60 w / w% or less, about 50 w / w% or less, about 40 w / w% or less, about 30 w / w% or less, about 20 w / w% or less, about 15 w / w% or less, about 10 w / w% or less, about 5 w / w% or less, about 4 w / w% or less, about 3 w / w% or less, about 2 w / w% or less, about 1 w / w% or less, about 0.5 w / w% or less, or about 0.1 w / w% or less, based on the total weight of the suppository. In some embodiments, the suppository may contain excipients, individually or in the aggregate, in an amount ranging from, for example, about 2 w / w% to about 50 w / w%, about 6 w / w% to about 40 w / w%, about 10 w / w% to about 30 w / w%, about 10 w / w% to about 40 w / w%, about 15 w / w% to about 35 w / w%, about 20 w / w% to about 30 w / w%, about 20 w / w% to about 25 w / w%, or about 15 w / w% to about 25 w / w%, based on the total weight of the suppository.

[0110] Preparation method In some embodiments, the present disclosure may be directed to a method of preparing any of the suppositories described herein. The method may include forming a suppository base into a suppository. With reference to Figures 1-7, the suppository may be formed having a length 110 measured along a horizontal axis X and a width 120 measured along a vertical axis Y, with the length 110 being greater than the width 120. The suppository may be formed with a proximal end 160 and a distal end 170 along the horizontal axis X. The proximal end 160 may be formed to be adapted for insertion into a body cavity. The distal end 170 may be formed with at least one indentation for easy gripping of the suppository to prevent slipping during manual insertion of the suppository into a body cavity (whether by finger or applicator). The "gripping area" at the distal end of the suppository indicates the direction in which the suppository should be used (i.e., proximal end first). Additionally, the shape of the "gripping area" at the distal end of the suppository makes it more difficult for the suppository to be expelled from the body cavity.

[0111] Similarly, the method may include forming the suppository base into a suppository having dimensions (length and / or diameter) and proximal and distal shapes as depicted with respect to Figures 8-35, described in more detail herein above.

[0112] The method for preparing any of the suppositories described herein may further include dispersing any of the active agents contemplated herein in a suppository base. In some embodiments, the active agent may be dispersed entirely throughout the suppository base. In other embodiments, the active agent may be dispersed only in a portion of the suppository base. For example, in one embodiment, the active agent may not be dispersed in at least a portion of the distal end of the suppository base. In embodiments in which a core and shell structure is prepared, the preparation method may include dispersing the active ingredient only in the core, only in the shell, or in both the core and the shell.

[0113] In certain embodiments, the method for preparing a suppository may further comprise applying a shell onto a suppository base to form a core and shell structure. In one embodiment, the core and shell structure suppository may be prepared by immersing the core in a shell composition. For example, the core may be solid at ambient temperature and may be immersed in a liquid shell composition.

[0114] In one embodiment, a core-and-shell suppository can be prepared by encapsulating a liquid containing a suppository base into a shell. For example, the core can be liquid and encapsulated by stamping (such as rotary die stamping). The encapsulation can be performed at ambient temperature or at a temperature higher than ambient temperature. For example, to facilitate processing and handling, the encapsulation can be performed at a temperature higher than ambient temperature when the core is liquid. In certain embodiments, a core that is liquid at an encapsulation temperature higher than ambient temperature may solidify at ambient temperature and melt again when inserted into a body cavity (i.e., when exposed to the core temperature of a human body).

[0115] In some embodiments, the suppository base may be encapsulated (including the active agent) using rotary die stamping / encapsulation. Encapsulation of the suppository base by rotary die encapsulation can utilize conventional rotary die equipment with dies designed to form a concave suppository capsule shape, such as those described herein. Similarly, in core and shell suppository structures, encapsulation of the core into the shell by rotary die encapsulation can utilize conventional rotary die equipment with dies designed to form a concave suppository capsule shape, such as those described herein.

[0116] According to embodiments, any of the suppository capsules disclosed herein may be prepared by a process comprising the steps of: (a) preparing a suppository base; (b) combining the suppository base of step (a) with an active agent to form a core; and, optionally, (c) applying a shell composition comprising the combined suppository base and active agent onto the core.

[0117] Preparing the suppository base according to step (a) may include mixing multiple pharmaceutically acceptable excipients or carriers.

[0118] In certain embodiments, step (b) may include mixing the active agent with the suppository base. In other embodiments, step (b) may include encapsulating the active agent in the suppository base using a rotary die encapsulation process to form a filled suppository base in the shape of a recessed suppository.

[0119] In certain embodiments, step (c) may include dipping the core from step (b) into a premixed shell composition. In other embodiments, step (c) may include encapsulating the core from step (b) in the shell composition using a rotary die encapsulation process to form a recessed suppository shape having a core and shell structure.

[0120] Treatment method In some embodiments, the present disclosure may be directed to methods of treating a disease or condition by administering any of the suppositories described herein to a body cavity of a patient in need thereof.

[0121] The step of administering the suppository may include grasping / holding the suppository in at least one depression at the distal end of the suppository. The grasping / holding of the suppository may be performed with at least one finger. In some embodiments, the grasping of the suppository may be performed with two, three, four, or five fingers. In certain embodiments, the grasping of the suppository may be performed using a tool such as an applicator, forceps, or the like. In other embodiments, the grasping of the suppository may be performed without a tool such as an applicator, forceps, or the like.

[0122] In certain embodiments, the step of administering the suppository may further include inserting the suppository (e.g., manually) into the body cavity via a proximal end direction (i.e., with the proximal end inserted into the body cavity first). The body cavity may be, but is not limited to, the rectum, vagina, or urethra, and the suppository may be adapted for vaginal, rectal, or urethral insertion accordingly.

[0123] Exemplary diseases or conditions that may be treated with any of the suppositories described herein may include, but are not limited to, pain, migraine, inflammation, fungal infection, bacterial infection, viral infection, vaginal pain, menopausal symptoms, vulvar and vaginal atrophy, cancer, nausea, vomiting, or a combination thereof.

[0124] The suppositories described herein may provide a local therapeutic effect, a systemic therapeutic effect, or both a local and a systemic therapeutic effect.

[0125] In the foregoing description, numerous specific details are set forth, such as particular materials, dimensions, processes, parameters, etc., to provide a thorough understanding of the present invention. Particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments. The word “example” or “exemplary” is used herein to mean serving as an example, instance, or illustration. Any aspect or design described herein as “example” or “exemplary” should not necessarily be construed as preferred or advantageous over other aspects or designs. Rather, use of the word “example” or “exemplary” is merely intended to present a concept in a concrete manner. As used in this application, the term “or” is intended to mean an inclusive “or” rather than an exclusive “or.” That is, unless otherwise specified or clear from context, “X includes A or B” is intended to mean any of the natural inclusive permutations. That is, if X includes A; X includes B; or X includes both A and B, then “X includes A or B” is satisfied in any of the foregoing cases. References throughout this specification to "one embodiment," "a particular embodiment," or "one embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. Thus, the appearances of the phrases "one embodiment," "a particular embodiment," or "one embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment.

[0126] The present invention has been described with reference to specific exemplary embodiments thereof. Accordingly, the specification and drawings are to be regarded in an illustrative rather than a restrictive sense. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims. The present invention also includes the following aspects. <1> 1. A suppository comprising a suppository base, the suppository having a length measured along a horizontal axis that is greater than a width measured along a vertical axis, the suppository having a proximal end along said horizontal axis adapted for insertion into a body cavity, and a distal end along said horizontal axis having at least one recess. <2> 10. The suppository of claim 1, further comprising an active agent. <3> 3. The suppository according to claim 2, wherein the active agent is dispersed in the suppository base. <4> 4. The suppository according to claim 2 or 3, wherein the active agent is dispersed in its entirety throughout the suppository base. <5> 4. The suppository according to claim 2 or 3, wherein the active agent is not dispersed throughout the suppository base in at least a portion of the distal end. <6> 6. A suppository according to any one of claims 1 to 5, wherein the distal end has two recesses. <7> 7. The suppository of claim 6, wherein each recess is on opposite sides of the distal end. <8> 8. A suppository according to any one of claims 1 to 7, wherein at least one of the depressions is adapted to be held with at least one finger. <9> 9. A suppository according to any one of 1 to 8 above, having a shape selected from a dimpled bullet, a dimpled oval, a dimpled egg, a dimpled teardrop, or a dimpled torpedo. <10> 10. A suppository according to any one of 1 to 9 above, wherein at least one of the depressions is flat. <11> 10. A suppository according to any one of 1 to 9 above, wherein at least one of the depressions is concave. <12> 10. A suppository according to any one of claims 1 to 9, wherein at least one of the depressions is perforated. <13> 13. A suppository according to any one of 1 to 12 above, having a core and shell structure. <14> 14. The suppository according to claim 13, wherein an active agent is contained in the core, the shell, or both the core and the shell. <15> 15. A suppository according to claim 13 or 14, wherein the core comprises the suppository base. <16> 16. A suppository according to any one of claims 13 to 15, wherein the shell comprises at least one of gelatin, starch, modified starch, carrageenan, alginate, a biodegradable polymer, or a combination thereof. <17> 17. The suppository of claim 16, wherein the shell comprises a biodegradable polymer, and the biodegradable polymer is selected from polylactic acid (PLA), poly(ε-caprolactone) (PCL), poly(lactide-co-glycolic acid) (PLGA), or a combination thereof. <18> 18. The suppository according to any one of 1 to 17 above, wherein the suppository base comprises at least one of cocoa butter, lauric fat, beef tallow, hard fat, theobroma oil, glycerides of fatty acids, glycerol-gelatin bases, or combinations thereof. <19> 18. A suppository according to any one of claims 13 to 17, wherein the core is solid at ambient temperature. <20> 18. A suppository according to any one of claims 13 to 17, wherein the core is liquid at ambient temperature. <21> 21. A suppository according to any one of 1 to 20 above, wherein the suppository base has a melting point at body temperature. <22> 22. A suppository according to any one of 1 to 21 above, adapted for vaginal, rectal or urethral insertion. <23> 23. A suppository according to any one of 1 to 22 above, which provides a local therapeutic effect. <24> 24. A suppository according to any one of 1 to 23 above, which provides a systemic therapeutic effect. <25> 25. The suppository of any one of claims 2 to 24, wherein the active agent is selected from an analgesic, antimigraine, anti-inflammatory, antifungal, antibiotic, antiviral, hormone, chemotherapeutic, antinausea, or antiemetic. <26> 26. The suppository of claim 25, wherein the active agent comprises an analgesic, and the analgesic is acetaminophen or an opioid. <27> 26. The suppository of claim 25, wherein the active agent comprises an antimigraine agent selected from ergotamine, dihydroergotamine, ergostine, butalbital, phenobarbital, sumatriptan, naratriptan, razatriptan, zolmitriptan, almotriptan, eletriptan, valproic acid, gabapentin, topiramate, divalproex, a pharmaceutically acceptable salt thereof, or a mixture thereof. <28> 26. The suppository of claim 25, wherein the active agent comprises an anti-inflammatory agent selected from ibuprofen, fenoprofen, naproxen, sulindac, diclofenac, piroxicam, ketoprofen, diflunisal, nabumetone, etodolac, oxaprozin, indomethacin, pharmaceutically acceptable salts thereof, or mixtures thereof. <29> The active agent comprises an antifungal agent, and the antifungal agent is selected from the group consisting of abafungin, albaconazole, amorolfine, amphotericin b, anidulafungin, bifonazole, butenafine, butoconazole, candicidin, caspofungin, ciclopirox, clotrimazole, econazole, fenticonazole, filipin, fluconazole, flucytosine, griseofulvin, haloprogin, hamycin, isavuconazole, isoconazole, itraconazole, 26. The suppository according to claim 25, which is selected from ketoconazole, micafungin, miconazole, naftifine, natamycin, nystatin, omoconazole, oxiconazole, poligodial, posaconazole, ravuconazole, rimocidin, sertaconazole, sulconazole, terbinafine, terconazole, tioconazole, tolnaftate, undecylenic acid, voriconazole, pharmaceutically acceptable salts thereof, or mixtures thereof. <30> 26. The suppository of claim 25, wherein the active agent comprises an antibiotic selected from mitomycin, ciprofloxacin, norfloxacin, ofloxacin, methanamine, nitrofurantoin, ampicillin, amoxicillin, nafcillin, trimethoprim, the sulfonamide trimethoprim-sulfamethoxazole, erythromycin, doxycycline, metronidazole, tetracycline, kanamycin, penicillin, cephalosporins, aminoglycosides, pharmaceutically acceptable salts thereof, or mixtures thereof. <31> 26. The suppository of claim 25, wherein the active agent comprises an antiviral agent selected from abacavir, acyclovir, adefovir, amprenavir, atazanavir, cidofovir, darunavir, delavirdine, zidabine, didanosine, docosanol, efavirenz, elvitegra, emtricitabine, entravirine, famciclovir, foscarnet, fomivirsen, ganciclovir, indinavir, idoxuridine, lamivudine, nelfinavir, nevirapine, penciclovir, raltegravir, rilpivirine, rilpavirine, ritonavir, saquinavir, stavudine, tenofovir, trifluridine, valacyclovir, valganciclovir, vidarabine, ibacitabine, tipranavir, zalcitabine, zidovudine, pharmaceutically acceptable salts thereof, and mixtures thereof. <32> 26. The suppository of claim 25, wherein the active agent comprises a hormone, and the hormone is estradiol or a pharmaceutically acceptable salt thereof. <33> 26. The suppository of claim 25, wherein the active agent comprises an anti-nausea agent selected from metoclopramide, prochlorperazine, domperidone, ondansetron, tropisetron, dolasetron, nabilone, dronabinol, levonantradol, aprepitant, cyclizine, promethazine, pharmaceutically acceptable salts thereof, or mixtures thereof. <34> 26. The suppository of claim 25, wherein the active agent comprises an antiemetic agent selected from chlorpromazine, dimenhydrinate, dolasetron, dronabinol, granisetron, meclizine, metoclopramide, ondansetron, perphenazine, prochlorperazine, promethazine, scopolamine, thiethylperazine, trimethobenzamide, pharmaceutically acceptable salts thereof, or mixtures thereof. <35> 21. A suppository according to any one of claims 13 to 17, 19 or 20, prepared by immersing the core in a shell composition. <36> A suppository according to any one of claims 13 to 17, 19 or 20, which is prepared by encapsulating a liquid containing the suppository base in the shell. <37> 37. The suppository of claim 36, wherein the encapsulating step comprises stamping. <38> 38. The suppository of claim 37, wherein the stamping comprises rotary die stamping. <39> 39. A suppository according to any one of claims 36 to 38, wherein the encapsulation is carried out at a temperature higher than ambient temperature. <40> 40. The suppository of claim 39, wherein the liquid solidifies at ambient temperature. <41> 17. The suppository of claim 16, wherein the shell composition further comprises a plasticizer. <42> 42. The suppository according to claim 41, wherein the plasticizer is selected from glycerol, sorbitol, or a mixture thereof. <43> 17. The suppository of claim 16, wherein the shell composition comprises gelatin, said gelatin being selected from type A gelatin, type B gelatin, or a mixture thereof. <44> 17. The suppository of claim 16, wherein the shell composition comprises gelatin, said gelatin being selected from the group consisting of fish gelatin, animal hide gelatin, bone gelatin, or mixtures thereof. <45> 45. The suppository according to any one of 16 or 41 to 44 above, wherein the shell composition comprises about 40 wt% to about 80 wt%, about 45 wt% to about 75 wt%, or about 50 wt% to about 70 wt% of gelatin relative to the total weight of the shell composition. <46> 43. The suppository according to claim 41 or 42, wherein the shell composition comprises about 15 wt% to about 40 wt%, about 20 wt% to about 35 wt%, or about 25 wt% to about 30 wt% of a plasticizer relative to the total weight of the shell composition. <47> A method of treating a disease or condition comprising the step of inserting any of the suppositories of 1 to 46 above into a body cavity of a patient in need thereof. <48> 48. The method of claim 47, wherein the body cavity is the rectum, vagina, or urethra. <49> 49. The method of claim 47 or 48, wherein the disease or condition is selected from pain, migraine, inflammation, fungal infection, bacterial infection, viral infection, vaginal pain, menopause, vulvar and vaginal atrophy, cancer, nausea, or vomiting. <50> 50. The method of any of claims 47 to 49, wherein the inserting step includes manually holding the suppository in at least one depression and manually inserting the suppository. <51> 1. A method of preparing a suppository, comprising forming a suppository base into a suppository, wherein the suppository has a length along a horizontal axis that is greater than its width along a vertical axis, and wherein the suppository has a proximal end along the horizontal axis adapted for insertion into a body cavity and a distal end along the horizontal axis having at least one recess. <52> 52. The method of claim 51, further comprising the step of dispersing an active agent in the suppository base. <53> 53. The method of claim 51 or 52, comprising applying a shell onto the suppository base to form a core and shell structure. <54> 54. The method according to any one of claims 51 to 53, wherein the active agent is contained in the core, the shell, or the core and the shell of the suppository. <55> 54. The method of claim 53, wherein the applying step comprises immersing the suppository base in a shell composition to form the core and shell structure. <56> 54. The method of claim 53, wherein the applying step comprises encapsulating a liquid containing the suppository base in the shell to form the core and shell structure. <57> 57. The method of claim 56, wherein said encapsulating comprises stamping. <58> 58. The method of claim 57, wherein the stamping comprises rotary die stamping. <59> 59. The method of any of claims 56 to 58, wherein the encapsulating is performed at a temperature higher than ambient temperature. <60> 59. The method of any of claims 56 to 59, wherein the liquid solidifies at ambient temperature. <61> 61. The method of claim 60, wherein the solidified liquid melts at human core temperature. [Explanation of symbols]

[0127] 100 suppository capsules 110 length 112 length 115 length 120 width 130 Edge 140 Edge 150 center 160 proximal end 170 distal end 180 depression 180A recess 180B recess 190 Borderline 800 suppository capsules 810 length 812 length 815 length 820 width 860 proximal end 870 distal end 880 depression 880A recess 880B recess 890 Borderline 1500 suppository capsules 1510 length 1512 length 1515 length 1560 proximal end 1570 distal end 1580 hollow 1580A recess 1580B recess 1590 Border 2200 suppository capsules 2210 length 2212 length 2215 length 2220 width 2260 Proximal end 2261 Shortest distance 2270 Distal end 2280 hollow 2280A recess 2280B recess 2290 Border 2900 suppository capsules 2910 length 2912 length 2915 length 2920 width 2920 diameter 2960 proximal end 2970 distal end 2980 hollow 2980A recess 2980B hollow 2990 Borderline

Claims

1. A suppository comprising a suppository base, the suppository having a length measured along a horizontal axis that is greater than a width measured along a vertical axis, a proximal end along the horizontal axis adapted for insertion into a body cavity, and a distal end along the horizontal axis; the suppository has a shape selected from a dimpled bullet, a dimpled oval, a dimpled egg, a dimpled teardrop, or a dimpled torpedo; The suppository, wherein the distal end has two recesses, one on each side of the distal end.

2. 10. The suppository of claim 1 further comprising an active agent.

3. 3. The suppository of claim 2, wherein the active agent is dispersed in the suppository base.

4. 4. The suppository of claim 2 or 3, wherein the active agent is not dispersed throughout the suppository base in at least a portion of the distal end.

5. 5. The suppository according to claim 1, wherein at least one of the depressions is flat, concave, or perforated.

6. 6. The suppository according to claim 1, having a core and shell structure.

7. 7. The suppository of claim 6, wherein an active agent is contained in the core, the shell, or the core and the shell.

8. 8. The suppository according to claim 6 or 7, wherein the core comprises the suppository base.

9. 9. The suppository of claim 6, wherein the shell comprises at least one of gelatin, starch, modified starch, carrageenan, alginate, a biodegradable polymer, or a combination thereof.

10. 10. The suppository of claim 9, wherein the shell comprises a biodegradable polymer, the biodegradable polymer being selected from polylactic acid (PLA), poly(ε-caprolactone) (PCL), poly(lactide-co-glycolic acid) (PLGA), or a combination thereof.

11. 11. The suppository of claim 1, wherein the suppository base comprises at least one of cocoa butter, lauric fat, beef tallow, hard fat, theobroma oil, glycerides of fatty acids, a glycerol-gelatin base, or a combination thereof.

12. 12. A suppository according to any one of claims 1 to 11 adapted for vaginal, rectal or urethral insertion.

13. 13. The suppository of any one of claims 2 to 12, wherein the active agent is selected from an analgesic, antimigraine, anti-inflammatory, antifungal, antibiotic, antiviral, hormone, chemotherapeutic, antinausea, or antiemetic.

14. 10. The suppository of claim 9, wherein the shell composition further comprises a plasticizer.

15. 15. The suppository of claim 14, wherein the plasticizer is selected from glycerol, sorbitol, or a mixture thereof.

16. 10. The suppository of claim 9, wherein the shell composition comprises gelatin, said gelatin being selected from the group consisting of fish gelatin, hide gelatin, bone gelatin, or mixtures thereof.

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