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Title:
DICHLORPHENAMIDE COMPOSITIONS AND METHODS OF USE
Document Type and Number:
WIPO Patent Application WO/2020/257037
Kind Code:
A1
Abstract:
Provided is a pharmaceutical composition comprising: (a) granules comprising dichlorphenamide, or a pharmaceutically acceptable salt thereof, and one or more intragranular excipients; and an extragranular portion comprising at least one release modifier. Also provided are process for the preparation and methods for the use of the pharmaceutical composition.

Inventors:
COHEN FREDRIC (US)
Application Number:
PCT/US2020/037169
Publication Date:
December 24, 2020
Filing Date:
June 11, 2020
Export Citation:
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Assignee:
STRONGBRIDGE DUBLIN LTD (US)
International Classes:
A61K31/18; C07C311/15
Foreign References:
US20120034272A12012-02-09
US20130122085A12013-05-16
US20200163911A12020-05-28
US20060182804A12006-08-17
US8105625B22012-01-31
US9867786B22018-01-16
Attorney, Agent or Firm:
STEVENS, Lauren (US)
Download PDF:
Claims:
What is claimed is:

1. A pharmaceutical composition comprising:

(a) granules comprising dichlorphenamide, or a pharmaceutically acceptable salt thereof, and one or more intragranular excipients; and

(b) an extragranular portion comprising at least one release modifier; wherein the release modifier is a hydroxypropyl methylcellulose or a mixture thereof,

wherein the composition has a dissolution profile of at least about 80% mean drug release between about 6 hours and about 10 hours as measured using the paddle method (USP apparatus 2) with a stirring rate of 75 rotations per minute in 900 mL of phosphate buffer pH 8.0 with 0.5% hexadecyltrimethylammonium bromide at 37+0.5° C.

2. The pharmaceutical composition of claim 1, wherein the granules comprise 100 mg dichlorphenamide, or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition of claim 1, wherein the granules comprise 200 mg dichlorphenamide, or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the

dichlorphenamide, or a pharmaceutically acceptable salt thereof is present in the granules in an amount of between about 50% w/w and about 70% w/w.

5. The pharmaceutical composition of claim 4, wherein the dichlorphenamide, or a pharmaceutically acceptable salt thereof is present in the granules in an amount of between about 60% w/w and about 65% w/w.

6. The pharmaceutical composition of claim 5, wherein the dichlorphenamide, or a pharmaceutically acceptable salt thereof is present in the granules in an amount of about 62% w/w.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the

dichlorphenamide, or a pharmaceutically acceptable salt thereof is present in the

pharmaceutical composition in an amount of between about 15% w/w and about 45% w/w.

8. The pharmaceutical composition of claim 7, wherein the dichlorphenamide, or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount of between about 15% w/w and about 25% w/w.

9. The pharmaceutical composition of claim 8, wherein the dichlorphenamide, or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount of about 20% w/w.

10. The pharmaceutical composition of claim 7, wherein the dichlorphenamide, or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount of between about 35% w/w and about 45% w/w.

11. The pharmaceutical composition of claim 10, wherein the dichlorphenamide, or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount of about 40% w/w.

12. The pharmaceutical composition of any one of claims 1 to 11, wherein the one or more intragranular excipients are chosen from fillers, binders, and glidants.

13. The pharmaceutical composition of claim 12, wherein the one or more fillers are chosen from dibasic calcium phosphate, tribasic calcium phosphate, carmellose, sugar alcohols, kaolin, lactose, sucrose, mannitol, cellulose, calcium carbonate, magnesium carbonate, starch, mixtures of isomaltulose derivatives, and mixtures thereof.

14. The pharmaceutical composition of claim 13, wherein the filler is lactose and the lactose is chosen from lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, spray-dried monohydrate lactose, lactose-316 Fast Flo, microcrystalline cellulose co processed with other excipients, and mixtures thereof.

15. The pharmaceutical composition of claim 14, wherein the lactose is lactose monohydrate.

16. The pharmaceutical composition of claim 13, wherein filler is starch and the starch is chosen from maize starch, potato starch, rice starch, wheat starch, pregelatinized starch, and mixtures thereof.

17. The pharmaceutical composition of claim 13, wherein the filler is cellulose and the cellulose is chosen from crystalline celluloses, powdered celluloses, and mixtures thereof.

18. The pharmaceutical composition of claim 17, wherein the crystalline cellulose is microcrystalline cellulose.

19. The pharmaceutical composition of claim 13, wherein the one or more fillers is a mixture of microcrystalline cellulose and lactose monohydrate.

20. The pharmaceutical composition of any one of claims 12 to 19, wherein the one or more fillers is present in the granules in an amount of between about 20 and about 40% w/w.

21. The pharmaceutical composition of claim 20, wherein the one or more fillers is present in the granules in an amount of between about 25% w/w and about 35% w/w.

22. The pharmaceutical composition of claim 21, wherein the one or more fillers is present in the granules in an amount of about 30% w/w.

23. The pharmaceutical composition of any one of claims 12 to 19, wherein the one or more fillers is present in the pharmaceutical composition in an amount of between about 15% w/w and about 50% w/w.

24. The pharmaceutical composition of claim 23, wherein the one or more fillers is present in the pharmaceutical composition in an amount of between about 15% w/w and about 25% w/w.

25. The pharmaceutical composition of claim 24, wherein the one or more fillers is present in the pharmaceutical composition in an amount of about 19% w/w.

26. The pharmaceutical composition of claim 23, wherein the one or more fillers is present in the pharmaceutical composition in an amount of between about 35% w/w and about 45% w/w.

27. The pharmaceutical composition of claim 26, wherein the one or more fillers is present in the pharmaceutical composition in an amount of about 42% w/w.

28. The pharmaceutical composition of claim 12, wherein the one or more binders are chosen from hydroxypropyl celluloses in various grades, hydroxypropyl methylcelluloses in various grades, polyvinylpyrrolidones in various grades, copovidones, powdered acacia, gelatin, guar gum, carbomers, methylcelluloses, polymethacrylates, starches, and mixtures thereof.

29. The pharmaceutical composition of claim 28, wherein the binder is starch and the starch is chosen from maize starch, potato starch, rice starch, wheat starch, pregelatinized starch, and mixtures thereof.

30. The pharmaceutical composition of claim 29, wherein the starch is pregelatinized starch.

31. The pharmaceutical composition of any one of claims 28 to 30, wherein the one or more binders is present in the granules in an amount of between about 5 and about 15% w/w.

32. The pharmaceutical composition of claim 31, wherein the one or more binders is present in the granules in an amount of between about 7 and about 10% w/w.

33. The pharmaceutical composition of any one of claims 28 to 32, wherein the one or more binders is present in the pharmaceutical composition in an amount of between about 2% w/w and about 10% w/w.

34. The pharmaceutical composition of claim 33, wherein the one or more binders is present in the granules in an amount of between about 2% w/w and about 5% w/w.

35. The pharmaceutical composition of claim 12, wherein the one or more glidants are chosen from talc, colloidal silica (colloidal silicon dioxide), cornstarch, calcium silicate, magnesium silicate, colloidal silicon, silicon hydrogel, and mixtures thereof.

36. The pharmaceutical composition of claim 35, wherein the one or more glidants is colloidal silica.

37. The pharmaceutical composition of claim 35 or 36, wherein the one or more glidants is present in the granules in an amount of between about 0% w/w and about 2% w/w.

38. The pharmaceutical composition of claim 37, wherein the one or more glidants is present in the granules in an amount of between about 0.3% w/w and about 0.5% w/w.

39. The pharmaceutical composition of any one of claims 35 to 38, wherein the one or more glidants is present in the pharmaceutical composition in an amount of between about 0 and about 2% w/w.

40. The pharmaceutical composition of claim 39, wherein the one or more glidants is present in the pharmaceutical composition in an amount of between about 0.3 and about 0.5% w/w.

41. The pharmaceutical composition of any one of the preceding claims, wherein the release modifier is a hydroxypropyl methylcellulose or a mixture thereof chosen from low to medium viscosity hydroxypropyl methylcellulose and mixtures thereof.

42. The pharmaceutical composition of claim 41, wherein the release modifier is a hydroxypropyl methylcellulose or a mixture thereof chosen from Methocel E, Methocel E3, Methocel E5, Methocel E6, Methocel E15, Methocel E50, Methocel K, Methocel K3, Methocel K4M, Methocel K15M, Methocel K100LV, Methocel K100M,

Methocel, Hypromellose type 1828, Hypromellose type 2208, Hypromellose type 2906, Hypromellose type 2910, Metolose 60SH (Type 2910), Metolose 65SH (Type 2906), Metolose 90SH (Type 2208), Methocel A, Methocel A15, Methocel A4C, Methocel A15C, Methocel A4m, Metolose SM, and mixtures thereof.

43. The pharmaceutical composition of any one of claims 1 to 41, wherein the release modifier is chosen from Hypromellose K100LV and Hypromellose E50, and mixtures thereof.

44. The pharmaceutical composition of any one of claims 1 to 41, wherein the release modifier is a mixture of Hypromellose K100LV and Hypromellose E50.

45. The pharmaceutical composition of any one of claims 1 to 44, wherein the release modifier is present in the pharmaceutical composition in an amount of between about 30% w/w and about 40% w/w.

46. The pharmaceutical composition of claim 45, wherein the release modifier is present in the pharmaceutical composition in an amount of about 35% w/w.

47. The pharmaceutical composition of any one of the preceding claims, wherein the extragranular portion further comprises one or more extragranular excipients.

48. The pharmaceutical composition of claim 47, wherein the one or more extragranular excipients comprises one or more lubricants.

49. The pharmaceutical composition of claim 47, wherein the one or more extragranular excipients comprises one or more fillers.

50. The pharmaceutical composition of any one of the preceding claims, wherein the granules comprise:

dichlorphenamide, or a pharmaceutically acceptable salt thereof;

microcrystalline cellulose;

lactose monohydrate;

pregelatinized starch; and

colloidal silica.

51. The pharmaceutical composition of any one of the preceding claims, wherein the extragranular portion comprises:

hydroxypropyl methylcellulose or a mixture thereof; microcrystalline cellulose;

colloidal silica; and

magnesium stearate.

52. A process for producing a pharmaceutical composition of any one of the preceding claims, comprising:

mixing the granules comprising the dichlorphenamide, or a pharmaceutically acceptable salt thereof, the at least one release modifier, and optionally, the one or more extragranular excipients to form a tablet blend; and

compressing the tablet blend to form a tablet.

53. The process of claim 52, wherein the granules are prepared by a process comprising: wet granulating a mixture of the dichlorphenamide, or a pharmaceutically acceptable salt thereof, and the one or more intragranular excipients; and

drying the wet granules.

54. A method of treating primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, or related variants in a patient in need thereof, comprising administering to the patient, a pharmaceutical composition of any one of claims 1 to 51.

Description:
DICHLORPHENAMIDE COMPOSITIONS AND METHODS OF USE

[0001] This application claims priority to U.S. application number 62/863,125, filed June 18, 2019, which is incorporated by reference in its entirety for all purposes.

[0002] Dichlorphenamide is a dichlorinated benzenedisulfonamide, known chemically as 4,5-dichloro-l,3-benzenedisulfonamide. Its empirical formula is C6H6CI2N2O4S2 and its structural formula is:

[0003] A formulation of dichlorphenamide has been previously reported in the United States Food and Drug Administration (FDA) approved drug label for KEVEYIS ® , which is indicated for treating primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants, a heterogenous group of conditions for which responses may vary. The initial dose is 50 mg/day once or twice daily (bis in diem, BID), which may be adjusted at weekly intervals up to 200 mg/day. The formulation includes lactose

monohydrate, magnesium stearate and pregelatinized maize starch as inactive ingredients.

[0004] There remains a need in the art to develop orally bioavailable dosage forms comprising dichlorphenamide, or a pharmaceutically acceptable salt thereof.

SUMMARY

[0005] Provided is a pharmaceutical composition comprising:

(a) granules comprising dichlorphenamide, or a pharmaceutically acceptable salt thereof, and one or more intragranular excipients; and

(b) an extragranular portion comprising at least one release modifier; wherein the release modifier is a hydroxypropyl methylcellulose or a mixture thereof,

wherein the composition has a dissolution profile of at least about 80% mean drug release between about 6 hours and about 10 hours as measured using the paddle method (USP apparatus 2) with a stirring rate of 75 rotations per minute in 900 mL of phosphate buffer pH 8.0 with 0.5% hexadecyltrimethylammonium bromide at 37+0.5° C.

[0006] Also provided is a process for producing a pharmaceutical composition described herein comprising: mixing the granules comprising the dichlorphenamide, or a pharmaceutically acceptable salt thereof, the at least one release modifier, and optionally, the one or more extragranular excipients to form a tablet blend; and compressing the tablet blend to form a tablet.

[0007] Also provided is a method of treating primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, or related variants in a patient in need thereof, comprising administering to the patient, a pharmaceutical composition disclosed herein.

[0008] These and other aspects of the invention will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds, and/or compositions, and are each hereby incorporated by reference in their entirety.

DETAILED DESCRIPTION

[0009] In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well- known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word“comprise” and variations thereof, such as, “comprises” and“comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0010] Reference throughout this specification to“one embodiment” or“an embodiment” or“some embodiments” or“a certain embodiment” means that a particular feature, structure or characteristic described for the embodiment is included in at least one embodiment. Thus, the appearances of the phrases“in one embodiment” or“in an embodiment” or“in some embodiments” or“in a certain embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0011] Also, as used in this specification and the appended claims, the singular forms“a,” “an,” and“the” include plural referents unless the content clearly dictates otherwise.

[0012] The term "and/or" when in a list of two or more items, means that any of the listed items can be employed by itself or in combination with one or more of the listed items. For example, the expression "A and/or B" means either or both of A and B, i.e. A alone, B alone or A and B in combination. The expression "A, B and/or C" is intended to mean A alone, B alone, C alone, A and B in combination, A and C in combination, B and C in combination or A, B, and C in combination.

[0013] When ranges of values are disclosed, and the notation“from n1 ... to n2” or “between n1 ... and n2” is used, where n1 and n2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range“from 1 to 3 mM (micromolar)” is intended to include 1 mM, 3 mM, and everything in between to any number of significant figures (e.g., 1.255 mM, 2.1 mM, 2.9999 mM, etc.).

[0014] As used herein, the term“about” qualifies the numerical values that it modifies, denoting such a value as variable within a margin of error. When no margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” means that range which would encompass the recited value and the range which would be included by rounding up or down to that figure, considering significant figures.

[0015] As used herein, the term“disease” is intended to be generally synonymous, and is used interchangeably with, the terms“disorder,”“syndrome,” and“condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

[0016] As used herein, "effective amount" and "therapeutically effective amount" of an agent, compound, drug, composition or combination is an amount which is nontoxic and effective for producing some desired therapeutic effect upon administration to a subject or patient (e.g., a human subject or patient). The precise therapeutically effective amount for a subject may depend upon, e.g., the subject’s size and health, the nature and extent of the condition, the therapeutics or combination of therapeutics selected for administration, and other variables known to those of skill in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.

[0017] As used herein, " patient " or "individual" or " subject" means a mammal, including a human, for whom or which therapy is desired, and generally refers to the recipient of the therapy.

[0018] As used herein, "pharmaceutically acceptable" refers to a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term "pharmaceutically acceptable" is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug

administration. "Pharmacologically active" (or simply "active") as in a "pharmacologically active" (or "active") derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree. The term "pharmaceutically acceptable salts" include acid addition salts which are formed with inorganic acids or organic acids. Salts formed with the free carboxyl groups can also be derived from inorganic bases and organic bases. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17.sup.th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002).

[0019] Pharmaceutically acceptable salts can be formed from, for example, the following acids: l-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2- oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); ascorbic acid (D); aspartic acid (L); aspartic acid (D); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphoric acid (-); camphor- 10-sulfonic acid (+); camphor-10-sulfonic acid (-); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid;

dodecylsulfuric acid; ethane- 1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); glucoheptonic acid (L); gluconic acid (D); gluconic acid (L); glucuronic acid (D); glucuronic acid (L); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; hydrobromic acid; hydrochloric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malic acid (D); malonic acid; mandelic acid (DL); methanesulfonic acid ; naphthalene- 1, 5 -disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; nitric acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); pyroglutamic acid (D); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); tartaric acid (D); thiocyanic acid; toluenesulfonic acid (p); and/or undecylenic acid. [0020] Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2- dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine,

methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0021] The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or on the effecting of a clinical endpoint.

[0022] The term“therapeutically acceptable” refers to those compounds (or salts, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

[0023] As used herein, reference to "treatment" of a patient is intended to include prophylaxis. Treatment may also be preemptive in nature, i.e., it may include prevention of disease. Prevention of a disease may involve complete protection from disease, for example as in the case of prevention of infection with a pathogen or may involve prevention of disease progression. For example, prevention of a disease may not mean complete foreclosure of any effect related to the diseases at any level, but instead may mean prevention of the symptoms of a disease to a clinically significant or detectable level. Prevention of diseases may also mean prevention of progression of a disease to a later stage of the disease.

[0024] As used herein,“up-titration” of a compound refers to increasing the amount of a compound to achieve a therapeutic effect that occurs before dose-limiting intolerability for the patient. Up-titration can be achieved in one or more dose increments, which may be the same or different.

[0025] As used herein, the term "stable" with respect to pharmaceutical compositions, the pharmaceutical composition exhibits total impurities not more than 1.0% at ambient temperature (15-25° C) and 75% relative humidity, when stored in high density polyethylene (HDPE) container for 7 or 35 days.

[0026] As used herein, the term "solid dosage form" or "dosage form" or "composition" as used herein means a solid dosage form suitable for administration, such as a tablet, capsule, spheroids, mini-tablets, pellets, granules, pills and the like.

[0027] As used herein, the term“filler” means an inert substance used to create the desired bulk, flow properties, and compression characteristics in the preparation of pharmaceutical composition.

[0028] As used herein, the term“binder” means an inert substance used to ensure that granules and/or tablets can be formed with the required mechanical strength and hold a tablet together after it has been compressed, preventing it from breaking down into its component powders during packaging, shipping and routine handling.

[0029] As used herein, the term " glidant" means an inert substance used to promote the flowability of a granulation.

[0030] As used herein, the term "low to medium" viscosity means a viscosity in the range of from about 15 mPas to about 1000 mPas. It is recognized in the art that determining the viscosity of cellulosic derivatives is based upon standard techniques and grading in the art e.g. for HPMC, viscosity may be determined at 20° C with a 2% solution using a Ubbelohde viscometer.

[0031] Provided is a pharmaceutical composition comprising:

(a) granules comprising dichlorphenamide, or a pharmaceutically acceptable salt thereof, and one or more intragranular excipients; and

(b) an extragranular portion comprising at least one release modifier; wherein the release modifier is a hydroxypropyl methylcellulose or a mixture thereof,

wherein the composition has a dissolution profile of at least about 80% mean drug release between about 6 and 10 hours as measured using the paddle method (USP apparatus 2) with a stirring rate of 75 rotations per minute in 900 mL of phosphate buffer pH 8.0 with 0.5% hexadecyltrimethylammonium bromide at 37+0.5° C.

[0032] The pharmaceutical composition is a solid dosage form intended for oral administration. In some embodiments, the pharmaceutical composition is a tablet.

[0033] In some embodiments, the granules comprise dichlorphenamide, or a

pharmaceutically acceptable salt thereof in an amount between about 25 mg and about 200 mg. In some embodiments, the granules comprise dichlorphenamide, or a pharmaceutically acceptable salt thereof in an amount between about 100 mg and about 200 mg. In some embodiments, the granules comprise 25 mg dichlorphenamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the granules comprise 50 mg

dichlorphenamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the granules comprise 100 mg dichlorphenamide, or a pharmaceutically acceptable salt thereof.

In some embodiments, the granules comprise 200 mg dichlorphenamide, or a

pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the dichlorphenamide, or a pharmaceutically acceptable salt thereof is present in the granules in an amount of between about 50% w/w and about 70% w/w. In some embodiments, the dichlorphenamide, or a pharmaceutically acceptable salt thereof is present in the granules in an amount of between about 60% w/w and about 65% w/w. In some embodiments, the dichlorphenamide, or a pharmaceutically acceptable salt thereof is present in the granules in an amount of about 62% w/w.

[0035] In some embodiments, the dichlorphenamide, or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount of between about 15% w/w and about 45% w/w. In some embodiments, the dichlorphenamide, or a

pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount of between about 15% w/w and about 25% w/w. In some embodiments, the dichlorphenamide, or a pharmaceutically acceptable salt thereof is present in the

pharmaceutical composition in an amount of about 20% w/w. In some embodiments, the dichlorphenamide, or a pharmaceutically acceptable salt thereof is present in the

pharmaceutical composition in an amount of between about 35% w/w and about 45% w/w. In some embodiments, the dichlorphenamide, or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount of about 40% w/w.

[0036] In some embodiments, the one or more intragranular excipients are chosen from fillers, binders, and glidants.

[0037] In some embodiments, the one or more fillers are chosen from dibasic calcium phosphate, tribasic calcium phosphate, carmellose, sugar alcohols (such as mannitol, sorbitol, and xylitol), kaolin, lactose, sucrose, mannitol, cellulose, calcium carbonate, magnesium carbonate, starch, mixtures of isomaltulose derivatives (such as galenlQ), and mixtures thereof.

[0038] In some embodiments, the filler is lactose. In certain embodiments, the lactose is chosen from lactose monohydrate (such as Lactose FastFlo), lactose DT (direct tableting), lactose anhydrous, spray-dried monohydrate lactose, lactose-316 Fast Flo, microcrystalline cellulose co-processed with other excipients (such as microcrystalline cellulose coprocessed with lactose mono hydrate (MicroceLac 100) and microcrystalline cellulose co-processed with colloidal silicon dioxide (SMCCSO, Prosolv 50 and Prosolv HD 90), and mixtures thereof. In some embodiments, lactose is lactose monohydrate. The lactose monohydrate is amorphous, crystalline or a mixture thereof.

[0039] In some embodiments, the filler is starch. In certain embodiments, the starch is chosen from maize starch, potato starch, rice starch, wheat starch, pregelatinized starch, and mixtures thereof.

[0040] In some embodiments, the filler is cellulose. In certain embodiments, the cellulose is chosen from crystalline celluloses, powdered celluloses, and mixtures thereof. In some embodiments, crystalline cellulose is microcrystalline cellulose (such as such as Avicel PH 101, Avicel PH102, Avicel PH 200, Avicel PH 105, Avicel DG, Ceolus KG 802, Ceolus KG 1000, SMCCSO and Vivapur 200).

[0041] In some embodiments, the one or more fillers is a mixture of microcrystalline cellulose and lactose monohydrate.

[0042] In some embodiments, the one or more fillers is present in the granules in an amount of between about 20% w/w and about 40% w/w. In some embodiments, the one or more fillers is present in the granules in an amount of between about 25% w/w and about 35% w/w. In some embodiments, the one or more fillers is present in the granules in an amount of about 30% w/w.

[0043] In some embodiments, the one or more fillers is present in the pharmaceutical composition in an amount of between about 15% w/w and about 50% w/w. In some embodiments, the one or more fillers is present in the pharmaceutical composition in an amount of between about 15% w/w and about 25% w/w. In some embodiments, the one or more fillers is present in the pharmaceutical composition in an amount of about 19% w/w. In some embodiments, the one or more fillers is present in the pharmaceutical composition in an amount of between about 35% w/w and about 45% w/w. In some embodiments, the one or more fillers is present in the pharmaceutical composition in an amount of about 42% w/w.

[0044] In some embodiments, the one or more binders are chosen from hydroxypropyl celluloses in various grades, hydroxypropyl methylcelluloses in various grades,

polyvinylpyrrolidones in various grades, copovidones, powdered acacia, gelatin, guar gum, carbomers, methylcelluloses, poly methacrylates, starches, and mixtures thereof.

[0045] In some embodiments, the binder is starch. In certain embodiments, the starch is chosen from maize starch, potato starch, rice starch, wheat starch, pregelatinized starch, and mixtures thereof. In some embodiments, starch is pregelatinized starch. [0046] In some embodiments, the one or more binders is present in the granules in an amount of between about 5% w/w and about 15% w/w. In some embodiments, the one or more binders is present in the granules in an amount of between about 7% w/w and about 10% w/w.

[0047] In some embodiments, the one or more binders is present in the pharmaceutical composition in an amount of between about 2% w/w and about 10% w/w. In some embodiments, the one or more binders is present in the granules in an amount of between about 2% w/w and about 5% w/w.

[0048] In some embodiments, the one or more glidants are chosen from talc, colloidal silica (colloidal silicon dioxide), cornstarch, calcium silicate, magnesium silicate, colloidal silicon, silicon hydrogel, and mixtures thereof.

[0049] In some embodiments, the one or more glidants is colloidal silica, such as anhydrous colloidal silica.

[0050] In some embodiments, the one or more glidants is present in the granules in an amount of between about 0% w/w and about 2% w/w. In some embodiments, the one or more glidants is present in the granules in an amount of between about 0.3% w/w and about 0.5% w/w.

[0051] In some embodiments, the one or more glidants is present in the pharmaceutical composition in an amount of between about 0 and about 2% w/w. In some embodiments, the one or more glidants is present in the pharmaceutical composition in an amount of between about 0.3 and about 0.5% w/w.

[0052] In some embodiments, the release modifier is a hydroxypropyl methylcellulose or a mixture thereof chosen from low to medium viscosity hydroxypropyl methylcellulose and mixtures thereof. In some embodiments, the release modifier is a hydroxypropyl

methylcellulose or a mixture thereof chosen from Methocel E, Methocel E3, Methocel E5, Methocel E6, Methocel E15, Methocel E50, Methocel K, Methocel K3, Methocel K4M, Methocel K15M, Methocel K100LV, Methocel K100M, Methocel, Hypromellose type 1828, Hypromellose type 2208, Hypromellose type 2906, Hypromellose type 2910, Metolose 60SH (Type 2910), Metolose 65SH (Type 2906), Metolose 90SH (Type 2208), Methocel A, Methocel A15, Methocel A4C, Methocel A15C, Methocel A4M, Metolose SM, and mixtures thereof. In some embodiments, the release modifier is chosen from Hypromellose K100LV and Hypromellose E50, and mixtures thereof. In some embodiments, the release modifier is a mixture of Hypromellose K100LV and Hypromellose E50. [0053] In some embodiments, the release modifier is present in the pharmaceutical composition in an amount of between about 30% w/w and about 40% w/w. In some embodiments, the release modifier is present in the pharmaceutical composition in an amount of about 35% w/w.

[0054] In some embodiments, the extragranular portion further one or more extragranular excipients. In some embodiments, the one or more extragranular excipients comprises one or more lubricants. Lubricants can be present in an amount of about 0% w/w to about 10% by weight. Non-limiting examples of lubricants include magnesium stearate, stearic acid (stearin), hydrogenated oil, polyethylene glycol, sodium stearyl fumarate, and glyceryl behenate. In some embodiments, the lubricant is magnesium stearate.

[0055] In some embodiments, the one or more extragranular excipients comprises one or more fillers.

[0056] In some embodiments, the granules comprise:

dichlorphenamide, or a pharmaceutically acceptable salt thereof;

microcrystalline cellulose;

lactose monohydrate;

pregelatinized starch; and

colloidal silica.

[0057] In some embodiments, the extragranular portion comprises:

hydroxypropyl methylcellulose or a mixture thereof;

microcrystalline cellulose;

colloidal silica; and

magnesium stearate.

[0058] In some embodiments, the pharmaceutical composition comprises:

[0059] In some embodiments, the pharmaceutical composition comprises:

[0060] In some embodiments, the pharmaceutical composition comprises: [0061] In some embodiments, the pharmaceutical composition comprises:

[0062] In some embodiments, the pharmaceutical composition comprises:

[0063] In some embodiments, the pharmaceutical composition comprises:

[0064] In some embodiments, the patient may receive a dose of between 50 mg twice daily and 100 mg twice daily. In some embodiments, the dose is 50 mg once daily. In some embodiments, the dose is 50 mg once every other day. In some embodiments, the dose is 25 mg once daily. In some embodiments, the dose is 25 mg once every other day.

[0065] In some embodiments, the therapeutically effective amount of the

dichlorphenamide, or a pharmaceutically acceptable salt thereof, is between 25 mg and 200 mg per day.

[0066] In some embodiments, the therapeutically effective amount of the

dichlorphenamide, or a pharmaceutically acceptable salt thereof, is 50 mg twice daily.

[0067] In some embodiments, the dichlorphenamide, or a pharmaceutically acceptable salt thereof, is administered via a titration scheme that comprises the up-titration of the dichlorphenamide, or a pharmaceutically acceptable salt thereof, at weekly intervals until a modified dose is administered. In some embodiments, the modified dose of the

dichlorphenamide, or a pharmaceutically acceptable salt thereof, is 200 mg.

[0068] Also provided is a method of treating primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, or related variants in a patient in need thereof, comprising administering to the patient, a pharmaceutical composition described herein.

[0069] In some embodiments, the disease chosen from primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants; Aland Island eye disease atrial fibrillation, Brugada syndrome, cardiomyopathy, cerebellar syndrome, cone-rod dystrophy, cystoid macular edema of retinitis pigmentosa, Dravet syndrome, epilepsy, epileptic encephalopathy, episodic ataxia, myokymia syndrome, episodic pain syndrome, hemiplegic migraine, febrile seizures, heart block, intracranial hypertension, long QT syndrome, neuropathy, night blindness, paroxysmal exercise-induced dyskinesia, Rett syndrome, sick sinus syndrome, spinocerebellar ataxia, sudden infant death syndrome (SIDS), Timothy syndrome, and ventricular fibrillation.

[0070] In some embodiments, the disease chosen from primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants. In some

embodiments, the disease primary hyperkalemic periodic paralysis. In some embodiments, the disease is primary hypokalemic periodic paralysis. In some embodiments, the disease is a related variant to primary hyperkalemic periodic paralysis. In some embodiments, the disease is a related variant to primary hypokalemic periodic paralysis.

[0071] In some embodiments, the disease is Aland Island eye disease. In some embodiments, the disease is atrial fibrillation, such as familial atrial fibrillation. In some embodiments, the disease is Brugada syndrome, such as type 1 or type 3. In some embodiments, the disease is cardiomyopathy, such as dilated cardiomyopathy. In some embodiments, the disease is cerebellar syndrome in phosphomannomutase 2 (PMM2) deficiency, a congenital disorder of glycosylation. In some embodiments, the disease is cone- rod dystrophy, such as X-linked cone-rod dystrophy. In some embodiments, the disease is cystoid macular edema of retinitis pigmentosa. In some embodiments, the disease is Dravet syndrome. In some embodiments, the disease is epilepsy, such as generalized epilepsy, epilepsy type two, or epilepsy with febrile seizures. In some embodiments, the disease is epileptic encephalopathy, early infantile epileptic encephalopathy, which is an autosomal dominant form of the disease. In some embodiments, the disease is episodic ataxia, such as type 1, type 2, or type 5, or myokymia syndrome. In some embodiments, the disease is episodic pain syndrome, such as familial episodic pain syndrome. In some embodiments, the disease is hemiplegic migraine types, familial hemiplegic migraine types 1 and 3. In some embodiments, the disease is febrile seizures, such as familial febrile seizures. In some embodiments, the disease is heart block, such as nonprogressive heart block, and progressive heart block type IA. In some embodiments, the disease is intracranial hypertension, such as idiopathic intracranial hypertension. In some embodiments, the disease is long QT syndrome- 3. In some embodiments, the disease is neuropathy, hereditary neuropathy, sensory neuropathy, and autonomic neuropathy type VII. In some embodiments, the disease is night blindness, such as congenital stationary night blindness, and X-linked night blindness. In some embodiments, the disease is paroxysmal exercise-induced dyskinesia. In some embodiments, the disease is Rett syndrome. In some embodiments, the disease is sick sinus syndrome. In some embodiments, the disease is spinocerebellar ataxia, such as

spinocerebellar ataxia type 6. In some embodiments, the disease is sudden infant death syndrome (SIDS). In some embodiments, the disease is Timothy syndrome. In some embodiments, the disease is ventricular fibrillation, such as familial ventricular fibrillation.

[0072] Also provided is a process for the production of a pharmaceutical composition of any one of the preceding claims comprising:

mixing the granules comprising the dichlorphenamide, or a pharmaceutically acceptable salt thereof, the at least one release modifier, and optionally, the one or more extragranular excipients to form a tablet blend; and

compressing the tablet blend to form a tablet.

[0073] In some embodiments, the granules are prepared by a process comprising: wet granulating a mixture of the dichlorphenamide, or a pharmaceutically acceptable salt thereof, and the one or more intragranular excipients; and drying the wet granules.

[0074] The various embodiments described above can be combined to provide further embodiments. All references, including the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments. The discussion of those references is intended merely to summarize the assertions made by their authors. No admission is made that any reference (or a portion of any reference) is relevant prior art (or prior art at all). Applicant reserves the right to challenge the accuracy and pertinence of the cited references.

[0075] These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

[0076] The pharmaceutical compositions, methods, and uses described herein will be better understood by reference to the following exemplary embodiments and examples, which are included as an illustration of and not a limitation upon the scope of the invention.

EXAMPLES

Example 1 [0077] The concept of“design space” in pharmaceutical development has gained increasing acceptance through the publication of ICH Q8 guidance

(EMEA/CHMP/167068/2004-ICH Q8) documentation. Based on the concept of design space, the formulations are selected within the dose and excipient‘design space’. The dose and excipient‘design space’ are bracketed by the four formulations with a range of quantitative compositions for the drug substance level and the ratio of the two hypromellose grades, as shown below. In addition, the extragranular microcrystalline cellulose (MCC) level is adjusted to compensate for the variation in drug dose; all other extragranular components of the formulation will remain constant.

Dichlorphenamide Intragranule

[0078] The active component dichlorphenamide and intragranular excipients were weighed and (microcrystalline cellulose, lactose monohydrate, pregelatinized starch and silica, colloidal anhydrous) were transferred to a suitably sized granulation vessel and mixed. The resultant blend was then screened, returned to the granulation vessel and mixed. Sterile water for irrigation was then used to granulate the blend. After granulation was complete, the resultant granulate was mixed to ensure homogeneity. The wet granules were then screened and dried. Loss on drying (LOD) testing was performed as an in-process control to ensure the water had been removed from the granule. The dried granules were then screened to produce the dichlorphenamide intragranule. The intragranule may be stored before further processing.

Dichlorphenamide Modified Release Prototype Tablet

[0079] The extragranular excipients (microcrystalline cellulose (if required),

Hypromellose K100LV, Hypromellose E50, silica, colloidal anhydrous and magnesium stearate) were pre-screened before use. The dichlorphenamide intragranule and screened extragranular excipients (with the exception of the magnesium stearate) were transferred into a suitably sized mixing vessel and blended. The blend was then screened, returned to the mixing vessel and blended. The pre-screened magnesium stearate was added to the mixing vessel and blended to produce the dichlorphenamide tablet blend. The tablet blend was compressed into tablets.

Assay, Identification and Related Substances

[0080] A reverse phase gradient HPLC method was used for the assay, identification and related substances tests. The method details are provided below.

Method for Assay, ID and Related Substances

Method for Dissolution

[0081] The Pharmacopoeial dissolution method (harmonized monograph Ph. Eur. 2.9.3 / USP <711 >) was used. Details are given below.

rpm: rotations per minute

[0082] Samples were analyzed for Dichlorphenamide content using the HPLC method as provided below. Method for HPLC Analysis for Dissolution

[0083] Batch analysis data for four representative batches (one batch of each presentation FPA - FPD) is provided below. As previously discussed, the composition of

Dichlorphenamide Modified Release Prototype Tablet, 100-200 mg FPA, FPB, FPC and FPD bracket the potential composition of any Dichlorphenamide Modified Release Prototype Tablet, 100 - 200 mg within the defined design space that will be manufactured and dosed in this clinical study.

Analysis Data for Dichlorphenamide Modified Release Prototype Tablet, 100 - 200 mg Formulation FPA, FPB, FPC, FPD

Stability Data

[0084] Stability data for the representative batches are shown below.

Stability Data for Dichlorphenamide Modified Release Prototype Tablet, 100 - 200 mg FPA (Low Dose, Slow Release)

Stability Data for Dichlorphenamide Modified Release Prototype Tablet, 100 - 200 mg FPB (Low Dose, Fast Release)

Stability Data for Dichlorphenamide Modified Release Prototype Tablet, 100 - 200 mg FPC (High Dose, Slow Release)

Stability Data for Dichlorphenamide Modified Release Prototype Tablet, 100 - 200 mg

FPD (High Dose, Fast Release)

[0085] Based on the above stability data, a shelf life of at least 35 days was assigned to the Dichlorphenamide Modified Release Prototype Tablet, 100 - 200 mg FPA, FPB, FPC and FPD when stored at 15°C to 25 °C.

[0086] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations, or methods, or any combination of such changes and modifications of use of the invention, may be made without departing from the spirit and scope thereof.




 
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