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US-12616693-B2 - Bromocriptine formulations

US12616693B2US 12616693 B2US12616693 B2US 12616693B2US-12616693-B2

Abstract

The present application describes pharmaceutical formulations of bromocriptine mesylate and methods of manufacturing and using such formulations. The formulations are useful for improving glycemic control in the treatment of type 2 diabetes.

Inventors

  • Anthony H. Cincotta
  • Craig Michael Bowe
  • Paul Clark Stearns
  • Laura Jean Weston

Assignees

  • VEROSCIENCE LLC

Dates

Publication Date
20260505
Application Date
20230426

Claims (7)

  1. 1 . A dosage form comprising micronized bromocriptine mesylate and one or more excipients in the form of an oral tablet; wherein the micronized bromocriptine mesylate is present in an amount that provides a dose of at least about 0.8 mg of bromocriptine per said oral tablet; and wherein the micronized bromocriptine mesylate has a Dv90 of less than about 20 μm, a Dv50 of about 7.2 μm or less, a Dv10 of about 2.5 μm or less, and has a particle size distribution with a span of about 1.8 or lower, and not more than about 20% of the bromocriptine mesylate has a particle size of less than 1 μm; and wherein the oral tablet has a dissolution profile wherein not more than 50% of the bromocriptine mesylate has been released at about 7 minutes, not more than about 75% of the bromocriptine mesylate has been released at about 10 minutes, and wherein at least about 90% of the bromocriptine mesylate has been released at about 30 minutes, when tested in USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloric acid at about 37° C.
  2. 2 . The dosage form of claim 1 , wherein the micronized bromocriptine mesylate has a Dv90 of less than about 10 μm.
  3. 3 . The dosage form of claim 1 , wherein said dosage form exhibits a pharmacokinetic profile wherein the time to maximum plasma concentration (T max ) of bromocriptine is between about 30 and about 60 minutes following administration of the dosage form to the subject under fasting conditions or the T max of bromocriptine is between about 90 and about 120 minutes following administration of the dosage form to the subject under high fat fed conditions.
  4. 4 . A method of improving glycemic control in a type 2 diabetes patient, comprising administering the dosage form of claim 1 to the patient.
  5. 5 . The method of claim 4 , wherein the bromocriptine mesylate is administered to the patient in an amount that provides a daily dose of about 0.8 mg to about 4.8 mg of bromocriptine.
  6. 6 . A method of improving glycemic control in a type 2 diabetes patient, comprising administering the dosage form of claim 2 to the patient.
  7. 7 . A method of improving glycemic control in a type 2 diabetes patient, comprising administering the dosage form of claim 3 to the patient.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of currently pending U.S. application Ser. No. 16/878,451, filed May 19, 2020, which is a continuation of currently pending U.S. application Ser. No. 16/393,463, filed Apr. 24, 2019, which is a continuation of U.S. application Ser. No. 15/981,752, filed May 16, 2018, now U.S. Pat. No. 10,307,421, which is a continuation of U.S. application Ser. No. 15/618,055, filed Jun. 8, 2017, now U.S. Pat. No. 9,993,474, which is a continuation of U.S. application Ser. No. 15/286,826, filed Oct. 6, 2016, now U.S. Pat. No. 9,700,555, which is a continuation of U.S. application Ser. No. 14/920,123, filed Oct. 22, 2015, now U.S. Pat. No. 9,522,117, which is a continuation of U.S. application Ser. No. 14/088,269, filed Nov. 22, 2013, now U.S. Pat. No. 9,192,576, which is a continuation of U.S. application Ser. No. 13/773,500, filed Feb. 21, 2013, now U.S. Pat. No. 8,613,947, which is a continuation of U.S. application Ser. No. 13/460,452, filed Apr. 30, 2012, now U.S. Pat. No. 8,431,155, the entire content of each of which is incorporated herein by reference. TECHNICAL FIELD This invention relates to pharmaceutical formulations and methods of their manufacture and use, and more particularly to formulations of bromocriptine mesylate that are useful for treating type 2 diabetes. BACKGROUND Bromocriptine ((5′α)-2-bromo-12′-hydroxy-T-(1-methylethyl)-5′-(2-methylpropyl)-ergotaman-3′,6′,18-trione, CAS Registry No. 25614-03-3) is an ergot alkaloid which is a potent dopamine D2 receptor agonist. The compound has the following formula: Solid oral dosage forms of bromocriptine are available as bromocriptine mesylate ((5′α)-2-bromo-12′-hydroxy-2′-(1-methylethyl)-5′-(2-methylpropyl)-ergotaman-3′,6′,18-trione monomethanesulfonate salt, CAS Registry No. 22260-51-1) in a tablet containing up to 2.5 mg bromocriptine or in capsule form containing 5 mg bromocriptine. Bromocriptine is useful in the treatment of certain hyperprolactinemia-associated dysfunctions and acromegaly, in the prevention of physiological lactation, and in the treatment of Parkinson's disease and prevention of tolerance to Levodopa therapy for Parkinson's disease. In clinical trials, adverse effects included nausea, headache, dizziness, fatigue, lightheadedness, vomiting, abdominal cramps, nasal congestion, constipation, diarrhea and drowsiness. When bromocriptine is used as described above, prolactin is reduced to low levels throughout a 24 hour period. U.S. Pat. Nos. 5,344,832, 5,554,623 and 5,716,957 discuss a method for modifying and regulating lipid and glucose metabolism by administering a dopamine agonist, e.g., bromocriptine, and/or a prolactin stimulator to reset hormonal timing in the neural centers of the brain to control insulin resistance, hyperinsulinemia and hyperglycemia. U.S. Pat. Nos. 5,468,755, 5,756,513 and 5,866,584 discuss a method to modify and regulate lipid and carbohydrate metabolism-generally to reduce obesity, insulin resistance, hyperinsulinemia and hyperglycemia, by administration of a dopamine agonist such as bromocriptine to inhibit prolactin over a limited period at a time of day to reset normal hormonal timing and control insulin resistance, hyperinsulinemia and hyperglycemia. U.S. Pat. No. 5,679,685 discusses accelerated release bromocriptine mesylate formulations for regulating prolactin levels that are abnormal during particular times during the day. WO/2009/091576 discusses compositions for parenteral administration using dopamine agonists such as bromocriptine, that are described as being useful for treating metabolic-related conditions such as type 2 diabetes. CYCLOSET®, a tablet form of bromocriptine mesylate providing a 0.8 mg dose of bromocriptine, is FDA approved for once-daily administration to improve glycemic control in adults with type 2 diabetes mellitus, at a dose of 2-6 tablets (1.6 to 4.8 mg total dose). SUMMARY In one aspect, the present application provides an oral dosage form, for example a tablet, which includes micronized bromocriptine mesylate and one or more excipients. The micronized bromocriptine mesylate is present in an amount that provides a dose of at least about 0.8 mg of bromocriptine per dosage form and has Dv90 of less than about 10 μm. The dosage form provides a dissolution profile, when tested in USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloric acid at about 37° C., wherein at least about 90% of the bromocriptine mesylate has been released at about 30 minutes. In a further aspect, the present application provides a further method for the manufacture of a bromocriptine mesylate tablet. The method includes processing bromocriptine mesylate to reduce the average particle size of the bromocriptine mesylate to provide bromocriptine mesylate that has a Dv90 of less than about 20 μm and blending the processed bromocriptine mesylate with excipients to form a mixture wherein the bromocriptine mesylate is sub