Improved bromocriptine formulations

Abstract

To provide improved bromocriptine formulations.SOLUTION: Disclosed herein are pharmaceutical formulations of bromocriptine and methods of manufacturing and using the formulations. The pharmaceutical formulations are useful for treating physiological disorders, including improving glycemic control in treatment of type 2 diabetes. Also disclosed is synthesis of bromocriptine citrate, and compositions and dosage forms containing bromocriptine citrate.SELECTED DRAWING: Figure 1A

Description

[Technical field]

[0001] The present invention relates to pharmaceutical formulations and methods of making and using same, and more particularly to formulations of bromocriptine useful for treating metabolic or physiological disorders, including type 2 diabetes mellitus (T2DM), and also to the synthesis of bromocriptine citrate, and compositions and dosage forms containing bromocriptine citrate that provide increased stability and water solubility compared to prior art bromocriptine dosage forms. The present invention also relates to the synthesis of bromocriptine citrate, and compositions and dosage forms containing bromocriptine citrate that provide increased heat and moisture resistance and water solubility and stability compared to prior art bromocriptine dosage forms. In another aspect, the present invention relates to methods of using these compositions and dosage forms for the treatment of metabolic disorders, including type 2 diabetes mellitus (T2DM). [Background technology]

[0002] Bromocriptine ((5'α)-2-bromo-12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl)-ergotaman-3',6',18-trione, CAS Registry No. 25614-03-3) is an ergot alkaloid that is a potent dopamine D2 receptor agonist. The compound has the formula:

[0003] [ka]

[0004] 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, CAS Registry No. 22260-51-1) in pharmaceutical preparations (e.g. tablets) containing up to 2.5 mg of bromocriptine or in capsules containing 5 mg of bromocriptine. This dosage form of bromocriptine is useful for treating certain hyperprolactinemia-related dysfunctions and acromegaly, preventing physiological lactation, and treating Parkinson's disease and preventing resistance to levodopa therapy for Parkinson's disease. In clinical trials, side effects include nausea, headache, dizziness, fatigue, lightheadedness, nausea, abdominal cramps, nasal congestion, constipation, diarrhea, and drowsiness. Bromocriptine is used as previously described in appropriate volumes. Prolactin is reduced to low levels for 24 hours. CYCLOSET®, a pharmaceutical formulation of bromocriptine mesylate providing a 0.8 mg dose of bromocriptine per tablet, is FDA approved for once daily administration, with 2-6 tablets (total dose of 1.6-4.8 mg) improving glycemic control in adults with type 2 diabetes. U.S. Patents Nos. 8,741,918 and 9,41,005 disclose compositions for parenteral administration using dopamine agonists such as bromocriptine that are useful for treating metabolic-related conditions such as type 2 diabetes.

[0005] Bromocriptine, particularly bromocriptine mesylate, is susceptible to photo-, thermal- and water-degradation by oxidation and isomerization to form bromocriptinine and other by-products, as well as chemical degradation in acidic environments. Bromocriptine and bromocriptine mesylate are particularly susceptible to water-promoted degradation, particularly acidic water-promoted degradation, limiting the bioavailability of bromocriptine.

[0006] US Pat. No. 4,654,345 describes a lyophilized formulation of bromocriptine for eye drop formulation that provides a reconstituted formulation with improved stability.

[0007] U.S. Pat. No. 5,066,495 describes a process for preparing bromocriptine formulations with improved stability by including in the excipients or by separate granulation of the excipients, and mixing the granulation with a mixture of the active ingredient and excipients having a low moisture content.

[0008] U.S. Patent Nos. 5,344,832, 5,554,623 and 5,716,957 discuss methods of modifying and controlling lipid and glucose metabolism by administering dopamine agonists, such as bromocriptine and / or prolactin stimulants, to reset hormone timing in neural centers of the brain to control insulin resistance, hyperinsulinemia and hyperglycemia.

[0009] U.S. Patent Nos. 5,468,755, 5,756,513, and 5,866,584 discuss methods of modifying and controlling lipid and glucose metabolism to generally reduce obesity, insulin resistance, hyperinsulinemia, and hyperglycemia by administering a dopamine agonist such as bromocriptine to inhibit prolactin for limited times of the day, resetting normal hormone timing, and controlling insulin resistance, hyperinsulinemia, and hyperglycemia.

[0010] US Patent No. 5,523,082 describes a lyophilized formulation of bromocriptine mesylate for an ophthalmic formulation that provides a solution with improved stability of bromocriptine in solution.

[0011] US Pat. No. 5,679,685 discusses accelerated release of bromocriptine mesylate to control abnormal prolactin levels at specific times during the day.

[0012] US Pat. No. 5,814,638 discusses lyophilized bromocriptine formulations containing cyclodextrins that have improved stability.

[0013] US Pat. Nos. 9,192,576, 8,613,947 and 8,431,155 describe pharmaceutical formulations of micronized bromocriptine mesylate for oral use. Summary of the Invention

[0014] Bromocriptine mesylate may become soluble under high temperature conditions, exposure to light, or in aqueous environments, especially acidic water. Bromocriptine is not stable in aqueous environments. Moreover, bromocriptine is very poorly soluble in aqueous environments. This situation limits the shelf life of the compound and, importantly, also limits the bioavailability of the compound since living systems (particularly plasma and cells) are largely aqueous. What is needed is a bromocriptine formulation that is highly water-soluble (extremely more water-soluble than bromocriptine mesylate) and at the same time stable in aqueous environments (not unstable to water-facilitated degradation). Since water destroys bromocriptine, it is highly counterintuitive to increase the stability of bromocriptine by making it more water-soluble (i.e., more accessible to water). The present invention provides such a unique bromocriptine formulation.

[0015] After substantial experimentation with various dosing regimens, it has been surprisingly found that bromocriptine formulated as a citrate salt (referred to as bromocriptine citrate) has significantly higher water solubility than bromocriptine mesylate, in contrast to the general teaching in the art that the mesylate salt provides higher water solubility than other salts, including the citrate salt. Furthermore, bromocriptine mesylate or bromocriptine citrate in certain excipient combinations have the unique ability to significantly improve the heat resistance (i.e., protection against thermal degradation), aqueous / aqueous stability (i.e., protection against aqueous / aqueous degradation of bromocriptine), and aqueous / aqueous solubility of bromocriptine in its traditional dosage form, as compared to bromocriptine mesylate (see Table 1). As a result, compared to bromocriptine mesylate in its traditional dosage form (see Table 1), especially in the formulations described herein in excipients containing short chain sugars, fatty acids or triglycerides, and citric acid, bromocriptine citrate exhibits better shelf life (storage stability) in pharmaceutical formulations and further provides longer stability characteristics (i.e., longer duration of adequate drug activity) in drug preparations with respect to bromocriptine dissolution, allowing longer storage periods between drug manufacture and drug administration, and / or less stringent storage conditions (in terms of humidity or temperature). This feature allows for a more flexible (and therefore less expensive) manufacturing process.

[0016] In one aspect, the disclosure provides a pharmaceutical formulation (e.g., a tablet) comprising bromocriptine (e.g., bromocriptine mesylate or a different bromocriptine salt, e.g., bromocriptine citrate) and an excipient, wherein the bromocriptine is present in an amount providing a dose of at least about 0.1 mg of bromocriptine per pharmaceutical formulation, and the excipient comprises a triglyceride.

[0017] In some embodiments, at least about 80% of the acyl groups of the triglyceride are C 14 -C 26In some embodiments, at least about 90% of the acyl groups of the triglyceride are C 14 -C 26 In some embodiments, at least about 80% of the acyl groups of the triglyceride are C 16 -C 20 In some embodiments, at least about 90% of the acyl groups of the triglyceride are C 16 -C 20 In some embodiments, at least about 80% of the acyl groups of the triglyceride are C 18 In some embodiments, at least about 90% of the acyl groups of the triglyceride are C 18 The fatty acid acyl group of the fatty acid. In some embodiments, at least about 80% of the acyl groups of the triglyceride are stearoyl or 12-hydroxystearoyl groups. In some embodiments, at least about 90% of the acyl groups of the triglyceride are stearoyl or 12-hydroxystearoyl groups. In some embodiments, at least about 80% of the acyl groups of the triglyceride are saturated. In some embodiments, at least about 90% of the acyl groups of the triglyceride are saturated.

[0018] In some embodiments, the excipient comprises hydrogenated vegetable oil. In some embodiments, the excipient comprises hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated palm kernel oil, hydrogenated soybean oil, or a combination thereof. In some embodiments, the excipient comprises hydrogenated castor oil. In some embodiments, the excipient comprises KOLLIWAX® HCO.

[0019] In some embodiments, the triglyceride excipient is present in an amount of about 0.5% to about 20% by weight of the formulation.

[0020] In some embodiments, the excipient is a particular sugar (eg, a monosaccharide or a disaccharide excluding lactose).

[0021] In some embodiments, the excipient is extragranular.

[0022] In some embodiments, the pharmaceutical formulation (e.g., tablet) is stable when prepared in a pharmaceutical standard foil sealed plastic container and desiccant included in the container in the following embodiments: In some embodiments, the pharmaceutical formulation (e.g., tablet) is stable such that it contains no more than 5% total related substances (degradants) after about 18 months of storage at a temperature of 25±2° C. and about 60±5% relative humidity, as determined by HPLC analysis using detection of UV absorbance at 300 nm. In some embodiments, the pharmaceutical formulation is stable such that it contains no more than 5% total related substances after about 24 months of storage at a temperature of 25±5° C. and about 60±5% relative humidity, as determined by HPLC analysis using detection of UV absorbance at 300 nm. In some embodiments, the pharmaceutical formulation is stable such that it contains no more than 5% bromocriptinine after about 18 months of storage at a temperature of 25±2° C. and about 60±5% relative humidity, as determined by HPLC analysis using detection of UV absorbance at 300 nm. In some embodiments, the pharmaceutical formulation is stable such that it contains 5% or less bromocriptinine as determined by HPLC analysis using detection of UV absorbance at 300 nm after about 24 months of storage at a temperature of 25±5° C. and a relative humidity of about 60±5%. In some embodiments, the pharmaceutical formulation is stable such that it contains 3% or less total related substances as determined by HPLC analysis using detection of UV absorbance at 300 nm after about 6 weeks of storage at a temperature of 40±2° C. and a relative humidity of about 70±5%.

[0023] In some embodiments, the pharmaceutical formulation (e.g., tablet) is stable such that it contains 8% or less total related substances (degradants) after storage for about 18 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0024] In some embodiments, the pharmaceutical formulation is stable such that it contains 8% or less total related substances after storage at a temperature of 25±5° C. and a relative humidity of about 60±5% for about 24 months, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0025] In some embodiments, the pharmaceutical formulation is stable such that it contains no more than 8% bromocriptine after storage for about 18 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0026] In some embodiments, the pharmaceutical formulation is stored at a temperature of 25±5° C. and at a relative humidity of about 60±5%. After storage at room temperature for approximately 24 months, the pharmaceutical formulation is stable to contain less than 8% bromocriptine as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0027] In some embodiments, the pharmaceutical formulation is stable such that it contains no more than 1% total related substances after storage for about 6 weeks at a temperature of 40±2° C. and a relative humidity of about 70±5%, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0028] In some embodiments, the pharmaceutical formulation is stable such that it contains 8% or less total related substances after storage for about 6 months at a temperature of 40±2° C. and a relative humidity of about 70±5%, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0029] In some embodiments, the disclosure provides a pharmaceutical formulation (e.g., tablet) comprising micronized bromocriptine in an amount providing a dose of at least about 0.1 mg per pharmaceutical formulation, wherein the pharmaceutical formulation is stable such that the pharmaceutical formulation contains no more than 5% bromocriptine after about 18 months of storage at a temperature of 25±2° C. and at a relative humidity of about 60±5% as determined by HPLC analysis using detection of UV absorbance at 300 nm. In some embodiments, the pharmaceutical formulation is stable such that the pharmaceutical formulation contains no more than 5% total related substances after about 18 months of storage at a temperature of 25±2° C. and at a relative humidity of about 60±5% as determined by HPLC analysis using detection of UV absorbance at 300 nm. In some embodiments, the pharmaceutical formulation is stable such that the pharmaceutical formulation contains no more than 5% bromocriptine after about 24 months of storage at a temperature of 25±2° C. and at a relative humidity of about 60±5% as determined by HPLC analysis using detection of UV absorbance at 300 nm. In some embodiments, the pharmaceutical formulation is stable such that after storage at a temperature of 25±2° C. and at a relative humidity of about 60±5%, the pharmaceutical formulation contains no more than 5% total related substances as determined by HPLC analysis using detection of UV absorbance at 300 nm after about 24 months. In some embodiments, the pharmaceutical formulation is stable such that after storage at a temperature of 25±2° C. and at a relative humidity of about 60±5%, the pharmaceutical formulation contains no more than 3% bromocriptine as determined by HPLC analysis using detection of UV absorbance at 300 nm after about 18 months. In some embodiments, the pharmaceutical formulation is stable such that after storage at a temperature of 25±2° C. and at a relative humidity of about 60±5%, the pharmaceutical formulation contains no more than 3% total related substances as determined by HPLC analysis using detection of UV absorbance at 300 nm after about 18 months. In some embodiments, the pharmaceutical formulation is stable such that it contains no more than 3% bromocriptine after storage for about 24 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, as determined by HPLC analysis using detection of UV absorbance at 300 nm.In some embodiments, the pharmaceutical formulation is stable such that it contains no more than 3% total related substances after storage for about 24 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0030] In some embodiments, the pharmaceutical formulation is stable such that it contains no more than 8% bromocriptinine after storage for about 18 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0031] In some embodiments, the pharmaceutical formulation is stable such that it contains 8% or less total related substances after storage for about 18 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, as determined by HPLC analysis using detection of UV absorbance at 300 nm. It is fixed.

[0032] In some embodiments, the pharmaceutical formulation is stable such that it contains no more than 8% bromocriptine after storage for at least 24 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0033] In some embodiments, the pharmaceutical formulation is stable such that it contains 8% or less total related substances after storage for about 24 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0034] In some embodiments, the pharmaceutical formulation is stable such that it contains no more than 1% total related substances after storage for about 6 weeks at a temperature of 40±2° C. and a relative humidity of about 70±5%, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0035] In some embodiments, the pharmaceutical formulation is stable such that it contains 8% or less total related substances after storage for about 6 months at a temperature of 40±2° C. and a relative humidity of about 70±5%, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0036] In some embodiments of the aforementioned pharmaceutical formulations, the bromocriptine is micronized.

[0037] In some embodiments, bromocriptine has a Dv90 of about 20 μm or less.

[0038] In some embodiments, bromocriptine has a Dv90 of about 10 μm or less.

[0039] In some embodiments, bromocriptine has a Dv90 of about 5 μm or less.

[0040] In some embodiments, bromocriptine has a Dv99 of about 20 μm or less.

[0041] In some embodiments, bromocriptine has a Dv99 of about 10 μm or less.

[0042] In some embodiments, the bromocriptine has a volume-based particle size distribution, with no more than about 20% of the bromocriptine having a particle size less than about 1 μm.

[0043] In some embodiments, the pharmaceutical formulation provides dissolution characteristics when tested in a USP Apparatus Type 2 Paddle Method at about 37° C. in 500 ml of 0.1 N hydrochloric acid at 50 rpm, where at least about 80% of the bromocriptine is released in about 30 minutes.

[0044] In some embodiments, the pharmaceutical formulation provides dissolution characteristics when tested in a USP Apparatus Type 2 Paddle Method at about 37° C. in 500 ml of 0.1 N hydrochloric acid at 50 rpm, where at least about 90% of the bromocriptine is released in about 30 minutes.

[0045] In some embodiments, the pharmaceutical formulation provides dissolution characteristics when tested in a USP Apparatus Type 2 Paddle Method at about 37° C. in 500 ml of 0.1 N hydrochloric acid at 50 rpm, where at least about 95% of the bromocriptine is released in about 30 minutes.

[0046] In some embodiments, the pharmaceutical formulation provides dissolution characteristics when tested in a USP Apparatus Type 2 Paddle Method at about 37° C. in 500 ml of 0.1 N hydrochloric acid at 50 rpm, where at least about 90% of the bromocriptine is released in about 20 minutes.

[0047] In some embodiments, the pharmaceutical formulation provides a dissolution profile when tested in a USP Apparatus Type 2 Paddle Method at about 37° C. in 500 ml of 0.1 N hydrochloric acid at 50 rpm, where about 50% or less of the bromocriptine is released in about 7 minutes.

[0048] In some embodiments, the pharmaceutical formulation provides a dissolution profile when tested in a USP Apparatus Type 2 Paddle Method at about 37° C. in 500 ml of 0.1 N hydrochloric acid at 50 rpm, where about 75% or less of the bromocriptine is released in about 10 minutes.

[0049] In some embodiments, the pharmaceutical formulation provides pharmacokinetic and time to maximum plasma concentration (T) following administration of the pharmaceutical formulation (e.g., six pharmaceutical formulations each containing a dose of 0.8 mg bromocriptine) to an adult subject. max ) is approximately 30 to 60 minutes when the pharmaceutical preparation is administered under fasting conditions.

[0050] In some embodiments, the pharmaceutical formulation provides a pharmacokinetic profile comprising: a) a Tmax from about 1 to about 90 minutes after administration of the parenteral dosage form, and b) a plasma drug concentration of at least 50% of Cmax for a duration of from about 90 to about 360 minutes after Tmax when the dosage form is administered parenterally.

[0051] In some embodiments, the pharmaceutical formulation comprises citric acid as an excipient, hi some embodiments, the citric acid is present in an amount of about 1% to about 7% by weight.

[0052] In some embodiments, the pharmaceutical formulation comprises a disintegrant, hi some embodiments, the disintegrant is present in an amount of about 5% to about 20% by weight.

[0053] In some embodiments, bromocriptine is present in an amount to provide a dose of about 0.8 mg per pharmaceutical formulation.

[0054] In some embodiments, the pharmaceutical formulation comprises a triglyceride or diglyceride or a phospholipid, including a phosphatidylcholine.

[0055] In some embodiments, the pharmaceutical formulation comprises short chain sugars excluding lactose.

[0056] In some embodiments, the short chain sugar comprises mannitol. In some embodiments, the pharmaceutical formulation comprises a fatty acid, stearic acid. In another aspect, the disclosure provides a method of making a bromocriptine pharmaceutical formulation comprising mixing bromocriptine with an excipient to form a mixture, wherein the bromocriptine is substantially uniformly distributed in the mixture, and compressing the mixture to form the pharmaceutical formulation.

[0057] In some embodiments, the methods process bromocriptine to reduce the average particle size of bromocriptine to provide bromocriptine having a Dv90 of about 20 μm or less prior to blending.

[0058] In some embodiments, the method includes determining that the bromocriptine has a particle size distribution equivalent to a volume-based particle size distribution with a Dv90 of about 20 μm or less prior to mixing.

[0059] In some embodiments, the bromocriptine can have a diameter of 0.1 to 100 um.

[0060] In one aspect, the disclosure provides a pharmaceutical formulation prepared according to such a method.

[0061] In some embodiments, the disclosure provides a method of treating a metabolic disorder, including T2DM, in a subject in need of such treatment, the method comprising administering to the subject a solid dosage form, such as a tablet or capsule, containing bromocriptine citrate, mannitol, and short chain sugars, such as stearic acid.

[0062] In another embodiment, the method can include orally and / or parenterally administering to the subject a solid dosage form containing bromocriptine citrate, mannitol, and short chain sugars such as stearic acid. The formulation can also include citric acid.

[0063] Any of the aforementioned methods can include administering to the subject about 0.05 μg to about 0.5 mg / kg per day of bromocriptine citrate.

[0064] Oral formulations generally contain 30-60% by weight of short-chain sugars, and parenteral (sublingual) formulations contain 60-90% by weight of short-chain sugars.

[0065] Any of the above methods can further include treating the subject with one or more additional therapeutic regimens.The additional therapeutic regimen can include, for example, administering one or more dopamine D1 receptor agonists, alpha-1 adrenergic antagonists, alpha-2 adrenergic antagonists, serotonergic inhibitors, and / or serotonin 5HT1b agonists.Alternatively, or in addition, the additional therapeutic regimen can include, for example, administering one or more peripheral acting agents.

[0066] In some embodiments, the disclosure provides a formulation containing micronized bromocriptine citrate, a short chain sugar such as mannitol, a fatty acid such as stearic acid or a triglyceride, and citric acid as excipients.

[0067] In some embodiments, the disclosure provides a formulation containing 0.1-10% bromocriptine citrate, 0.1-10% citric acid, 30-90% non-lactose short chain saccharides, and 0.2-10% free fatty acids, phospholipids, or triglycerides.

[0068] In some embodiments, the disclosure provides a formulation containing 0.1-10% bromocriptine citrate, 0.1-10% citric acid, 60-90% non-lactose short chain saccharides, and 0.2-10% free fatty acids, phospholipids, or triglycerides.

[0069] In another embodiment, the present disclosure provides a composition comprising (by weight) 0.1-8% bromocriptine citrate, 0.5-8% citric acid, 65-90% non-lactose short chain saccharides, and 0.2-5 % free fatty acid, phospholipid or triglyceride.

[0070] In one preferred embodiment, the disclosure provides a formulation containing (by weight) 0.1-5% bromocriptine citrate, 0.5-5% citric acid, 70-90% non-lactose short chain saccharides, and 0.2-3.0% free fatty acids, phospholipids, or triglycerides.

[0071] In some embodiments, the present disclosure provides methods of treating metabolic disorders, including T2DM, in a subject in need of such treatment by administering to the subject a solid dosage form, such as a tablet or capsule, containing (micronized) bromocriptine citrate, a short chain sugar, such as mannitol, a fatty acid, such as stearic acid or a triglyceride, and citric acid.

[0072] In another embodiment, the method can include orally and / or parenterally administering to the subject a solid dosage form that includes bromocriptine citrate, a short chain sugar such as mannitol, a fatty acid such as stearic acid or a triglyceride. The formulation can also include citric acid.

[0073] The term "parenteral administration" is defined herein to mean a dosage form or formulation that results in absorption of a substantial amount of a drug through other than the gastric and / or intestinal mucosa of the gastrointestinal tract.

[0074] Any of the aforementioned methods can include administering to the subject about 0.05 μg to about 0.5 mg / kg per day of bromocriptine citrate.

[0075] Any of the foregoing methods can further include treating the subject with one or more additional therapeutic regimens. Alternatively, or in addition, the additional therapeutic regimen can include, for example, administering one or more peripheral acting agents. In one aspect, the present disclosure provides a method of treatment for improving glycemic control in a patient with type 2 diabetes, comprising administering to or providing to the patient one or more bromocriptine pharmaceutical formulations described herein.

[0076] In one aspect, the disclosure provides a method of treatment for improving glycemic control or key elements of metabolic disorders in a patient with type 2 diabetes, comprising manufacturing one or more bromocriptine pharmaceutical formulations according to the manufacturing methods disclosed herein, administering the one or more pharmaceutical formulations to a patient, or providing the one or more pharmaceutical formulations to a patient for administration.

[0077] In one aspect, the disclosure provides a method or key elements thereof for treating a metabolic disorder by administering a bromocriptine formulation described herein within 4 hours after awakening in the morning, or within about 4 hours after awakening in the morning, to produce a daily peak of dopamine agonist activity in the body.

[0078] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages will be apparent from the description and drawings, and from the claims. [Brief description of the drawings]

[0079] [Figure 1A] Figure 1 shows plots of total related substance impurities measured for micronized bromocriptine mesylate and bromocriptine mesylate pharmaceutical formulations prepared using various lubricants after storage for 1, 2 or 3 months at 40±2°C and 75±5% RH at the beginning of an experiment to measure product stability (T=0). [Figure 1B] Figure 1 shows plots of total related substance impurities measured for micronized bromocriptine mesylate and bromocriptine mesylate pharmaceutical formulations prepared using various lubricants after storage for 3 months at 30±2°C and 65±5% RH at the beginning of an experiment to measure product stability (T=0). [Figure 1C] Figure 1 shows plots of total related substance impurities measured for micronized bromocriptine mesylate and bromocriptine mesylate pharmaceutical formulations prepared using various lubricants after storage for three months at 25±2°C and 60±5% RH at the beginning of an experiment to measure product stability (T=0). [Diagram 2] 1 shows plots of the effect of various additives on the degradation of bromocriptine (as assessed through the formation of browning compounds) as a function of time exposed to a heated aqueous environment. [Diagram 3]1 shows typical chromatograms of a blank solution, a reference bromocriptine mesylate solution containing 0.112 mg / ml bromocriptine mesylate, and a sample solution prepared from a bromocriptine mesylate pharmaceutical formulation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0080] "About" or "approximately" as used herein means approximately, for example, about ±10% of the indicated value.

[0081] "Particle," as used herein, refers to an aggregated physical unit, i.e., a speck or grain, of a compound (eg, bromocriptine mesylate or a different bromocriptine salt, such as bromocriptine citrate).

[0082] "Particle size," as used herein, refers to the average linear dimension of a particle of a compound, for example, the diameter of a spherical particle of the compound.

[0083] "Micronization," as used herein, refers to the process of reducing the average particle size of a solid material to provide particles typically a few microns in size.

[0084] "Micronized," as used herein, refers to a material that has been subjected to micronization.

[0085] "Short chain sugars" as used herein refers to mono- or disaccharides (excluding lactose) and includes, but is not limited to, mannitol, xylitol, glucose, maltose, sucrose, galactose, fructose and sorbitol.

[0086] The term "oral dosage form" refers to a form of a drug that results in absorption of a substantial amount of the drug through the gastric and / or intestinal mucosa of the intestinal tract.

[0087] The term "pharmaceutical formulation" refers to an oral dosage form that comprises a mixture of active substances and excipients, usually in powder form, that are pressed or compressed from the powder into a solid dose.

[0088] "Particle size distribution" as used herein refers to the relative distribution of particles of a compound, such as bromocriptine mesylate or different bromocriptine salts, e.g., bromocriptine citrate, having a given particle size. The particle size of a spherical object can be clearly and quantitatively defined by its diameter, and particles containing active pharmaceutical ingredients, such as bromocriptine mesylate, can be non-spherical and irregular in shape. There are several ways for those skilled in the art to measure and represent non-spherical and irregular particles, such as using laser diffraction methods to measure the size of such particles, and representing the size of such particles based on replacing a given particle with a hypothetical sphere that has one of several properties of the particle. Such properties can be selected from, for example, but not limited to, the diameter of a hypothetical sphere having the same volume as the particle being measured (particle size based on volume), the diameter of a hypothetical sphere having the same weight as the particle being measured (particle size based on weight), and the diameter of a hypothetical sphere having the same surface area as the particle being measured (particle size based on area). Those skilled in the art are familiar with such methods, and the results of such methods are presented and can be applied to the embodiments disclosed herein without undue experimentation. Particle size distributions can be shown graphically, for example as plots. A common type of plot is a cumulative undersize plot, showing the fraction of particles (e.g., by number, volume, or mass) that are smaller than a stated particle size.

[0089] The parameters Dv10, Dv50, Dv90 and Dv99 refer to the particle size at the 10%, 50%, 90% and 99% points of the cumulative volume undersize particle size distribution. Thus, for a material, "Dv10" refers to a particle size where 10% of the volume of the material is made up of particles with a particle size equal to or smaller than the Dv10 value. For a material, "Dv50" refers to a particle size where 50% of the volume of the material is made up of particles with a particle size equal to or smaller than the Dv50 value. For a material, "Dv90" refers to a particle size where 90% of the volume of the material is made up of particles with a particle size equal to or smaller than the Dv90 value. For a material, "Dv99" refers to a particle size where 99% of the volume of the material is made up of particles with a particle size equal to or smaller than the Dv99 value.

[0090] The term "span" as used herein means a measurement of the width of the distribution of a given particle size of a given compound, including one embodiment disclosed herein. In particular, the span of a given embodiment can be provided by measuring the particle size of a given compound using a volume-based particle size distribution method and applying the following formula, where Dv90, Dv10 and Dv50 are as previously described.

[0091]

number

[0092] The term "fatty acid," as used herein, is a carboxylic acid having a long aliphatic chain (tail) containing from about 4 to about 26 carbon atoms. An "unsaturated" fatty acid is a fatty acid that contains at least one C=C double bond between the carbon atoms of the fatty acid aliphatic chain. A "saturated" fatty acid is a fatty acid that lacks any C=C double bonds between the carbon atoms of the aliphatic chain.

[0093] A "triglyceride" is an ester derived from glycerol and three fatty acids, formally a triacylglyceride, where the acyl groups are derived from the fatty acids.

[0094] The terms "treating" or "treatment", as used herein, mean treating or curing a disease or medical condition (such as type 2 diabetes) in a patient, such as a mammal (particularly a human), and include alleviating the disease or medical condition, i.e., eliminating or causing the regression of the disease or medical condition in the patient, inhibiting the disease or medical condition, i.e., slowing or arresting the onset of the disease or medical condition in the patient, or alleviating the symptoms of the disease or medical condition in the patient.

[0095] The present disclosure describes improved bromocriptine formulations for improving glycemic control and treating type 2 diabetes, methods of preparation of such formulations, and methods of using such formulations. The formulations may contain bromocriptine (e.g., bromocriptine mesylate or a different bromocriptine salt, e.g., bromocriptine citrate) in an amount that provides a dose of at least about 0.1 mg, e.g., about 0.8 mg, of bromocriptine. Bromocriptine may be present as the sole pharmacoactive ingredient. The bromocriptine formulation may be in an oral dosage form, e.g., a pharmaceutical formulation (e.g., a tablet). Bromocriptine may be administered as a medicament. It can be substantially uniformly distributed in the formulation.

[0096] Bromocriptine citrate can be prepared directly from bromocriptine free base, or from bromocriptine mesylate after desalting to bromocriptine free base. Bromocriptine mesylate and free base are commercially available from several sources (e.g., Sigma Aldrich and Euticals). In contrast to mesylate, bromocriptine citrate is not an alkylating agent and is therefore safer for long-term parenteral (e.g., sublingual) administration. Desalting bromocriptine mesylate to produce bromocriptine free base can be achieved by any of a variety of known desalting techniques. Such techniques are generally known in the art and include, for example, desalting by gel filtration (e.g., Sephadex (cross-linked dextran gel) filtration columns), dialysis, ion exchange column purification (affecting the removal of mesylate by binding to a charged column), and / or diafiltration or ultrafiltration (using a permeable membrane to separate molecules based on size). The solvent for the desalting step can be various organic solvents and / or combinations of solvents, such as, for example, methanol, ethanol, and / or chloroform. The desalting step can also additionally use a phase separation between an aqueous and an organic solvent phase, where the salt is separated into the aqueous phase and bromocriptine is separated into the organic phase. Furthermore, the free base of bromocriptine can be produced from the mesylate by extracting the mesylate from bromocriptine by dissolving the bromocriptine mesylate in an organic solvent (not miscible in water) that forms two layers upon addition of an aqueous solution at a pH where the mesylate migrates to the aqueous phase and the bromocriptine remains in the organic phase. The free base bromocriptine can be washed with repeated organic / aqueous separations and dried until it is substantially pure.

[0097] Citric acid is a tribasic compound with pKa values ​​of 3.13, 4.76, and 6.40. Thus, the bromocriptine citrate salts described herein may be in the mono-, di-, or tri-citrate form, or combinations thereof. Starting with bromocriptine free base, preparation of the citrate salt can be accomplished by any of the following general methods.

[0098] Method 1: Citric acid (about 1-3 g) is dissolved in absolute ethanol (i.e. about 100%) in a reaction vessel at room temperature, and an ethanolic solution of bromocriptine (about 2-10 g) is then added in an amount equimolar to the citric acid. Citric acid can also be present in excess of bromocriptine free base. The resulting solution is stirred at room temperature for about several hours, for example 2-24 hours, and then evaporated under vacuum, for example on a rotary evaporator. The resulting semi-solid or solid product is then dissolved, for example, in an ethanol type mixture, for example straight ethanol or an acetone-ethanol mixture (for example a 50:50 mixture), and subsequently dried under vacuum. Other mixtures (e.g., other organic solvent systems, such as methanol) and / or other mixing ratios (e.g., mixtures of 5:95, 10:90, 20:80, 25:75, 30:70, 40:60, 60:40, 70:30, 75:25, 80:20, 90:10, or 95:5) can be used. The resulting precipitate is bromocriptine citrate.

[0099] Method 2: Citric acid (about 1-3 g) is dissolved in methanol. Bromocriptine (about 2-10 g) is also dissolved in methanol and then added directly to the citrate-citric acid solution in an equimolar amount to the citric acid. Citric acid can also be present in excess of the bromocriptine free base. The two solutions are then mixed, then stirred (at room temperature for about 2-24 hours), and then evaporated to dryness (e.g., under vacuum using a rotary evaporator). The resulting residue is bromocriptine citrate.

[0100] Method 3: Citric acid (approximately 1-3 g) is dissolved in butanol and Bromocriptine (approximately 2-10 g) is then added to this solution in an equimolar amount with citric acid (citric acid can also be present in excess of bromocriptine free salt) and stirred at room temperature for approximately 2-24 hours. The solvent is removed under vacuum and the resulting precipitate is bromocriptine citrate. The separated precipitate can be redissolved in butanol and water to create a two-phase system. The phases are separated and the organic layer is evaporated to dryness to obtain purified bromocriptine citrate.

[0101] Method 4: Citric acid (about 1-3 g) is dissolved in a water / ethanol solvent, and a water / ethanol solution containing bromocriptine (about 2-10 g) is added in an equimolar amount to the citric acid. Citric acid can also be present in excess of bromocriptine free base. Various organic solution(s) containing bromocriptine can be used. For example, bromocriptine can be dissolved in one or more organic solvents, such as methanol, propanol, or butanol. The resulting solution is stirred at room temperature for about 2-24 hours, and the solution is then evaporated to dryness. The dried solid can be washed in methanol and reprecipitated by evaporation to dryness. The resulting residue is bromocriptine citrate.

[0102] Method 5: Citric acid (about 1-3 g) is dissolved in any organic solvent or aqueous / organic solvent in which bromocriptine can be dissolved. Bromocriptine (about 2-10 g) is dissolved in the same organic solvent or aqueous / organic solvent as citric acid or a solvent that is miscible with the solvent used to solvate citric acid, and then added to the citric acid / organic solution in an equimolar amount to citric acid and mixed. Citric acid can also be present in excess of bromocriptine free base. The resulting solution is stirred at room temperature for about 2-24 hours. The solution is evaporated to dryness to obtain bromocriptine citrate.

[0103] In each of the foregoing examples, it is preferred to use citric acid and bromocriptine solutions near their saturation points. One or more chemical modifications generally known in the art can be performed in the foregoing methods to increase or optimize the purity and / or yield of bromocriptine citrate. For example, the pH of the bromocriptine and citric acid solutions can be adjusted to optimize the formation of bromocriptine citrate. As a further non-limiting example, one or more organic solvents (e.g., methanol, propanol, or butanol) can be used to dissolve, resuspend, and / or reprecipitate citric acid, bromocriptine, and / or bromocriptine citrate. The pKa of bromocriptine and citric acid can be adjusted, for example, by changing the solvent used to prepare the citric acid or bromocriptine solution. Although base forms of citric acid can also be used in these methods (e.g., sodium citrate), the citric acid form is preferred. One or more steps of any of the foregoing methods can be performed at different temperatures (i.e., lower or higher temperatures) or pH, or, alternatively or in addition, the temperature can be changed over time during one or more steps. The final product (i.e., bromocriptine citrate) can be resuspended to remove any impurities (e.g., bromocriptine free base or unassociated / unbound citric acid or water). In each method, the product can be "washed" (e.g., using one or more of the techniques described above, e.g., dissolution, resuspension, and / or reprecipitation) to remove unreacted bromocriptine or citrate. Water can be removed by fractional distillation or other standard dehydration techniques known to those of skill in the art.

[0104] Moreover, bromocriptine citrate provides pharmaceutical preparations with more efficient absorption across biological cell membranes than bromocriptine mesylate. Furthermore, the unexpected improved resistance to degradation of bromocriptine citrate to heat and water (e.g., in a physiological environment) and the concomitant increased water solubility (as disclosed in the art) of bromocriptine citrate versus bromocriptine mesylate. Due to the fact that the minimum and preferred doses of bromocriptine citrate for treating vertebrates are lower than the minimum and preferred doses of bromocriptine mesylate for equivalent therapeutic efficacy and duration of treatment, due to the fact that the minimum and preferred doses of bromocriptine citrate are lower than the minimum and preferred doses of bromocriptine mesylate for equivalent therapeutic efficacy and duration of treatment. In summary, the unexpected advantages of bromocriptine citrate provide a substantial improvement over the use of bromocriptine mesylate in currently marketed bromocriptine pharmaceutical preparations (e.g., CYCLOSET® or PARLODEL®), providing a more stable, more efficient, more biocompatible compound with more predictable and reproducible efficacy for bromocriptine pharmaceutical preparations for treating any of a variety of medical disorders, including prediabetes, obesity, insulin resistance, hyperinsulinemia, hyperglycemia, and type 2 diabetes mellitus (T2DM). The enhanced properties of bromocriptine citrate pharmaceutical preparations cannot be mimicked by simply adding citrate to bromocriptine mesylate pharmaceutical preparations. Due to its increased solubility in water, bromocriptine citrate exhibits increased absorption in vivo compared to bromocriptine mesylate.

[0105] Bromocriptine citrate may be used in combination with dopamine D-receptor antagonists such as SKF-38393, SKF-82958 or SKF-82957 to treat one or more metabolic disorders associated with MS, including, for example, T2DM, hypertension, hypertriglyceridemia, anti-inflammatory state, insulin resistance, fatty liver, NASH, CVD and / or obesity. 1 Bromocriptine citrate may be administered with or without a receptor agonist. Bromocriptine citrate may also be administered, optionally in combination with one or more of an alpha-1 adrenergic antagonist, an alpha-2 adrenergic antagonist, or a serotonergic inhibitor, or a serotonin 5HT 1bBromocriptine citrate can be optionally administered in combination with an agonist. Examples of such agents are known in the art and are disclosed, for example, in U.S. Pat. No. 5,877,183. Bromocriptine citrate can be optionally administered in combination with various peripherally acting agents, such as HMGCoA reductase inhibitors, antihypertensive agents, such as postprandial insulin secretagogues, or insulin itself, anti-inflammatory agents, and anticoagulants. Examples of such agents are known in the art and are disclosed, for example, in International Patent Application No. 2009 / 091576A2.

[0106] Bromocriptine citrate is administered preferably orally or sublingually, and optionally parenterally, to a vertebrate, animal or human to treat any one or more conditions in which it is desirable to alter, for example, obesity or hyperglycemia.

[0107] The solid pharmaceutical composition of the present invention should contain an amount of the compound of the present invention effective for the treatment of metabolic diseases and disorders, including, but not limited to, T2DM, obesity, pre-diabetes, metabolic syndrome, cardiometabolic risk, hypertension, dyslipidemia, insulin resistance, hyperinsulinemia, fatty liver, renal disease, cardiovascular disease, cerebrovascular disease, and peripheral vascular disease and biomarkers of impending vascular disease. Effective doses will depend on the severity of the disease and the activity of the particular compound(s) used, and therefore can be determined for any particular host mammal or other host organism by one of skill in the art. A suitable amount of bromocriptine citrate for a vertebrate (e.g., human) may be, for example, about 0.05 μg to about 0.5 mg / kg BW, optionally 0.1 μg to about 0.3 mg / kg BW, or in a preferred embodiment, about 2 μg to 0.1 mg / kg BW per day. Suitable pharmaceutical dosage forms containing bromocriptine citrate can have a total weight (including excipients) of, for example, about 2.5 mg to about 2000 mg.

[0108] In each of the foregoing examples, it is preferred to use citric acid and bromocriptine solutions near their saturation points. One or more chemical modifications generally known in the art can be made to the foregoing methods to increase or optimize the purity and / or yield of bromocriptine citrate. For example, the pH of the bromocriptine and citric acid solutions can be adjusted to The formation of bromocriptine citrate can be optimized by adjusting the solvent content of the citric acid, bromocriptine, and / or bromocriptine citrate. As a further non-limiting example, one or more organic solvents (e.g., methanol, propanol, or butanol) can be used to dissolve, resuspend, and / or reprecipitate citric acid, bromocriptine, and / or bromocriptine citrate. The pKa of bromocriptine and citric acid can be adjusted, for example, by changing the solvent used to prepare the citric acid or bromocriptine solution. Although the base form of citric acid can also be used in these methods (e.g., sodium citrate), the citric acid form is preferred. One or more steps of any of the foregoing methods can be carried out at different temperatures (i.e., lower or higher temperatures) or pH, or, alternatively or additionally, the temperature can be changed over time during one or more steps. The final product (i.e., bromocriptine citrate) can be resuspended to remove any impurities (e.g., bromocriptine free base or unassociated / unbound citric acid or water). In each method, the product can be washed (e.g., using one or more of the techniques described above, e.g., dissolution, resuspension, and / or reprecipitation) to remove unreacted bromocriptine or citrate. Water can be removed by fractional distillation or other standard dehydration techniques known to those of skill in the art.

[0109] In addition, bromocriptine citrate provides pharmaceutical preparations with much higher water solubility (about 7 times greater) than would be expected for bromocriptine mesylate, and therefore provides more efficient absorption across biological cell membranes compared to bromocriptine mesylate. Furthermore, due to the unexpected improved resistance to degradation of bromocriptine citrate in water (e.g., in a physiological environment) and the concomitant increased water solubility relative to bromocriptine mesylate (a phenomenon not predicted in the art), the minimum and preferred doses of bromocriptine citrate for treating vertebrates are lower than the minimum and preferred doses of bromocriptine mesylate for equivalent therapeutic efficacy and duration of treatment. In summary, the unexpected advantages of bromocriptine citrate provide a substantial improvement over the use of bromocriptine mesylate in currently marketed bromocriptine pharmaceutical preparations (e.g., CYCLOSET® or PARLODEL®), providing a more stable, more efficient, more biocompatible and useful compound with more predictable and reproducible effects in pharmaceutical preparations of bromocriptine for treating any of a variety of medical disorders, including pre-diabetes, obesity, insulin resistance, hyperinsulinemia, hyperglycemia and type 2 diabetes mellitus (T2DM). Due to its increased solubility in water, bromocriptine citrate exhibits increased absorption in vivo compared to bromocriptine mesylate. The enhanced physical and biological properties of pharmaceutical preparations of bromocriptine citrate cannot be mimicked by simply adding citric acid to pharmaceutical preparations of bromocriptine mesylate. Furthermore, incorporating bromocriptine citrate into a pharmaceutical formulation containing an acidic compound, such as a fatty acid, combined with citric acid unexpectedly and counterintuitively enhances the stability of bromocriptine to the same extent that the stability of bromocriptine is hindered in an acidic environment. Substituting stearic acid for magnesium stearate surprisingly enhances the stability of the bromocriptine molecule, particularly in the presence of acid, citric acid. This stability is further enhanced by removing or omitting lactose and replacing it with mannitol.Moreover, the stability of bromocriptine citrate can be further enhanced by the presence of triglycerides in the formulation without altering its water solubility. It is surprising that lubricants such as triglycerides have no known use in enhancing the stability of bromocriptine and are known to be hydrophobic rather than hydrophilic. The resulting formulation of (i) bromocriptine citrate, (ii) a non-lactose short chain saccharide such as mannitol, (ii) stearic acid or triglyceride, and (iv) citric acid produces a unique and unexpected bromocriptine formulation that is highly water soluble and stable in water, an environment that normally destroys bromocriptine and bromocriptine mesylate, a situation that is not true for bromocriptine or bromocriptine mesylate, and this is achieved in part by the addition of certain acidic excipients along with other certain excipients and certain salts of bromocriptine.

[0110] Bromocriptine citrate is a dopamine D 1 It can be administered with or without a receptor agonist to treat one or more of the metabolic disorders associated with MS, including, for example, T2DM, hypertension, hypertriglyceridemia, anti-inflammatory state, insulin resistance, fatty liver, NASH, CVD and / or obesity. Bromocriptine citrate can also be administered, optionally, in combination with one or more agents that increase central dopaminergic neuroactivity or decrease central noradrenergic neuroactivity. Examples of such agents are known in the art and are disclosed, for example, in U.S. Patent Nos. 5,877,183 and 9,655,865.

[0111] Bromocriptine citrate can also be optionally administered in combination with various peripherally acting agents, such as HMGCoA reductase inhibitors, antihypertensives, such as postprandial insulin secretagogues, or insulin itself, anti-inflammatory agents, and anti-diabetic agents, including anticoagulants. Examples of such agents are known in the art and are disclosed, for example, in International Patent Application No. WO 2009 / 091576 A2.

[0112] Bromocriptine citrate is administered preferably orally or sublingually, and optionally parenterally, to a vertebrate, animal or human to treat any one or more conditions in which it is desirable to alter, for example, obesity or hyperglycemia.

[0113] The solid pharmaceutical composition of the present invention should contain an amount of the compound(s) of the present invention effective for treating metabolic diseases and disorders such as, but not limited to, T2DM, obesity, pre-diabetes, metabolic syndrome, cardiometabolic risk, hypertension, dyslipidemia, insulin resistance, hyperinsulinemia, fatty liver, renal disease, cardiovascular disease, cerebrovascular disease, and peripheral vascular disease and biomarkers of impending vascular disease and its major components such as arteriosclerosis, coronary artery disease, peripheral vascular disease or cerebrovascular disease, congestive heart failure, obesity, elevated plasma norepinephrine, increased cardiovascular-related inflammatory factors, hyperlipoproteinemia, atherosclerosis, hyperphagia, hyperglycemia, hyperlipidemia, and hypertension or elevated blood pressure, increased postprandial triglyceride or free fatty acid levels, increased cellular oxidative stress or plasma indicators thereof, increased circulating hypercoagulable states, renal disease including renal failure. Effective doses will depend on the severity of the disease and the activity of the particular compound(s) used, and therefore can be determined for any particular host mammal or other host organism by those skilled in the art. A suitable amount of bromocriptine citrate for a vertebrate (e.g., human) may be, for example, about 0.05 μg to about 0.5 mg / kg BW, optionally 0.1 μg to about 0.3 mg / kg BW, or in a preferred embodiment, about 2 μg to 0.2 mg / kg BW per day. Suitable pharmaceutical dosage forms containing bromocriptine citrate may have a total weight (including excipients) of, for example, about 2.5 mg to about 2000 mg.

[0114] In one aspect, the present disclosure has discovered that in preparing bromocriptine formulations for improving glycemic control and treating type 2 diabetes, including certain excipients in the formulation can improve the stability of bromocriptine. The present disclosure thus describes bromocriptine pharmaceutical formulations with improved stability, including excipients that improve the stability of bromocriptine in the formulation.

[0115] The bromocriptine pharmaceutical formulations are manufactured to have a uniform amount, where the bromocriptine is uniformly distributed in the mixture of ingredients that are compressed to form the pharmaceutical formulations, and each pharmaceutical formulation contains substantially the same amount of bromocriptine, thereby providing substantially the same amount of bromocriptine to the patient. This characteristic is desirable to provide consistent efficacy of bromocriptine by providing an effective amount of bromocriptine with each pharmaceutical formulation, but not so high that it could lead to side effects.

[0116] The mode of action involved in the use of bromocriptine to improve glycemic control and treat type 2 diabetes presents a challenge to develop and manufacture formulations suitable for this purpose. Many drugs work best if the pharmacological action of the drug (e.g., blocking a receptor or inhibiting an enzyme) is maintained throughout the treatment period. Without being bound by theory, results of preclinical studies suggest that appropriately timed daily administration of bromocriptine in the morning normalizes the abnormal hypothalamic neurotransmitter activity that induces, enhances, and maintains the insulin-resistant, glucose intolerant state.

[0117] Therefore, it is believed that a formulation of bromocriptine manufactured to improve glycemic control and treat type 2 diabetes should consistently, rapidly, and substantially completely release bromocriptine from the formulation to provide an optimal pharmacokinetic profile for treating diabetes. For example, without being bound by theory, it is understood that bromocriptine for improving glycemic control should be formulated into a pharmaceutical formulation that provides a volume of at least about 0.1 mg of bromocriptine and releases at least about 80%, or preferably at least about 90%, of bromocriptine within about 30 minutes. Drug release can be measured using methods and apparatus described, for example, in US Pharmacopoeia (USP), General Chapter 711, Dissolution, 34th Edition, 2011. A suitable method for measuring the release of bromocriptine from the pharmaceutical formulations described in this disclosure can use the USP Apparatus Type 2 Paddle Method at 50 rpm in 500 ml of 0.1 N hydrochloric acid. Dissolution experiments are typically performed at about 37°C. Bromocriptine citrate products described herein can be manufactured that consistently provide specific amounts and release characteristics, and the resulting products are effective in treating and preventing the development of a number of conditions, including, but not limited to, type 2 diabetes, its major components, pre-diabetes (poor fasting glucose or impaired glucose tolerance), metabolic syndrome or indicators thereof (major components) (increased waist circumference, increased fasting blood glucose, increased fasting plasma triglycerides, decreased fasting high density lipoprotein levels, elevated blood pressure), insulin resistance, hyperinsulinemia, cardiovascular disease (or atherosclerosis, coronary artery disease, peripheral vascular disease or or cerebrovascular disease), congestive heart failure, obesity, increased plasma norepinephrine, increased inflammatory factors related to the cardiovascular system, hyperlipoproteinemia, atherosclerosis, hyperphagia, hyperglycemia, hyperlipidemia, and metabolic disorders including major components thereof including hypertension or elevated blood pressure, increased postprandial plasma triglyceride or free fatty acid levels, increased cellular oxidative stress or plasma indicators thereof, increased circulating hypercoagulable states, and renal disease including renal failure (all of which can be treated with the formulations disclosed herein).

[0118] Besides providing suitable consistent release characteristics, another important aspect of producing a safe and effective bromocriptine formulation is that the bromocriptine in the formulation must be stable over an extended period of time so that the formulation provides a consistent therapeutic dose of bromocriptine as well as avoid potential side effects from the presence of bromocriptine degradation products that do not provide therapeutic benefit. The degradation of bromocriptine to bromocriptinine, with or without the concomitant formation of browning reactions (i.e., the brown color associated with the degradation of white pharmaceutical formulations and / or powder excipients), represents the major degradants of bromocriptine formulations with magnesium stearate and lactose, both of which occur at increased levels under stress conditions (i.e., conditions of heat and / or humidity higher than normal bromocriptine storage conditions, e.g., temperatures of 25±2° C. and relative humidity of about 60±5%).

[0119] Without wishing to be bound by theory, it is believed that the production of bromocriptine and possible accelerators of the browning reaction occurs in an alkaline environment (e.g., magnesium stearate [Mg stearate]). The interaction of bromocriptine with lactose in the presence of magnesium (or in the presence of magnesium phosphate) in an environment resulting from the presence of phosphate salts. Such an interaction may result in a reaction based on the normal base catalysis of lactose. Alternatively, or in addition, Mg stearate may directly interact with bromocriptine (either in the presence or absence of lactose) to catalyze its isomerization to bromocriptinine. Bromocriptinine itself may potentially participate in the browning reaction with lactose. Surprisingly, the interaction of Mg with lactose in the presence of bromocriptine may be expected to promote degradative browning reactions (see FIG. 2). That is, magnesium, but not magnesium stearate, may be particularly damaging to bromocriptine, especially in the presence of lactose. Any or all of the aforementioned degradative reactions may be accelerated by increased heat and / or humidity, e.g., heat and / or humidity higher than normal bromocriptine storage conditions. Any or all of the above reactions may be accelerated by an increase in pH, for example, an increase in pH caused by the presence of one or more impurities in the bromocriptine formulation. Thus, it would be counterintuitive to add an acidic compound in combination with bromocriptine in a pharmaceutical formulation to enhance the stability of bromocriptine. Furthermore, it would be counterintuitive to add a compound such as a lubricant to enhance the stability of bromocriptine, which is not normally accepted for this function.

[0120] As shown in Example 4, various bromocriptine formulations were studied to investigate the effect of reducing or eliminating Mg stearate and / or lactose from the presence of bromocriptine mesylate on browning. It was found that reducing or removing Mg stearate, lactose, or both Mg stearate and lactose from bromocriptine mesylate formulations reduced the rate of decomposition of bromocriptine to bromocriptinine and the rate of browning formation. Removing both Mg stearate and lactose reduced the rate of browning formation to the greatest extent (vs. removing only Mg stearate or removing only lactose). Additionally, Mg stearate can be replaced with one or more acidic compounds, such as stearic acid, or one or more non-magnesium salt lubricants (e.g., solid castor oil) to reduce the rate of decomposition of bromocriptine and the rate of browning formation. Alternatively or additionally to the above-mentioned bromocriptine formulation changes, lactose can be replaced with mannitol and / or one or more other short chain sugars to reduce the rate of bromocriptine decomposition and the formation of browning reactions.Alternatively, or in addition, one or more acidic compounds, such as citric acid or stearic acid, can be added to the bromocriptine formulation of mannitol to reduce the rate of bromocriptine decomposition and the formation of browning reactions.Similarly, this particular decomposition reaction of bromocriptine is counterintuitively reduced by adding acid to the formulation, an interaction that is normally known to destroy bromocriptine.

[0121] Bromocriptine mesylate accelerated release agents are described in U.S. Patent No. 5,679,685, which discusses that accelerated release from bromocriptine mesylate can be achieved by compounding bromocriptine, an antioxidant, a filler, a disintegrant, a water scavenging agent, and a lubricant. In a preferred formulation, the bromocriptine formulation contained bromocriptine mesylate together with citric acid, cornstarch, a non-lactose filler, silicon dioxide, and magnesium stearate. The use of anhydrous fillers is preferred to minimize water content. Citric acid is an antioxidant. Cornstarch is a disintegrant. Colloidal silicon dioxide acts as a water scavenging agent. Magnesium stearate acts as a lubricant.

[0122] The '685 patent describes the preparation of immediate release bromocriptine mesylate on a laboratory scale, and difficulties were encountered in manufacturing such formulations on a large scale suitable for commercial use because there was high variability in the dissolution and release rates of bromocriptine mesylate from the final formulation, and problems were found in achieving acceptable product uniformity. Moreover, the formulation was found to be incompatible with standard It exhibits poor long-term stability on storage under typical pharmaceutical conditions (25°C and 60% humidity), and even worse stability at 40°C and 75% RH, and is very poorly water soluble and highly unstable to hydrolysis.

[0123] It has been found that the manufacture of bromocriptine mesylate pharmaceutical formulations for improving glycemic control in patients with type 2 diabetes can be significantly improved by carefully controlling the size of the particles of bromocriptine mesylate used in manufacturing the pharmaceutical formulation. By controlling particle size, pharmaceutical formulations can be manufactured that provide consistent release characteristics, with greater than about 90% of the bromocriptine mesylate being released in about 30 minutes, or even 20 minutes, thereby ensuring the manufacture of products with consistently acceptable performance and safety characteristics for improving glycemic control and treating type 2 diabetes. This is achieved by using manufacturing methods that achieve improved content uniformity, for example, by using direct transport of the bromocriptine formulation mixture for tableting after mixing, without time to allow the ingredients to settle in the mixed mixture. Advantages include the ability to reproducibly manufacture formulations with defined drug content and drug release characteristics to meet quality standards mandated by drug regulatory agencies such as the Food and Drug Administration.

[0124] In particular, it is desirable to control the particle size of bromocriptine used in bromocriptine pharmaceutical formulations for improving glycemic control in patients with type 2 diabetes, such that bromocriptine has a Dv90 of about 20 μm or less, and thus the bromocriptine pharmaceutical formulations described herein have a particular particle size distribution. In some embodiments, the bromocriptine used in the manufacture of the pharmaceutical formulation may have a Dv90 of about 20 μm or less, about 18 μm or less, about 16 μm or less, about 15 μm or less, about 10 μm or less, or about 5 μm or less. In some embodiments, the bromocriptine used in the manufacture of the pharmaceutical formulation may have a Dv99 of about 15 μm or less, about 10 μm or less, or about 5 μm or less. In some embodiments, the bromocriptine used in the manufacture of the pharmaceutical formulation may have a Dv50 of about 10 μm or less, about 8 μm or less, about 7 μm or less, about 5 μm or less, or about 2 μm or less. In some embodiments, the bromocriptine used to prepare the pharmaceutical formulation may have a Dv10 of about 5 μm or less, about 3 μm or less, or about 2 μm or less. In some embodiments, the bromocriptine used to prepare the pharmaceutical formulation may have a volume-based particle size distribution such that about 40% or less, about 20% or less, 10% or less, or about 5% or less of the bromocriptine has a particle size less than about 1 μm.

[0125] In some embodiments, bromocriptine used in the manufacture of pharmaceutical formulations may have a particle size such that the particle size distribution has a Dv90 of about 20 μm or less, a Dv50 of about 10 μm or less, and a Dv10 of about 5 μm or less. In some embodiments, bromocriptine used in the manufacture of pharmaceutical formulations may have a particle size such that the particle size distribution has a Dv90 of about 15 μm or less, a Dv50 of about 8 μm or less, and a Dv10 of about 3 μm or less. In some embodiments, bromocriptine used in the manufacture of pharmaceutical formulations may have a particle size such that the particle size distribution has a Dv90 of about 10 μm or less, a Dv50 of about 5 μm or less, and a Dv10 of about 3 μm or less. In some embodiments, bromocriptine used in the manufacture of pharmaceutical formulations may have a particle size such that the particle size distribution has a Dv90 of about 8 μm or less, a Dv50 of about 5 μm or less, and a Dv10 of about 3 μm or less. In some embodiments, the bromocriptine used in the manufacture of the pharmaceutical formulation may have a particle size such that the particle size distribution has a Dv90 of about 5 μm or less, a Dv50 of about 3 μm or less, and a Dv10 of about 1 μm or less.

[0126] In some embodiments, the bromocriptine used to manufacture the pharmaceutical formulation may have a particle size based on volume such that the particle size span is about 5 or less, about 3 or less, about 2.5 or less, or about 2 or less, or about 1.5 or less.

[0127] In some embodiments, the bromocriptine has a particle size diameter of 0.1-100 um.

[0128] In one embodiment, the bromocriptine has a mean particle size diameter of 0.5 to 3.0 um.

[0129] By using bromocriptine with a controlled particle size, bromocriptine pharmaceutical formulations can be produced that consistently improve glycemic control and provide effective drug release profiles for treating type 2 diabetes.

[0130] Bromocriptine pharmaceutical formulations prepared using bromocriptine having controlled particle size are formulated to provide dissolution characteristics such that the pharmaceutical formulation releases at least about 80%, preferably at least about 90%, of bromocriptine in about 30 minutes when tested in 500 ml of 0.1 N hydrochloric acid at 50 rpm in a USP Apparatus Type 2 Paddle Method at about 37° C. In some embodiments, the bromocriptine pharmaceutical formulation provides dissolution characteristics such that the pharmaceutical formulation releases at least about 95% of bromocriptine in about 30 minutes. In some embodiments, the bromocriptine pharmaceutical formulation provides dissolution characteristics such that the pharmaceutical formulation releases at least about 80%, or at least about 90% of bromocriptine in about 20 minutes. The pharmaceutical formulation is formulated to provide dissolution characteristics such that at least about 80%, and preferably about 90%, of the bromocriptine is released in about 30 minutes when tested in 500 ml of 0.1 N hydrochloric acid at 50 rpm in a USP Apparatus Type 2 Paddle Method at about 37° C.; it may be undesirable to release bromocriptine too quickly from the formulation as such a formulation may result in undesirable spikes in drug levels in vivo that may not be suitable for treating type 2 diabetes or may cause side effects. Thus, in some embodiments, bromocriptine pharmaceutical formulations prepared using micronized bromocriptine are formulated to provide dissolution characteristics such that about 75% or less, about 60% or less, or about 50% or less of the bromocriptine is released in about 7 minutes and / or about 90% or less, about 85% or less, about 80% or less, or about 75% or less of the bromocriptine is released in about 10 minutes when tested in 500 ml of 0.1 N hydrochloric acid at 50 rpm in a USP Apparatus Type 2 Paddle Method at 37° C. By producing bromocriptine pharmaceutical formulations using bromocriptine with a particular particle size distribution, the release characteristics can be achieved and the finished formulation consistently provides dissolution characteristics suitable for the treatment of type 2 diabetes.

[0131] Bromocriptine pharmaceutical formulations prepared using bromocriptine having controlled particle size are formulated to provide a time to maximum plasma concentration (T) following administration of the bromocriptine pharmaceutical formulation (e.g., administration of six bromocriptine pharmaceutical formulations each providing a dose of about 0.8 mg of bromocriptine), when the pharmaceutical formulation is administered to an adult subject under fasting conditions. max ) is about 30 to about 60 minutes, such as about 50 minutes, for example about 53 minutes, or about 90 to 120 minutes when the pharmaceutical formulation is administered to an adult subject under high fat feeding conditions.

[0132] Bromocriptine pharmaceutical formulations can contain, for example, an amount of bromocriptine that provides a dose of at least about 0.1 mg of bromocriptine per pharmaceutical formulation, or, for example, about 0.8 mg of bromocriptine citrate per pharmaceutical formulation. Bromocriptine pharmaceutical formulations can contain, for example, an amount of bromocriptine that provides a dose of about 0.8 mg, about 1.6 mg, about 2.4 mg, about 3.2 mg, about 4.0 mg, about 4.8 mg, about 5.6 mg, about 6.4 mg, about 7.2 mg, about 8.0 mg, about 8.8 mg, or about 9.6 mg of bromocriptine per pharmaceutical formulation.

[0133] In some embodiments, particle size can be controlled by the use of micronized bromocriptine. It has been discovered that superior bromocriptine formulations for improving glycemic control and treating type 2 diabetes can be prepared by using micronized bromocriptine to manufacture bromocriptine pharmaceutical formulations. Micronized bromocriptine can have Dv99, Dv90, Dv50, Dv10, span of particle size distribution with the aforementioned values, and other properties, including any embodiment or combination thereof. Pharmaceutical formulations manufactured using micronized bromocriptine can have any of the aforementioned dissolution properties that are effective for improving glycemic control and treating type 2 diabetes, including any embodiment or combination thereof. Furthermore, formulations manufactured using micronized bromocriptine can provide the aforementioned pharmacokinetic properties and can include the aforementioned amounts of bromocriptine.

[0134] Micronization provides particle size reduction to provide particles that are on the order of a few microns in diameter, as measured by methods known to those skilled in the art, such as volume distribution methods. Methods for micronizing bromocriptine to obtain the formulations disclosed herein include methods known to those skilled in the art, including, but not limited to, grinding, grinding, and the use of supercritical fluids. For example, in one method of micronization (the "rapid expansion of supercritical solutions" or RESS method), materials are dissolved in supercritical fluids under high temperature and pressure, and the resulting solution is expanded through a nozzle to form small particles.

[0135] Micronization by jet milling can be used to produce particles in the low micron range and is the preferred method for micronizing bromocriptine. Briefly, raw material with a maximum size of about 1-2 mm is introduced into a grinding chamber via a gas flow. Inside the grinding chamber, a circular gas flow accelerates the particles to be micronized by colliding with each other or with the walls of the chamber. The ground particles are removed from the grinding chamber by the gas flow, while the larger particles are retained inside by centrifugal force. In a preferred process for micronizing bromocriptine, micronization is carried out using a jet mill under a nitrogen atmosphere at a controlled temperature of about 0°C. However, reducing bromocriptine particle size as mentioned above also increases the instability of bromocriptine very significantly. As a result, there is a need to develop new methods that can retain the stability of micronized bromocriptine while being highly water soluble in environments that destroy bromocriptine.

[0136] It has been surprisingly found that the inclusion of certain excipients traditionally used as lubricants in bromocriptine formulations can improve the stability of the pharmaceutical formulation. It has also been surprisingly found that the exclusion of certain excipients used as lubricants (e.g. magnesium stearate) or fillers / disintegrants (e.g. lactose) in bromocriptine formulations can improve the stability of the pharmaceutical formulation of micronized bromocriptine. Lubricants are agents that are usually added in small amounts to pharmaceutical and capsule formulations to improve certain processing properties. Lubricants have the role of reducing friction at the interface between the pharmaceutical formulation and the die wall during the formation of the pharmaceutical formulation, for example, to aid in the ejection of the pharmaceutical formulation from the die and to reduce wear on the punch and die. In addition, lubricants can have an anti-adhesive role, for example, to prevent the pharmaceutical formulation from sticking to the surface of the punch or capsule filling equipment. Lubricants can also have a glidant role, for example, to increase product flow by reducing friction between particles. Lubricants, especially acidic lubricants, are not usually used to reduce the decomposition reaction of drugs such as bromocriptine.

[0137] Excipients or lubricants that are effective in improving the stability of the micronized bromocriptine pharmaceutical formulations described herein include triglycerides or free fatty acids. Triglycerides are fatty acids having 6 to 14 carbon atoms (C 6 -C 14 fatty acids), 14-26 carbon atoms (C 14 -C 26 fatty acid) , 14 to 24 carbon atoms (C 14 -C 24 fatty acids), 14-22 carbon atoms (C 14 -C 22 fatty acids), 14-20 carbon atoms (C 14 -C 20 fatty acids), 14-18 carbon atoms (C 14 -C 18 fatty acids), 16-24 carbon atoms (C 16 -C 24 fatty acids), 16-22 carbon atoms (C 16 -C 22fatty acids), 16-20 carbon atoms (C 16 -C 20 fatty acids), 16-18 carbon atoms (C 16 -C 18 fatty acids), 18-24 carbon atoms (C 18 -C 24 fatty acids), 18-22 carbon atoms (C 18 -C 22 fatty acids) or 18 to 20 carbon atoms (C 18 -C 20 In some embodiments, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the acyl groups of the triglyceride are C 14 -C 26 In some embodiments, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the acyl groups of the triglyceride are C 6 -C 14 In some embodiments, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the acyl groups of the triglyceride are C 14 -C 24 In some embodiments, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the acyl groups of the triglyceride are C 14 -C 22 In some embodiments, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the acyl groups of the triglyceride are C 14 -C 20In some embodiments, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the acyl groups of the triglyceride are C 14 -C 18 In some embodiments, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the acyl groups of the triglyceride are C 16 -C 26 In some embodiments, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the acyl groups of the triglyceride are C 16 -C 24 In some embodiments, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the acyl groups of the triglyceride are C 16 -C 22 In some embodiments, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the acyl groups of the triglyceride are C 16 -C 20 In some embodiments, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the acyl groups of the triglyceride are C 16 -C 18 In some embodiments, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the acyl groups of the triglyceride are C 18 -C 26In some embodiments, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the acyl groups of the triglyceride are C 18 -C 24 In some embodiments, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the acyl groups of the triglyceride are C 18 -C 22 In some embodiments, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the acyl groups of the triglyceride are C 18 -C 20 It may be a fatty acid acyl group of a fatty acid. In some embodiments, the acyl group of a triglyceride. At least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of 18 The acyl group of the triglyceride may be a fatty acyl group of a fatty acid. In some embodiments, the acyl group of the triglyceride may be a fatty acyl group of a saturated fatty acid. In some embodiments, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the acyl groups of the triglyceride may be a fatty acyl group of a saturated fatty acid. In some embodiments, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the acyl groups of the triglyceride may be a stearoyl group or a 12-hydroxystearoyl group.

[0138] Examples of suitable excipients or lubricants include, but are not limited to, wax, glycerides, vegetable oils and hydrogenated vegetable oils.Examples of vegetable oils include almond oil, apricot kernel oil, canola oil, castor oil, cinnamon oil, coconut oil, corn oil, cottonseed oil, linseed oil, palm oil, palm kernel oil, olive oil, peanut oil, rapeseed oil, safflower oil, soybean oil and sunflower oil and mixtures thereof.Examples of hydrogenated vegetable oils include hydrogenated castor oil (castor wax), hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated palm kernel oil, hydrogenated soybean oil and combinations thereof. Suitable excipients or lubricants include, but are not limited to, BBS (partially hydrogenated vegetable oils); BBS-C (partially hydrogenated vegetable oils); CASTORWAX® (hydrogenated castor oil), CASTORWAX® MP-70 (hydrogenated castor oil), CASTORWAX® MP-80 (hydrogenated castor oil), CENWAX® G (hydrogenated castor oil), CERIT® SH (hydrogenated castor oil), CUTINA® HR (hydrogenated castor seed oil); HYDRO-KOTE® 112 ( Hydrogenated palm kernel oil; HYDRO-KOTE® C (hydrogenated cottonseed oil); HYDRO-KOTE® M (hydrogenated palm kernel oil); HYDRO-KOTE® S (hydrogenated soybean oil); KOLLIWAX® HCO (hydrogenated castor oil), LUBRITAB® (hydrogenated cottonseed oil, STEROTEX® K (hydrogenated soybean oil and castor wax), STEROTEX® (hydrogenated cottonseed oil), STEROTEX® FL (hydrogenated soybean oil).

[0139] The lubricant, the formulation, or both, can be substantially free of lactose.

[0140] The lubricant, the formulation, or both can be substantially free of magnesium. "Substantially free" in this context means that magnesium ions may be present in parts per million (preferably less than about 10 ppm), and preferably are absent in the percentage range.

[0141] The lubricant included in the pharmaceutical formulation may comprise less than about 0.75% by weight of magnesium stearate relative to the total weight of the pharmaceutical formulation.

[0142] Excipients or lubricants used to stabilize the formulation may be used in an amount of about 0.1% to about 25% by weight. In some embodiments, the excipients or lubricants are used in an amount of about 0.5% to about 5% by weight. In some embodiments, the excipients or lubricants are used in an amount of about 1% to about 5% by weight. In some embodiments, the excipients or lubricants are used in an amount of about 1.5% to about 5% by weight. In some embodiments, the excipients or lubricants are used in an amount of about 2% to about 5% by weight. In some embodiments, the excipients or lubricants are used in an amount of about 0.1% to about 3% by weight. In some embodiments, the excipients or lubricants are used in an amount of about 0.5% to about 3% by weight. In some embodiments, the excipients or lubricants are used in an amount of about 1.5% to about 3% by weight. In some embodiments, the excipients or lubricants are used in an amount of about 2% to about 3% by weight. In some embodiments, the excipients or lubricants are used in an amount of about 0.5% to about 2.5% by weight. In some embodiments, the excipient or lubricant is used in an amount of about 0.5 to about 1.5% by weight. In some embodiments, the excipient or lubricant is used in an amount of about 1.5 to about 2.5% by weight. In some embodiments, the excipient or lubricant is used in an amount of about 2% by weight.

[0143] In some embodiments, the excipient or lubricant is extragranular. The excipient or lubricant can be added after the remaining ingredients have been mixed, e.g., prior to tabletting.

[0144] The present application also describes pharmaceutical formulations comprising micronized bromocriptine that include, exclude or reduce the amount of certain excipients in the pharmaceutical formulation, which can reduce the amount of related substances or impurities contained in the pharmaceutical formulation when stored under certain conditions for a period of time. In one aspect, a pharmaceutical formulation is provided that includes micronized bromocriptine in the total weight of the pharmaceutical formulation and does not include magnesium stearate. In a further aspect, a pharmaceutical formulation is provided that includes micronized bromocriptine and stearic acid, a fatty acid, and at least one triglyceride, or a combination thereof. The triglyceride can be or have any of the characteristics of the triglyceride containing lubricant or excipient described above.

[0145] Exemplary pharmaceutical formulations were prepared using micronized bromocriptine mesylate with various lubricants (see, e.g., Example 6). The formulations had the compositions shown in Table 8. Formulation A was a control using magnesium stearate (0.76% by weight) as the lubricant. Formulation B used stearic acid (2%) as the lubricant. Formulation C used sodium stearyl fumarate (2%) as the lubricant. Formulation D used hydrogenated castor oil (KOLLIWAX® HCO) (2%) as the lubricant. Finally, Formulation E used magnesium stearate as the lubricant (a reduced amount from Formulation A, 0.44%). Each pharmaceutical formulation was stored at 25±2° C. and 60±5% RH, 30±2° C. and 65±5% RH, or 40±2° C. and 75±5% RH for up to 3 months and analyzed for impurities of relevant material at the start of the study and at 1, 2, and / or 3 months. The results shown in Table 9 and Figures 1A, 1B and 1C indicate that the formulations using hydrogenated castor oil as a lubricant were much more stable than any other formulation and formed smaller amounts of related substance impurities. The formulations using sodium stearyl fumarate or magnesium stearate less than about 0.75% by weight based on the total weight of the pharmaceutical formulation were also more stable than the control formulation A and formed smaller amounts of related substance impurities. Furthermore, the dissolution of formulations A and CE were tested both before and after storage at 25±2°C and 60±5% RH for 3 months, and the results are shown in Table 10, indicating that the aforementioned lubricants did not have a significant effect on the dissolution of any of the formulations before or after storage.

[0146] Formulations containing the above formulation stabilizing excipients or lubricants can be prepared using bromocriptine of controlled particle size and can have other properties of particle size distribution with the above values, including Dv99, Dv90, Dv50, Dv10, span, and any embodiment or combination thereof. The particle size of bromocriptine can be controlled by micronization or any of the other methods described above. Pharmaceutical formulations made using bromocriptine of controlled particle size and diluents can have any of the above dissolution properties as being effective in improving metabolic disorders or key factors such as hyperglycemic control and type 2 diabetes, including any embodiment or combination thereof. Furthermore, formulations made using the above formulation stabilizing excipients or lubricants can provide the above pharmacokinetic properties and can contain the above amounts of bromocriptine.

[0147] In another embodiment, the present disclosure provides a bromocriptine pharmaceutical formulation containing micronized bromocriptine with enhanced stability. The stability of the pharmaceutical formulation is measured by measuring the stability of the pharmaceutical formulation at 25±2 After storage at 25° C. and about 60±5% relative humidity for about 18 months, the pharmaceutical formulation can contain no more than 8% of the total related substances. In some embodiments, the stability of the pharmaceutical formulation can be such that after storage at 25±2° C. and about 60±5% relative humidity for about 24 months, the pharmaceutical formulation can contain no more than 8% of the total related substances. In some embodiments, the stability of the pharmaceutical formulation can be such that after storage at 25±2° C. and about 60±5% relative humidity for about 36 months, the pharmaceutical formulation can contain no more than 8% of the total related substances. In some embodiments, the stability of the pharmaceutical formulation can be such that after storage at 25±2° C. and about 60±5% relative humidity for about 48 months, the pharmaceutical formulation can contain no more than 8% of the total related substances. The stability of the pharmaceutical formulation can be such that after storage at 25±2° C. and about 60±5% relative humidity for about 18 months, the pharmaceutical formulation can contain no more than 8% bromocriptinine. In some embodiments, the stability of the pharmaceutical formulation can be such that after storage of the pharmaceutical formulation at a temperature of 25±2° C. and a relative humidity of about 60±5% for about 24 months, the pharmaceutical formulation contains no more than 8% bromocriptinine. In some embodiments, the stability of the pharmaceutical formulation can be such that after storage of the pharmaceutical formulation at a temperature of 25±2° C. and a relative humidity of about 60±5% for about 36 months, the pharmaceutical formulation contains no more than 8% bromocriptinine. In some embodiments, the stability of the pharmaceutical formulation can be such that after storage of the pharmaceutical formulation at a temperature of 25±2° C. and a relative humidity of about 60±5% for about 48 months, the pharmaceutical formulation contains no more than 8% bromocriptinine. The stability of the pharmaceutical formulation can be such that after storage of the pharmaceutical formulation at a temperature of 25±2° C. and a relative humidity of about 60±5% for about 18 months, the pharmaceutical formulation contains no more than 5% total related substances. In some embodiments, the stability of the pharmaceutical formulation may be such that the pharmaceutical formulation contains no more than 5% of the total relevant substances after storage for about 24 months at a temperature of 25±2° C. and a relative humidity of about 60±5%. In some embodiments, the stability of the pharmaceutical formulation may be such that the pharmaceutical formulation contains no more than 5% of the total relevant substances after storage for about 36 months at a temperature of 25±2° C. and a relative humidity of about 60±5%.In some embodiments, the stability of the pharmaceutical formulation can be such that after storage of the pharmaceutical formulation at a temperature of 25±2° C. and a relative humidity of about 60±5% for about 48 months, the pharmaceutical formulation contains no more than 5% total related substances. The stability of the pharmaceutical formulation can be such that after storage of the pharmaceutical formulation at a temperature of 25±2° C. and a relative humidity of about 60±5% for about 18 months, the pharmaceutical formulation contains no more than 5% bromocriptinine. The stability of the pharmaceutical formulation can be such that after storage of the pharmaceutical formulation at a temperature of 25±2° C. and a relative humidity of about 60±5% for about 18 months, the pharmaceutical formulation contains no more than 3% bromocriptinine. In some embodiments, the stability of the pharmaceutical formulation can be such that after storage of the pharmaceutical formulation at a temperature of 25±2° C. and a relative humidity of about 60±5% for about 24 months, the pharmaceutical formulation contains no more than 5% bromocriptinine. In some embodiments, the stability of the pharmaceutical formulation can be such that after storage of the pharmaceutical formulation at a temperature of 25±2° C. and a relative humidity of about 60±5% for about 36 months, the pharmaceutical formulation contains no more than 5% bromocriptinine. In some embodiments, the stability of the pharmaceutical formulation can be such that after storage of the pharmaceutical formulation at a temperature of 25±2° C. and a relative humidity of about 60±5% for about 48 months, the pharmaceutical formulation contains no more than 5% bromocriptinine. The stability of the pharmaceutical formulation can be such that after storage of the pharmaceutical formulation at a temperature of 25±2° C. and a relative humidity of about 60±5% for about 18 months, the pharmaceutical formulation contains no more than 3% total related substances. In some embodiments, the stability of the pharmaceutical formulation can be such that after storage of the pharmaceutical formulation at a temperature of 25±2° C. and a relative humidity of about 60±5% for about 24 months, the pharmaceutical formulation contains no more than 3% total related substances. In some embodiments, the stability of the pharmaceutical formulation can be such that after storage of the pharmaceutical formulation for about 36 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, the pharmaceutical formulation contains no more than 3% total related substances. In some embodiments, the stability of the pharmaceutical formulation can be such that after storage of the pharmaceutical formulation for about 48 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, the pharmaceutical formulation contains no more than 3% total related substances. In some embodiments, the stability of the pharmaceutical formulation can be such that after storage of the pharmaceutical formulation for about 18 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, the pharmaceutical formulation contains no more than 3% bromocriptinine.In some embodiments, the stability of the pharmaceutical formulation can be such that after the pharmaceutical formulation is stored at a temperature of 25±2° C. and a relative humidity of about 60±5% for about 24 months, the pharmaceutical formulation contains no more than 3% bromocriptinine. In some embodiments, the stability of the pharmaceutical formulation can be such that after the pharmaceutical formulation is stored at a temperature of 25±2° C. and a relative humidity of about 60±5% for about 36 months, the pharmaceutical formulation contains no more than 3% bromocriptinine. In some embodiments, the stability of the pharmaceutical formulation can be such that after the pharmaceutical formulation is stored at a temperature of 25±2° C. and a relative humidity of about 60±5% for about 48 months, the pharmaceutical formulation contains no more than 3% bromocriptinine.

[0148] The amount of total related substances or the amount of bromocriptine is determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0149] In some embodiments, the pharmaceutical formulation is stable such that it contains no more than 1% total related substances after storage for about 6 weeks at a temperature of 40±2° C. and a relative humidity of about 70±5%, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0150] In some embodiments, the pharmaceutical formulation is stable such that it contains 8% or less total related substances after storage for about 6 months at a temperature of 40±2° C. and a relative humidity of about 70±5%, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0151] In some embodiments, the pharmaceutical formulation is stable such that it contains no more than 8% total related substances after storage for at least six months at a temperature of 40±2° C. and a relative humidity of about 70±5%, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0152] In some embodiments, the pharmaceutical formulation is stable such that it contains 8% or less total related substances as determined by HPLC analysis using detection of UV absorbance at 300 nm after storage for at least 12 months at a temperature of 40±2° C. and a relative humidity of about 70±5%. The amount of total related substances or the amount of bromocriptine is determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0153] The formulations disclosed herein may also include permeation enhancers, bioadhesives, film-forming agents, plasticizers, stabilizers, fillers, and mucosal tissue irritation reducing agents, binders, disintegrants, lubricants, and fillers.

[0154] Bioadhesives are found, for example, in adhesive tablets, solutions, colloidal suspensions, gels, ointments, patches, films, pastes and lozenges. Examples of bioadhesive polymers include, but are not limited to, Klucel, Benecel® MP814, Kollidon, chitosan, cellulose derivatives, Carbopol 934P, Carbopol 974P, 1Voveou AA-1, carbopole resins, carbomers, xanthan gum, polycarbophil and polyethylene oxide in combination with inert diluents and active ingredients, and ionic polysaccharides. Some synthetic and semi-synthetic bioadhesive polymers with different molecular weights and different degrees of substitution include, but are not limited to, hydroxyethylcellulose, polyvinyl alcohol, polyacrylic acid, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol and others. The mucoadhesion of these bioadhesive formulations is based on the interpenetration of the hydrated hydrocolloid chains of the bioadhesive and the glycoprotein chains of the oral mucosa.

[0155] Examples of suitable film formers include, but are not limited to, hydroxypropyl methylcellulose, ethyl cellulose, and polymethacrylates.

[0156] Examples of suitable plasticizers include, but are not limited to, polyethylene glycols of different molecular weights (eg, 200-8000 Da), vegetable gums and propylene glycol and triethyl citrate.

[0157] Examples of permeation enhancers include, but are not limited to, bile salts, fatty acids, fatty acid derivatives, surfactants, laureate, stearic acid monoesters of myristic acid and polyethylene glycol, fatty acid esters such as enamine derivatives and α-ketoaldehyde, sodium cholate, sodium glycolate, sodium deoxycholate, sodium lauryl sulfate, sodium salicylate, sodium ethylenediaminetetraacetate (EDTA), aprotinin, azone, sodium 5-methoxysalicylate, 1-oleylazacycloheptan-2-one, and / or silicas with high affinity to aqueous solvents, such as suspended silicas commonly known by the trademark Syloid®, maltodextrin, β-cyclodextrin, surfactants, chelating agents, cyclodextrin, chitosan, and lower alcohols.

[0158] Examples of stabilizers include, but are not limited to, citric acid, ascorbic acid, oleic acid, caprylic acid, capric acid, polyvinylpyrrolidone, waxes, block copolymers, poloxamer, poloxamer 188 and 407, poloxamine, poloxamine 908, polyvinylpyrrolidone, polyvinyl alcohol, gelatin, polysaccharides, hyaluronic acid, chitosan, derivatives of chitosan, polyacrylic acid, derivatives of polyacrylic acid, polycarbophil, cellulose derivatives, methylcellulose, hydroxypropylcellulose, carboxymethylcellulose, sugar esters, sucrose monostearate, sodium citrate individually, fatty acids, fatty alcohols, alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinyl ethers, polyvinyl alcohol, hydrocarbons, hydrophobic polymers, hygroscopic polymers, and combinations thereof.

[0159] Examples of anhydrous mucosal tissue irritation reducing agents include, but are not limited to, vegetable oils such as olive oil, corn oil, or mineral oil. Examples of fillers include, but are not limited to, microfine cellulose, such as ProSolv, Pharmaburst, Cab-o-sil, and sugars, such as mannitol, lactose, xylitol, and mixtures thereof.

[0160] Examples of suitable binders include, but are not limited to, binding agents such as sucrose, gelatin, glucose, starch, cellulosic materials, polyethylene glycol, povidone, methylcellulose, sodium carboxymethylcellulose, sodium alginate, agar, alginic acid and salts of alginic acid, calcium carrageenan, magnesium aluminum silicate, polyethylene glycol, guar gum, polysaccharide acids, bentonite, polyvinylpyrrolidone (Povidone), hydroxymethyl polyvinylpyrrolidone, polymethacrylic acid (such as Eudragit), methylcellulose, hydroxypropyl ... Cellulose (HPMC), hydroxypropyl cellulose (Klucel™), ethyl cellulose (Ethocel™), hydroxypropyl methylcellulose, pregelatinized starch (such as National™ 1511 and Starch 1500), sucrose, lactose, starch paste, povidone polyethylene glycol, Pullulan and corn syrup, waxes and natural and synthetic gums such as acacia, tragacanth, vegetable gums, castor oil, microcrystalline cellulose, dextrin, liquid glucose, guar gum, pectin, PEG, povidone, pregelatinized starch, and the like.

[0161] Examples of suitable disintegrants include, but are not limited to, starches such as Klucel, corn starch and rice starch, cross-linked N-vinyl-2-pyrrolidone (CLPVP), alginic acid and alginates, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives. Examples of effervescent disintegrants include, but are not limited to, starch, potassium bicarbonate, and sodium bicarbonate in combination with citric or tartaric acid. Disintegrants may be present as intragranular or extragranular disintegrants. Examples of effervescent disintegrants include, but are not limited to, starch, potassium bicarbonate, and sodium bicarbonate in combination with citric or tartaric acid. Disintegrants may be present as intragranular or extragranular disintegrants.

[0162] Examples of suitable lubricants include, but are not limited to, sodium oleate, sodium stearate, sodium stearyl fumarate, starch, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, calcium stearate or other metallic stearates, talc, waxes and glycerides, light mineral oils, PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils, corn starch, sodium stearyl fumarate, polyethylene glycol, alkyl sulfates, sodium benzoate and sodium acetate.

[0163] Examples of suitable flavors include, but are not limited to, menthol, peppermint, vanilla, fruit flavors, and sweeteners, such as aspartame or sodium saccharin.

[0164] The formulations disclosed herein may further include citric acid as an excipient. Citric acid as an excipient can improve the stability of bromocriptine citrate in water (opposite the known effect of bromocriptine being degraded in an acidic environment) and also increase bromocriptine solubility and absorption. Other agents used as antioxidants include, but are not limited to, vitamins A, C, E, β-carotene, zinc, selenium, glutathione, coenzyme Q-10, and echinacea. Citric acid or other antioxidants can be used in an amount of about 0.1% to about 5% by weight. In some embodiments, citric acid or other antioxidants can be used in an amount of about 0.5% to about 5% by weight. In some embodiments, citric acid or other antioxidants can be used in an amount of about 1% to about 5% by weight. In some embodiments, citric acid or other antioxidants can be used in an amount of about 0.5% to about 3% by weight. In some embodiments, citric acid or other antioxidants can be used in an amount of about 1% to about 2% by weight. In some embodiments, citric acid or other antioxidants can be used in an amount of about 1.5% by weight. The citric acid used in the formulation can have a particle size such that, when sieved, not more than about 3% of the citric acid is greater than 600 μm, and more than about 5% of the citric acid is less than 150 μm.

[0165] The formulations disclosed herein may also include one or more (non-lactose) disintegrants. Examples of suitable disintegrants include, but are not limited to, starches such as corn starch, maize starch, pregelatinized starch, rice starch, sodium starch glycolate, sodium starch glycolate, alginic acid or alginates such as sodium alginate, croscarmellose sodium, crospovidone, cross-linked N-vinyl-2-pyrrolidone (CLPVP), cellulose derivatives such as sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose and lower alkyl-substituted hydroxypropylcellulose, formaldehyde casein and polacrilin potassium. Effervescent disintegrants include, but are not limited to, starch, potassium bicarbonate, and sodium bicarbonate in combination with citric acid or tartaric acid. Disintegrants can be used in amounts of about 2% to about 50% by weight. In some embodiments, disintegrants are used in amounts of about 5% to about 20% by weight. In some embodiments, the disintegrant is used in an amount of about 5% to about 15% by weight, in some embodiments, the disintegrant is used in an amount of about 10% by weight.

[0166] The formulations disclosed herein may also include one or more diluents, such as short chain sugars (monosaccharides or disaccharides excluding lactose). Examples of such short chain sugars include, but are not limited to, mannitol, xylitol, glucose, maltose, sucrose, galactose, fructose, and sorbitol. In some embodiments, the diluent is used in an amount of about 60% to about 90% by weight. In some embodiments, the diluent is used in an amount of about 65% to about 90% by weight. In some embodiments, the diluent is used in an amount of about 70% to about 90% by weight. In some embodiments, the disintegrant is used in an amount of about 85% by weight. A preferred formulation is one in which lactose is excluded from the formulation.

[0167] In some embodiments, the pharmaceutical formulation is formulated to provide a time to maximum plasma concentration (T) following administration of the bromocriptine pharmaceutical formulation (e.g., administration of six pharmaceutical formulations each providing a dose of about 0.8 mg of bromocriptine) when the pharmaceutical formulation is administered to an adult subject under fasting conditions. max ) is about 30 to about 60 minutes, such as about 50 minutes, for example about 53 minutes, or about 90 to 120 minutes when the pharmaceutical formulation is administered to an adult subject under high fat feeding conditions.

[0168] Bromocriptine pharmaceutical formulations described herein (e.g., tablets) and bromocriptine pharmaceutical formulations prepared by the methods herein can be used to treat type 2 diabetes by improving glycemic control in individuals with type 2 diabetes. The pharmaceutical formulations can be administered within about 2 hours after awakening in the morning with a meal. Initial doses can be about 0.1 mg of bromocriptine daily, which can be increased weekly until a maximum tolerated daily dose of about 1.6 to about 7.2 mg is achieved.

[0169] It will be appreciated that certain features of the invention are, for clarity, described in the context of separate embodiments, and can also be provided in combination in a single embodiment (the embodiments are intended to be combined as described in increasing subembodiments). Conversely, various features of the invention are, for brevity, described in the context of a single embodiment, and can also be provided separately or in any suitable subcombination.

[0170] So, in summary: ¶ 1. The present disclosure thus provides a pharmaceutical formulation (e.g., tablet) comprising bromocriptine (e.g., bromocriptine mesylate or a different bromocriptine salt, e.g., bromocriptine citrate) and an excipient, wherein the bromocriptine is present in an amount providing a dose of at least about 0.1 mg of bromocriptine per pharmaceutical formulation, and the excipient comprises a fatty acid or triglyceride. The excipient can be devoid of magnesium, magnesium stearate, and / or lactose. The excipient can comprise one or more non-lactose sugars. Additionally, the present disclosure provides pharmaceutical formulations of bromocriptine that are heat and humidity stable, have a water solubility of at least 500 mg / ml of water, and can be stable in an aqueous environment. In particular, the present disclosure provides pharmaceutical formulations comprising bromocriptine citrate, a free fatty acid such as stearic acid or a triglyceride, a non-lactose sugar such as mannitol, and citric acid as an excipient. The excipient can be devoid of magnesium or magnesium stearate. More specifically, the present disclosure provides a pharmaceutical formulation of bromocriptine citrate, a free fatty acid such as stearic acid or a triglyceride, a non-lactose sugar such as mannitol, and citric acid as an excipient, wherein the bromocriptine formulation is stable to heat and humidity, the bromocriptine formulation has high water solubility (e.g., solubility of at least 200 mg / L or 500 mg / L in water) and can be stable in an aqueous environment (minimal decomposition at 25° C. for 6 hours). Even more specifically, the present disclosure provides formulations comprising bromocriptine citrate, a free fatty acid such as stearic acid or a triglyceride, a non-lactose sugar such as mannitol, and citric acid as an excipient, wherein the bromocriptine formulation is more stable to heat and humidity than traditional pharmaceutical formulations comprising bromocriptine as a mesylate + lactose, magnesium stearate, and citric acid as an excipient, and the bromocriptine formulation has a higher water solubility (e.g., soluble in water at least 500 mg / L or 200 mg / L) and can be more stable in an aqueous environment.

[0171] ¶ 2. The present disclosure relates to a method for the preparation of glycerol-based glycerols in which at least about 80% of the acyl groups in the triglycerides are C 6 -C 14is a fatty acyl group of a fatty acid.

[0172] The present disclosure provides a method for treating a glycerol-containing glycerol-containing glycerol comprising administering to a patient a glycerol-containing ... 14 -C 26 is a fatty acyl group of a fatty acid.

[0173] ¶ 3. The present disclosure relates to a method for the preparation of glycerol-based glycerols in which at least about 90% of the acyl groups in the triglycerides are C 14 -C 26 The pharmaceutical formulation of paragraph ¶2 is provided, wherein the fatty acid is a fatty acyl group of a fatty acid.

[0174] ¶ 4. The present disclosure relates to a method for the preparation of glycerol-based glycerols in which at least about 80% of the acyl groups in the triglycerides are C 16 -C 20 The pharmaceutical formulation of paragraph ¶2 is provided, wherein the fatty acid is a fatty acyl group of a fatty acid.

[0175] ¶ 5. The present disclosure relates to a method for the preparation of glycerol-based glycerols in which at least about 90% of the acyl groups in the triglycerides are C 16 -C 20 The pharmaceutical formulation of claim ¶3 is provided, wherein the fatty acid is a fatty acyl group of a fatty acid.

[0176] ¶ 6. The present disclosure relates to a method for the preparation of glycerol-based glycerols in which at least about 80% of the acyl groups in the triglycerides are C 18 The pharmaceutical formulation is provided as described in paragraph ¶4, wherein the fatty acid acyl group is a fatty acid.

[0177] ¶ 7. The present disclosure provides a method for the preparation of glycerol-based glycerols in which at least about 90% of the acyl groups in the triglycerides are C 18 The pharmaceutical formulation of paragraph ¶5 is provided, wherein the fatty acid is a fatty acyl group of a fatty acid.

[0178] ¶ 8. The disclosure provides a pharmaceutical formulation according to paragraph ¶ 6, wherein at least about 80% of the acyl groups of the triglycerides are stearoyl or 12-hydroxystearoyl groups.

[0179] ¶ 9. The disclosure provides a pharmaceutical formulation according to paragraph ¶ 5, wherein at least about 90% of the acyl groups of the triglycerides are stearoyl or 12-hydroxystearoyl groups.

[0180] ¶ 10. The disclosure provides a pharmaceutical formulation according to any one of paragraphs ¶ 1-9, wherein at least about 80% of the acyl groups of the triglycerides are saturated.

[0181] ¶ 11. The present disclosure provides a pharmaceutical formulation according to paragraph ¶ 10, wherein at least about 90% of the acyl groups of the triglycerides are saturated.

[0182] ¶ 12. The disclosure provides a pharmaceutical formulation according to any one of paragraphs ¶ 1-11, wherein the excipient comprises hydrogenated vegetable oil.

[0183] ¶ 13. The disclosure provides a pharmaceutical formulation according to any one of paragraphs ¶ 1-12, wherein the excipient comprises hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated palm kernel oil, hydrogenated soybean oil, or a combination thereof.

[0184] ¶ 14. The disclosure provides a pharmaceutical formulation according to any one of paragraphs ¶ 1-13, wherein the excipient comprises hydrogenated castor oil.

[0185] ¶ 15. The disclosure provides a pharmaceutical formulation as described in paragraphs ¶ 1-14, wherein the excipient comprises KOLLIWAX® HCO.

[0186] ¶ 16. The disclosure provides a pharmaceutical formulation according to any one of paragraphs ¶ 1-15, wherein the excipient is present in an amount of from about 0.5 to about 3% by weight of the formulation.

[0187] ¶ 17. The disclosure provides a pharmaceutical formulation according to any one of paragraphs ¶ 1-16, wherein the excipient is extragranular.

[0188] ¶ 18. The disclosure provides a pharmaceutical formulation according to any one of paragraphs ¶ 1-17, wherein the pharmaceutical formulation is stable after storage for about 18 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, such that the pharmaceutical formulation contains no more than 5% total related substances, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0189] ¶ 19. The disclosure provides a pharmaceutical formulation according to paragraph ¶ 18, wherein the pharmaceutical formulation is stable such that after storage for about 24 months at a temperature of 25±5° C. and a relative humidity of about 60±5%, the pharmaceutical formulation contains no more than 5% total related substances as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0190] ¶ 20. The disclosure provides a pharmaceutical formulation according to any one of paragraphs ¶ 1-17, wherein the pharmaceutical formulation is stable such that after storage for about 18 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, the pharmaceutical formulation contains no more than 5% bromocriptinine, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0191] ¶ 21. The present disclosure provides a pharmaceutical formulation as described in paragraph ¶ 20, wherein the pharmaceutical formulation is stable such that after storage for about 24 months at a temperature of 25±5° C. and a relative humidity of about 60±5%, the pharmaceutical formulation contains no more than 5% bromocriptine, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0192] ¶ 22. The disclosure provides a pharmaceutical formulation according to any one of paragraphs ¶ 1-17, wherein the pharmaceutical formulation is stable after storage for about 18 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, such that the pharmaceutical formulation contains no more than 3% total related substances, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0193] ¶ 23. The disclosure provides a pharmaceutical formulation according to paragraph ¶ 22, wherein the pharmaceutical formulation is stable such that after storage for about 24 months at a temperature of 25±5° C. and a relative humidity of about 60±5%, the pharmaceutical formulation contains no more than 3% total related substances as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0194] ¶ 24. The disclosure provides a pharmaceutical formulation according to any one of paragraphs ¶ 1-17, wherein the pharmaceutical formulation is stable such that after storage for about 18 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, the pharmaceutical formulation contains no more than 3% bromocriptinine, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0195] ¶ 25. The disclosure provides a pharmaceutical formulation according to paragraph ¶ 20, wherein the pharmaceutical formulation is stable such that after storage for about 24 months at a temperature of 25±5° C. and a relative humidity of about 60±5%, the pharmaceutical formulation contains no more than 3% bromocriptinine, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0196] ¶ 26. The present disclosure provides a pharmaceutical formulation comprising micronized bromocriptine in an amount of at least about Provided is a pharmaceutical formulation comprising micronized bromocriptine (e.g., bromocriptine mesylate or a different bromocriptine salt, e.g., bromocriptine citrate), present in an amount to provide a dose of 0.8 mg, wherein the pharmaceutical formulation is stable such that it contains no more than 5% bromocriptine after storage at a temperature of 25±2° C. and at a relative humidity of about 60±5% for about 18 months, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0197] ¶ 27. The disclosure provides a pharmaceutical formulation according to paragraph ¶ 26, wherein the pharmaceutical formulation is stable such that after storage for about 18 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, the pharmaceutical formulation contains no more than 5% total related substances as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0198] ¶ 28. The disclosure provides a pharmaceutical formulation according to paragraph ¶ 26, wherein the pharmaceutical formulation is stable such that after storage for about 24 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, the pharmaceutical formulation contains no more than 5% bromocriptinine, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0199] ¶ 29. The disclosure provides a pharmaceutical formulation according to paragraph ¶ 26, wherein the pharmaceutical formulation is stable such that after storage for about 24 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, the pharmaceutical formulation contains no more than 5% total related substances as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0200] ¶ 30. The disclosure provides a pharmaceutical formulation according to paragraph ¶ 26, wherein the pharmaceutical formulation is stable such that after storage for about 18 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, the pharmaceutical formulation contains no more than 3% bromocriptinine, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0201] ¶ 31. The disclosure provides a pharmaceutical formulation as described in paragraph ¶ 26, wherein the pharmaceutical formulation is stable such that after storage for about 18 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, the pharmaceutical formulation contains no more than 3% total related substances as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0202] ¶ 32. The disclosure provides a pharmaceutical formulation according to paragraph ¶ 26, wherein the pharmaceutical formulation is stable such that after storage for about 24 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, the pharmaceutical formulation contains no more than 3% bromocriptinine, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0203] ¶ 33. The disclosure provides a pharmaceutical formulation as described in paragraph ¶ 26, wherein the pharmaceutical formulation is stable such that after storage for about 24 months at a temperature of 25±2° C. and a relative humidity of about 60±5%, the pharmaceutical formulation contains no more than 3% bromocriptinine, as determined by HPLC analysis using detection of UV absorbance at 300 nm.

[0204] ¶ 34. The present disclosure provides a pharmaceutical formulation according to any one of paragraphs ¶ 1-25, wherein the bromocriptine is micronized.

[0205] ¶ 35. The disclosure provides a pharmaceutical formulation according to any one of paragraphs ¶ 1-34, wherein the bromocriptine has a Dv90 of about 20 μm or less.

[0206] ¶ 36. The present disclosure provides a pharmaceutical formulation as described in paragraph ¶ 35, wherein the bromocriptine has a Dv90 of about 10 μm or less.

[0207] ¶ 37. The disclosure provides a pharmaceutical formulation as described in paragraph ¶ 35, wherein the bromocriptine has a Dv90 of about 5 μm or less.

[0208] ¶ 38. The disclosure provides a pharmaceutical formulation according to any one of paragraphs ¶ 1-37, wherein the bromocriptine has a Dv99 of about 20 μm or less.

[0209] ¶ 39. The present disclosure provides a pharmaceutical formulation as described in paragraph ¶ 38, wherein the bromocriptine has a Dv99 of about 10 μm or less.

[0210] ¶ 40. The disclosure provides a pharmaceutical formulation as described in paragraphs ¶ 1-39, wherein the bromocriptine has a volume-based particle size distribution, with no more than about 20% of the bromocriptine having a particle size less than about 1 μm.

[0211] ¶ 41. The disclosure provides a pharmaceutical formulation as described in any one of paragraphs ¶ 1-40, wherein the pharmaceutical formulation provides a dissolution profile when tested in a USP Apparatus Type 2 Paddle Method at about 37° C. in 500 ml of 0.1 N hydrochloric acid at 50 rpm, wherein at least about 80% of the bromocriptine is released in about 30 minutes.

[0212] ¶ 42. The disclosure provides a pharmaceutical formulation as described in paragraph ¶ 41, wherein the pharmaceutical formulation provides a dissolution profile when tested in a USP Apparatus Type 2 Paddle Method at about 37° C. in 500 ml of 0.1 N hydrochloric acid at 50 rpm, wherein at least about 90% of the bromocriptine is released in about 30 minutes.

[0213] ¶ 43. The disclosure provides a pharmaceutical formulation as described in paragraph ¶ 41, wherein the pharmaceutical formulation provides dissolution characteristics when tested in a USP Apparatus Type 2 Paddle Method at about 37° C. in 500 ml of 0.1 N hydrochloric acid at 50 rpm, wherein at least about 95% of the bromocriptine is released in about 30 minutes.

[0214] ¶ 44. The disclosure provides a pharmaceutical formulation as described in paragraph ¶ 41, wherein the pharmaceutical formulation provides a dissolution profile when tested in a USP Apparatus Type 2 Paddle Method at about 37° C. in 500 ml of 0.1 N hydrochloric acid at 50 rpm, wherein at least about 90% of the bromocriptine is released in about 20 minutes.

[0215] The present disclosure provides stable bromocriptine formulations, where the dissolution of the formulation (as tested in Example 11) is greater than 90% within 10 minutes, within 5 minutes, or within 2 minutes.

[0216] ¶ 45. The disclosure provides a pharmaceutical formulation as described in paragraphs ¶ 41-44, wherein the pharmaceutical formulation provides a dissolution profile when tested in a USP Apparatus Type 2 Paddle Method at about 37° C. in 500 ml of 0.1 N hydrochloric acid at 50 rpm, where about 50% or less of the bromocriptine is released in about 7 minutes.

[0217] ¶ 46. The disclosure provides a pharmaceutical formulation as described in any one of paragraphs ¶ 41-45, wherein the pharmaceutical formulation provides a dissolution profile when tested in a USP Apparatus Type 2 Paddle Method at about 37° C. in 500 ml of 0.1 N hydrochloric acid at 50 rpm, where about 75% or less of the bromocriptine is released in about 10 minutes.

[0218] ¶ 47. The disclosure provides pharmaceutical formulation pharmacokinetic and time to maximum plasma concentration (T max ) is about 30 to 60 minutes when the pharmaceutical preparation is administered under fasting conditions. provide.

[0219] ¶ 48. The disclosure provides pharmaceutical formulation pharmacokinetic and time to maximum plasma concentration (T max ) is about 90 to 120 minutes when the pharmaceutical formulation is administered under high fat fed conditions.

[0220] In another embodiment, the dosage form is suitable for parenteral administration and has a plasma T max Pharmacokinetic properties having a duration of about 90 to about 360 minutes and a C max , and a decrease in plasma levels that can approximate a one-time elimination rate.

[0221] ¶ 49. The disclosure provides a pharmaceutical formulation according to any one of paragraphs ¶ 1-48, wherein the pharmaceutical formulation comprises citric acid.

[0222] ¶ 50. The disclosure provides a pharmaceutical formulation as described in paragraph ¶ 49, wherein the citric acid is present in an amount of about 1 to about 10% by weight.

[0223] ¶ 51. The disclosure provides a pharmaceutical formulation according to any one of paragraphs ¶ 1-50, wherein the pharmaceutical formulation comprises a disintegrant.

[0224] ¶ 52. The disclosure provides a pharmaceutical formulation as described in ¶ 51, wherein the disintegrant is present in an amount of about 5 to about 90% by weight.

[0225] ¶ 53. The present disclosure provides a pharmaceutical formulation according to any one of paragraphs ¶ 1-52, wherein bromocriptine is provided in a dosage of at least about 0.1 mg per pharmaceutical formulation of the formulation.

[0226] ¶ 54. The disclosure provides a method of making a pharmaceutical formulation according to any one of paragraphs ¶ 1-53, the method comprising mixing bromocriptine with an excipient to form a mixture, wherein the bromocriptine is substantially uniformly distributed in the mixture, and compressing the mixture to form the pharmaceutical formulation.

[0227] ¶ 55. The disclosure provides a method as described in paragraph ¶ 54, comprising processing bromocriptine to reduce the average particle size of bromocriptine to provide bromocriptine having a Dv90 of about 20 μm or less prior to blending.

[0228] ¶ 56. The present disclosure provides a method as described in paragraph ¶ 54 or 55, comprising determining that the bromocriptine has a particle size distribution equivalent to a volume-based particle size distribution with a Dv90 of about 20 μm or less prior to mixing.

[0229] ¶ 57. The disclosure provides a pharmaceutical formulation prepared by the method described in any one of paragraphs ¶ 54-56.

[0230] ¶ 58. The present disclosure provides a method of treatment for improving glycemic control in a patient with type 2 diabetes comprising administering to the patient a bromocriptine pharmaceutical formulation described in any one of paragraphs ¶ 1-53 or 57.

[0231] ¶ 59. The present disclosure provides a method of treatment for improving glycemic control in a patient with type 2 diabetes comprising administering to the patient a bromocriptine pharmaceutical formulation described in any one of paragraphs ¶ 1-53 or 57.

[0232] ¶ 60. The present disclosure provides a method of treatment for improving glycemic control in a patient with type 2 diabetes comprising preparing at least one pharmaceutical formulation by the method described in any one of paragraphs ¶ 54-56, and providing the pharmaceutical formulation for administration to the patient.

[0233] ¶ 61. The present disclosure provides a method of treating a metabolic disorder or a key component thereof, such as improving glycemic control in a patient with type 2 diabetes, comprising preparing at least one pharmaceutical formulation by the method described in any one of paragraphs ¶ 54-56, and administering the pharmaceutical formulation to the patient.

[0234] 62. The disclosure provides a pharmaceutical formulation comprising bromocriptine citrate, a free fatty acid or triglyceride, a non-lactose short chain sugar such as mannitol, and citric acid.

[0235] 63. The present disclosure provides a method of treating a metabolic disorder, or a key component of a metabolic disorder, such as type 2 diabetes, by administering to a patient in need of treatment a pharmaceutical formulation comprising bromocriptine citrate, a free fatty acid or triglyceride, a non-lactose short chain sugar such as mannitol, and citric acid.

[0236] 64. The disclosure provides an oral pharmaceutical formulation containing 0.1-10% bromocriptine citrate, 0.1-10% citric acid, 30-90% non-lactose short chain saccharides, and 0.2-10% free fatty acids, phospholipids, or triglycerides.

[0237] 65. The disclosure provides a parenteral pharmaceutical formulation containing 0.1-10% bromocriptine citrate, 0.1-10% citric acid, 60-90% non-lactose short chain saccharides, and 0.2-10% free fatty acids, phospholipids, or triglycerides. EXAMPLES

[0238] The inventors' discoveries are illustrated by the following examples, which are not intended to limit the scope of the claims. Other variations or embodiments of the invention will be apparent to those skilled in the art from the foregoing and following examples.

[0239] Example 1. Preparation of a stable micronized bromocriptine formulation Milling of bromocriptine (to prepare micronized bromocriptine) was accomplished using a Fluid Energy Model 00 Jet-O-Mizer jet mill. Enhanced stability of bromocriptine pharmaceutical formulations can be obtained by replacing either or both of the two reactive excipients, magnesium and lactose, with non-reactive lubricants and sugars, respectively. Therefore, non-reactive alternatives to these reactive excipients were investigated to increase the stability of bromocriptine pharmaceutical formulations.

[0240] Stearic acid or triglycerides (as potential replacements for magnesium stearate) and mannitol (as a potential replacement for lactose) were evaluated. Tablet formulations were prepared using these non-reactive alternatives and accelerated stability studies were performed. The compositions of the formulations manufactured and evaluated in this project are found in Tables 1-4 below.

[0241] 350 tablets of each were produced. The tablets were formulated using a dry granulation method and compressed using a single stage tablet press. The tablets were flat round tablets with a diameter of 6.0 mm and an average weight of 90 mg + / - 5%.

[0242] [Table 1]

[0243] Table 1: Formulation Guide for VS-54F-A (Bromocriptine Pharmaceutical Formulation with Magnesium Stearate and Lactose). The hardness of the formulation was approximately 8-10 KP. The tablet appearance was white. The disintegration time of this formulation was approximately 5-8 minutes. The flow characteristics of this granulation mixture were suitable for the use of a gravity fed press.

[0244] [Table 2]

[0245] Table 2: Formulation guide for VS-54F-B (Bromocriptine pharmaceutical formulation with stearic acid replacing magnesium stearate and mannitol replacing lactose). The hardness of the formulation was approximately 8-10 KP. The tablet appearance was white. The disintegration time of this formulation was approximately 5-8 minutes. The flow characteristics of this granulation mixture were suitable for the use of a gravity fed press.

[0246] [Table 3]

[0247] Table 3: Formulation guide for VS-54F-C (Bromocriptine pharmaceutical formulation with castor oil replacing magnesium stearate and mannitol replacing lactose). The hardness of the formulation was about 8-10 KP. The tablet appearance was white. The disintegration time of this formulation was about 5-8 minutes. The flow characteristics of this granulation mixture were suitable for the use of a gravity fed press.

[0248] [Table 4]

[0249] Table 4: Formulation Guide for VS-54F-B.1 (Bromocriptine pharmaceutical formulation with stearic acid replacing magnesium stearate and mannitol replacing lactose). The hardness of the formulation was approximately 8-10 KP. The tablet appearance was white. The disintegration time of this formulation was approximately 5-8 minutes. The flow characteristics of this granulation mixture were suitable for the use of a gravity fed press.

[0250] Each of the foregoing formulations was prepared and tested for starting bromocriptine (the major degradation product of bromocriptine; BCI) content prior to being subjected to analysis, content uniformity, and 40° C. / 75% RH stress. Three tablets from each formulation were tested for content uniformity. The lot numbers for each of these formulations are provided below. VS-54F-A VS-54F-B VS-54F-C VS-54F-B.1 (Second preparation of formulation B)

[0251] Example 2. Stability and dissolution studies of three tablet bromocriptine formulations HPLC was used to set up a calibration curve and analyze each of the formulations described in Example 1. For analysis and determination of % Bromocriptine (major degradation product of Bromocriptine; BCI), one tablet was dissolved in 10 ml of 0.1% citric acid solution in a volumetric flask to obtain a theoretical concentration of approximately 0.0945 mg / ml. Stability and T 0 Based on new information regarding our need for, we analyzed tablets of each formulation stored at 5°C sandwiched between two tablets stressed at 40°C / 75%RH. All four formulations were analyzed at T=2, 4, and 6 weeks for analysis and %BCI. The %BCI was calculated based on the area of ​​the BCI peak and the combined area of ​​the BCI and API peaks.

[0252] [Table 5] Table 5: Bromocriptine analysis for formulations. Analysis of all formulations during stability study.

[0253] [Table 6] Table 6: Bromocriptine in formulations. % BCI for each formulation based on the area of ​​the bromocriptine API and BCI peaks (degradation products of bromocriptine).

[0254] As expected, there was a slight increase in %BCI in all of the 40 / 75 stressed samples during the study. Formulation C (VS-54F-C) had the lowest %BCI initially and the %BCI remained low throughout the study (i.e., Formulation C provided the best stability with respect to bromocriptine degradation as evidenced by the %BCI). Formulation B had the next lowest %BCI during the study. The highest amount of degradation was seen in Formulation A. Compared to Formulation A, Formulations B and C significantly reduced the degradation of bromocriptine under the test conditions used by 63% and 88%, respectively.

[0255] Each formulation was also tested for dissolution using the basket apparatus, paddle apparatus, and flow-through cell (formulation C only). For the basket and paddle apparatus, 11 tablets from each formulation were weighed and added to 1,000 ml of 0.2% citric acid solution. Time points were taken at 10, 15, 20, 25, 30, 45, and 60 minutes. Samples were prepared for analysis by centrifugation and injection of the resulting mother liquor. For the flow-through cell, one tablet was used with 100 ml of solvent flowing continuously through the cell. Samples were prepared the same as for the basket and paddle apparatus. All dissolution tests of the tablet formulations showed a fast and high recovery of release of API at 1 hour. In all cases, release after 30 minutes was >90% of theory and in many cases reached the 90th percentile early in sampling.

[0256] From a comparison study of bromocriptine degradation from formulations lacking magnesium stearate and lactose (e.g., see Tables 5 and 6, Formulations B and C at 40° C. / 75% RH for 6 weeks) versus formulations containing magnesium stearate and lactose, it can be seen that the impact of reducing bromocriptine degradation is greater in the absence of both magnesium stearate and lactose as components of the formulation.

[0257] Example 3. Methods used in Examples 1 and 2 Bromocriptine HPLC analysis. HPLC settings: Agilent 1100; Column: Waters Symmetry Shield RP18, 3.5 micron, 4.6x150mm; P / N 186000180 Mobile phase A: 0.1% TFA in water Mobile phase B: 0.1% TFA acetonitrile

[0258] [Table 7]

[0259] Flow rate: 1 ml / min; Detection UV: 300 nm; Sample diluent: 0.1% citric acid; Column oven temperature: 30° C.; Injection volume: 100 μl Reduction of Bromocriptine Particle Size Using a Jet Mill. Excipient: Bromocriptine Mesylate; Equipment: Malvern Mastersizer Particle Size Analyzer (Model MS / S); Scale 0.0000 readable; Spatula; Amber glass bottle with 500 ml Teflon lid rim; Fluid Energy Model 00 Jet-O-Mizer, compressed air; TA Instruments Differential Scanning Calorimeter, TA Instruments Thermogravimetric Analyzer, Olympus Microscope.

[0260] In a weighing pan, 1.0 g of bromocriptine was weighed to the nearest 0.000 g. The material was then loaded into the vibratory feeder. After loading the sample, a compressed air line set at 100 psi was connected to the mill and the gas inlet switch to the machine was moved to the on position. The grinding pressure was set to 40 psi and the feed pressure was set to 50 psi. After the pressures were set for the mill, the feeder power knob was set to the zero position and the feeder current was turned on. After the current was turned on, the feeder power button was illuminated until the desired feed rate in the hopper was achieved, going from a 1-10 scale to a dial reading of approximately 1.5 (approximately 0.500 g API / min). Cutting at this feed pressure continued until all material had been fed into the mill. When all material (initially weighed out at 1.000 g) had been ground, the gas was turned off. The milled material from this run was removed from the collection filter, then another 1.000 g of bromocriptine was weighed out and milling resumed. After milling was completed, all milled material was placed into a single 20 ml glass container with a lid. The total amount of product recovered was 1.500 g (75% yield). The milled product was then characterized using the following methods: microscopy, HPLC and particle size analysis.

[0261] Microscopy: Approximately 2-3 mg of KPT-350 was placed on a glass slide. Using a cover slip, the material was carefully spread evenly over the surface of the slide. The spread material was covered with a cover slip and observed at 50x magnification. Examination of these materials with polarized light revealed that the materials were crystalline in nature. No amorphous regions were observed. The unmilled material had particles ranging in size from approximately 0.5-10 μm. The jet mill had an average particle size of approximately 0.5-3.0 μm.

[0262] HPLC: HPLC analysis of the unmilled and milled material confirmed no change in chemical composition.

[0263] Tableting Chemicals for Milled Bromocriptine: Milled Bromocriptine Mesylate (NAT) Lot#: VS-ER-001; Anhydrous Citric Acid (Fisher) Lot#: 100610; Starch 1500 (Colorcon) Lot#: IN510883; Mannitol (SPI Pharma) Lot#: 06N129; Lactose Lactopress Anhydrous 250 (DFE Pharma); Aerosil R202 (Evonik) Lot#: 3150090932; Magnesium Stearate (Spectrum Chemicals) Lot#: UL0756; Stearic Acid (Spectrum Chemicals) Lot#: TB1349; Fully Hydrogenated Castor Acid (ACME Hardesty) Lot#: 07-H-29.

[0264] Equipment: Laboratory scale (0.000 readability); TDP1.5 table top tablet press; 6mm concave circular punch; 6mm circular die; 50ml lidded vials; variable speed rollers.

[0265] Mixing procedure for formulation VS-54F-A: A 50 ml round bottom flask with lid was charged with 0.331 g of bromocriptine and 0.473 g of citric acid. The mixture was shaken vigorously for a few seconds and then placed on a roller that allowed the mixture to roll (at maximum speed) for 10 minutes.

[0266] After 10 minutes of rolling, the mixing was stopped and 3.150 g of Starch 1500 was added to the mixture. The mixture was then shaken vigorously for a few seconds and then placed on a roller that allowed the mixture to roll (at maximum speed) for 10 minutes.

[0267] After rolling for 10 minutes, the mixing was stopped and 27.153 g of anhydrous lactose and 0.158 g of fumed silica were added to the mixture. The mixture was then shaken vigorously for a few seconds and then placed on a roller that allowed the mixture to roll (at maximum speed) for 10 minutes.

[0268] After 10 minutes of rolling, mixing was stopped and 0.236 g of magnesium stearate was added to the mixture. After adding the magnesium stearate, the mixture was then shaken vigorously for a few seconds and rolled at maximum speed for 2 minutes.

[0269] After rolling for 2 minutes, the mixture was loaded into the feeder of a tablet press. The mixture was then compressed into tablets at the maximum pressure it could withstand at TDP1.5 (approximately 1.5 tons of pressure). The tablets were 6mm flat round in shape with an average weight of approximately 0.090+ / -5%g.

[0270] After the hardness testing was completed, disintegration testing was performed and observations were made.

[0271] Mixing procedure for formulation VS-54F-B: A 50 ml round bottom flask with lid was charged with 0.331 g of bromocriptine and 0.473 g of citric acid. The mixture was shaken vigorously for a few seconds and then placed on a roller that allowed the mixture to roll (at maximum speed) for 10 minutes.

[0272] After 10 minutes of rolling, the mixing was stopped and 3.150 g of Starch 1500 was added to the mixture. The mixture was then shaken vigorously for a few seconds and then placed on a roller that allowed the mixture to roll (at maximum speed) for 10 minutes.

[0273] After rolling for 10 minutes, the mixing was stopped and 27.153 g of anhydrous mannitol and 0.158 g of fumed silica were added to the mixture. The mixture was then shaken vigorously for a few seconds and then placed on a roller that allowed the mixture to roll (at maximum speed) for 10 minutes.

[0274] After 10 minutes of rolling, mixing was stopped and 0.473 g of stearic acid was added to the mixture. After adding the stearic acid, the mixture was then shaken vigorously for a few seconds and rolled at maximum speed for 2 minutes.

[0275] After rolling for 2 minutes, the mixture was loaded into the feeder of a tablet press. The mixture was then compressed into tablets at the maximum pressure it could withstand at TDP1.5 (approximately 1.5 tons of pressure). The tablets were 6mm flat round in shape with an average weight of approximately 0.090+ / -5%g.

[0276] After the hardness testing was completed, disintegration testing was performed and observations were made.

[0277] Mixing procedure for formulation VS-54F-C: A 50 ml round bottom flask with lid was charged with 0.331 g of bromocriptine and 0.473 g of citric acid. The mixture was shaken vigorously for a few seconds and then placed on a roller that allowed the mixture to roll (at maximum speed) for 10 minutes.

[0278] After 10 minutes of rolling, the mixing was stopped and 3.150 g of Starch 1500 was added to the mixture. The mixture was then shaken vigorously for a few seconds and then placed on a roller that allowed the mixture to roll (at maximum speed) for 10 minutes.

[0279] After rolling for 10 minutes, mixing was stopped and 27.153 g of anhydrous mannitol and 0.158 g of fumed silica were added to the mixture. The mixture was shaken vigorously for a few seconds and then placed on a roller that allowed the mixture to roll (at maximum speed) for 10 minutes.

[0280] After 10 minutes of rolling, mixing was stopped and 0.236 g of fully hydrogenated castor oil was added to the mixture. After adding the castor oil, the mixture was then shaken vigorously for a few seconds and rolled at maximum speed for 2 minutes.

[0281] After rolling for 2 minutes, the mixture was loaded into the feeder of a tablet press. The mixture was then compressed into tablets at the maximum pressure it could withstand at TDP1.5 (approximately 1.5 tons of pressure). The tablets were 6mm flat round in shape with an average weight of approximately 0.090+ / -5%g.

[0282] After the hardness testing was completed, disintegration testing was performed and observations were made.

[0283] Mixing procedure for formulation VS-54F-B.1: A 50 ml round bottom flask with lid was charged with 0.331 g of bromocriptine and 0.473 g of citric acid. The mixture was shaken vigorously for a few seconds and then placed on a roller that allowed the mixture to roll (at maximum speed) for 10 minutes.

[0284] After 10 minutes of rolling, mixing was stopped and 3.150 g of Starch 1500 was added to the mixture. The mixture was shaken vigorously for a few seconds and then placed on a roller that allowed the mixture to roll (at maximum speed) for 10 minutes.

[0285] After rolling for 10 minutes, mixing was stopped and 27.153 g of anhydrous mannitol and 0.158 g of fumed silica were added to the mixture. The mixture was shaken vigorously for a few seconds and then placed on a roller that allowed the mixture to roll (at maximum speed) for 10 minutes.

[0286] After 10 minutes of rolling, mixing was stopped and 0.473 g of stearic acid was added to the mixture. After adding the stearic acid, the mixture was then shaken vigorously for a few seconds and rolled at maximum speed for 2 minutes.

[0287] After rolling for 2 minutes, the mixture was loaded into the feeder of a tablet press. The mixture was then compressed into tablets at the maximum pressure it could withstand at TDP1.5 (approximately 1.5 tons of pressure). The tablets were 6mm flat round in shape with an average weight of approximately 0.090+ / -5%g.

[0288] After the hardness testing was completed, disintegration testing was performed and observations were made.

[0289] Example 4. Study of the browning (decomposition) reaction of bromocriptine + magnesium stearate with and without lactose

[0290] A series of reaction vessels containing various combinations of bromocriptine mesylate, magnesium stearate, and / or lactose, with and without citric acid, were prepared in aqueous suspension and reacted for 55 hours at 60° C. Additionally, samples were prepared in which magnesium stearate was replaced with stearic acid.

[0291] Magnesium stearate was from Sigma (MAGNESIUM STEARATE EXTRA PURE DAB, PH.E, Sigma Product Number: 26454), stearic acid was from (STEARIC ACID, REAGENT GRADE, 95%, Sigma Product Number: 175366); lactose was from Sigma (LACTOSE ANHYDROUS, PH EUR, Sigma Product Number: 17814), and citric acid was from Sigma (CITRIC ACID ANHYDROUS, Sigma Product Number: 27109). Any or all of these reagents may be obtained from other sources known in the art.

[0292] The reagents were weighed out as shown in Table 7 below. 2 ml of distilled water was added to the samples, which were then mixed by vortexing and placed in a reaction chamber with a thermostat set at 50° C. for 24 hours, and then (after 24 hours) set at 60° C. The color change of the sample solutions / mixtures was assessed by comparing the color of the solutions with a standard color chart, and the color intensity (clear to dark brown) of the sample solutions / mixtures was graded at specified time points from 0 hours to 55 hours (see FIG. 2). In FIG. 2, the number "0" indicates a clear or white solution, and the number "40" indicates the thickest solution / suspension observed.

[0293] [Table 8]

[0294] Thus, the following was observed: 1) When magnesium stearate was able to interact with bromocriptine in an aqueous environment, a brown product was produced even in the absence of lactose. 2) When bromocriptine was exposed to both magnesium stearate and lactose, the browning reaction was more intense. 3) The addition of citric acid attenuated the degradation and browning reaction of bromocriptine when bromocriptine was exposed to magnesium stearate alone and when bromocriptine was exposed to both magnesium stearate and lactose. 4) Substitution of magnesium stearate with stearic acid attenuated the degradation and browning of bromocriptine when it was not exposed to lactose and when it was exposed to lactose. 5) The addition of citric acid and the replacement of magnesium stearate with stearic acid attenuated the degradation and browning reaction of bromocriptine to the greatest extent (i.e., greater than the addition of citric acid alone or the replacement of magnesium stearate with stearic acid alone). 6) Substitution of solid castor oil for magnesium stearate attenuated the degradation of bromocriptine to a greater extent than substitution of stearic acid for magnesium stearate.

[0295] In summary, removing magnesium stearate from a bromocriptine formulation enhances its stability in terms of the formation of browning products, regardless of the presence or absence of lactose. Lactose in the presence of magnesium stearate further enhances the browning reaction. Importantly, of the two components of magnesium stearate, it is magnesium (Mg) that promotes the browning reaction, not stearic acid, and replacing magnesium stearate with stearic acid significantly improves the stability of bromocriptine. Removing magnesium stearate from a bromocriptine formulation and replacing it with stearic acid or another non-magnesium salt lubricant (e.g., solid castor oil) enhances the stability of the bromocriptine formulation. Removing lactose from a bromocriptine formulation and replacing it with mannitol or another short chain sugar enhances the stability of the bromocriptine formulation. Citric acid is substantially free of magnesium and lactose. Adding bromocriptine to a formulation may further reduce (i.e., protect against) any / all of these degradations to a finite order, but is not, in itself, sufficient to prevent these degradations.

[0296] Example 5. Stability study of bromocriptine pharmaceutical formulations formulated by replacing magnesium stearate with stearic acid or triglycerides and lactose with mannitol To test the relative stability of bromocriptine pharmaceutical formulations formulated with and without magnesium stearate and lactose, several different bromocriptine formulations (e.g., tablets) were formulated by standard blending and tabletting procedures known in the art.

[0297] Formulation A: A tableted bromocriptine formulation with magnesium stearate and lactose. 0.945 mg bromocriptine mesylate; 9.00 mg cornstarch 1500; 1.350 mg anhydrous citric acid; 77.58 mg anhydrous lactose; 0.450 mg silicon dioxide; 0.675 mg magnesium stearate. Formulation B: A tableted bromocriptine formulation in which magnesium stearate is replaced with stearic acid and lactose is replaced with mannitol. 0.945 mg bromocriptine mesylate; 9.00 mg cornstarch 1500; 1.350 mg anhydrous citric acid; 77.58 mg anhydrous mannitol; 0.450 mg silicon dioxide; 1.350 mg stearic acid. Formulation C: Magnesium stearate is replaced with solid castor oil and lactose is replaced with mannitol. A modified tableted bromocriptine formulation. 0.945 mg bromocriptine mesylate; 9.00 mg cornstarch 1500; 1.350 mg anhydrous citric acid; 77.58 mg anhydrous mannitol; 0.450 mg silicon dioxide; 0.675 mg solid castor oil.

[0298] The prepared bromocriptine formulations were placed in sealed containers and then subjected to 40° C. and 75% relative humidity for 6 weeks. After 6 weeks of exposure to this environment, the formulations were dissolved and analyzed for content of bromocriptinine (the major degradant of bromocriptine) by HPLC analysis. Relative to bromocriptine formulation A (which contained magnesium stearate and lactose), bromocriptine formulation B (stearic acid replaced for magnesium stearate and mannitol replaced for lactose) showed a 63% and 88% reduction in the amount of bromocriptine degradation products (i.e., bromocriptinine), respectively.

[0299] Example 6. Preparation, stability and dissolution of micronized bromocriptine mesylate pharmaceutical formulations prepared with various lubricants Test pharmaceutical formulations of micronized bromocriptine mesylate (identified as Formulations A through E) were prepared using micronized bromocriptine mesylate and various lubricants. The ingredients used for each formulation are listed in Table 8 below.

[0300] [Table 9]

[0301] The formulations were then stored at 25±2°C and 60±5% RH, 30±2°C and 65±5% RH or 40±2°C and 75±5% RH for up to 3 hours.

[0302] The total relevant substance impurities in each batch of formulation were measured using HPLC methods and determined at the beginning of the study (T=0), 1, 2, and / or 3 months. Since bromocriptine is light sensitive, brown glassware was used for the preparation of all solutions. To determine the amount of relevant substances, at least five formulations were weighed to determine the average formulation weight. An aliquot of the ground sample equivalent to 3.5 formulation (2.8 mg bromocriptine) was accurately weighed and this sample was quantitatively transferred to a 25 ml volumetric flask. Aqueous methanol (1:1 v / v, 15 ml) was added and the solution was sonicated for 10 minutes, then diluted to a total volume of 25 ml and mixed well. The sample solution was then filtered and analyzed by reversed-phase HPLC using a Waters 250x4.6mm SUNFIRE C18 column (5 μm particle size), 0.1 M potassium phosphate buffer (pH 7.5) / acetonitrile (1:1 v / v), an autosampler temperature of 5 °C, an isocratic mobile phase, an injection volume of 100 μL, a flow rate of 1.5 μL / min, ambient column temperature, and detection by UV absorption at 300 nm. Under these conditions, bromocriptine elutes at approximately 11-15 minutes and the impurity bromocriptinine elutes at approximately 35-45 minutes (relative retention time of approximately 2.6). The relative impurities are calculated using the following formula: % Individual Related Substances = A i / A t X100 % Total Impurities = Σ% Individual Related Substances where: A i = Peak area for individual related substances in the sample solution chromatogram A t = the total area of ​​all peaks in the sample chromatogram, ignoring void interferences and any peaks observed in the diluent chromatogram.

[0303] The results of the stability test are shown in Table 9 and Figures 1A, 1B and 1C. Figure 3 shows typical chromatograms of the blank solution, the reference solution containing 0.112 mg / ml bromocriptine mesylate and the sample solution.

[0304] [Table 10]

[0305] The results summarized in Table 9 are also shown in Figures 1A, 1B and 1C.

[0306] FIG. 1A shows plots of total related substance impurities measured at the start of the experiment (T=0) and after storage at 40±2° C. and 75±5% RH for 1, 2, or 3 months for bromocriptine mesylate pharmaceutical formulations prepared using micronized bromocriptine mesylate and various lubricants (Formulations A-E).

[0307] FIG. 1B shows plots of total related substance impurities measured at the start of the study (T=0) and after storage at 30±2° C. and 65±5% RH for 3 months for micronized bromocriptine mesylate and bromocriptine mesylate pharmaceutical formulations prepared using various lubricants (Formulations A and C-E).

[0308] FIG. 1C shows plots of total related substance impurities measured at the start of the experiment (T=0) and after storage at 25±2° C. and 60±5% RH for 3 months for micronized bromocriptine mesylate and bromocriptine mesylate pharmaceutical formulations prepared using various lubricants (Formulations A and C-E).

[0309] The results of this study demonstrate that substitution of magnesium stearate in the described tableted micronized bromocriptine formulations (Formulation A) with either stearic acid (Formulation B), sodium stearyl fumarate (Formulation C), or hydrogenated castor oil (Formulation D) for the otherwise same micronized bromocriptine formulations (and all containing lactose and citric acid) each significantly enhanced the heat and humidity stability of the micronized bromocriptine at the test conditions used and for the test period.

[0310] In addition to testing for the presence of impurities, dissolution tests were performed on Formulations A and C through E at the start of the study (T=0) and after storage for 3 months at 25±2°C and 60±5% RH. The results of the dissolution tests are shown in Table 10. Samples were tested in 500 ml of 0.1 N hydrochloric acid at 37±0.5°C using a USP Type 2 apparatus at 50 RPM with the sample drawn for 30 minutes. Bromocriptine mesylate in the samples was quantified by HPLC as previously described.

[0311] [Table 11]

[0312] Example 7. Citric acid was dissolved in separate reaction vessels at room temperature in approximately 4 mg per ml of either methanol, ethanol, or butanol. Free base bromocriptine was dissolved in separate reaction vessels at approximately 12 mg per 5-30 ml of either methanol, ethanol, or butanol. Similar organic solutions of citric acid and bromocriptine (i.e., ethanol-ethanol, methanol-methanol, butanol-butanol) were then mixed in equimolar amounts of bromocriptine and citrate. The three resulting solutions were stirred at room temperature for approximately 2-24 hours until the solvent was evaporated to dryness. The resulting solid product in each reaction vessel contained bromocriptine citrate.

[0313] Example 8: Solubility of Bromocriptine Citrate Versus Bromocriptine Mesylate Equal amounts of solid samples of bromocriptine mesylate and bromocriptine citrate were added to equal amounts of water or water / organic solutions in different containers under various pH conditions, and the dissolution (water solubility) of the bromocriptine samples was evaluated over time. Bromocriptine citrate was found to dissolve very quickly and with significantly higher solubility (increased mg of bromocriptine dissolved per ml of water in citrate vs. mesylate form) compared to bromocriptine mesylate.

[0314] Example 9: In separate reaction vessels, citric acid was dissolved in ethanol and free base bromocriptine was dissolved in an organic solvent. The organic solutions of citric acid and bromocriptine were then mixed in equimolar amounts of bromocriptine and citrate. The resulting solution was stirred at low temperature for about 2-24 hours and the solvent was evaporated to dryness. The resulting solid product contained bromocriptine citrate, which is 7 times more water soluble at 20° C. than bromocriptine mesylate.

[0315] Example 10. Effect of ingredients on stability and solubility of bromocriptine formulations Relative to the traditional formulations of bromocriptine mesylate set forth in Table 1, different pharmaceutical formulations of bromocriptine are prepared varying the inclusion / substitution of ingredients as described herein and in Table 11 (below). The stability and water solubility of the formulations are evaluated relative to the traditional formulations of bromocriptine mesylate set forth in Table 1. Relative to the traditional formulations of bromocriptine mesylate set forth in Table 1, the pharmaceutical formulations of bromocriptine citrate, fatty acid or triglyceride, non-lactose short chain sugar, and citric acid exhibited a higher stability relative to the traditional pharmaceutical formulations of bromocriptine mesylate and any combination of one, two, or three of the pharmaceutical formulations of bromocriptine citrate, fatty acid or triglyceride, non-lactose short chain sugar, and citric acid exhibited a higher stability relative to the traditional pharmaceutical formulations of bromocriptine mesylate. The combination is found to have improved stability to heat and humidity (tested at 40° C. and 75% RH) and water solubility (at 20° C.).

[0316] [Table 12]

[0317] Example 11. Mixing procedure for formulations VS-55F-A, B, C, D: [Table 13]

[0318] Mixing procedure for formulation VS-55F-A: A 50 mL round bottom flask with lid was charged with 0.075 g of bromocriptine and 0.150 g of citric acid. The mixture was then vigorously shaken for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 10 minutes.

[0319] After 10 minutes of rolling, mixing was stopped and 0.250 g of Klucel was added to the mixture. EF Pharm, 0.350 g of croscarmellose, and 0.050 g of fumed silica were added. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 10 minutes.

[0320] After 10 minutes of rolling, mixing was stopped and 1.725 g of Avicel was added to the mixture. PH102 and 2.350 g of mannitol were added. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 10 minutes.

[0321] After 10 minutes of rolling, mixing was stopped and 0.050 g of stearic acid was added to the mixture. After adding the stearic acid, the mixture was then shaken vigorously for a few seconds and rolled at maximum speed for 5 minutes.

[0322] After rolling for 2 minutes, the mixture was loaded into the feeder of a tablet press. The mixture was then compressed into tablets at the maximum pressure it could withstand at TDP1.5 (approximately 1.5 tons of pressure). The tablets were 6mm convex round in shape and had an average weight of approximately 0.100+ / -5%g.

[0323] [Table 14]

[0324] Mixing procedure for formulation VS-55F-B: A 50 ml round bottom flask with lid was charged with 0.050 g of bromocriptine and 0.105 g of citric acid. The mixture was then vigorously shaken for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 10 minutes.

[0325] After rolling for 5 minutes, mixing was stopped and 0.175 g of Klucel was added to the mixture. EF Pharm, 0.245 g of croscarmellose and 0.035 g of fumed silica were added. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0326] After 5 minutes of rolling, mixing was stopped and 1.725 g of Avicel PH 102 and 1.645 g of mannitol were added to the mixture. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0327] After rolling for 5 minutes, mixing was stopped and 0.035 g of stearic acid was added to the mixture. After adding the stearic acid, the mixture was then shaken vigorously for a few seconds and rolled at maximum speed for 5 minutes.

[0328] After rolling for 5 minutes, the mixture was loaded into the feeder of a tablet press. The mixture was then compressed into tablets at the maximum pressure it could withstand at TDP1.5 (approximately 1.5 tons of pressure). The tablets were 6mm convex round in shape and had an average weight of approximately 0.070+ / -5%g.

[0329] Results and Observations for VS-55F-B The hardness of the formulation was approximately 6.0-6.9 KP. The tablet appearance was white. The disintegration time of this formulation was approximately 3.17-3.65 minutes. The flow characteristics of this granulation mixture were suitable for use in a gravity feed press. Content uniformity was not within specification.

[0330] [Table 15]

[0331] Mixing procedure for formulation VS-55F-C: A 50 ml round bottom flask with lid was charged with 0.050 g of bromocriptine and 0.105 g of citric acid. The mixture was then vigorously shaken for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 10 minutes.

[0332] After rolling for 5 minutes, mixing was stopped and 0.125 g of Klucel was added to the mixture. EF Pharm, 0.295 g of croscarmellose and 0.035 g of fumed silica were added. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0333] After 5 minutes of rolling, the mixing was stopped and 1.210 g of Avicel PH 102 and 1.645 g of mannitol were added to the mixture. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0334] After rolling for 5 minutes, mixing was stopped and 0.035 g of stearic acid was added to the mixture. After adding the stearic acid, the mixture was then shaken vigorously for a few seconds and rolled at maximum speed for 5 minutes.

[0335] After rolling for 5 minutes, the mixture was loaded into the feeder of a tablet press. The mixture was then compressed into tablets at the maximum pressure it could withstand at TDP1.5 (approximately 1.5 tons of pressure). The tablets were 6mm convex round in shape and had an average weight of approximately 0.070+ / -5%g.

[0336] Results and Observations for VS-54F-C The hardness of the formulation was approximately 7-8 KP. The tablet appearance was white. The disintegration time of this formulation was approximately 3.17-3.83 minutes. The flow characteristics of this granulation mixture were suitable for use in a gravity feed press. Content uniformity was within specifications.

[0337] [Table 16]

[0338] Mixing procedure for formulation VS-55F-D: A 50 mL round bottom flask with lid was charged with 0.075 g of bromocriptine and 0.150 g of citric acid. The mixture was then vigorously shaken for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 10 minutes.

[0339] After 10 minutes of rolling, mixing was stopped and 0.250 g of Klucel was added to the mixture. EF Pharm, 0.350 g of croscarmellose, and 0.050 g of fumed silica were added. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 10 minutes.

[0340] After 10 minutes of rolling, mixing was stopped and 1.725 g of Avicel was added to the mixture. PH102 and 2.350 g of sorbitol were added. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 10 minutes.

[0341] After 10 minutes of rolling, mixing was stopped and 0.050 g of stearic acid was added to the mixture. After adding the stearic acid, the mixture was then shaken vigorously for a few seconds and rolled at maximum speed for 5 minutes.

[0342] After rolling for 2 minutes, the mixture was loaded into the feeder of a tablet press. The mixture was then compressed into tablets at the maximum pressure it could withstand at TDP1.5 (approximately 1.5 tons of pressure). The tablets were 6mm convex round in shape and had an average weight of approximately 0.100+ / -5%g.

[0343] After the hardness testing was completed, disintegration testing was performed and observations were made.

[0344] Results and Observations for VS-54F-B.1 The hardness of the formulation was approximately 16-16.5 KP. The tablet appearance was white. The disintegration time of this formulation was approximately 8.67-9.0 minutes. The flow characteristics of this granulation mixture were suitable for use in a gravity feed press. Content uniformity was within specification.

[0345] Mixing procedure for formulations VS-56F-A, B, C, D and F:

[0346] [Table 17]

[0347] Mixing procedure for formulation VS-56F-A: A 50 ml round bottom flask with lid was charged with 0.050 g bromocriptine, 0.105 g citric acid, 0.018 g menthol, and 0.175 g Klucel EF Pharm. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0348] After 5 minutes of rolling, mixing was stopped and 1.193 g of Avicel PH 102, 0.245 g of croscarmellose, and 0.035 g of fumed silica were added to the mixture. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0349] After rolling for 5 minutes, mixing was stopped and 1.645 g of mannitol was added to the mixture, which was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0350] After rolling for 5 minutes, mixing was stopped and 0.035 g of stearic acid was added to the mixture. After adding the stearic acid, the mixture was then shaken vigorously for a few seconds and rolled at maximum speed for 5 minutes.

[0351] After rolling for 5 minutes, the mixture was loaded into the feeder of a tablet press. The mixture was then compressed into tablets at a pressure less than the maximum of TDP1.5 (approximately 0.75 tons of pressure). The tablet shape was 6mm flat round with an average weight of approximately 0.070 + / - 5% g.

[0352] After the hardness testing was completed, disintegration testing was performed and observations were made. Results and Observations for VS-56F-A: The hardness of the formulation was approximately 2.8 KP. The tablet appearance was white. The disintegration time of this formulation was approximately 1.5 minutes. The flow characteristics of this granulation mixture were suitable for use in a gravity feed press. Content uniformity was within specifications.

[0353] Conclusion about VS-56F-A: The formulation meets the specifications for content uniformity and disintegration. The tablet formulation was evaluated for API release.

[0354] [Table 18]

[0355] Mixing procedure for formulation VS-56F-B: A 50 ml round bottom flask with lid was charged with 0.075 g bromocriptine, 0.105 g citric acid, 0.018 g menthol, and 0.175 g Klucel EF Pharm. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0356] After 5 minutes of rolling, mixing was stopped and 1.168 g of Avicel PH 102, 0.245 g of croscarmellose, and 0.035 g of fumed silica were added to the mixture. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0357] After rolling for 5 minutes, mixing was stopped and 1.645 g of mannitol was added to the mixture, which was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0358] After rolling for 5 minutes, mixing was stopped and 0.035 g of stearic acid was added to the mixture. After adding the stearic acid, the mixture was then shaken vigorously for a few seconds and rolled at maximum speed for 5 minutes.

[0359] After rolling for 5 minutes, the mixture was loaded into the feeder of a tablet press. The mixture was then compressed into tablets at a pressure less than the maximum of TDP1.5 (approximately 1.5 tons of pressure). The tablet shape was 6mm flat round with an average weight of approximately 0.070 + / - 5%g.

[0360] After the hardness testing was completed, disintegration testing was performed and observations were made.

[0361] Results and Observations for VS-56F-B: The hardness of the formulation was approximately 3.9 KP. The tablet appearance was white. The disintegration time of this formulation was approximately 1.38 minutes. The flow characteristics of this granulation mixture were suitable for use in a gravity feed press. Content uniformity was within specifications.

[0362] Conclusion about VS-56F-B: The formulation meets content uniformity and disintegration specifications. The tablet formulation was evaluated for API release. Ta.

[0363] [Table 19]

[0364] Mixing procedure for formulation VS-56F-C: A 50 ml round bottom flask with lid was charged with 0.050 g bromocriptine, 0.105 g citric acid, 0.018 g menthol, and 0.175 g Klucel EF Pharm. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0365] After 5 minutes of rolling, mixing was stopped and 1.193 g of Avicel PH 102, 0.245 g of croscarmellose, and 0.035 g of fumed silica were added to the mixture. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0366] After rolling for 5 minutes, mixing was stopped and 1.645 g of mannitol was added to the mixture, which was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0367] After rolling for 5 minutes, mixing was stopped and 0.035 g of stearic acid was added to the mixture. After adding the stearic acid, the mixture was then shaken vigorously for a few seconds and rolled at maximum speed for 5 minutes.

[0368] After rolling for 5 minutes, the mixture was loaded into the feeder of a tablet press. The mixture was then compressed into tablets at a pressure less than the maximum of TDP1.5 (approximately 1.5 tons of pressure). The tablet shape was 6mm flat round with an average weight of approximately 0.070 + / - 5%g.

[0369] After the hardness testing was completed, disintegration testing was performed and observations were made.

[0370] Results and Observations for VS-56F-C: The hardness of the formulation was approximately 3-3.5 KP. The tablet appearance was white. The disintegration time of this formulation was approximately 1.33 minutes. The flow characteristics of this granulation mixture were suitable for use in a gravity feed press. Content uniformity was within specifications.

[0371] Conclusion about VS-56F-C: The formulation meets content uniformity and disintegration specifications. The tablet formulation was evaluated for release of API.

[0372] [Table 20]

[0373] Mixing procedure for formulation VS-56F-D: A 50 ml round bottom flask with lid was charged with 0.050 g bromocriptine, 0.105 g citric acid, 0.005 g PEG3350, and 0.175 g Klucel EF Pharm. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0374] After 5 minutes of rolling, mixing was stopped and 1.205 g of Avicel PH 102, 0.245 g of croscarmellose, and 0.035 g of fumed silica were added to the mixture. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0375] After rolling for 5 minutes, mixing was stopped and 1.645 g of mannitol was added to the mixture, which was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0376] After rolling for 5 minutes, mixing was stopped and 0.035 g of stearic acid was added to the mixture. After adding the stearic acid, the mixture was then shaken vigorously for a few seconds and rolled at maximum speed for 5 minutes.

[0377] After rolling for 5 minutes, the mixture was loaded into the feeder of a tablet press. The mixture was then compressed into tablets at a pressure less than the maximum of TDP1.5 (approximately 1.5 tons of pressure). The tablet shape was 6mm flat round with an average weight of approximately 0.070 + / - 5%g.

[0378] After the hardness testing was completed, disintegration testing was performed and observations were made.

[0379] Results and Observations for VS-56F-D: The hardness of the formulation was approximately 3.8 KP. The tablet appearance was white. The disintegration time of this formulation was approximately 1.08 minutes. The flow characteristics of this granulation mixture were suitable for use in a gravity feed press. Content uniformity was within specifications.

[0380] Conclusion about VS-56F-D: The formulation meets content uniformity and disintegration specifications. The tablet formulation was evaluated for release of API.

[0381] [Table 21]

[0382] Mixing procedure for formulation VS-56F-E: A 50 ml round bottom flask with lid was charged with 0.075 g bromocriptine, 0.105 g citric acid, 0.018 g menthol, and 0.175 g Klucel EF Pharm. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0383] After 5 minutes of rolling, the mixing was stopped and 1.168 g of Avicel PH 102, 0.245 g of Explotab, and 0.035 g of fumed silica were added to the mixture. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0384] After rolling for 5 minutes, mixing was stopped and 1.645 g of mannitol was added to the mixture, which was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0385] After rolling for 5 minutes, mixing was stopped and 0.035 g of stearic acid was added to the mixture. After adding the stearic acid, the mixture was then shaken vigorously for a few seconds and rolled at maximum speed for 5 minutes.

[0386] After rolling for 5 minutes, the mixture was loaded into the feeder of a tablet press. The mixture was then compressed into tablets at a pressure less than the maximum of TDP1.5 (approximately 1.5 tons of pressure). The tablet shape was 6mm flat round with an average weight of approximately 0.070 + / - 5%g.

[0387] After the hardness testing was completed, disintegration testing was performed and observations were made.

[0388] Results and Observations for VS-56F-E: The hardness of the formulation was approximately 4.0 KP. The tablet appearance was white. The disintegration time of this formulation was approximately 1.5 minutes. The flow characteristics of this granulation mixture were suitable for use in a gravity feed press. Content uniformity was within specifications.

[0389] Conclusion about VS-56F-E: The formulation meets content uniformity and disintegration specifications. The tablet formulation was evaluated for release of API.

[0390] [Table 22]

[0391] Mixing procedure for formulation VS-56F-F: A 50 ml round bottom flask with lid was charged with 0.050 g bromocriptine, 0.105 g citric acid, 0.018 g menthol, 0.005 g PEG3350, and 0.175 g Klucel EF Pharm. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0392] After 5 minutes of rolling, the mixing was stopped and 1.188 g of Avicel PH 102, 0.245 g of croscarmellose, and 0.035 g of fumed silica were added to the mixture. The mixture was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0393] After rolling for 5 minutes, mixing was stopped and 1.645 g of mannitol was added to the mixture, which was then shaken vigorously for a few seconds and then placed on a roller capable of rolling the mixture (at maximum speed) for 5 minutes.

[0394] After rolling for 5 minutes, mixing was stopped and 0.035 g of stearic acid was added to the mixture. After adding the stearic acid, the mixture was then shaken vigorously for a few seconds and rolled at maximum speed for 5 minutes.

[0395] After rolling for 5 minutes, the mixture was loaded into the feeder of a tablet press. The mixture was then compressed into tablets at a pressure less than the maximum of TDP1.5 (approximately 1.5 tons of pressure). The tablet shape was 6mm flat round with an average weight of approximately 0.070 + / - 5%g.

[0396] After the hardness testing was completed, disintegration testing was performed and observations were made.

[0397] Results and Observations for VS-56F-F: The hardness of the formulation was approximately 3.8 KP. The tablet appearance was white. The disintegration time of this formulation was approximately 1.5 minutes. The flow characteristics of this granulation mixture were suitable for use in a gravity feed press. Content uniformity was within specifications.

[0398] Conclusion about VS-56F-F: The formulation meets content uniformity and disintegration specifications. The tablet formulation was evaluated for release of API.

[0399] Example 11. Two disintegration studies were performed on the tablet formulations produced in this project shown below (Sets 1 and 2). 1st set (4 tablets) VS-ER-NL-55F-A (1.5%BC) VS-ER-NL-55F-B (1.43%BC) VS-ER-NL-55F-C (1.43%BC) VS-ER-NL-55F-D.1 (1.5%BC) 2nd set (6 tablets) VS-ER-NL-56F-A (1.43%BC) VS-ER-NL-56F-B (2.14%BC) VS-ER-NL-56F-C (1.43%BC) VS-ER-NL-56F-D (1.43%BC) VS-ER-NL-56F-E (2.14%BC) VS-ER-NL-56F-F (1.43%BC)

[0400] HPLC method description: The following describes the HPLC conditions (instrument, settings, etc.) for the analysis of the samples. Column: Waters Symmetry Shield RP18, 3.5 micron, 4.6x150mm P / N 186000180 Mobile phase A: 0.1% TFA in water Mobile phase B: 0.1% TFA acetonitrile.

[0401] [Table 23]

[0402] Flow rate: 1ml / min Detection UV: 300nm Diluent: 0.5% citric acid Column oven temperature: 30°C Injection volume: 100μl Sample tray at 5°C.

[0403] HPLC standard preparation The primary stock solution was prepared by accurately weighing and dissolving 30 mg of BC in a 25 ml volumetric flask (diluent-0.5% citric acid) (approximately 1.2 mg / ml). The secondary stock solution was prepared by taking 1 ml of the primary stock and diluting it into a 10 ml volumetric flask (approximately 0.12 mg / ml). Different volumes of the secondary stock solution were taken into separate 10 ml volumetric flasks to prepare directly injected standards for the calibration curve. The volumes and approximate concentrations are shown below; 0.125ml=about 0.0015mg / ml, 0.250ml=about 0.003mg / ml, 0.500ml=about 0.006mg / ml, 1.000ml=about 0.012mg / ml, 1.500ml=about 0.018mg / ml. A spreadsheet was developed to plot the area versus the concentration of the standards. The slope and intercept of this line equation were used to calculate the concentration of each of the pull points in the lysis run.

[0404] Dissolution method From each of the aforementioned lots, eleven tablets were weighed and added to 1000 ml of 0.5% citric acid solution at 37° C. The dissolution apparatus was set with the paddles at 100 RPM. (Apparatus 2) For the first series of experiments described above, samples were withdrawn at 5, 10, 15, 20, 30, 45 and 60 minutes. For the second series of experiments, withdrawal points were more frequent and were performed at earlier time points to capture faster drug release. These time points were: 5, 7.5, 10, 15, 30 and 60 minutes.

[0405] For each withdrawal point, approximately 1 ml of solution was collected. The samples were centrifuged to remove any particles and the supernatant was directly injected.

[0406] The solubility curve was plotted in a spreadsheet. The concentration was determined using the calibration curve and the release rate was determined using the total weight and percent BC of the 11 tablets.

[0407] Dissolution test results for 55F and 56F series 55F series Series results: 1st set (4 tablets) VS-ER-NL-55F-A (1.5%BC) VS-ER-NL-55F-B (1.43%BC) VS-ER-NL-55F-C (1.43%BC) VS-ER-NL-55F-D.1 (1.5%BC)

[0408] Graph 1. Calibration curve for dissolution test of 55F series

number

[0409] [Table 24]

[0410] Graph 2: Graph showing the results of the dissolution test for VS-ER-NL-55F-A (1.5% BC)

number

[0411] Conclusions about VS-ER-NL-55F-A (1.5%BC): The tablets are submitted for use in animal testing.

[0412] [Table 25]

[0413] Graph 3: Results of dissolution test for VS-ER-NL-55F-B (1.43% BC) Results graph

number

[0414] Conclusions about VS-ER-NL-55F-B (1.43%BC): The tablets are submitted for use in animal testing.

[0415] [Table 26]

[0416] Graph 4: Graph showing the results of the dissolution test for VS-ER-NL-55F-C (1.43% BC)

number

[0417] [Table 27]

[0418] Graph 5: Graph of dissolution test results for VS-ER-NL-55F-D (1.5% BC)

number

[0419] Conclusions about VS-ER-NL-55F-D (1.5%BC): Form into tablets as in the previous experiment.

[0420] 56F Series Results: 2nd set (6 tablets) VS-ER-NL-56F-A (1.43%BC) VS-ER-NL-56F-B (2.14%BC) VS-ER-NL-56F-C (1.43%BC) VS-ER-NL-56F-D (1.43%BC) VS-ER-NL-56F-E (2.14%BC) VS-ER-NL-56F-F (1.43%BC)

[0421] Graph 6: Calibration curve for dissolution test of 56F series

number

[0422] [Table 28]

[0423] FIG. 7: Graph of dissolution test results for VS-ER-NL-56F-A (1.43% BC)

number

[0424] Conclusions about VS-ER-NL-56F-B (2.14%BC): The tablets are submitted for animal testing.

[0425] [Table 29]

[0426] Graph 8: Graph of dissolution test results for VS-ER-NL-56F-B (2.14% BC)

number

[0427] Conclusions about VS-ER-NL-56F-B (2.14%BC): The tablets are submitted for animal testing.

[0428] [Table 30]

[0429] Graph 9: Graph of dissolution test results for VS-ER-NL-56F-C (1.43% BC)

number

[0430] Conclusions about VS-ER-NL-56F-C (1.43%BC): The tablets are submitted for animal testing.

[0431] [Table 31]

[0432] Graph 10: Graph of dissolution test results for VS-ER-NL-56F-D (1.43% BC)

number

[0433] Conclusions about VS-ER-NL-56F-D (1.43%BC): The tablets are submitted for animal testing.

[0434] [Table 32]

[0435] Graph 11: Graph of dissolution test results for VS-ER-NL-56F-E (2.14% BC)

number

[0436] Conclusions about VS-ER-NL-56F-F (2.14%BC): The tablets are submitted for animal testing.

[0437] [Table 33]

[0438] Graph 12: Graph showing the results of the dissolution test for VS-ER-NL-56F-F (=1.43% BC)

number

[0439] Conclusions about VS-ER-NL-56F-F (1.43%BC): The tablets are submitted for animal testing.

[0440] Each reference mentioned in the text of this disclosure is incorporated herein by reference in its entirety. Several embodiments of the invention have been described. However, it will be understood that various modifications can be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. Other aspects of the present disclosure include, for example, the following. [1] A pharmaceutical formulation comprising bromocriptine and an excipient, A pharmaceutical formulation, wherein the excipient comprises a fatty acid or triglyceride, a non-lactose short chain sugar, and citric acid. [2] The pharmaceutical formulation of [1], wherein the bromocriptine is present in an amount providing a dose of at least about 0.1 mg. [3] The pharmaceutical formulation according to [1], wherein the bromocriptine comprises bromocriptine mesylate or bromocriptine citrate. [4] At least about 80% of the acyl groups of the triglyceride are C 6 -C 14 The pharmaceutical formulation according to [1], wherein the fatty acid acyl group is a fatty acid. [5] At least about 80% of the acyl groups of the triglyceride are C 14 -C 26 The pharmaceutical formulation according to [1], wherein the fatty acid acyl group is a fatty acid. [6] At least about 80% of the acyl groups of the triglyceride are C 16 -C 20 The pharmaceutical formulation according to [1], wherein the fatty acid acyl group is a fatty acid. [7] At least about 80% of the acyl groups of the triglyceride are C 18 Fatty acid fatty acid The pharmaceutical formulation according to [6], wherein the aryl group is a aryl group. [8] The pharmaceutical formulation of [1], wherein at least about 80% of the acyl groups of the triglycerides are stearoyl or 12-hydroxystearoyl groups. [9] The pharmaceutical preparation according to any one of [1] to [8], wherein at least about 80% of the acyl groups of the triglyceride are saturated.

[10] The pharmaceutical formulation according to any one of [1] to [9], wherein the excipient comprises hydrogenated vegetable oil.

[11] The pharmaceutical formulation according to any one of [1] to

[10] , wherein the excipient comprises hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated palm kernel oil, hydrogenated soybean oil, or a combination thereof.

[12] The pharmaceutical formulation according to any one of [1] to

[11] , wherein the excipient comprises KOLLIWAX (registered trademark) HCO.

[13] A pharmaceutical formulation comprising bromocriptine and an excipient, The excipient comprises a triglyceride or stearic acid; the pharmaceutical formulation is substantially free of magnesium or lactose; and Optionally, the bromocriptine is present in an amount to provide a dose of at least about 0.1 mg of bromocriptine.

[14] The pharmaceutical formulation described in

[13] , wherein the pharmaceutical formulation is substantially free of magnesium or lactose.

[15] The pharmaceutical formulation of

[13] , wherein the pharmaceutical formulation comprises a tablet or oral dosage form.

[16] The pharmaceutical formulation according to any one of

[13] to

[15] , wherein the bromocriptine comprises bromocriptine mesylate or bromocriptine citrate.

[17] The pharmaceutical formulation according to any one of

[13] to

[16] , wherein the excipient comprises citric acid and / or mannitol.

[18] The pharmaceutical formulation according to any one of

[13] to

[16] , wherein the excipient comprises solid castor oil.

[19] A pharmaceutical formulation comprising bromocriptine and an excipient, The excipient comprises a short chain saccharide; Substantially free of magnesium or lactose; and Optionally, the bromocriptine is present in an amount to provide a dose of at least about 0.1 mg of bromocriptine.

[20] The pharmaceutical formulation described in

[19] , wherein the pharmaceutical formulation is substantially free of magnesium or lactose.

[21] The pharmaceutical formulation according to

[19] or

[20] , wherein the short-chain saccharide is mannitol.

[22] The pharmaceutical formulation according to any one of

[19] to

[21] , wherein the excipient comprises a triglyceride or stearic acid.

[23] The pharmaceutical formulation according to any one of

[19] to

[22] , wherein the pharmaceutical formulation comprises a tablet or an oral dosage form.

[24] The pharmaceutical formulation according to any one of

[19] to

[23] , wherein the bromocriptine comprises bromocriptine mesylate.

[25] The pharmaceutical formulation according to any one of

[19] to

[24] , wherein the excipient comprises citric acid.

[26] The pharmaceutical formulation according to any one of

[19] to

[25] , wherein the excipient comprises solid castor oil.

[27] A pharmaceutical formulation comprising bromocriptine and an excipient, The excipients include mannitol or stearic acid, and The pharmaceutical formulation is substantially free of magnesium or lactose.

[28] The pharmaceutical formulation described in

[27] , wherein the pharmaceutical formulation is substantially free of magnesium or lactose.

[29] The pharmaceutical formulation of

[27] or

[28] , wherein the pharmaceutical formulation comprises a tablet or an oral dosage form.

[30] The pharmaceutical formulation according to any one of

[27] to

[29] , wherein the bromocriptine comprises bromocriptine mesylate.

[31] The pharmaceutical formulation according to any one of

[27] to

[30] , wherein the excipient comprises citric acid.

[32] The pharmaceutical formulation according to any one of

[27] to

[31] , wherein the excipient comprises solid castor oil.

[33] The pharmaceutical formulation according to any one of

[27] to

[32] , wherein the bromocriptine is present in an amount providing a dose of at least about 0.1 mg of bromocriptine.

[34] A method of reducing degradation of a pharmaceutical formulation comprising bromocriptine, comprising preparing the pharmaceutical formulation such that the pharmaceutical formulation is substantially free of magnesium and lactose.

[35] The method of

[34] , wherein the pharmaceutical formulation is substantially free of magnesium or lactose.

[36] A pharmaceutical formulation of an oral dosage form of bromocriptine that is substantially free of magnesium and lactose.

[37] The method according to

[36] , wherein the pharmaceutical formulation comprises a non-lactose disintegrant.

[38] A pharmaceutical formulation comprising bromocriptine citrate, non-lactose short chain saccharides, triglycerides and citric acid.

[39] A pharmaceutical formulation comprising bromocriptine citrate, non-lactose short chain saccharides, stearic acid and citric acid.

[40] A pharmaceutical formulation comprising bromocriptine citrate, non-lactose short chain saccharides, phospholipids and citric acid.

[41] A pharmaceutical formulation comprising bromocriptine citrate, mannitol, triglyceride and citric acid.

[42] A pharmaceutical formulation comprising bromocriptine citrate, mannitol, stearic acid and citric acid.

[43] A pharmaceutical formulation comprising bromocriptine citrate, mannitol, stearic acid and citric acid, and substantially free of magnesium and lactose.

[44] A pharmaceutical formulation comprising bromocriptine citrate, short chain sugars, triglycerides, free fatty acids and citric acid. The pharmaceutical formulation comprises bromocriptine citrate, non-lactose short chain sugars, fatty acids and citric acid, wherein the bromocriptine is water soluble to at least 500 mg / L at 20° C., the formulation provides a dissolution profile when tested in a USP Apparatus Type 2 Paddle Method at about 37° C. in 500 ml of 0.1 N hydrochloric acid at 50 rpm, wherein at least about 90% of the bromocriptine is released in about 20 minutes, does not produce more than 8% bromocriptinine after 6 months under conditions of 40° C. or less and 75% RH, and is more stable in an aqueous environment than bromocriptine mesylate.

[45] A pharmaceutical formulation comprising bromocriptine citrate, non-lactose short chain saccharides, triglycerides, and citric acid, wherein the bromocriptine is water soluble to at least 500 mg / L at 20°C, the formulation provides a dissolution profile when tested in a USP Apparatus Type 2 Paddle Method at about 37°C in 500 ml of 0.1 N hydrochloric acid at 50 rpm, wherein at least about 90% of the bromocriptine is released in about 20 minutes, does not produce more than 8% bromocriptinine after 6 months under conditions of 40°C or less and 75% RH, and is more stable in an aqueous environment than bromocriptine mesylate.

[46] A pharmaceutical formulation comprising bromocriptine citrate, mannitol, triglyceride and citric acid, wherein the bromocriptine is water soluble to at least 500 mg / L at 20°C, the formulation provides a dissolution profile when tested in 500 ml of 0.1 N hydrochloric acid at about 37°C in a USP Apparatus Type 2 Paddle Method at 50 rpm, wherein at least about 90% of the bromocriptine is released in about 20 minutes, does not produce more than 8% bromocriptinine after 6 months under conditions of 40°C or less and 75% RH, and is more stable in an aqueous environment than bromocriptine mesylate. .

[47] A pharmaceutical formulation comprising bromocriptine citrate, mannitol, a fatty acid, and citric acid, wherein the bromocriptine is water soluble to at least 500 mg / L at 20°C, and the formulation is dissolved in 500 ml of 0.1 N hydrochloric acid at about 37°C at 50 rpm according to USP A pharmaceutical formulation that provides dissolution characteristics when tested in a Paddle Method, in which at least about 90% of the bromocriptine is released in about 20 minutes, does not produce more than 8% bromocriptine after 6 months under conditions of 40° C. or less and 75% RH, and is more stable in aqueous environments than bromocriptine mesylate.

[48] ​​A pharmaceutical formulation comprising bromocriptine citrate, non-lactose short chain saccharides, fatty acids and citric acid, wherein the bromocriptine is water soluble to at least 500 mg / L at 20°C, the formulation provides a dissolution profile when tested in 500 ml of 0.1 N hydrochloric acid at about 37°C in a USP Apparatus Type 2 Paddle Method at 50 rpm, wherein at least about 90% of the bromocriptine is released in about 20 minutes, does not produce more than 1% bromocriptinine after 6 weeks under conditions of 40°C or less and 75% RH, and is more stable in an aqueous environment than bromocriptine mesylate.

[49] A pharmaceutical formulation comprising bromocriptine citrate, mannitol, a fatty acid, and citric acid, wherein the bromocriptine is water soluble to at least 500 mg / L at 20°C, and the formulation is dissolved in 500 ml of 0.1 N hydrochloric acid at about 37°C at 50 rpm according to USP A pharmaceutical formulation that provides dissolution characteristics when tested in a Paddle Method, in which at least about 90% of the bromocriptine is released in about 20 minutes, does not produce more than 1% bromocriptinine after 6 weeks under conditions of 40° C. or less and 75% RH, and is more stable in an aqueous environment than bromocriptine mesylate.

[50] A pharmaceutical formulation comprising bromocriptine citrate, mannitol, triglyceride, and citric acid, wherein the bromocriptine is water soluble to at least 500 mg / L at 20°C, the formulation provides a dissolution profile when tested in a USP Apparatus Type 2 Paddle Method at about 37°C in 500 ml of 0.1 N hydrochloric acid at 50 rpm, wherein at least about 90% of the bromocriptine is released in about 20 minutes, does not produce more than 1% bromocriptinine after 6 weeks under conditions of 40°C or less and 75% RH, and is more stable in an aqueous environment than bromocriptine mesylate.

[51] A pharmaceutical formulation comprising bromocriptine citrate, mannitol, a fatty acid, and citric acid, wherein the bromocriptine is water soluble to at least 500 mg / L at 20°C, and the formulation is dissolved in 500 ml of 0.1 N hydrochloric acid at about 37°C at 50 rpm according to USP A pharmaceutical formulation that provides dissolution characteristics when tested in a Paddle Method, in which at least about 90% of the bromocriptine is released in about 20 minutes, does not produce more than 1% bromocriptinine after 6 weeks under conditions of 40° C. or less and 75% RH, and is more stable in an aqueous environment than bromocriptine mesylate.

[52] The pharmaceutical formulation according to

[43] , wherein the short-chain saccharide is mannitol.

[53] The pharmaceutical formulation according to

[44] , further comprising stearic acid.

[54] A pharmaceutical formulation comprising bromocriptine citrate and an excipient, the excipients include triglycerides or stearic acid, short chain sugars and citric acid, the pharmaceutical formulation being substantially free of magnesium or lactose; and Optionally, the bromocriptine is present in an amount to provide a dose of at least about 0.1 mg of bromocriptine.

[55] The bromocriptine is water soluble to at least 500 mg / L, the formulation provides dissolution characteristics when tested in 500 ml of 0.1 N hydrochloric acid at about 37° C. in a USP Apparatus Type 2 Paddle Method at 50 rpm, in which at least about 90% of the bromocriptine is released in about 20 minutes, does not produce more than 8% bromocriptine after 6 months at or below 40° C. and 75% RH, and The pharmaceutical formulation described in

[54] , which is more stable in an aqueous environment than lomocriptine mesylate.

[56] A pharmaceutical formulation comprising bromocriptine citrate, non-lactose short chain saccharides, phospholipids and citric acid, wherein the bromocriptine is water soluble to at least 500 mg / L at 20°C, the formulation provides a dissolution profile when tested in 500 ml of 0.1 N hydrochloric acid at about 37°C in a USP Apparatus Type 2 Paddle Method at 50 rpm, wherein at least about 90% of the bromocriptine is released in about 20 minutes, does not produce more than 1% bromocriptinine after 6 weeks under conditions of 40°C or less and 75% RH, and is more stable in an aqueous environment than bromocriptine mesylate.

[57] A method for administering one or more of the pharmaceutical preparations described in any one of

[38] to

[56] for treating a metabolic disorder, including a major component of the metabolic disorder.

[58] The method of

[57] , wherein the pharmaceutical preparation is administered to increase central nervous system dopamine activity at the daily peak of its natural circadian rhythm in healthy individuals of the same species and sex.

[59] The method of

[58] , wherein the pharmaceutical preparation is administered to increase dopamine activity within 4 hours of awakening.

[60] A pharmaceutical formulation containing 0.1-10% bromocriptine citrate, 0.1-10% citric acid, 30-90% non-lactose short-chain saccharides, and 0.2-10% free fatty acids, phospholipids, or triglycerides.

[61] The pharmaceutical formulation according to

[60] , comprising 60 to 90% non-lactose short-chain saccharides.

Claims

1. A pharmaceutical formulation comprising bromocriptine citrate.

2. 10. The pharmaceutical formulation of claim 1, further comprising a fatty acid and citric acid.

3. 3. The pharmaceutical formulation of claim 1 or 2, wherein the bromocriptine citrate is present in an amount to provide a dose of at least 0.1 mg of bromocriptine.

4. The pharmaceutical formulation according to any one of claims 1 to 3, wherein the pharmaceutical formulation does not contain magnesium or lactose.

5. The pharmaceutical formulation according to any one of claims 1 to 4, wherein the pharmaceutical formulation is in the form of a tablet or an oral dosage form.

6. A pharmaceutical formulation according to any one of claims 1 to 5 for treating type 2 diabetes.

7. Use of the pharmaceutical formulation according to any one of claims 1 to 5 in the manufacture of a medicament for treating type 2 diabetes.

8. The pharmaceutical preparation according to any one of claims 1 to 5 for treating fatty liver.

9. The pharmaceutical preparation according to any one of claims 1 to 5, for treating coronary artery disease, peripheral vascular disease, cerebrovascular disease, or congestive heart failure.

10. The pharmaceutical formulation according to any one of claims 1 to 5 for treating obesity, high plasma norepinephrine, or increased cardiovascular-related inflammatory factors.

11. The pharmaceutical preparation according to any one of claims 1 to 5, for treating hyperlipoproteinemia, atherosclerosis, hyperphagia, hyperglycemia, hyperlipidemia, or hypertension.

12. A pharmaceutical formulation according to any one of claims 1 to 5 for treating increased postprandial plasma triglyceride or free fatty acid levels, or increased cellular oxidative stress or plasma indicators thereof.

13. A pharmaceutical formulation according to any one of claims 1 to 5 for treating increased circulating blood hypercoagulable states or renal diseases including renal failure.

14. The pharmaceutical formulation according to any one of claims 1 to 5 for treating pre-diabetes, insulin resistance or hyperinsulinemia.

15. A pharmaceutical formulation according to any one of claims 1 to 5 for increasing dopamine activity in the central nervous system in healthy individuals of the same species and sex, at the time of day which is the peak of its natural circadian cycle.

16. 15. The pharmaceutical formulation of claim 14, wherein the pharmaceutical formulation is administered to increase dopamine activity within 4 hours of awakening.

17. The pharmaceutical preparation is administered to increase central nervous system dopamine activity in healthy individuals of the same species and sex at the time of day that is the peak of their natural circadian rhythm. The pharmaceutical formulation according to claim 14.

18. 16. The pharmaceutical formulation of claim 15, wherein the pharmaceutical formulation is administered within 4 hours of awakening to increase dopamine activity.

19. 2. The pharmaceutical formulation of claim 1, comprising at least 0.1 mg of bromocriptine citrate and 0.1-10% citric acid.

20. 6. The pharmaceutical formulation of any one of claims 1 to 5, wherein the pharmaceutical formulation contains less than 3% total related substances as determined by HPLC analysis using detection of UV absorbance at 300 nm after storage for 6 weeks at a temperature of 40±2°C and a relative humidity of 70±5%.

21. 6. The pharmaceutical formulation of any one of claims 1 to 5, wherein the pharmaceutical formulation contains no more than 5% bromocriptinine as determined by HPLC analysis using detection of UV absorbance at 300 nm after storage for 18 months at a temperature of 25±2°C and a relative humidity of 60±5%.

22. 6. The pharmaceutical formulation of any one of claims 1 to 5, wherein the pharmaceutical formulation provides a dissolution profile when tested in USP Apparatus Type 2 Paddle Method at 37°C in 500 ml of 0.1 N hydrochloric acid at 50 rpm, whereby at least 80% of the bromocriptine is released in 30 minutes.

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