WO2019014201A1 - Extended release molindone compositions - Google Patents

Abstract

The present disclosure provides extended-release formulations of molindone that do not utilize polymeric release rate-controlling agents. Methods of making said extended-release molindone formulations are also disclosed.

Description

EXTENDED RELEASE MOLINDONE COMPOSITIONS

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of the filing date of U.S. Provisional Patent Application Serial No. 62/530,604, filed July 10, 2017, the contents of which are hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The invention is directed towards new extended release stabilized formulations of molindone hydrochloride that do not employ the use of a polymeric release rate controlling agent, methods of their preparation, and uses in certain medical treatment.

BACKGROUND OF THE INVENTION

[0003] Molindone, chemically known as 3-ethyl-6, 7-dihydro-2-methyl-5- (morpholinomethyl) indol-4(5H)-one, has the following chemical structure:

The hydrochloride salt of molindone, molindone hydrochloride, is a medium potency antipsychotic marketed as Moban® for the management of schizophrenia in adults.

[0004] Pharmaceutical manufacturers are continuously attempting to improve methods for delivering drugs to enhance and sustain their effects in human therapy. A significant development in drug delivery systems occurred in 1972 with the development of osmotic delivery systems as described by U.S. Pat. Nos. 3,845,770 and 3,916,899.

[0005] In 1987, Urquhart et al. developed an extended-release drug delivery system for delivering a quantity of tiny pills to the gastrointestinal tract. The system includes a pharmaceutical oral capsule prepared with a drug carrier formed of an aqueous polymer and oil capable of controlling the rate of transit of the capsule and the release of the drug from the capsule to the gastrointestinal tract.

[0006] Products formulated for controlled release are generally described as sustained release, extended release, prolonged action, depot, repository, d e l ay e d action, ret ard e d release, and timed release. Drug products which are formulated for prolonging absorption include dosage forms for oral, injectable and topical use as well as suppositories for insertion in the body cavities. Extended-release tablets are defined herein as pharmaceutical solid dosage forms containing drug substances which are released from the tablet or delivery system over an extended period of time using specific ingredients and include mechanisms as discussed above such as timed release, intermittent release and retarded release. They are produced by compression of a formulation containing the drug and certain excipients selected to aid in the processing and release of the drugs. Excipients are classified in accordance with their intended function. Exemplary components for such formulations include fillers, binders, lubricants, and glidants. Without excipients, most drugs and pharmaceutical components cannot be directly compressed into tablets primarily due to the poor flow and/or cohesive properties of most drugs. Extended-release tablets may be coated or uncoated, and are generally formed of powdered, crystalline materials.

[0007] Drugs can be administered from a delivery system that releases the drug as it passes through the gastrointestinal tract. Extended-release delivery systems are used because they reduce the need for multiple dosing. The convenience of extended-release preparations which maintain the blood concentration of the drug at a desired level over a prolonged period of time has been recognized. Extended release preparations such as a slow-release matrix type tablet in which the ingredients are embedded in a matrix, such as polymeric resins, release the active ingredient by diffusion and erosion.

[0008] Most extended-release forms are designed so that the administration of a single dosage unit provides the immediate release of an amount of drug that promptly produces the desired therapeutic effect as well as a gradual and continual release of additional amounts of drug to maintain this level of effect over an extended period of time. In this type of dosage form, the design is based on the particular qualities of each individual drug. [0009] What may be an effective type of dosage form design for one drug may be ineffective in promoting the extended release of another drug because of peculiar physical, chemical, and biological qualities of the different drugs. To maintain a constant level of drug in the system, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.

[0010] Other advantages of extended-release products are reduced side effects and increased patient convenience. These advantages relate to the fact that extended-release preparations maintain the blood concentration of the drug at a desired level over a prolonged period of time which allows patients to reduce the frequency of dosing. This is considered an advantage in ensuring patient compliance in taking medication.

[0011] The method of preparation and type of excipients used in making such dosage forms must be carefully selected to give the formulation the desired physical characteristics that allow for rapid compression of tablets. After compression, the tablets must have a number of additional attributes such as appearance, hardness, and an acceptable dissolution profile. Choice of fillers and other excipients will depend on the chemical and physical properties of the drug, behavior of the mixture during processing, and the properties of the final tablets. Such determinations are typically done by pre-formulation studies which determine the physical and chemical compatibility of the active component with the proposed excipients. The properties of the drug, its dosage forms, and the economics of the process will determine selection of the best process for tableting. Generally, either dry (e.g., roll compaction and/or slugging followed by milling) or wet granulation together with direct compression are used in developing a tablet.

[0012] Moban® is an immediate release tablet formulation provided at the dose strengths of 5 mg, 10 mg, 25 mg, 50 mg, and 100 mg. The immediate-release dosage form is taken 3 to 4 times daily with a typical maintenance dose range of 50 mg - 100 mg per day. The drug substance has a reported bioavailability of 60%-70% relative to an intramuscular dose. It is absorbed rapidly following oral administration with a Tmax observed between 1 to 1.5 hours. The drug substance is extensively and rapidly metabolized with an oral dose plasma elimination half-life of about 2 hours.

[0013] Molindone is a weak base, exhibiting greater solubility in acidic to slightly acidic media than in neutral to slightly alkaline pH (i.e., the physiologic pH range of the gastro- intestinal tract). As a weakly basic drug, molindone is typically included into formulations in the form of a hydrochloride salt.

[0014] Molindone salts are chemically stable in the solid state. However, stable immediate release or extended-release formulations of molindone presents a significant challenge because it appears that molindone salts, for example molindone hydrochloride, are not compatible with many commonly used pharmaceutical excipients. Combination of molindone with these excipients to produce a dosage form results in significant degradation of the active agent.

[0015] Therefore, there is a need in the art for a drug delivery system that has a sufficiently long transit time in the stomach and acts as an in vivo reservoir, and which releases the drug at a controlled rate and continuously over a prolonged period of time for absorption in the stomach and the intestine.

SUMMARY OF THE INVENTION

[0016] The present disclosure provides a once-a-day extended-release dosage form of molindone, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates thereof, delivering from 0.1 mg to 200 mg of molindone for the treatment of CNS disorders, including, but not limited to, the treatment of impulsive aggression, aggression, or other conduct disorders that may be associated with neurological disorders such as attention deficit/hyperactivity disorder (AD/HD). In addition, the disclosed embodiments provide a formulation that provides a therapeutically effective blood concentration of molindone for from 4 to 24 hours. In particular embodiments the disclosed embodiments provide a formulation that provides a therapeutically effective blood concentration of molindone for about 6 to about 24 hours. In further embodiments, the disclosed embodiments provide a formulation that provides a therapeutically effective blood concentration of molindone for about 8 hours to 24 hours.

[0017] In one or more embodiments, a pharmaceutical composition including a stable, physiologically acceptable formulation of molindone or a pharmaceutically acceptable salt and/or solvate thereof (e.g., hydrochloride salt) includes a therapeutically effective amount of molindone hydrochloride or dihydrate and a release rate controlling agent as a functional excipient, wherein the composition does not include any polymer for controlling the drug release. In certain embodiments, the pharmaceutical composition including molindone does not include a stabilizer.

[0018] In one or more embodiments, the amount of drug release-controlling excipient is from 10% to 60% w/w. In still further embodiments, the amount of drug release controlling excipient is from 15% to 50% w/w. In still further embodiments, the amount of drug release controlling excipient is from 15% w/w to 45% w/w.

[0019] The composition may include at least one filler. In some embodiments, suitable filler is lactose monohydrate present in an amount of from 40% to 70% w/w. In other embodiments the lactose monohydrate is present in an amount of from 50% to 65% w/w. In still other embodiments the at least one filler is corn starch present in an amount of from 6% to 12%) w/w. In another embodiment, the corn starch is present in an amount of from 5% to 10%) w/w. YThe composition may include at least one glidant. In some embodiments, a suitable glidant is colloidal silicon dioxide present in an amount of from 0.5% to 3.0% w/w. In other embodiments colloidal silicon dioxide is present in an amount of from 1% to 1.5% w/w.

[0020] The composition may include at least one lubricant. In some embodiments, suitable filler is magnesium stearate present in an amount of from 0.5% to 2.5% w/w. In other embodiments magnesium stearate is present in an amount of from 1% to 1.5% w/w

[0021] In still further embodiments, the composition includes an extended-release component including molindone and an immediate-release component including molindone wherein the mass ratio (w/w) of the immediate-release component to the extended-release component is from 0.1 :50 to 50:0.1. In other embodiments the ratio of immediate-release to extended-release components is from 2.5:40 to 40:2.5.

[0022] In still further embodiments, the composition includes an extended-release component including molindone and an immediate-release component including molindone wherein the mass ratio (w/w) of the molindone in the immediate-release component to the molindone in the extended-release component may be from about 1 :8 to 2:7.

[0023] The composition may be formulated as numerous dosage forms well known in the art, such as, but not limited to, a tablet, mini-tablet, or capsule. Capsules may be filled with molindone-containing particles such as granules, pellets, mini-tablets, and beads. The molindone-containing particles filled may be extended-release particles, immediate-release particles, particles having a combination of immediate-release components and extended- release components, or mixtures thereof. In particular embodiments, capsules contain extended-release particles. In other embodiments, capsules contain a mixture of extended- release particles and immediate-release particles. It yet other embodiments, capsules contain particles having a combination of immediate-release components and extended- release components. In yet other embodiments, capsules contain a mixture of immediate- release particles and particles having a combination of immediate-release components and extended-release components. In yet other embodiments, capsules contain a mixture of extended-release particles and particles having a combination of immediate-release components and extended-release components.

[0024] The immediate-release component or immediate-release particles may be any form, for example, a powder, granules, pellets, mini-tablets, and beads. Such components may be incorporated into a diversity of dosage forms including tablets and capsules.

[0025] The formulation may be also presented in the form of particles in a capsule, where the capsule may be swallowed whole or can be opened and the pellets sprinkled on to soft food or in a liquid and then swallowed.

[0026] In some embodiments, the mass ratio (w/w) of molindone the non-polymeric release rate controlling excipient is from 1 : 1 to 1 : 10. In other embodiments the mass ratio is from 1 :3 to 1 :8.

[0027] The non-polymeric molindone formulations disclosed herein may be useful in the treatment of impulsive aggression in patients with attention-deficit/hyperactivity disorder (AD/HD) that are 6-12 years old. In particular embodiments, compositions disclosed herein may be formulated for once-a-day administration.

[0028] In still further embodiments, the composition has a release rate of molindone which is:

(a) not more than 40% in one hour,

(b) from about 30% to about 60% in 2 hours; (c) from about 45% to about 70% in 4 hours;

(d) from about 65% to about 85% in 8 hours;

(e) from about 75% to about 90% in 12 hours; and

(f) not less than (NLT) about 85% in 18 hours.

[0029] In still further embodiments, the composition has a release rate of molindone which is: not more than 40% in one hour, from about 35% to about 60% in 2 hours; from about 50% to about 70% in 4 hours; from about 70% to about 80% in 8 hours; from about 80% to about 90% in 12 hours; and not less than (NLT) about 85% in 18 hours.

[0030] In other embodiments, a stabilized, physiologically acceptable formulation of molindone includes a physiologically effective amount of molindone, and one or more excipients which control the drug-release function.

[0031] In yet further embodiments, methods are disclosed for making a stabilized formulation of molindone, the method including mixing a physiologically effective amount of molindone, and one or more excipients which perform the function of controlling the drug release.

BRIEF DESCRIPTION OF THE DRAWINGS

[0032] For the purposes of illustration, there are forms shown in the drawings that are presently contemplated, it being understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown.

[0033] FIG. 1 is a graphical depiction of drug dissolution % of Examples 1 and 2 according to embodiments of the present disclosure; and [0034] FIG. 2 is a graphical depiction of drug dissolution % of Examples 3-6 according to embodiments of the present disclosure.

DETAILED DESCRIPTION OF THE INVENTION

[0035] The present invention now will be described more fully hereinafter with reference to the accompanying examples and experiments, in which illustrative embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

[0036] Well-known functions or constructions may not be described in detail for brevity and/or clarity. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

[0037] As used herein, the term "about" is meant to include the recited value plus or minus 10% of said value.

[0038] With respect to the extended-release formulations and methods of preparing said extended-release formulations as disclosed herein, the molindone active pharmaceutical ingredient utilized for the preparation and in the preparation of such formulations may be any pharmaceutically acceptable form, including salts and solvates (e.g., hydrates) thereof.

[0039] For example, as molindone is a weak base, it exhibits greater solubility in acidic to slightly acidic media than in neutral to slightly alkaline pH (i.e., the physiologic pH range of the gastro-intestinal tract). Thus, molindone is often included into formulations in the form of a salt, such as chloride, sulfate, phosphate, monohydrogenphosphate, dihydrogen phosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, formate, oxalate, malonate, succinate, fumarate, maleate, citrate, lactate, tartrate, methane sulfonate, mandelate, and the like. In particularly useful embodiments herein, molindone hydrochloride is used.

[0040] Thus, in many embodiments of the formul ations herein, molindone may be included in the form of a hydrochloride salt.

[0041] Molindone employed in herein may be in the form of a single (— ) enantiomer, or in the form of a single (+) enantiomer, or in the form of a racemic mixture, or in the form of a non-racemic mixture of enantiomers with various amounts of (-) and (+) enantiomers.

[0042] As used herein, "molindone" and "molindone hydrochloride" are used interchangeably. It is contemplated that recitation of molindone may also apply to salts and solvates thereof, or, conversely, recitation of a salt or solvate also includes the free base form.

[0043] In one aspect, extended-release dosage forms of molindone, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof, are provided that can deliver from 0.1 mg to 200 mg of molindone. In some embodiments, the extended-release dosage form delivers from between 3 mg to about 100 mg molindone, including dosages of In some embodiments, the extended-release dosage form includes molindone (or salts/solvates thereof) and a non-polymeric release rate controlling agent. In some embodiments, the extended-release dosage form includes molindone (or salts/solvates thereof) and hydrogenated castor oil as the non-polymeric release rate controlling agent. In particularly useful embodiment, the extended- release dosage form includes molindone hydrochloride and hydrogenated castor oil. In some embodiments, the extended-release dosage form further contains other excipients, including (but not limited to) binders, fillers, lubricants, glidants, and combinations thereof.

[0044] In particular embodiments, the molindone hydrochloride (3-ethyl-6,7-dihydro-2-methyl- 5-(morpholinomethyl)indol-4(5H)-one monohydrochloride) that is incorporated into the extended-release dosage form is about 98% to about 100% pure. In some embodiments, the molindone hydrochloride is incorporated into the extended-release formulation is a white crystalline powder having a particle size which ranges from about 4 microns to about 350 microns. In some embodiments, said molindone crystalline powder may be capable of passing through a mesh size accommodating approximately 8 microns to 300 microns. All particle size ranges referred to herein represent an average particle size and are measured in accordance with standard methods known to those of ordinary skill in the art.

[0045] The dosage forms herein include a non-polymeric release rate-controlling agent. In some embodiments, the mass ratio (w/w) of molindone hydrochloride to the non-polymeric release rate controlling excipient is from about 1 : 1 to about 1 : 10. In one or more embodiments, the amount of drug release controlling excipient is from 10% to 60% w/w with respect to the extended-release dosage form. In still further embodiments the amount of drug release controlling excipient is from 15% to 50% w/w. In still further embodiments the amount of drug release controlling excipient is from 15% w/w to 45% w/w. In one or more embodiments, hydrogenated castor oil is used as a release rate-controlling agent in the formulation. "Hydrogenated Castor Oil" [CAS # 8001-78-3] as used herein refers to hydrogenated castor oil satisfying US Pharmacopeia- F Monograph {USP41-NF36, Page 5272) as a refined, bleached, hydrogenated, and deodorized Castor Oil, consisting mainly of not less than 70.0% of the triglyceride of hydroxystearic acid.

[0046] In particularly useful embodiments, hydrogenated castor oil is incorporated into the extended-release formulation at a higher weight percentage than other excipients. Optionally, additional release rate-controlling agents such as stearic acid, carnauba wax, hydrogenated vegetable oil, etc. may be included for cost savings purposes or to achieve modified properties. In such embodiments, additional fillers should be selected to have particle size, density, and viscosity characteristics which would not significantly affect the homogeneity or compressibility of the formulation or the dissolution profile of the dosage form.

[0047] In some embodiments, the binder is pharmaceutically acceptable lactose. In some embodiments, lactose monohydrate is used. In some embodiments, lactose monohydrate demonstrates an increase in compressibility of the formulation, has good binding characteristics, and provides sufficient hardness to tablets formed by the methods disclosed herein.

[0048] In one or more embodiments, lactose or lactose monohydrate may be both the binder and filler. In particularly useful embodiments, it is included at a weight percentage higher than other fillers. In some embodiments the filler is lactose monohydrate present in an amount of from 40%) to 70%) w/w. In other embodiments the lactose monohydrate is present in an amount of from 50%) to 65% w/w. The use of lactose as a filler and binder enables the methods disclosed herein to form hard, strong tablets at low machine pressure which reduces instances of chipping and capping of the resulting tablets as well as reducing the friability of the resulting tablets. The grade of lactose chosen has been determined in the course of the evaluation of the formulations herein to contribute to improved, superior flow properties as well as to enhancing lubrication of the powders in the die cavity and on punch faces for forming indentations on the tablet surface such that the lactose aids in preventing adherence of tablets to the punches during compression. Lactose contributes to many favorable properties in the tablet and functions well within the overall formulations. In one or more embodiments, corn starch is used as general filler in the formulation. In some embodiments, the filler is corn starch present in an amount of from 6% to 12% w/w. In another embodiment, the corn starch is present in an amount of from 5% to 10% w/w.

[0049] . In some embodiments, a suitable filler is a combination of a lactose (e.g., lactose monohydrate) and a starch (e.g., corn starch). In other embodiments, lactose monohydrate is present in an amount of from 40% to 70% w/w and corn starch present in an amount of from 6% to 12% w/w. In other embodiments, lactose monohydrate is present in an amount of from 50% to 65% w/w and corn starch present in an amount of from 6% to 12% w/w. In other embodiments, lactose monohydrate is present in an amount of from 50% to 65% w/w and corn starch present in an amount of from 5% to 10% w/w. In other embodiments, lactose monohydrate is present in an amount of from 40% to 70% w/w and corn starch present in an amount of from 5% to 10% w/w.

[0050] It is contemplated that additional fillers may be included in the formulation. Any additional filler need not provide the same level of cohesive properties as the binders selected, but may still contribute to formulation homogeneity and resist segregation from the formulation once blended. Further, such fillers should not have a detrimental effect on the flowability of the composition or dissolution profile of the formed tablets. Additional fillers should be selected with flow properties and particle size profiles compatible with those of the other excipients as described herein. Examples of additional suitable fillers include sodium starch glycolate, talc, sucrose, dextrose, glucose, lactose, xylitol, fructose, sorbitol, calcium phosphate, calcium sulfate, calcium carbonate, and mixtures thereof. Microcrystalline cellulose may also be used as a filler and may be any suitable form of microcrystalline cellulose as is known and used in the art. [0051] In some embodiments, the only filler is lactose monohydrate, in an amount as noted above and having a density of from about 0.5 to about 1.0 g/mL. In particularly useful embodiments, the lactose monohydrate has a bulk density of about 0.678 g/mL. In addition, in some embodiments, the lactose has a particle size distribution in which about 25% - 50% of the lactose particles have a particle size of less than or equal to 106 microns, and about 55% - 75% of the particles have a particle size of less than or equal to 75 microns.

[0052] The formulations made in accordance with the methods disclosed herein may include at least one glidant and at least one lubricant. The glidants and lubricants may be any suitable glidants and lubricants which contribute to the compressibility, flowability, and homogeneity of the formulation and which minimize segregation and do not significantly interfere with the slow release mechanism of the binders as set forth above.

[0053] The glidant may be selected to improve the flow of the formulation. In particularly useful embodiments, the glidant is colloidal silicon dioxide. In some embodiments the at least one glidant is colloidal silicon dioxide present in an amount of from 0.5% to 3.0% w/w. In other embodiments colloidal silicon dioxide is present in an amount of from 1% to 1.5% w/w. In one or more embodiments, colloidal silicon dioxide having a density of from about 0.029 to about 0.040 g/mL may be used to improve the flow characteristics of the formulation and be provided in an amount of from about 0.1 to about 2 percent by weight of the formulation on a solids basis. The colloidal silicon dioxide may have a BET surface area of 175 to 225 m²/g, a density of from about 35 to about 40 g/L, and a nominal particle diameter of 14 nm. It will be understood, based on this disclosure, however, that while colloidal silicon dioxide may be employed as a glidant, other glidants having similar properties which are known or to be developed could be used provided they are compatible with the other excipients and the molindone hydrochloride in the formulation and which do not significantly affect the flowability, homogeneity, and compressibility of the formulation.

[0054] The lubricant may be any lubricant which substantially prevents segregation of the powder by contributing to homogeneity of the formulation and which exhibits good flowability. In some embodiments, the lubricant functions to facilitate compression of the tablets and ejection of the tablets from the die cavity. Such lubricants may be hydrophilic or hydrophobic and can include magnesium stearate, Lubritab®, stearic acid, calcium stearate, and sodium stearyl fumarate, talc, and other lubricants known in the art or to be developed which exhibit acceptable or comparable properties.

[0055] In particularly useful embodiments, the lubricant is magnesium stearate. In some embodiments the lubricant is magnesium stearate present in an amount of from 0.5% to 2.5% w/w. In other embodiments magnesium stearate is present in an amount of from 1% to 1.5% w/w. In some embodiments, magnesium stearate exhibits excellent properties in combination with the other excipients of the formulation explicitly named herein. Magnesium stearate may contribute to reducing friction between the die wall and tablet formulation during compression and to the easy ejection of the molindone hydrochloride tablets. It also may render the formulation resistant to adhesion to punches and dies. The lubricant, such as magnesium stearate, should be selected to aid in the flow of the powder in the hopper and into the die. In particularly useful embodiments, magnesium stearate has a particle size of from about 5 to about 50 microns and a density of from about 0.1 to about 1.1 g/mL is used in the formulation. The lubricant may make up from about 0.1 to about 2 percent by weight of the formulation on a solids basis.

[0056] Other components, such as flavors, colors, inserts, and the like which are standard in the art or to be developed may also be provided so long as they do not significantly affect the flowability, homogeneity, direct compressibility of the tablet formulation, or dissolution profile of the finished tablets. In some embodiments, these components collectively represent no greater than about 10 percent of the formulation by weight. In particularly useful embodiments, these components represent no greater than 2 percent by weight of the formulation on a solids basis.

[0057] Stabilizers or preservatives for molindone hydrochloride or for the other excipients in the formulation may optionally be included in the extended-release formulation, however in many embodiments, stabilizers are not necessary and are not included. Examples of suitable stabilizers include organic acids, carboxylic acids, acid salts of amino acids, and sulfites such as potassium metabisulfite and sodium bisulfite. The acid salts of amino acids can be hydrochloride salts such as cysteine hydrochloride, glycine hydrochloride, or cysteine dihydrochloride. Other examples of stabilizers include: ascorbic acid, malic acid, isoascorbic acid, citric acid, and tartaric acid. In some embodiments, a stabilizer is not used. In embodiments where stabilizers are used, stabilizers are present in amounts of less than about 20 weight percent of the formulation. In particular embodiments, stabilizers are present in amounts less than about 10 weight percent. In further embodiments, a stabilizer is present at an amount less than about 5 weight percent of the entire formulation on a solids basis.

[0058] Suitable formulation ranges are as described above. However, the formulation should not be considered limited to the ranges shown and may be adjusted in accordance with the disclosure for various formulations provided flowability, powder homogeneity, and compressibility are maintained and provided the dissolution profile is not significantly affected.

[0059] Optionally, the extended-dosage form may contain an immediate-release component. Immediate-release formulations and methods of making immediate-release formulations are well known to one of skill in the art and any may be combined with the extended-release formulation to provide the desired release of molindone hydrochloride. One of skill in the art would readily recognize immediate-release formulations that are compatible with and may be combined with the extended-release formulations herein.

[0060] In some embodiments, the composition includes an extended-release component including molindone and an immediate-release component including molindone wherein the mass ratio (w/w) of the immediate-release component to the extended-release component is from 0.1 :50 to 50:0.1. In other embodiments the ratio of immediate-release to extended- release components is from 2.5:40 to 40:2.5.

[0061] In still further embodiments, the composition includes an extended-release component including molindone and an immediate-release component including molindone wherein the mass ratio (w/w) of the molindone in the immediate-release component to the molindone in the extended-release component may be from about 1 :8 to 2:7.

[0062] In other embodiments, the composition includes an extended-release component including molindone and an immediate-release component including molindone wherein the mass ratio (w/w) of the immediate-release component to the extended-release component is from 0.1 :50 to 50:0.1 , wherein the mass ratio (w/w) of the molindone in the immediate- release component to the molindone in the extended-release component may be from about 1 :8 to 2:7.

[0063] In other embodiments, the composition includes an extended-release component including molindone and an immediate-release component including molindone wherein the mass ratio (w/w) of the immediate-release component to the extended-release component is from 2.5:40 to 40:2.5, wherein the mass ratio (w/w) of the molindone in the immediate- release component to the molindone in the extended-release component may be from about 1 :8 to 2:7.

[0064] The extended-release dosage form may be a tablet or capsule of which any component may be an extended-release component containing molindone (or salts/solvates thereof) and a non-polymeric release rate-controlling agent. A tablet or mini-tablet may include only an extended release portion, or both an extended release and an immediate release portion (e.g., an extended release portion coated with an immediate release portion). A capsule may be filled with particles such as beads, pellets, mini-tablets, and/or granules that individually are extended release, immediate release, or a combination of both extended and immediate release, provided that the capsule contains a portion of particles that have extended-release properties.

[0065] In another aspect, methods are provided for making an extended-release dosage form of molindone, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof, delivering from 0.1 mg to 200 mg of molindone. In particular embodiments, the dosage form has 3 mg, 6 mg, 9 mg, 12 mg, 15 mg, 18 mg, 36, mg, 54 mg, 72 mg, 90 mg, or 100 mg of molindone or molindone equivalent.

[0066] In one embodiment, the extended-release dosage form may be prepared by a process that includes the steps of: a. weighing molindone hydrochloride; and b. combining the molindone hydrochloride with a non-polymeric release rate- controlling agent to form an extended-release mixture.

[0067] Within the scope of this embodiment, 3 mg to about 100 mg molindone hydrochloride may be weighed for combining with the non-polymeric release rate-controlling agent. In some embodiments, the mass ratio (w/w) of molindone hydrochloride to the non-polymeric release rate-controlling excipient is from about 1 : 1 to about 1 : 10. In other embodiments the mass ratio is from about 1 :3 to about 1 :8. Within the scope of this embodiment, the non- polymeric release rate-controlling agent may be hydrogenated castor oil. In some embodiments, the hydrogenated castor oil is melted before combining it with the molindone hydrochloride active ingredient.

[0068] As used herein, the extended-release mixture is meant to describe a formulation that comprises at least molindone (or salts and/or solvates thereof) and the non-polymeric release rate-controlling agent. In some embodiments, the method of preparing the extended-release dosage form may further include steps of adding additional pharmaceutically acceptable excipients.

[0069] In one or more embodiments, the method may further include adding a binder, filler, glidant, or mixtures thereof. In some embodiments, the binder, filler, glidant and molindone hydrochloride are combined before adding to the release rate-controlling agent. In other embodiments, the method may include adding a lubricant. In some embodiments, the lubricant is added to the extended release mixture containing hydrochloride and the release rate- controlling agent. In some embodiments, a binder, filler, lubricant, and glidant are included in the extended release mixture, and said extended release mixture is a directly compressible formulation. Examples of suitable binders, fillers, lubricants, and glidants along with particularly useful properties of each are expressly discussed in detail above with regard to components of the extended-release dosage form herein.

[0070] Excipients disclosed in further detail below provide good flow and compression characteristics. In some embodiments, the extended release mixture is compressed an extended- release dosage form that is a tablet or mini-tablet. In other embodiments, the extended release mixture may be formed into beads, pellets, granules which may be used to fill capsules with extended release properties.

[0071] In some embodiments, the extended-release dosage form includes, on a solids basis, from about 0.5 to about 4.5 percent by weight of molindone hydrochloride and from about 5 to about 65 percent by weight of a release controlling excipient. In some embodiments, the excipients are weighed such that the extended-release dosage form includes on a solid basis about 25 to about 40 percent by weight of a binder, from about 10 to about 60 percent by weight of a filler, from about 0.1 to about 2 percent by weight of a glidant, from about 0.1 to about 2 percent by weight of a lubricant, or any combination thereof.

[0072] In some embodiments of the extended-release dosage form disclosed herein, a binder may also function as a diluent in that it not only acts to impart cohesive qualities to the material within the formulation, but also tends to increase the bulk weight of the extended- release formulation to achieve an acceptable formulation weight, particularly for compression.

[0073] The formulations include excipients having particle size ranges as set forth below to allow for improved homogeneity of the powder mix and to minimize segregation. In addition the excipients are selected to achieve good content uniformity and to ensure the slow release of the active ingredient. The excipients, by having excellent binding properties, and homogeneity, as well as good compressibility, cohesiveness, and flowability in blended form, minimize segregation of powders in the hopper during direct compression.

[0074] In particularly useful embodiments, extended release (ER) tablets may be prepared by methods disclosed herein. In one embodiment, extended release (ER) tablets may be prepared by a process that includes the steps of: a. blending molindone hydrochloride with a giidant; b. adding a binder, a filler, or mixtures thereof to form an admixture; c. adding the admixture to melted hydrogenated castor oil under continuous mixing; d. adding a lubricant; and e. compressing the blend into a tablet.

[0075] Within the scope of this embodiment, the giidant, binder, filler, and lubricant may be any giidant, binder, and filler as disclosed above. In particularly useful embodiments, the giidant is colloidal silicon dioxide, the binder and filler is lactose monohydrate, and the lubricant is magnesium stearate.

[0076] In one embodiment, the extended release (ER) tablets may be prepared by a process that includes the steps of: a. blending particles of molindone hydrochloride with colloidal silicon dioxide; b. geometrically diluting with lactose monohydrate to form an admixture of blended powders; c. adding the admixture to melted hydrogenated castor oil with continuous mixing; d. sifting using a suitable sieve to form a blend; e. lubricating the blend with screened magnesium stearate; and f. compressing the lubricated blend into tablets

[0077] Thereafter, the tablet (sometimes referred to as the core) may be film coated with a moisture barrier coating or color coating such as Opadry Purple, Opadry Blue, or Opadry White for identification, taste masking, and appearance purposes to provide a film-coated tablet. The film coating does not substantially affect the release rate of the molindone hydrochloride from the tablet since the coating rapidly dissolves in the stomach. The outer film coating may be from between 0.03 mm to 1 .0 mm in thickness.

[0078] Optionally, tablets may contain both extended release and immediate-release component. One of skill in the art would readily recognize methods for preparing a formulation, such as a bi- layer tablet, that contains both the extended release mixture as disclosed herein and an immediate-release formulation of molindone. For example, granulations of each of the extended release mixture and an immediate-release formulation may be compressed into a tablet by a bi- layer tablet press. Alternatively, granulations of each of the extended release mixture and an immediate-release formulation may be blended and compressed into a uniform tablet.

[0079] It has been surprisingly discovered that by using the particular excipients described herein, the hygroscopic, sensitive, and incompressible nature of the molindone hydrochloride is overcome allowing for a formulation exhibiting good cohesion and directly compressible properties. As noted above, in some embodiments, in contrast to many prior art formulations, the molindone extended-release dosage form lacks a conventional stabilizer, as use of a stabilizer is not necessary in forming a stable and effective dosage form.

[0080] In additional embodiments, dosage forms molindone as disclosed above may comprise an additional active pharmaceutical ingredient selected from, rnazindol, viloxazine, amphetamines, methylphenidate, and other drugs known in the art for the treatment of ADHD. In one embodiment the additional active is viloxazine, which may be incorporated into the formulation in amount of from 0.1 mg to 800 mg. In another embodiment, the additional active is rnazindol, which may be incorporated into the formulation in the amounts of from 0.1 mg to 20 mg.

[0081] Extended-release dosage forms disclosed herein may be suitable for oral administration by swallowing whole. In other embodiments, the formulation may be also presented in the form of particles in a capsule, where the capsule may be swallowed whole or can be opened and the pellets sprinkled on to soft food or in a liquid and then swallowed.

[0082] The molindone extended-release dosage forms disclosed herein may be useful in the treatment of conduct disorder or impulsive aggression in patients with attention- deficit/hyperactivity disorder (AD/HD) optionally as added as an adjunctive therapy to a stimulant monotherapy, a behavioral therapy, or both. Molindone extended-release therapy may be particularly beneficial in patients that are 6-12 years old. In particular embodiments, compositions disclosed herein may be formulated for once-a-day administration. Said therapy may include administrating molindone extended-release dosage forms herein in dosing ranges of from 10 mg/day to 200 mg/day. In other embodiments, molindone is administered in dose ranges of from 3 mg/day to 200 mg/day; 15 mg/day to 120 mg/day; 15 mg/day to 90 mg/day; 30 mg/day to 90 mg/day; or 36 mg/day to 72 mg/day.

[0083] In some embodiments, the extended-release dosage forms disclosed herein achieve similar properties, such as release rate, to extended-release molindone dosage forms known in the art, for example, those disclosed in U.S. Patent No. 8,748,472. Surprisingly, similar release rates as those disclosed in U.S. Patent No. 8,748,472 have been achieved with the tableted dosage forms herein without the use of polymeric release rate-controlling agents and, in certain embodiments, without the use of a stabilizer. Release rates of molindone hydrochloride from dosage forms prepared as disclosed herein, were tested using the following parameters:

Apparatus: USP Rotating Paddle (Apparatus II)

Stirring Rate: 50 rpm

Sample Size: a single tablet per vessel

Temperature: 37 °C ± 0.5 °C

Medium for Dissolution of tablet: 900 niL of distilled water.

The test for dissolution (release rates) is performed as specified below in the U.S. Pharmacopoeia under "Drug Release" and the medium is sampled at 1, 2, 4, 8, 12 and 18 hours. [0084] For example, extended-release molindone dosage forms (e.g., extended-release tablets) herein have a release rate satisfying one or more of:

(a) not more than 40% in one hour,

(b) from about 30% to about 60% in 2 hours;

(c) from about 45% to about 70% in 4 hours;

(d) from about 65% to about 85% in 8 hours;

(e) from about 75% to about 90% in 12 hours; and

(f) not less than (NLT) about 85% in 18 hours.

[0085] In certain embodiments, the extended-release molindone dosage forms herein (e.g., extended-release tablets) have a release rate satisfying:

(a) not more than 40% in one hour, and

(b) not less than (NLT) about 85% in 18 hours.

[0086] In certain embodiments, the extended-release molindone dosage forms (e.g., extended- release tablets) herein have a release rate satisfying one or more of:

(a) not more than 40% in one hour,

(b) from about 30% to about 60% in 2 hours; and

(c) not less than (NLT) about 85% in 18 hours.

[0087] In certain embodiments, the extended-release molindone dosage forms (e.g., extended- release tablets) herein have a release rate satisfying one or more of:

(a) not more than 40% in one hour,

(b) from about 30% to about 60% in 2 hours;

(c) from about 45% to about 70% in 4 hours; and

(d) not less than (NLT) about 85% in 18 hours. [0088] In certain embodiments, the extended-release molindone dosage forms (e.g., extended- release tablets) herein have a release rate satisfying one or more of:

(a) not more than 40% in one hour,

(b) from about 30% to about 60% in 2 hours;

(c) from about 45% to about 70% in 4 hours;

(d) from about 65% to about 85% in 8 hours; and

(e) not less than (NLT) about 85% in 18 hours.

[0089] In certain embodiments, the extended-release molindone dosage forms herein (e.g., extended-release tablets) have a release rate satisfying:

(a) not more than 40% in one hour, and

(b) from about 30% to about 60% in 2 hours.

[0090] In certain embodiments, the extended-release molindone dosage forms herein (e.g., extended-release tablets) have a release rate satisfying:

(a) not more than 40% in one hour,

(b) from about 30% to about 60% in 2 hours; and

(c) from about 45% to about 70% in 4 hours.

[0091] In certain embodiments, the extended-release molindone dosage forms herein (e.g., extended-release tablets) have a release rate satisfying:

(a) not more than 40% in one hour,

(b) from about 30% to about 60% in 2 hours;

(c) from about 45% to about 70% in 4 hours; and

(d) from about 65% to about 85% in 8 hours. [0092] In certain embodiments, the extended-release molindone dosage forms herein (e.g., extended-release tablets) have a release rate satisfying:

(a) not more than 40% in one hour,

(b) from about 30% to about 60% in 2 hours;

(c) from about 45% to about 70% in 4 hours;

(d) from about 65% to about 85% in 8 hours; and

(e) from about 75% to about 90% in 12 hours.

[0093] In certain embodiments of the molindone extended-release dosage form (e.g., extended- release tablets), the release rate of molindone is:

(a) not more than 40% in one hour,

(b) from about 30% to about 60% in 2 hours;

(c) from about 45% to about 70% in 4 hours;

(d) from about 65% to about 85% in 8 hours;

(e) from about 75% to about 90% in 12 hours; and

(f) not less than (NLT) about 85% in 18 hours.

[0094] In still further embodiments, the molindone extended-release dosage form (e.g., extended-release tablets) has a release rate of molindone which is:

(a) not more than 40% in one hour,

(b) from about 35% to about 60% in 2 hours;

(c) from about 50% to about 70% in 4 hours;

(d) from about 70% to about 80% in 8 hours;

(e) from about 80% to about 90% in 12 hours; and

(f) not less than (NLT) about 85% in 18 hours. [0095] In addition and as evidenced by the properties disclosed above, the disclosed embodiments provide a formulation that provides a therapeutically effective blood concentration of molindone for from 4 to 24 hours. In particular embodiments the disclosed embodiments provide a formulation that provides a therapeutically effective blood concentration of molindone for about 6 to about 24 hours. In further embodiments, the disclosed embodiments provide a formulation that provides a therapeutically effective blood concentration of molindone for about 8 hours to 24 hours. Thus, the extended-release molindone dosage forms herein are suitable for once-a-day administration.

[0096] For example, the formulations disclosed herein may be useful in methods of treating aggression in a human subject suffering from ADHD, Tourette's, and/or autism comprising administering a daily dose of molindone between 15 mg and 60 mg for human subjects weighing over 30 kg and a daily dose of molindone less than 25 mg for human subjects weighing less than 30 kg. Preferable ranges for low, medium, and high doses for the under 30 kg group are 10-14 mg, 22-26 mg, and 34-38 mg, respectively. Similarly, preferable ranges for the low, medium, and high doses for the 30kg and over group are 16-20 mg, 34- 38 mg, and 52-56 mg, respectively. See, for example, those methods described in U.S. Pat. App. Pub. No. 2014/0135326.

[0097] In another embodiment, the formulations disclosed herein may be useful in methods for the treatment of aggression in humans, in particular children, diagnosed with ADHD, bipolar disorder, autism, and post-traumatic stress disorder by administering, molindone in a dose range of from 10 mg/day to 200 mg/day. In other embodiments, molindone is administered in dose ranges of from 3 mg/day to 200 mg/day; 15 mg/day to 120 mg/day; 15 mg/day to 90 mg/day; 30 mg/day to 90 mg/day; or 36 mg/day to 72 mg/day.

[0098] The success of the treatment is evident in the marked decrease in the number instances of undesirable behavior exhibiting aggression, irritability, and impulsivity. Such behavior may be exemplified, without limitation, by disobedience; negativism; provocative opposition to authority figures; violations of minor rules; temper tantrums; argumentativeness; provocative behavior; stubbornness; blaming others for his or her own mistakes; being touchy, easily annoyed, angry, resentful, spiteful or vindictive; and swearing. [0099] In another embodiment, the formulations disclosed herein may be useful in methods of treatment of aggression in children with ADHD with molindone that is characterized by an improved adverse effect profile. The adverse effects that are diminished by the methods herein may be, but are not limited to, drowsiness, depression, hyperactivity and euphoria, extrapyramidal reactions, akathisia, akinesia, dystonic syndrome, tardive dyskinesia, tachycardia, nausea, dry mouth, urinary retention, and constipation. See, for example, those methods described in U.S. Pat. App. Pub. No. 2010/0173907.

Examples and Experiments

[0100] Examples 1 and 2

Table 1 sets forth extended-release formulations prepared in accordance with the above- described methods. Table 2 and FIG. I set forth the dissolution profiles for Examples 1 and 2.

[0101] Table 1 - Molindone Extended Release Compositions

[0102] Table 2 - Drug Dissolution % of Examples 1 and 2

[0103] Examples 3-6

Table 3 sets forth combined immediate release and extended-release formulations prepared in accordance with the above-described methods. Table 4 and FIG.2 set forth the dissolution profiles for Examples 3-6.

[0104] Table 3 - Molindone Immediate Release/Extended Release Compositions

Hydrogenated

57.85 28.93 45.90 27.50 62.63 31.32 58.50 29.25 Castor Oil NF

Colloidal Silicon

5.34 2.67 5.0 3.00 5.01 2.51 4.68 2.34 dioxide NF

Magnesium

1.78 0.89 1.70 1.00 1.67 0.84 1.56 0.78 Stearate NF

Weight of ER

178.00 89.00 167.00 83.50 167.00 83.50 156.00 78.00 portion

Total Weight of

200.00 100.00 200.00 100.00 200.00 200.00 200.00 100.00 tablet

[0105] Table 4 - Drug Dissolution % of Exampl

[0106] Although the compositions, schemes and methods of the present disclosure have been described with reference to exemplary embodiments thereof, the present disclosure is not limited thereby. Indeed, the exemplary embodiments are implementations of the disclosed methods are provided for illustrative and non-limitative purposes. Changes, modifications, enhancements and/or refinements to the disclosed methods may be made without departing from the spirit or scope of the present disclosure. Accordingly, such changes, modifications, enhancements and/or refinements are encompassed within the scope of the present invention.

Claims

CLAIMS What is claimed is:

1. A solid oral pharmaceutical extended release composition, comprising: a. molindone or pharmaceutically acceptable salts thereof; and b. a non-polymeric release-controlling agent.

2. The composition of claim 1, wherein the pharmaceutically acceptable salt of is

molindone hydrochloride, and wherein the non-polymeric release rate-controlling agent is hydrogenated castor oil.

3. The composition of claim 2, further comprising an excipient selected from the group consisting of a filler, a binder, a lubricant, a glidant, and mixtures thereof.

4. The composition of claim 3, comprising from about 0.1 to about 2 percent by weight of glidant; from about 0.1 to about 2 percent by weight lubricant; and from about 10 to about 60 percent by weight filler.

5. The composition of claim 4, wherein the filler is lactose monohydrate, the lubricant is magnesium stearate, and the glidant is colloidal silicon dioxide.

6. The composition of claim 2, comprising between about 10% and about 60% of

hydrogenated castor oil.

7. The composition of any of claims 1-6, wherein the composition does not contain a

stabilizer.

8. A tablet, comprising the extended release composition of claim 3.

9. The tablet of claim 2, further comprising an immediate-release composition comprising molindone.

10. The tablet of either of claims 8 or 9, providing an effective blood concentration of

molindone for a time period of between 4 hours and 24 hours.

11. The tablet of either of claims 8 or 9, wherein when subjected to stirring at a rate of 50 rpm in 900 mL distilled water at 37 °C ± 0.5 °C, the release rate of molindone from the composition is a. not more than 40% in one hour, b. from about 30% to about 60% in 2 hours; c. from about 45% to about 70% in 4 hours; d. from about 65% to about 85% in 8 hours; e. from about 75% to about 90% in 12 hours; and f. not less than (NLT) about 85% in 18 hours.

12. The composition of claim 11, wherein when stirred at a rate of 50 rpm in 900 mL distilled water at 37 °C ± 0.5 °C, the release rate of molindone from the composition is a. not more than 40% in one hour, b. from about 35% to about 60% in 2 hours; c. from about 50% to about 70% in 4 hours; d. from about 70% to about 80% in 8 hours; e. from about 80% to about 90% in 12 hours; and f. not less than (NLT) about 85% in 18 hours.

13. A method of preparing a solid oral pharmaceutical extended composition comprising the steps of: a. combining molindone or a pharmaceutically acceptable salt thereof with a glidant; b. adding a filler to form a dry mixture; c. adding the dry mixture to melted hydrogenated castor oil; d. adding a lubricant; and e. compressing to form a tablet.

14. The method of claim 14, wherein the filler is lactose monohydrate, the lubricant is

magnesium stearate, and the glidant is colloidal silicon dioxide.