EA046180B1 - PHARMACEUTICAL COMPOSITION OF PHLOROGLUCINOL AND TRIMETHYLPHLOROGLUCINOL - Google Patents

Description

Cross reference to related applications

This application claims benefit to U.S. Provisional Patent Application No. 62/468,501, filed March 8, 2017, the entire contents of which are incorporated herein by reference.

Field of invention

The present invention relates to pharmaceutical compositions containing phloroglucinol, trimethylphloroglucinol, pharmaceutically acceptable salts thereof, and combinations thereof.

State of the art to which the invention relates

Phloroglucinol is chemically a benzenetriol, specifically 1,3,5-benzenetriol. It has a symmetrical arene substitution pattern characteristic of trisubstituted benzene. An enol type, it exists in two tautomeric forms that exist in equilibrium: 1,3,5-trihydroxybenzene, which has a phenol-like character, and 1,3,5-cyclohexantrione (phloroglucinol), which has a ketone-like character.

The three hydroxyl groups can be methylated to form 1,3,5-trimethoxybenzene (trimethylphloroglucinol). Acylated phloroglucinol derivatives have fatty acid synthase inhibitory activity.

Phloroglucinol (Phloroglucin™, Phloroglucinol™, Spasfon) is used in medicine as a nonspecific antispasmodic agent. It has very weak anticholinergic properties and its main effect is through direct relaxation of smooth muscle cells. It is used to treat spasms, defined as involuntary contractions of the muscles of the blood and other vessels, bronchi, intestines, ureters and gallbladder. Specific uses include the treatment of, for example, urinary tract spasms, gallstones, cramping pain and associated gastrointestinal disorders, renal colic and biliary spasms associated with mild abdominal pain. Relaxation of smooth muscle cells is highly selective, affecting the ureter and bile ducts to a greater extent than the intestines and vasculature. Part of its relaxing properties results from inhibition of the enzyme catechol-O-methyltransferase. Trimethylphloroglucinol has a similar pharmacological and toxicological profile to phloroglucinol, but the duration of action of trimethylphloroglucinol is approximately six times longer than that of phloroglucinol.

Administration of phloroglucinol is contraindicated in patients with hypersensitivity to phloroglucinol or its methylated form, but contraindications have not been defined. It is known to infrequently cause skin hypersensitivity (allergic skin reactions). Anaphylactic shock has been reported with both intravenous and intramuscular administration of phloroglucinol.

Phloroglucinol is used to treat functional bowel disorders (FBD), also called functional bowel disease. Diagnostic criteria (Rome III) are symptoms lasting more than six months that occur on at least three days per month based on a three-month assessment; Typical initial complaints are abdominal pain relieved by defecation and transit disturbance. Diagnosis is made by excluding underlying organic disorders such as Crohn's disease or colorectal cancer. The main goal of treatment is to restore normal gastrointestinal transit and relieve pain by alleviating the predominant symptoms of constipation and diarrhea.

Irritable bowel syndrome (IBS) is the most common cause of FBD. The current estimated prevalence of IBS in the general adult population is approximately 8%. IBS is a chronic condition with acute episodes characterized by abdominal pain and/or bloating associated with bowel movements and/or changes in bowel movements (diarrhea and/or constipation). Symptoms fluctuate and tend to worsen under stress from life circumstances. Pathogenesis includes visceral hypersensitivity and/or increased or disorganized motility of the small intestine and/or large intestine. Individuals with diarrhea-predominant IBS have more jejunal contractions during phase II of the migratory digestive complex and postprandially than healthy individuals, and there is a relationship between the occurrence of painful episodes and the onset of jejunal motility. Episodes of pain are also associated with altered phasic contractions of the colon and an increased ability to respond to both the effects of food intake and stress. Visceral pain and altered bowel motility may be influenced by altered motor reflexes as a result of increased gastrointestinal sensitivity, justifying the use of antispasmodics such as phloroglucinol for the short-term treatment of acute painful episodes.

- 1 046180

Overactive bladder and urge urinary incontinence are colloquial terms for a condition in which the sensation of needing to empty the bladder occurs suddenly, often intensely, and without warning. The bladder muscle contracts, pushing urine out of the bladder and causing leakage. The cramps are described as cramping pain similar to intense menstrual pain or labor pains, and sometimes with a burning sensation. Causes of bladder spasms may include diet, medications, changes in the blood supply to the nerves that relax the bladder, infection, recent surgery, nerve damage, muscle damage, etc.

Individuals with FBS, IBS, and overactive bladder have decreased quality of life. The goal of therapy is to restore regular intestinal transit, controlled bladder emptying and pain relief. Therapy is combined with lifestyle (avoiding foods that aggravate symptoms, regular exercise) and dietary changes (increasing fiber intake if constipation is a symptom and decreasing fiber intake if diarrhea is a symptom). Pharmacological treatment is the administration of antispasmodics, particularly when the main symptoms are abdominal pain and bloating.

Phloroglucinol can treat FBS and IBS by enhancing the motor response of the rectosigmoid region. However, its regulatory performance was insufficient, so it was not approved for therapy in the United States.

Phloroglucinol is administered orally, in one embodiment at a dose of 80 mg up to 6 times daily, and in another embodiment at a dose of 80 mg up to 3 times daily. The typical oral dose for control of urinary tract spasticity is 80 mg six times daily; some studies described an orally administered dose of 80 mg three times daily. The parenteral route is used at a dose of 40 mg 2-3 times a day, but is currently not recommended. The typical dose for rectal administration for bladder spasms and biliary spasms is 150 mg three times daily.

Phloroglucinol has a maximum blood concentration of 677 ng/ml, achieved 20 minutes after a single oral dose of 160 mg. Its bioavailability (absorption) after an oral dose is 47% and metabolism occurs primarily in the kidneys. Phloroglucinol is excreted in the urine mainly in the form of hydroxylated metabolites, glucurono- and sulfonic conjugates, and partly in the form of an unmodified drug. It has a short plasma half-life of 1.5 hours.

The prevalence of IBS is associated with the country and diagnostic criteria used; it varies from 1% to 20%. One French study was based on a survey and administered a self-administered questionnaire to 20,000 individuals, yielding a prevalence of 4.7% determined according to Rome II criteria (4.36%-5.04%). Another French study was a survey based on a telephone interview of 8221 individuals and it gave an estimated prevalence of 12% according to Manning criteria (excluding symptom duration, 2.5% including symptom duration), 2.1% according to Rome I and 1% according to Rome II criteria. There are no epidemiological studies that have assessed the prevalence of IBS according to current criteria (Rome 111); the prevalence according to the Rome III criteria should be higher than the prevalence according to the Rome II criteria because the Rome III criteria are less restrictive in terms of duration of active symptoms (symptoms must be present for at least six months for the Rome III criteria). compared to one year for Rome II criteria).

What is needed are new compositions containing one or more of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, which release phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof.

The essence of the invention

In some embodiments, the invention relates to oral dosage units. The oral dosage units include an immediate release formulation containing phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, wherein at least about 90% by weight of the phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, based on the weight of the immediate release formulation, is released from the dosage unit in about 5 minutes to approximately 2 hours when determined using the USP 2 paddle method at approximately 50 rpm in approximately 750 ml of an aqueous solution containing approximately 0.1 N HCl at approximately 37°C. The oral dosage units also contain a modified-release formulation containing phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, wherein at least about 90% by weight of the phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, by weight of the modified-release formulation, is released from the dosage unit through at least as close as possible

- 2 046180 approximately 2 hours when determined using the USP 2 paddle stirrer method at approximately 50 rpm in approximately 1000 ml of an aqueous solution containing approximately 0.1 N HCl and approximately 20 mM tribasic sodium phosphate at a pH of approximately 6.8 at approximately 37 °C.

In other embodiments, the invention provides oral dosage units containing a plurality of spheres, each sphere containing an immediate release composition containing phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, wherein at least about 90% by weight of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof Based on the weight of the immediate release formulation, it is released from the dosage unit within approximately 5 minutes to approximately 2 hours when determined by the USP 2 paddle method at approximately 50 rpm in approximately 750 mL of an aqueous solution containing approximately 0.1 N HCl solution at approximately 37°C; and a plurality of spheres, wherein each sphere contains a modified release composition containing phloroglucinol, trimethylphloroglucinol or a pharmaceutically acceptable salt thereof, wherein at least about 90 wt.% phloroglucinol, trimethylphloroglucinol or a pharmaceutically acceptable salt thereof, based on the weight of the modified release composition, is released from the dosage units after at least about 2 hours when determined by the USP 2 paddle method at about 50 rpm in about 1000 ml of an aqueous solution containing about 0.1 N HCl and about 20 mM tribasic sodium phosphate at a pH of about 6.8 at approximately 37°C.

In further embodiments, the invention relates to oral dosage units containing a plurality of spheres. In some aspects, each sphere contains a core that is in the form of an immediate release formulation containing phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, wherein at least about 90 weight percent of the phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, by weight of the immediate release formulation, is released from the dosage unit for about 5 minutes to about 2 hours, when determined by the USP 2 paddle method at about 50 rpm in about 750 ml of an aqueous solution containing about 0.1 N HCl solution at about 37°C. The spheres also contain a coating over the core that is (i) a modified release formulation containing phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, wherein at least about 90% by weight of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, based on the weight of the modified release formulation. release, is released from the dosage unit after at least about 2 hours when determined by the USP 2 paddle method at approximately 50 rpm in approximately 1000 ml of an aqueous solution containing approximately 0.1 N HCl and approximately 20 mM tribasic sodium phosphate at pH approximately 6.8 at approximately 37°C; (ii) a modified release formulation containing phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, wherein at least about 90% by weight of the phloroglucinol, trimethylphloroglucinol, or pharmaceutically acceptable salt thereof, based on the weight of the modified release formulation, is released from the dosage unit within a period of about 4 to about 6 hours, when determined by the USP 2 paddle method at about 50 rpm in about 1000 ml of an aqueous solution containing about 0.1 N HCl and about 20 mM tribasic sodium phosphate at a pH of about 6.8 at about 37°C; or (iii) a combination of (i) and (ii).

In other embodiments, the invention provides methods for treating a spastic condition in an individual, comprising administering to the individual an oral dosage unit described herein.

Other aspects and embodiments of the invention will become better understood from the following detailed description of the invention.

Brief description of drawings

This application will be better understood when read in conjunction with the accompanying drawings. To illustrate the present invention, the drawings show illustrative embodiments of the present invention; however, the invention described herein is not limited to the specific compositions, methods, devices and systems described. In addition, the drawings are not necessarily drawn to scale.

In fig. 1 shows a representative drug release profile for an immediate release (IR) formulation and a modified release formulation of the invention.

In fig. 2 shows a simulated plasma phloroglucinol profile from an immediate release portion and a modified release portion of the invention.

In fig. 3 shows a two-layer tablet of the invention with immediate release and modified release layers.

In fig. 4 shows a three-layer tablet according to the invention, containing immediate release, modified release and buffer layers.

- 3 046180

In fig. 5 shows a tablet of the invention with a modified release matrix and immediate release coating.

In fig. 6 shows a capsule according to the invention containing an immediate release tablet, a stopper and a modified release tablet with an osmotic system.

In fig. 7 shows a capsule of the invention containing immediate release and modified release spheres.

In fig. 8 shows a capsule according to the invention containing immediate and modified release minitablets.

In fig. 9 shows a capsule of the invention containing immediate release and modified release granules.

In fig. 10 shows a capsule of the invention containing modified release spheres coated with an immediate release layer.

In fig. 11 shows a compressed tablet of the invention containing immediate release granules and a coated modified release tablet enclosed within the compressed tablet.

In fig. 12 shows a compressed immediate release tablet of the invention, wherein the immediate release tablet contains a modified release tablet.

In fig. 13 shows a modified release tablet of the invention suspended in immediate release liquid.

In fig. 14 shows a sachet according to the invention containing a mixture of immediate release and modified release spheres or granules.

In fig. 15 shows a sachet according to the invention containing immediate release effervescent spheres or granules and coated modified release spheres or granules.

In fig. 16 shows a tablet according to the invention, in which the intermediate layers are separated by stripes.

In fig. 17 shows an orally disintegrating tablet of the invention containing coated particles, spheres or granules of a delayed/modified release drug; The inset shows the drug in a polymer matrix.

In fig. 18 shows a capsule of the invention containing a drug solution and coated delayed/modified release drug particles, granules or spheres.

In fig. 19 shows a soft gel of the invention containing a drug solution and coated delayed/modified release drug particles, granules or spheres.

In fig. 20 shows a liquid carrier of the invention containing coated spheres, particles or granules of a modified release drug.

In fig. 21 shows the delayed release profile for the immediate release/modified release formulation of Example 1.

Detailed Description of the Invention

For the purposes of the present invention, the singular form includes the plural of the specified entities, and reference to a specific numerical value includes at least that specific value unless the context indicates otherwise. Thus, for example, a reference to a material is a reference to at least one of such materials and their equivalents known to those skilled in the art, etc.

The definition of approximately should be considered to describe a range defined by the absolute values of two finite quantities. For example, the expression from about 2 to about 4 also describes the range from 2 to 4. When used to define a single number, the term approximately can refer to plus or minus 10% of the specified number and includes the specified number. For example, about 10% may indicate a range from 9% to 11%, and about 1 means from 0.9 to 1.1.

When a list is provided, unless otherwise indicated, it is understood that each individual element of this list and each combination of this list should be interpreted as a separate embodiment. For example, a listing of embodiments represented as A, B, or C should be interpreted to include embodiments A, B, C, A or B, A or C, B or C, or A, B, or C.

It should also be understood that certain features of the invention, which for clarity are described herein in the context of individual embodiments, may also be provided in combination in one embodiment. Thus, each individual embodiment, unless expressly incompatible or excluded, may be combined with any other embodiment(s), and such combination is considered another embodiment. On the contrary, various features of the invention, which for brevity are described in the context of one embodiment

- 4 046180 and implementations can also be provided separately or in any subcombination. In addition, it should be noted that the claims may be drafted to exclude any optional element. In this regard, this statement provides an antecedent basis for the use of such exclusionary terminology as solely, only, etc. in relation to listing the elements of the claims, or to apply a negative limitation. Finally, although an embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself.

Pharmaceutically acceptable means approved or worthy of approval by a regulatory agency of the federal or state government or an appropriate agency in countries other than the United States, or listed in the United States Pharmacopoeia or other generally accepted pharmacopoeia for use in animals, and more specifically, in humans.

The terms patient or individual, as used herein, refer to a mammalian animal, and they are used interchangeably. In some embodiments, the patient or individual is a human. In other embodiments, the patient or individual is a veterinary patient or individual or a farm animal, a pet or companion animal, or an animal commonly used for clinical trials.

Treating a disease or disorder refers, in some embodiments, to alleviating the disease or disorder (ie, stopping or reducing the progression of the disease or at least one of its clinical symptoms). Treatment refers to the mitigation of the disease or disorder using phloroglucinol, trimethylphloroglucinol, or a combination thereof. In some embodiments, administering a treatment or treatment refers to alleviating at least one physical parameter that may not be noticeable to the individual. In other embodiments, administering a treatment or treatment refers to modulating a disease or disorder, either physically (eg, stabilizing a noticeable symptom), physiologically (eg, stabilizing a physical parameter), or both. In further embodiments, administering a treatment or treating refers to delaying the onset of a disease or disorder.

The term phloroglucinol, as used herein, refers to the following compound.

Phloroglucinol also includes any of its tautomeric forms, including its known ketotautomer presented below.

Likewise, the term trimethylphloroglucinol as used herein refers to the following compound.

As discussed herein, the present invention relates to dosage units that are formulated for oral administration, i.e. to oral dosage units. The oral dosage unit can take a variety of different delivery forms. In some embodiments, the dosage unit is a tablet, capsule (hard or soft), sachet, soft gel, liquid, gel, strip, film, or capsule tablet. In other embodiments, the dosage unit is a tablet, capsule, sachet, soft gel, or liquid. In further embodiments, the oral dosage unit is

- 5 046180 fight tablet. In other embodiments, the oral dosage unit is a capsule. In further embodiments, the oral dosage unit is a sachet.

The term tablet, as used herein, refers to a solid dosage unit. The tablet may have any shape or size suitable for oral administration, such as round, elliptical, etc. A tablet is prepared by compressing one or both of an immediate release formulation and a modified release formulation. In some embodiments, the tablet is prepared by compressing an immediate release formulation. In other embodiments, a tablet is prepared by compressing one or more modified release formulations. In further embodiments, a tablet is prepared by compressing an immediate release formulation and one or more modified release formulations. Depending on the tablet base, it may be coated with a layer containing an immediate release formulation or a modified release formulation. In some embodiments, the tablet is a bilayer tablet containing an immediate release (IR) layer and a modified release layer adjacent; see, for example, Fig. 3. In other embodiments, the tablet is a three-layer tablet comprising an immediate release layer and a modified release layer separated by a layer, such as a buffer layer; see, for example, Fig. 4. In further embodiments, the tablet contains enclosed granules coated with an immediate release composition and spheres coated with a modified release composition; see, for example, Fig. 11. In other embodiments, the tablet comprises a tablet containing a modified release formulation enclosed in a tablet containing an immediate release formulation; see, for example, Fig. 12. In further embodiments, the tablet comprises a tablet containing a modified release formulation that is suspended in a liquid solution containing an immediate release formulation, wherein the liquid solution is contained in a capsule; see, for example, Fig. 13. In other embodiments, the capsule of the invention contains a solution containing the immediate release composition and spheres or granules coated with the modified release composition; see, for example, Fig. 18. In further embodiments, the soft gel of the invention comprises a solution containing an immediate release formulation and spheres or granules coated with a modified release formulation; see, for example, Fig. 19. In other embodiments, FIG. 20 shows a liquid carrier containing the immediate release formulation and spheres or granules coated with the modified release formulation.

The term capsule, as used herein, refers to a solid dosage unit. The capsule is typically elliptical in shape, but may take other shapes as determined by those skilled in the art. The capsule may optionally be a hard or soft gelatin capsule. In some embodiments, the capsule contains a tablet containing an immediate release formulation and a tablet containing a modified release formulation. In further embodiments, the capsule contains an immediate release tablet, a stopper, and a modified release tablet; see, for example, Fig. 6. In other embodiments, the capsule contains spheres coated with an immediate release composition and spheres coated with a modified release composition; see, for example, Fig. 7. In further embodiments, the capsule contains immediate release minitablets and modified release minitablets; see, for example, Fig. 8. In other embodiments, the capsule contains immediate release granules, and the granules are coated with a modified release composition; see, for example, Fig. 9. In other embodiments, the capsule contains a plurality of spheres coated with a modified release formulation and an immediate release formulation as layers.

The term sachet as used herein refers to a package that contains a mixture of immediate release granules and modified release granules, or granules containing an immediate release formulation and granules or spheres containing a modified release formulation; see, for example, Fig. 14. Packaging may be selected by those skilled in the art.

Regardless of the form of the dosage unit, it may alternatively or additionally comprise spheres, granules, or a combination thereof. As used herein, spheres are solid particles produced by extrusion and beading of an immediate release formulation, a modified release formulation, or a combination thereof. Similarly, granules are solid particles, but are produced through granulation. One skilled in the art will be able to select an appropriate granulation process to produce granules for use in the present invention. In some embodiments, the granulation method includes high shear granulation, melt granulation, dry granulation, or wet granulation, among others. In some embodiments, the dosage unit comprises spheres containing an immediate release formulation. In other embodiments, the dosiro

- 6 046180 bath unit contains spheres containing a modified release composition. In further embodiments, the dosage unit comprises spheres containing an immediate release formulation and spheres containing a modified release formulation. In other embodiments, the dosage unit comprises spheres containing an immediate release formulation. In other embodiments, the dosage unit comprises spheres containing a modified release formulation. In further embodiments, the dosage unit comprises granules containing an immediate release formulation and spheres containing a modified release formulation.

Typically, a plurality of spheres or granules are included in the dosage unit described herein. The term plurality, as used herein, refers to the number of spheres or granules that provide the amount of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof required per dosage unit. In some embodiments, the dosage unit contains a plurality of spheres. In further embodiments, the dosage unit contains a plurality of granules. In other embodiments, the dosage unit contains a plurality of spheres and a plurality of granules.

The spheres and/or granules contain one or both of an immediate release formulation or a modified release formulation. In some embodiments, the spheres contain an immediate release formulation. In other embodiments, the spheres contain a modified release formulation. In further embodiments, the spheres contain an immediate release formulation and a modified release formulation. In other embodiments, the granules contain an immediate release formulation. In further embodiments, the granules contain a modified release formulation. In other embodiments, the granules contain an immediate release formulation and a modified release formulation.

Each sphere or granule contains a core and one or more optional coating layers. Thus, the core contains one or both of an immediate release composition or a modified release composition. In some embodiments, the core also contains an inactive pharmaceutical agent, such as an excipient, as described herein. The cores have a diameter of from about 50 to about 1500 microns. In some embodiments, the cores have a diameter of from about 50 to about 1300 microns, from about 50 to about 1100 microns, from about 50 to about 900 microns, from about 50 to about 800 microns, from about 50 to about 700 microns, from about 50 to about 600 microns, from about 50 to about 500 microns, from about 50 to about 400 microns, from about 50 to about 300 microns, from about 50 to about 200 microns, from about 100 to about 1500 microns, from about 100 to about 1300 microns, from about 100 to about 1100 microns, from about 100 to about 900 microns, from about 100 to about

800 µm, from about 100 to about 700 µm, from about 100 to about

600 µm, from about 100 to about 500 µm, from about 100 to about

400 µm, from about 100 to about 300 µm, from about 100 to about

200 microns. In other embodiments, the core diameter is from about 100 to about 800 microns.

The dosage unit may have a plurality of active substance cores with different dissolution properties. Thus, the core can be covered with one or more layers. In some embodiments, the cores are coated with two or more layers, i.e. form a multilayer tablet. In further embodiments, the cores are coated with a layer of immediate release composition. In other embodiments, the cores are coated with a layer of a modified release composition. In a further embodiment, the core is coated with an immediate release composition and a modified release composition.

Other layers can be applied as a top coat or between other layers. The layers may contain pharmaceutically inert components, i.e. as a buffer layer, or pharmaceutically active components, as determined by those skilled in the art.

The oral dosage units contain one or more of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt of phloroglucinol or trimethylphloroglucinol. In some embodiments, the oral dosage unit contains phloroglucinol or a pharmaceutically acceptable salt thereof. In other embodiments, the oral dosage unit contains trimethylphloroglucinol or a pharmaceutically acceptable salt thereof. In further embodiments, the oral dosage unit contains phloroglucinol or a pharmaceutically acceptable salt thereof and trimethylphloroglucinol or a pharmaceutically acceptable salt thereof.

In some embodiments, pharmaceutically acceptable salts may be formed from organic and inorganic acids, including, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phtha

- 7 046180 left, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalene sulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic or similar known acceptable acids.

In other embodiments, pharmaceutically acceptable salts may also be formed from inorganic bases, preferably alkali metal salts, including, for example, sodium, lithium or potassium hydroxides, such as alkali metal hydroxides. Examples of inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide. Pharmaceutically acceptable salts may also be formed from organic bases such as ammonium salts, mono-, di- and trimethylammonium, mono-, di- and triethylammonium, mono, di- and tripropylammonium, ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium, benzylammonium, dibenzylammonium, piperidinium , morphilinium, pyrrilidine, pipeperizinium, 1 methylpiperidine, 4-eylmorpholinium, 1-izpropylpyrrolidine, 1.4-deimetilpipherapinium, 1-tulpiperidinium, 2-methylpiperidine, 1-ethyl-2-methylpiperidine, mono-di-di-di-di-di-di-di-di-di-di-di- and ethytanolamony -butylmonoethanolammonium, tris(hydroxymethyl)methylammonium, phenylmonoethanolammonium, diethanolamine, ethylenediamine, etc. In one example, the base is sodium hydroxide, lithium hydroxide, potassium hydroxide, or mixtures thereof.

The compounds described above can be used in the form of salts formed from pharmaceutically or physiologically acceptable acids, bases, alkali metals and alkaline earth metals.

Desirably, the amount of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof is sufficient to treat the patient, as indicated below. In some embodiments, the oral dosage units contain from about 50 to about 1000 mg of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, or a combination thereof. In other embodiments, the oral dosage unit contains from about 50 to about 900 mg, from about 50 to about 800 mg, from about 50 to about 700 mg, from about 50 to about 600 mg, from about 50 to about 500 mg, from about 50 to about 400 mg, from about 50 to about 300 mg, from about 50 to about 200 mg, from about 50 to about 100 mg, from about 100 to about 900 mg, from about about approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately

800

600

400

200

900

700

500

300

800

600

400

800

600

900

700 mg, from mg, from mg, from mg, from mg, from mg, from mg, from mg, from mg, from mg, from mg, from mg, from mg, from mg, from mg, from approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately

100

100

100

100

200

200

200

300

300

300

400

400

400

500

500 to to to to to to to to to to to to to to approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately

700

500

300

100

800

600

400

900

700

500

900

700

500

800

600 mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, from from from from from from from from from from from from from from from from approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately

100

100

100

100

200

200

200

200

300

300

300

400

400

500

500

600 to about 900 mg, about 600 to about 800 mg, or about 600 to about 700 mg of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, or a combination thereof.

The oral dosage unit contains one or more immediate release components and one or more modified release components. In some embodiments, the oral dosage unit contains at least one immediate release formulation and at least one modified release formulation. In other embodiments, the dosage unit contains at least one immediate release formulation and at least two modified release formulations, i.e. a first modified release composition and a second modified release composition. In further embodiments, the dosage unit contains at least one immediate release formulation and at least three modified release formulations, i.e. a first modified release composition, a second modified release composition and a third modified release composition. In other embodiments, the dosage unit contains at least one immediate release formulation and at least four modified release formulations, i.e. a first modified release formulation, a second modified release formulation, a third modified release formulation and a fourth modified release formulation.

- 8 046180

Both the immediate release formulation and the modified release formulation contain phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof. In some embodiments, the immediate release formulation contains phloroglucinol or a pharmaceutically acceptable salt thereof. In other embodiments, the immediate release formulation contains trimethylphloroglucinol or a pharmaceutically acceptable salt thereof. In the following embodiments, the immediate release composition contains: (i) phloroglucinol or a pharmaceutically acceptable salt thereof and (ii) trimethylphloroglucinol or a pharmaceutically acceptable salt thereof. In other embodiments, the modified release formulation contains phloroglucinol or a pharmaceutically acceptable salt thereof. In further embodiments, the modified release formulation contains trimethylphloroglucinol or a pharmaceutically acceptable salt thereof. In other embodiments, the modified release formulation contains: (i) phloroglucinol or a pharmaceutically acceptable salt thereof and (ii) trimethylphloroglucinol or a pharmaceutically acceptable salt thereof.

The oral dosage unit contains from about 10 to about 50% by weight of the immediate release composition, based on the weight of the oral dosage unit. In some embodiments, the oral dosage unit contains from about 10 to about 50 wt.%, from about 10 to about 40 wt.%, from about 10 to about 30 wt.%, from about 10 to about 20 wt.%, from about 20 to about 50 wt.%, from about 20 to about 40 wt.%, from about 20 to about 30 wt.%, from about 30 to about 50 wt.%, or from about 40 to about 50 wt.% calculated per weight of the oral dosage unit of the immediate release formulation. In other embodiments, the oral dosage unit contains approximately 10, 15, 20, 25, 30, 35, 40, 45, or 50 weight percent immediate release formulation, based on the weight of the oral dosage unit.

The oral dosage unit contains from about 10 to about 50% by weight of the modified release formulation, based on the weight of the oral dosage unit. In some embodiments, the oral dosage unit contains from about 10 to about 50% by weight, from about 10 to about 40% by weight, from about 10 to about 30% by weight, from about 10 to about 20% by weight, from about 20 to about 50 wt.%, from about 20 to about 40 wt.%, from about 20 to about 30 wt.%, from about 30 to about 50 wt.%, or from about to about 50 wt.% of the modified release composition in based on the weight of the oral dosage unit. In other embodiments, the oral dosage unit contains approximately 10, 15, 20, 25, 30, 35, 40, 45, or 50 weight percent of the modified release formulation, based on the weight of the oral dosage unit.

With respect to the oral dosage unit described above, one or both of the immediate release formulation or the modified release formulation is a tablet, capsule (hard or soft), sachet, soft gel, liquid, gel, strip, film or capsule tablet. In other embodiments, one or both of the immediate release formulation or the modified release formulation is a tablet, capsule, sachet, soft gel, or liquid.

The term immediate release, as used herein, refers to a dosage unit that, when administered orally to a human, releases substantially all of the phloroglucinol, trimethylphloroglucinol, or pharmaceutically acceptable salts thereof, by weight, into a portion of the gastrointestinal tract (e.g., the stomach or intestines, preferably the stomach) for biological absorption within a short period of time. Methods for determining the in vitro release profile of a dosage unit to determine whether the dosage unit exhibits an immediate release or extended release dissolution profile are known in the pharmaceutical field. By such methods, it can be determined that the dosage units as described herein are capable of releasing substantially all of the total amount of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof contained in the immediate release formulation. In some embodiments, at least about 90% by weight of the phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, by weight of the immediate release formulation, is released into the solution (eg, an acidic aqueous solution). In other embodiments, about 90 to about 100 wt%, about 95 to about 100 wt%, about 98 to 100 wt%, about 99 to 100 wt%, or 90, 91, 92, 93 94, 95, 96, 97, 89, 99, or 100% by weight of the phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof is released from the immediate release formulation.

Phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof is released from the immediate release formulation within about 5 minutes to about 2 hours, such as about 5 minutes to about 1.5 hours, about 5 minutes to about

- 9 046180 1 hour, approximately 5 minutes to approximately 45 minutes, approximately 5 minutes to approximately 30, approximately 15, or approximately 10 minutes. In some embodiments, the release profile of an immediate release formulation portion from a dosage unit described herein is determined by the method of USP 711. In some embodiments, the release profile of an immediate release formulation portion from a dosage unit described herein is determined by the method of USP 2 paddle mixer. In other embodiments, the release profile of the immediate release formulation portion of a dosage unit described herein is determined by a method that exposes the immediate release formulation portion to a speed of about 45 to about 55 rpm (eg , 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 or 55 rpm, preferably about 50 rpm) and in volumes up to about 900 ml (for example, about 300 ml, 750 ml or about 900 ml, based on various testing methods) of hydrochloric acid (about 0.01 to about 0.2 N, preferably about 0.1 N, for example, aqueous hydrochloric acid) and at a temperature of about 35 to about 40 ( for example 35, 36, 37, 38, 39 or 40°C, preferably about 37°C). For example, the release profile of the immediate release dosage unit composition of the present invention can be determined by a method that exposes the dosage unit to a speed of approximately 50 rpm in approximately 750 ml of an aqueous solution containing approximately 0.1 N HCl solution at approximately 37°C.

The term modified release, as used herein, refers to the slow release of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof over several hours into the gastrointestinal tract (eg, stomach or intestines) and colon for bioabsorption over an extended period of time. Methods for determining the release profile from a dosage unit in vitro to determine whether the dosage unit exhibits a dissolution profile consistent with a modified release are known in the pharmaceutical field. By such methods, the dosage units as described herein can be measured to be capable of releasing substantially all of the total amount of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof contained in the modified release formulation. In some embodiments, at least about 90 weight percent of the phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, based on the weight of the modified release formulation, is released into the solution (eg, an acidic aqueous solution). In other embodiments, about 90 to about 100 wt%, about 95 to about 100 wt%, about 98 to 100 wt%, about 99 to 100 wt%, or 90, 91, 92, 93 94, 95, 96, 97, 89, 99, or 100% by weight of the phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof is released from the modified release formulation.

Phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof is released from the modified release formulation within at least about 2 hours, about 2 to about 12 hours, about 2 to about 11 hours, about 2 to about 10 hours, about 2 to about 9 hours, about 2 to about 8 hours, about 2 to about 7 hours, about 2 to about 6 hours, about 2 to about 5 hours, about 2 to about 4 hours, about 2 to about 3 hours, from about 4 to about 12 hours, from about 4 to about 11 hours, from about 4 to about 10 hours, from about 4 to about 9 hours, from about 4 to about 9 hours, from about 4 to about 8 hours, from about 4 to about 7 hours, from about 4 to about 6 hours, from about 6 to about 12 hours, from about 6 to about 11 hours, from about 6 to about 10 hours, from about 6 to about 9 hours, from about 6 to about 8 hours, about 8 to about 12 hours, about 8 to about 11 hours, about 8 to about 10 hours, or about 10 to about 12 hours. Desirably, each modified release formulation has a different release profile. In some embodiments, the first modified release composition releases phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof from the modified release composition within about 5 minutes to about 2 hours. In other embodiments, the second modified release composition, if present, releases phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof from the modified release formulation for at least about 2 hours. In further embodiments, the second modified release formulation, if present, releases phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof from the modified release formulation for at least about 4 to approximately 6 hours.

In some embodiments, the release profile of a portion of an immediate release dosage unit formulation described herein is determined by a method

- 10 046180 USP 2 mixer. In other embodiments, the release profile of the modified release formulation portion of a dosage unit described herein is determined by a method that exposes the modified release formulation portion to a speed of about 45 to about 55 rpm (e.g., 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 or 55 rpm, preferably about 50 rpm) and in volumes up to about 1100 ml (e.g., about 300 ml, about 500 ml, about 750 ml or about 1000 ml, preferably about 1000 ml, based on various testing methods) of an aqueous solution containing a phosphate buffer (for example, an aqueous solution containing hydrochloric acid (from about 0.01 to about 0. 2 N, preferably about 0.1 N, e.g. aqueous hydrochloric acid) and tribasic sodium phosphate (about 10 to about 30 mM, about 10 to about 20 mM, about 20 to about 30 mM, about 15 to about 25 mM, preferably about 20 mM) and at a pH of about 6.5 to about 7 (e.g., 6.5, 6.6, 6.7, 6.8, 6.9 or 7, preferably 6.8) , and at a temperature of from about 35 to about 40 (for example, 35, 36, 37, 38, 39 or 40°C, preferably about 37°C). In some embodiments, the release profile of a modified release formulation from a dosage unit as defined herein is determined by a method that exposes the dosage unit to about 50 rpm in about 1000 mL of an aqueous solution containing about 0.1 N HCl and about 20 mM tribasic sodium phosphate at pH approximately 6.8 at approximately 37°C. In other embodiments, the release profile of the modified release formulation from a dosage unit is determined by a method that exposes the dosage unit to about 50 rpm in about 1000 mL of an aqueous solution containing about 0.1 N HCl and about 20 mM tribasic sodium phosphate at a pH of about 6 ,8 at approximately 37°C. In further embodiments, the dosage unit comprises a modified release formulation wherein at least about 90% by weight of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, based on the weight of the modified release formulation, is released from the dosage unit after at least about 2 hours when determined by the method USP 2 paddle mixer at approximately 50 rpm in approximately 1000 ml of an aqueous solution containing approximately 0.1 N HCl and approximately 20 mM tribasic sodium phosphate at a pH of approximately 6.8 at approximately 37°C. In other embodiments, the dosage unit comprises a modified release formulation wherein at least about 90% by weight of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, based on the weight of the modified release formulation, is released from the dosage unit over about 4 to about 6 hours, at determined by the USP 2 paddle method at approximately 50 rpm in approximately 1000 ml of an aqueous solution containing approximately 0.1 N HCl and approximately 20 mM tribasic sodium phosphate at a pH of approximately 6.8 at approximately 37°C. In other embodiments, the dosage unit contains two modified release formulations: (i) a modified release formulation, wherein at least about 90% by weight of the phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, by weight of the modified release formulation, is released from the dosage unit through at least about 2 hours when determined by the USP 2 paddle method at about 50 rpm in about 1000 ml of an aqueous solution containing about 0.1 N HCl and about 20 mM tribasic sodium phosphate at a pH of about 6.8 at about 37° WITH; and (ii) a modified release formulation, wherein at least about 90% by weight of the phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, based on the weight of the modified release formulation, is released from the dosage unit in about 4 to about 6 hours when determined by the paddle method. stirrer USP 2 at approximately 50 rpm in approximately 1000 ml of an aqueous solution containing approximately 0.1 N HCl and approximately 20 mM tribasic sodium phosphate at a pH of approximately 6.8 at approximately 37°C.

In some embodiments, the oral dosage unit has an immediate release profile and a modified release profile. In other embodiments, the oral dosage unit has an immediate release profile, defined as the release of at least 90% of the phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, over about 5 minutes to about 2 hours, and a sustained release profile, defined as the release of at least about 90% by weight phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof for at least about 2 hours.

In some embodiments, the immediate release formulation contains from about 50 to about 800 mg of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof. In other embodiments, the immediate release formulation contains from about 600 mg, from about 400 mg, from about 200 mg, from about 800 mg, from about 600 mg, from about 400 mg, from about 200 mg, from about 800 mg, from about 600 mg, from about 400 mg, from about 800 mg, from about 600 mg, from about 400 mg, from about 700 mg, from about 500 mg, from about 700 mg, from about to about 700 to about 500 to approximately 300 to approximately 100

100 to approximately 700

100 to approximately 500

100 to approximately 300

100 to approximately 100

200 to approximately 700

200 to approximately 500

200 to approximately 300

300 to approximately 700

300 to approximately 500

400 to approximately 800

400 to approximately 600

500 to approximately 800

500 to about 600 mg, from about 50 mg, from about 50 mg, from about 50 mg, from about 100 mg, from about 100 mg, from about 100 mg, from about 100 mg, from about 200 mg, from about 200 mg , from about 200 mg, from about 300 mg, from about 300 mg, from about 300 mg, from about 400 mg, from about 400 mg, from about 500 mg, from about 600 to to to to to to to to to to to to to to to to to to to to approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately

800 mg, or about 600 to about 700 mg phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof.

Likewise, the modified release formulation contains from about 50 to about 800 mg of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof. In other embodiments, the modified release formulation contains from about 50 to about 700 mg, from about 50 to about 600 mg, from about 50 to about 500 mg, from about 50 to about 400 mg, from about 50 to about 300 mg, from about 50 to about 200 mg, about 50 to about 100 mg, about 100 to about 800 mg, about 100 to about 700 mg, about 100 to about 600 mg, about 100 to about 500 mg, about 100 to about approximately 400 mg, from approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately

300

100

700

500

300

700

500

800

600

800 mg, from mg, from mg, from mg, from mg, from mg, from mg, from mg, from mg, from mg, from approximately approximately approximately approximately approximately approximately approximately approximately approximately

100

200

200

200

300

300

300

400

400

500 to to to to to to to to to to approximately approximately approximately approximately approximately approximately approximately approximately approximately

200

800

600

400

800

600

400

700

500

700 mg, mg, mg, mg, mg, mg, mg, mg, mg, mg, from from from from from from from from from from approximately approximately approximately approximately approximately approximately approximately approximately approximately approximately

100

100

200

200

200

300

300

400

400

500

500 to about 600 mg, about 600 to about 800 mg, or about 600 to about 700 mg of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof.

When the dosage unit described herein contains both phloroglucinol and trimethylphloroglucinol, or pharmaceutically acceptable salts thereof, the ratio of phloroglucinol to trimethylphloroglucinol (or salts thereof) is from about 90:10 to about 10:90. In some embodiments, the ratio of phloroglucinol to trimethylphloroglucinol (or salts thereof) is from about 80:20 to about 20:80, from about 70:30 to about 30:70, from about 60:40 to about 40:60, from about 50 :50 to about 50:50, from about 40:60 to about 60:40, from about 30:70 to about 70:30, or from about 20:80 to about 80:20. In other embodiments, the ratio of phloroglucinol to trimethylphloroglucinol (or salts thereof) is about 90:10, about 85:15, about 80:20, about 75:25, about 70:30, about 65:35, about 60:40, about 55:45, approximately 50:50, approximately 45:55, approximately 40:60, approximately 35:65, approximately 30:70, approximately 25:75, approximately 20:80, approximately 15:85 or approximately 10:90.

The dosage unit may contain separate or discrete portions of an immediate release formulation and one or more modified release formulations, i.e. they are physically separated. Thus, in some embodiments, the dosage unit may comprise an immediate release formulation and a modified release formulation. In other embodiments, the dosage unit may comprise an immediate release formulation, a first modified release formulation, and a second modified release formulation.

Alternatively, the immediate release portion and the modified release portion are combined, i.e. one composition is layered on top of another composition. The term part is like

- 12 046180 used within the scope of the invention, relates to the surface of the composition. In some embodiments, a portion refers to at least about 50% by weight, such as at least about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 98 , approximately 99 or 100 wt.%, based on the weight of the composition. In some embodiments, the immediate release composition comprises a layer of modified release composition. In other embodiments, the modified release formulation comprises a layer of immediate release formulation. When the dosage unit contains two or more modified release formulations, in some embodiments, the immediate release formulation is coated with a first modified release formulation, which is then coated with a second modified release formulation. In other embodiments, the immediate release formulation is coated with a second modified release formulation, which is then coated with a first modified release formulation. In some embodiments, the oral dosage unit contains a plurality of spheres, each sphere containing a core that is in the form of an immediate release formulation containing phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, coating the core that is: (i) a modified release formulation containing phloroglucinol , trimethylphloroglucinol or a pharmaceutically acceptable salt thereof, (ii) a modified release formulation containing phloroglucinol, trimethylphloroglucinol or a pharmaceutically acceptable salt thereof, (iii) or a combination of (i) and (ii).

The modified release formulation contains an agent that provides the modified release profile described above. In some embodiments, the modified release formulation comprises an enteric polymer. An enteric polymer refers to a polymer that is resistant to degradation by gastric juice (ie, relatively insoluble at low pH levels in the stomach) but dissolves at higher pH levels present in the intestine. Examples of enteric polymers include, but are not limited to, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate such as Sureteric® polymer, carboxymethyl ethyl cellulose, methacrylic acid/methacrylic acid methyl ester copolymer such as EUDRAGIT® L12.5 , EUDRAGIT® L100 or EUDRAGIT® S12.5, S100, methacrylic acid-ethyl acrylate copolymer, such as Acryl-EZE® polymer, or aleuric acid esters, such as shellac. Aqueous colloidal dispersions or polymer redispersions can also be used, for example EUDRAGIT® L 30D-55, EUDRAGIT® L100-55, EUDRAGIT® S100, EUDRAGIT® 4110D preparation (Rohm Pharma); AQUATERIC®, AQUACOAT® CPD 30 (FMC); KOLLICOAT MAE® 30D and 30DP (BASF); EASTACRYL® 30D (Eastman Chemical). In some embodiments, the enteric polymer is a copolymer of methacrylic acid and ethyl acrylate, such as Acryl-EZE® polymer. In further embodiments, the enteric polymer is a phthalate polymer, such as Sureteric® polymer.

The compositions described may contain one or more pharmaceutically acceptable excipients that are considered safe and effective and can be administered to individuals without causing unwanted biological side effects or unwanted interactions.

Illustrative excipients include, but are not limited to, antimicrobial agents, antioxidants, binders, diluents, disintegrants, emulsifiers, flavoring agents, glidants, tonicity modifying agents, lubricants, pH modifying agents, plasticizers, preservatives, sweeteners, stabilizers, suspending agents, increasing the viscosity of the product or combinations thereof.

Binders include gum arabic, gum tragacanth, corn starch, gelatin, sucrose, pregelatinized starch, starch, sodium alginate, calcium ammonium alginate, methylcellulose, sodium cellulose derivatives such as methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, Ilicate aluminum and polyacrylamide.

Disintegrants or disintegrants include corn starch, potato starch, pregelatinized starch, cross-linked carboxymethylcellulose (AC-DI-SOL®), sodium starch glycolate (EXPLOTAB®), cross-linked polyvinylpyrrolidone (PLASDONE XL®), etc.

Dyes or coloring agents include synthetic and natural dyes and combinations thereof.

Diluents or carriers may include, among others, water, alcohols, oils, glycols such as polyethylene glycols. Examples of diluents include, but are not limited to, peanut oil, almond oil, ground nut oil, palm oil, palm kernel oil, peppermint oil, black currant seed oil, rice bran oil, soybean oil, canola oil, corn oil, coconut oil, cottonseed oil, castor oil, olive oil, magnolia oils

- 13 046180 (neema), sesame oil, primrose oil, vegetable oil, LIPEX® 108 (abitec), wheat germ oil, fish oil, rapeseed oil, sunflower oil and safflower oil, polyethylene glycols, polyoxyethylene lauric glycerides 32 (ACCONON® M- 44), polyoxyethylene 8 Caprillic/Caprine glycerides (AcConon® MC-8), glyceralsterata (IMWITOR®), polyoxyechemed oleic glycerides (Labraft®), mineral oil, mono and digitzeridal emulsifiers, such as glyceralmonooleat, glyceril monocracyplaces, glycyriumonomonomonomo Caprilat, propylene glycol monocaprilate and propylene glycol monolaurate (CAPMUL®), dimethylpolysiloxanes such as simethicone, glycofurol, glycerin, ethanolglycerol, propylene glycol or polyethylene glycols (PEG)-400. In some embodiments, the carrier is water or alcohol.

Flavoring agents or flavourings can be used to mask the unpleasant odors and tastes of filler formulations. Suitable flavoring agents include synthetic and natural flavoring agents.

Humectants can be used to suppress the water activity of the soft gel. Suitable humectants include glycerin and sorbitol, which are often components of plasticizer compositions.

Opacifiers are used to opacify the capsule shell when the encapsulated active substances are sensitive to light. Suitable opacifiers include titanium dioxide, zinc oxide, calcium carbonate, and combinations thereof.

Plasticizers are chemicals added to gelatin to make the material softer and more elastic. Suitable plasticizers include, but are not limited to, glycerin, sorbitol solutions, which are mixtures of sorbitol and sorbitan, and other polyols such as propylene glycol and maltitol, or combinations thereof.

Preservatives include alkyl esters of p-hydroxybenzoic acid such as methyl, ethyl, propyl, butyl and heptyl esters (collectively known as parabens) or combinations thereof.

Solubilizers include, among others, citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid, sodium bicarbonate, sodium carbonate.

Sweeteners include sucrose, lactose, dextrose, mannitol or saccharin.

Surfactants include ionic, non-ionic and/or bile salt surfactants, anionic surfactants include sodium alkyl sulfate (sodium lauryl sulfate) and sulfosuccinate derivatives such as docusate sodium, non-ionic surfactants include polyoxyethylene sorbitan fatty acid esters (polysorbates), such as TWEEN® 20, TWEEN® 80, TWEEN® 40, SPAN® 20, polyethylene glycol fatty acid esters, such as GELUCIRE® 44/14, GELUCIRE® 50/13, saturated polyglycolated (including mono, di or tri)glycerides, medium chain monoglycerides (6-10 carbons), such as glyceryl monocaprylate (IMWITOR® 308), glyceryl monocaproate (CAPMUL® MSM C-8), glyceryl caprylate/caprate (CAPMUL® MSM), polyoxyethylene glyceryl caprylate and polyoxyethylene glyceryl caproate (LABRASOL®), medium chain fatty acid esters such as glyceryl tricaprate and glyceryl tricaprylate (MIGLYOL® 612), ethylene oxide and propylene oxide block polymers, polyoxyethylene-polyoxypropylene block copolymers such as poloxamer 188 (PLURONIC® F-6 8 ), poloxamer 237 (PLURONIC® F-87), poloxamer 338 (PLURONIC® F-108), poloxamer 407 (PLURONIC® F-127), poloxamer 124 (PLURONIC® L-44), polyoxystearate-polyethoxylated (40) stearic acid (MYRJ™ 52), ethoxylated castor oil-polyethoxylated (60) hydrogenated castor oil (CREMOPHOR® EL), polyethylene glycol 660 ethoxylated hydrostearic acid hydrostearate (SOLUTOL® HS 15), polyoxyethylene alkyl esters (12-18 carbons) such as polyoxy 20 cetostearyl ether (ATLAS™ G-3713), polyoxy 10 oleyl ether (BRIJ™ 96, BRIJ™ 97, Oleth 10), polyethylene glycol ether (TRITON™ X-100, TRITON™ X-114, TRITON™ X-405, TRITON™ N-101) and lecithins such as phospholipids (dimyristoyl DL-alpha-phosphatidylcholine), bile salt surfactants include deoxycholic acid, sodium deoxycholate, cholic acid, sodium taurocholate, etc.

Stabilizers include antioxidants, buffers, acids, etc. Examples of antioxidants may include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), diethylenetriaminepentaacetic acid (DTPA), edetates (EDTA), monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, bisulfite sodium, triglycomate, vitamin E or its derivatives, propyl gallate, combinations thereof, etc.

Viscosity enhancers include gelatin, glycerin, carrageenan, colloidal silica, hydrogenated vegetable oil; povidone or propylene glycol alginate.

- 14 046180

In addition to phloroglucinol or trimethylphloroglucinol, the dosage units may contain other pharmaceutically active ingredients. In some embodiments, the dosage units may also contain, among others, antispasmodics such as alverine citrate, meberverine, otolonium bromide, pinaverium bromide, dicylomine hydrochloride, XIFASAN (rifaximin), VIBERZI® (eluxadoline) or LOTRONEX® (alosetron). Other antispasmodic agents include those described in Annahazi, Role of antispasmodics in the treatment of irritable bowel syndrome, World J. Gastroenterol., May 28, 2014, 20(20): 6031-6043, which is incorporated herein by reference.

Other layers/coatings can be applied as a top coat or between other layers/coatings. Thus, coatings may be provided to minimize dust generation during processing, improve appearance, ease of ingestion, provide gloss, insulate, minimize static properties, and/or provide color, among others. Suitable coating thickness can be determined by those skilled in the art. The layers may contain pharmaceutically inert components or pharmaceutically active components, as determined by those skilled in the art.

In some embodiments, an oral dosage unit is provided and contains: (i) an immediate release formulation comprising phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, wherein at least about 90% by weight of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, based on the weight of the immediate release formulation is released from the dosage unit over about 5 minutes to about 2 hours, when determined by the USP 2 paddle method at about 50 rpm in about 750 mL of an aqueous solution containing about 0.1 N HCl at about 37°C; and (ii) a modified release formulation containing phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, wherein at least about 90% by weight of the phloroglucinol, trimethylphloroglucinol, or pharmaceutically acceptable salt thereof, by weight of the modified release formulation, is released from the dosage unit through at least approximately 2 hours using the USP 2 paddle method at approximately 50 rpm in approximately 1000 mL of an aqueous solution containing approximately 0.1 N HCl and approximately 20 mM tribasic sodium phosphate at a pH of approximately 6.8 at approximately 37°C.

In other embodiments, an oral dosage unit is provided and contains: (i) a plurality of spheres, each sphere containing an immediate release composition containing phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, wherein at least about 90% by weight of phloroglucinol, trimethylphloroglucinol, or their pharmaceutically acceptable salt, based on the weight of the immediate release formulation, is released from the dosage unit after approximately 1 hour when determined by the USP 2 paddle method at approximately 50 rpm in approximately 750 ml of an aqueous solution containing approximately 0.1 N HCl at approximately 37 °C; and (ii) a plurality of spheres, each sphere containing a modified release composition containing phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, wherein at least about 90% by weight of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, based on the weight of the modified release composition, released from the dosage unit after at least about 2 hours when determined by the USP 2 paddle method at approximately 50 rpm in approximately 1000 ml of an aqueous solution containing approximately 0.1 N HCl and approximately 20 mM tribasic sodium phosphate at a pH of approximately 6 ,8 at approximately 37°C.

In the following embodiments, an oral dosage unit is provided and contains a plurality of spheres, each sphere containing: (a) a core which is in the form of an immediate release composition containing phloroglucinol, trimethylphloroglucinol or a pharmaceutically acceptable salt thereof, wherein at least about 90 wt. The % phloroglucinol, trimethylphloroglucinol, or pharmaceutically acceptable salt thereof, based on the weight of the immediate release formulation, is released from the dosage unit in approximately 1 hour when determined by the USP 2 paddle method at approximately 50 rpm in approximately 750 mL of an aqueous solution containing approximately 0.1 N HCl at approximately 37°C; and (b) a core coating that is: (i) a modified release composition containing phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, wherein at least about 90% by weight of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, by weight of the composition modified release is released from the dosage unit after at least about 2 hours when determined by the USP 2 paddle method at approximately 50 rpm in approximately 1000 ml of an aqueous solution containing approximately 0.1 N HCl and approximately 20 mM tribasic sodium phosphate at pH approximately 6.8 at approximately 37°C; or (ii) a modified release formulation containing phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, wherein

- 15 046180 At least about 90 wt.% phloroglucinol, trimethylphloroglucinol or a pharmaceutically acceptable salt thereof, based on the weight of the modified release formulation, is released from the dosage unit within about 4 to about 6 hours when determined by the USP 2 paddle method at about 50 rpm in approximately 1000 ml of an aqueous solution containing approximately 0.1 N HCl and approximately 20 mM tribasic sodium phosphate at a pH of approximately 6.8 at approximately 37°C; or (iii) a combination of (i) and (ii).

The dosage units and compositions described herein can be used to treat spasmodic conditions in an individual. The methods involve administering to an individual an oral dosage unit described herein. In some embodiments, the spasmodic condition is a sudden involuntary contraction of the muscles of a body part, such as an organ or muscle, of an individual. In other embodiments, the spasmodic condition is a sudden involuntary contraction of the muscles of the bronchi, stomach, intestines, ureter, gallbladder, kidney, or bile ducts. In further embodiments, the spasmodic condition is a urinary tract spasm, gallstones, gastrointestinal disorder, inflammatory bowel syndrome, renal colic, or biliary spasm.

Unless otherwise indicated, the composition is in dosage form. A non-limiting example of a dosage form is a tablet. Dispersion and disintegration of the composition are used as synonyms. As used herein, the active ingredient, also referred to as active substance, is phloroglucinol, trimethylphloroglucinol, or combinations of phloroglucinol and trimethylphloroglucinol. As used herein, extended release and sustained release are used interchangeably.

Each of the spheres and granules represents any discrete component of the dosage form, for example, the capsule shell may be filled with a plurality of spheres and/or a plurality of granules.

The immediate release formulation and the delayed release formulation indicate the onset of release of the active substance relative to administration. An immediate release formulation indicates the release of the active substance from the formulation beginning within a relatively shorter period of time after administration, for example, within a few minutes or less. Delayed release formulation indicates that the release of the active substance from the formulation does not begin within a relatively shorter period of time after administration, but is instead delayed and begins and is triggered over a relatively longer period of time after administration, for example, more than one hour .

Fast release formulation and slow release formulation indicate the rate of release once initiated. Once delivery of the active agent has begun, the active agent may be released relatively quickly or relatively slowly. Rapid release indicates that once initiated, the maximum or peak dose is achieved within a relatively shorter period of time. Slow release indicates that once initiated, the maximum or peak dose is achieved over a relatively longer period of time. Once the maximum dose is reached, it can be decreased at any rate, such as fast, slow or constant.

Sustained release formulation and continuous release formulation indicate a period of continued release and mean that delivery of the active substance is continued or sustained for an extended period of time after initiation, typically greater than one hour, regardless of the form of the dose release profile. For example, the release of the active substance continues between a maximum and a minimum value greater than zero for some relatively longer period of time. This release may occur at a constant dose or at a dose that decreases over time.

The sustained release composition indicates the dose that is released. Sustained release means that the active substance is delivered in a relatively constant dose over a moderate to long period of time. This corresponds to a dose release profile that is relatively flat or only slightly inclined after onset, i.e. without highly distinct peaks and valleys. Thus, sustained release is typically sustained or continuous, however sustained or continuous release may not be sustained.

A pulsed release formulation indicates that the active substance is delivered in one or more doses that oscillate between a maximum dose and a minimum dose over a period of time. This can be indicated by a dose release profile having one or more distinct peaks or valleys. However, two or more pulsed releases can provide an overlapping, complete, or composite release profile that is apparently or essentially constant. When two or more pulsed releases occur, there may or may not be a non-release period between the pulses. Typically, pulsing release results in essentially

- 16 046180 vu of the total active substance within approximately 60 minutes or less.

A sustained release formulation provides either release of the active substance within a given dose range over a relatively longer period of time, or plasma drug levels within a given dose range over a relatively longer period, without regard to a particular mechanism or nature of release, e.g. sustained release, pulsed or constant.

The release profile for an orally administered drug indicates the manner and timing by which the formulation releases or delivers the active substance to the stomach, intestines, etc. upon introduction. Various methods are known for assessing drug release and providing release profiles, including in vitro tests that simulate the in vivo behavior of the formulation and which include USP dissolution testing for immediate release and controlled release solid dosage forms.

Drug release profiles differ from plasma profiles. The plasma profile indicates the dose or level of active substance in the bloodstream of a mammal, such as a patient, to whom a drug formulation is administered. When the active substance is released from the formulation, for example into the intestines, the amount of active substance present in the bloodstream over time can be determined.

The drug release profile may be designed to provide a desired or desired plasma profile, and the plasma profile may mimic the release profile. For example, while a sustained release of an active agent might be expected to provide maintenance of the plasma dose, a pulsed release might be expected to provide a bursty (peak and trough) plasma profile, but this is not necessarily the case. The half-life (T _1/2 ) of the active substance in the bloodstream (its rate of decay) may be such that a slow or continuous plasma profile may result from a pulsed delivery profile. Other factors such as bioabsorption, bioavailability and first pass effect may also play a role. The plasma profile provided by the release profile of a particular active substance may also vary from patient to patient.

Measures of bioavailability are known in the art and include the area under the plasma concentration-time curve (AUC), maximum concentration ( _Cmax ) and time to _Cmax ( _Tmax ).

AUC is determined by the area under the plasma concentration-time curve and represents the amount of drug absorbed after administration of a single dose of drug (Remington: The Science and Practice of Pharmacy, Gennaro Ed. 2000, p. 999).

Cmax is the maximum plasma concentration achieved after oral administration of a drug (Remington, page 999). Oral administration of the drug results in a single Cmax, but may result in more than one peak plasma concentration, for example, following administration of a pulse dose formulation.

Tmax is the amount of time required to reach Cmax after oral administration of a drug and is related to the rate of absorption of the active substance (Remington p. 999).

Controlled release coating covers coatings that delay release, delay release, inhibit release, and/or otherwise prolong the release of a drug from a particle coated with a controlled release coating. The term controlled release includes sustained release, delayed release, and timed pulsed release. Thus, a controlled release coating covers a delayed release coating, a timed pulse release coating, and a delayed period coating.

An enteric polymer refers to a pH-sensitive polymer that is resistant to gastric acid (ie, relatively insoluble at the low pH levels found in the stomach) and that dissolves at higher pH levels found in the intestine.

Immediate release, with respect to a pharmaceutical composition, which may be a dosage form or a component of a dosage form, refers to a pharmaceutical composition that releases more than or exactly about 50% of the active substance, in another embodiment, more than about 75% of the active substance, in another embodiment implementation of more than about 90% of the active substance and in other embodiments, implementation of more than about 95% of the active substance within about one hour after administration of the dosage form. The term may also refer to pharmaceutical compositions in which a relatively rapid release of the active substance occurs after a delay period during which little or no release of the active substance occurs.

Immediate release spheres (IR) or immediate release particles broadly refer to spheres or particles containing an active substance that exhibit immediate release properties of the active substance.

- 17 046180

Sustained release spheres (SR) or sustained release particles broadly refer to spheres or particles containing an SR coating applied to a core containing the active substance.

Delay coating or timed pulse release (TPR) coating refers to a controlled release coating that combines water-insoluble and enteric polymers; The TPR coating itself provides a pulse of immediate release of the active substance after a predetermined delay period. Timed sustained release (TSR) spheres, having a TPR coating applied to a barrier coating (SR coating), provide a delayed release profile of the active substance after a predetermined delay period.

Delayed release (DR) spheres or delayed release particles broadly refer to the core containing the active substance. A DR coating refers to a controlled release coating containing an enteric polymer, optionally in combination with a plasticizer.

Controlled release spheres (CRs) or controlled release particles broadly refer to a core containing an active substance having an inner SR coating, optionally followed by an outer DR or TPR coating, or an inner TPR coating followed by an outer DR coating.

The lag period refers to the period of time when less than about 10% of the active substance is released from the pharmaceutical composition after administration of the composition or dosage form containing the composition, or after exposure of the composition or dosage form containing the composition to simulated body fluid(s), e.g. when assessed with the USP device using a two-stage dissolution medium (first 2 hours in 700 ml 0.1 N HCl at 37°C, then testing dissolution at pH 6.8 achieved by adding 200 ml pH modifier).

Applied to, for example, in relation to a coating on a substrate, refers to the relative position, for example, of the coating relative to the substrate, but it does not require the coating to be in direct contact with the substrate. For example, the first coating applied to the substrate may be in direct contact with the substrate, or one or more intermediate materials or coatings may be located between the first coating and the substrate. For example, the SR coating applied to the active substance-containing core may refer to the SR coating applied directly to the active substance-containing core or the acid crystalline or acid-containing core, or may refer to the SR coating applied to the protective insulating coating applied onto the core containing the active substance.

An insulating layer or protective insulating coating refers to a protective coating applied to the core particle containing the active substance or a functional polymer coating that protects the particle from abrasion and wear during processing and/or minimizes electrostatic charge during processing.

An orally disintegrating tablet or ODT refers to a tablet that disintegrates quickly in the mouth after administration without chewing; see, for example, Fig. 17. The rate of disintegration may vary, but is greater than the rate of disintegration of conventional solid dosage forms (e.g., tablets or capsules) that are intended to be swallowed immediately after administration, or greater than the rate of disintegration of chewable solid dosage forms when tested, e.g. using USP Test Method <701>.

The term substantially disintegrates refers to a level of disintegration that is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% disintegrated. . Disintegration is different from dissolution; disintegration refers to the disintegration or loss of structural cohesion, such as the particles that make up a tablet, while dissolution refers to the solubilization of a solid in a liquid, such as the solubilization of a drug in a solvent or gastric fluids.

A water-insoluble polymer is a polymer that is insoluble or very slightly soluble in an aqueous environment, regardless of pH, or over a wide pH range (eg, pH 0 to pH 14). A polymer that swells but does not dissolve in an aqueous environment may be insoluble in water.

A water-insoluble polymer is a polymer that is soluble, i.e. dissolves in significant quantities in an aqueous environment, regardless of pH.

An enteric polymer is a polymer that is soluble, i.e. a significant amount dissolves under intestinal conditions, i.e. in aqueous environments under neutral to alkaline conditions, and insoluble under acidic conditions (i.e., low pH values).

Reversible enteric polymer or gastric soluble polymer refers to a polymer that is soluble under acidic conditions and insoluble under neutral and alkaline conditions.

- 18 046180

Unless otherwise specified, the number of different coatings or layers (coating weight) is expressed as the percentage increase in the mass of particles or spheres provided by the dry coating relative to the initial mass of particles or spheres before coating; for example, a 10% coating weight refers to a dry coating that increases the particle weight by 10%.

Bioequivalence is the absence of a significantly different rate and extent of absorption of an available active ingredient when administered at the same dose under similar conditions. Bioequivalence can be determined using pharmacokinetic parameters, for example, AUC and _Cmax .

One embodiment is an oral phloroglucinol formulation that contains a modified release (MR) formulation. In this embodiment, the unit dosage form contains both an immediate release (IR) dosage form and an extended release (XR) dosage form. As used herein, the immediate release dosage form releases the active substance immediately upon administration. As used herein, extended release dosage form includes delayed release, timed release, controlled release or sustained release forms. As used herein, an extended release dosage form releases the active substance at a predetermined rate over a period of time to maintain a constant drug concentration over a specified period of time with minimal side effects. Sustained release formulations can be provided through a variety of formulations, as described below by way of illustrative but non-limiting examples, including polymer-active agent conjugates and liposomal active agent formulations.

The delivery system may comprise a core, seed or matrix, which may or may not be loaded with active agent, and one or more coating layers containing the active agent and/or containing a layer having release characteristics that control the onset of action and release characteristics of the active. substances. The core, seed or matrix can be manufactured or obtained from commercial sources. As one example, the core may be sugar or microcrystalline cellulose with a hydrophilic matrix made from, for example, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), poly(ethylene oxide), poly(vinyl alcohol), xanthan gum, carbomer, carrageenan, zooglan etc.

The coating layers may provide immediate release, delayed pulse release, or immediate release. Immediate release of the active substance from the immediate release layer can be achieved, for example, by using a very thin layer or coating through which gastric juice can quickly penetrate, promoting rapid release of the active substance; or which includes the active substance in a mixture that includes a supporting binder or other inert material that rapidly dissolves and releases the active substance into gastric juice; or by using a supporting binder or other inert material which disintegrates rapidly upon contact with gastric juice, both material and active substance being rapidly dispersed in the gastric juice as fine particles. Such rapidly disintegrating and dispersing materials include, for example, lactose and microcrystalline cellulose. An example of a suspending agent and a binder is hydroxypropyl methylcellulose.

Enteric coatings for a delayed-pulse release component may be pH-dependent or pH-independent. Enteric coatings for the sustained release component are pH dependent. The pH-sensitive coating is activated to release the drug within a known pH range, which typically coincides with the local pH of the environment in which delayed release is desired. Exemplary pH-sensitive coatings include cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid/methacrylic acid methyl esters, for example, such as those known under the trade name EUDRAGIT® L12.5, L100 or EUDRAGIT® S12.5, S100 or similar compounds used to prepare enteric coatings. You can also use aqueous colloidal polymer dispersions and redispersions, for example, EUDRAGIT® L 30D-55, EUDRAGIT® L100-55, EUDRAGIT® S100, EUDRAGIT® 4110D preparation (Rohm Pharma); AQUATERIC®, AQUACOAT® CPD 30 (FMC); KOLLICOAT MAE® 30D and 30DP (BASF); EASTACRYL® 30D (Eastman Chemical).

pH-independent coatings include materials that are sensitive to enzymatic activation by azoreductases in intestinal bacteria (ie, azopolymers) or materials that are sensitive to degradation by polysaccharidases in the colon (natural polysaccharides). Non-limiting examples of azopolymers include copolymers of 2-hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA). Non-limiting examples of natural polysaccharides include amylose, chitosan, chondroitin, dextran and xylan.

- 19 046180

The sustained release component may include sustained release coatings, sustained release matrices, and sustained release osmotic systems. Sustained release coatings can be made using a water-insoluble polymer, a combination of water-insoluble polymers, or a combination of water-insoluble and water-soluble polymers. For the sustained release matrix, conventional sustained release polymers known to those of ordinary skill in the art may be used.

Exemplary sustained release coatings include polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, fatty acids and their esters, alkyl alcohols, waxes, zein (prolamine from corn) and aqueous polymer dispersions such as EUDRAGIT® RS and RL30D, EUDRAGIT® NE30D, AQUACOAT®, SURELEASE®, KOLLICOAT® SR30D and cellulose acetate latex.

Granules or spheres can be prepared from any pharmaceutically acceptable materials based on compatibility with the active substance and the physicochemical properties of the granules or spheres.

Binders include cellulose derivatives such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, etc.

Disintegrants include corn starch, pregelatinized starch, cross-linked carboxymethylcellulose (AC-DI-SOL®), sodium starch glycolate (EXPLOTAB®), cross-linked polyvinylpyrrolidone (PLASDONE XL®), etc.

Excipients include lactose, calcium carbonate, calcium phosphate, calcium sulfate, microcrystalline cellulose, dextran, starches, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, etc.

Surfactants include sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, bile salts, glyceryl monostearate, PLURONIC® line (BASF), etc.

Solubilizers include citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid, sodium bicarbonate, sodium carbonate, etc.

Stabilizers include antioxidants, buffers, acids, etc. Examples of antioxidants may include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), diethylenetriamine pentaacetic acid (DTPA), edetates (EDTA), monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite, triglycomate, vitamin E or its derivatives, propyl gallate, combinations thereof, etc.

The following information illustrates exemplary, but not limiting, production methods.

The core can be produced by extrusion-pelletizing, high shear granulation, layering in solution or suspension.

In extrusion-pelletization, the active substance and other additives are granulated by adding a binder solution. The wet mass is passed through an extruder equipped with a sieve of a certain size. The extrudate is rolled in a pelletizer. The resulting granules are dried and sifted.

In high shear granulation, the active ingredient and other additives are dry mixed and the mixture is then wetted by adding a binder solution in a high shear granulator/mixer. The granules are formed after wetting by the combined action of mixing and grinding. The resulting granules or balls are dried and sieved.

In solution or suspension layering, a drug solution or dispersion with or without a binder is sprayed onto seeds of a specific particle size in a fluid bed dryer or other suitable device, thereby depositing the active agent on the surface of the seeds. The granules loaded with the active substance are dried.

The core particles have a diameter in the range of approximately 50 µm - 1500 µm; preferably 100 µm - 800 µm. The core particles can be coated in a fluidized bed device through an alternating series of coating layers. The core may be directly coated with a layer or layers of active agent and/or the active agent may be included in the core material. A separating or protective layer can be added on top of the active substance containing layer and/or between the active substance layers. A separating or protective layer can be added to the surface of the active-loaded core, which can then be coated with an enteric delayed-pulse or sustained-release layer. Also, another layer of active agent can be added to the delayed pulsed or sustained release enteric layer to deliver the initial dose. The protective coating layer can be applied directly to the outside of either the active substance-containing core or the active substance-layered core using conventional coating methods using

- 20 046180 known in the art, such as panning or fluidized bed coating using solutions of polymers in water or suitable organic solvents, or aqueous dispersions of polymers. Suitable materials for the protective layer include derivatives of cellulose, such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, underlyprication of polyvinylpyrrolidon/vinyl acetate, water -waterlulose vehicles (Aquacouat®, Surelease®) 30D, OPADRY®, cellulose acetate, cellulose acetate boutirate, cellulose acetate propionate, ethylcellulose, fatty acids and their esters, waxes, zein and aqueous polymer dispersions such as EUDRAGIT® RS and RL 30D, EUDRAGIT® NE 30D, AQUACOAT®, SURELEASE®, and/or cellulose acetate latex, separately or in combination with hydrophilic polymers such as hydroxyethylcellulose, hydroxypropylcellulose (KLUCEL®, Hercules Corp.), hydroxypropylmethylcellulose (METHOCEL®, Dow Chemical Corp.), polyvinylpyrrolidone, etc. Coverage levels range from about 1% w/w to about 6% w/w, preferably from about 2% w/w to about 4% w/w.

The enteric delayed-pulse-release or sustained-release layer is applied to the core, with or without an insulating coating, by conventional coating methods known in the art, for example, pan coating or fluidized bed coating, using solutions of polymers in water or suitable organic solvents, or using aqueous polymer dispersions. Suitable coating agents are known in the art, for example commercially available pH-sensitive polymers, so that the active substance is not released in the acidic environment of the stomach (pH < 4.5), but is released and becomes available when the pH-sensitive layer dissolves at higher pH value after a certain period of delay or after the dosage unit has passed through the stomach.

Enteric polymers for the delayed pulse release component and sustained release component include, for example, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid/methacrylic acid methyl esters, for example, such as materials known under the trade name called EUDRAGIT® L12.5, L100 or EUDRAGIT® S12.5, S100 or similar compounds used for the preparation of enteric coatings. Aqueous colloidal dispersions or polymer redispersions can also be used, for example EUDRAGIT® L 30D-55, EUDRAGIT® L100-55, EUDRAGIT® S100, EUDRAGIT® 4110D preparation (Rohm Pharma); AQUATERIC®, AQUACOAT® CPD 30 (FMC); KOLLICOAT MAE® 30D and 30DP (BASF); EASTACRYL® 30D (Eastman Chemical).

Enteric delayed pulse release and sustained release polymers can be modified by mixing with other known coating products that are not pH sensitive, for example neutral methacrylic acid esters with a small portion of trimethylammonium chloride ethyl methacrylate, commercially available as EUDRAGIT® RS and EUDRAGIT® RL; a dispersion of neutral esters without any functional groups, commercially available as EUDRAGIT® NE30D; and other pH-independent coating products.

The modifying component of the protective layer used on a delayed pulse release or sustained release enteric coating may include a water permeable barrier layer (semi-permeable polymer) that can be applied sequentially after the enteric coating to reduce the rate of water penetration through the enteric coating layer and thus , increasing the delay time for the release of the active substance. Coating is carried out as described previously.

Optionally, a protective or colored topcoat may be applied. OPADRY®, OPADRY II® (Colorcon) and the corresponding colored and clear categories from Colorcon can protect the granules from stickiness and impart color to the product. In one embodiment, the protective or color coating is in the range of 1% w/w, to 6% w/w, preferably from about 2% w/w. to approximately 3% w/w. You can also use talc.

Components may be included in the top layer, for example, to facilitate or provide even faster release. Such components include, for example, plasticizers, including acetyl triethyl citrate, triethyl citrate, acetyl tributyl citrate, dibutyl sebacate, triacetin, polyethylene glycols, propylene glycols, etc.; lubricants, including talc, colloidal silicon dioxide, magnesium stearate, calcium stearate, titanium dioxide, magnesium silicate, etc.

The composition may be included in hard gelatin capsules, either alone or with additional excipients. The composition may be included in a tablet, for example, by incorporating it into a tablet matrix that rapidly disperses the particles upon swallowing. To prevent particle breakdown during tableting, a filler/binder is required, e.g. microcrystalline cellulose (AVICEL®), soy polysaccharide (EMCOSOY®), pregelatinized

- 21 046180 bath starches (STARCH® 1500, NATIONAL® 1551), and polyethylene glycols (CARBOWAX®) present in the range from about 5% w/w to about 75% w/w, with a preferred range from about 25% w/w, up to approximately 50% w/w.

Excipients generally include, but are not limited to, one or more excipients including microcrystalline cellulose, soy polysaccharides, calcium phosphate dihydrate, calcium sulfate, lactose, sucrose, sorbitol, etc.; one or more materials that impart fluidity to the powders, including highly dispersed silica, silica gel, magnesium stearate, calcium stearate, etc.; one or more lubricants to ensure proper tabletting, including polyethylene glycol, leucine, glyceryl behenate, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, etc., present in the range of about 0.1% w/w, to about 10% w/w, with a preferred range of about 0.3% w/w. to approximately 3.0% w/w.

Disintegrants are added to disperse the spheres after the tablets are swallowed. Disintegrants include, but are not limited to, cross-linked sodium carboxymethylcellulose (AC-DI-SOL®), sodium starch glycolate (EXPLOTAB®, PRIMOJEL®), cross-linked polyvinylpolypyrrolidone (Plasone-XL), etc., present in the range of about 3 % w/w, up to approximately 15% w/w. with a preferred range of about 5%wt./wt. up to approximately 10% w/w.

In one embodiment, tablets are formed from particles that are fed into a mixer with AVICEL®, disintegrants and lubricant, mixed for a certain period of time (minutes) to obtain a homogeneous mixture, and then the mixture is placed in the feed compartment of a tablet press, which then compresses it into tablets. The compression force used is sufficient to form a tablet but not to break the spheres or coatings.

The tablet may be constructed with three layers where the immediate release component is dry mixed and the delayed pulse and sustained release components are wet granulated. The tablet is then formed through single-layer or three-layer compression. Upon dissolution of the layers, each component is released and acts depending on the formulation: for example, immediate release particles provide immediate release, delayed pulse release particles provide delayed pulse release, and sustained release particles provide delayed release after a delay period.

The polymer film coating can be applied to the active particles in any suitable manner. In one embodiment, the polymer film is applied as a uniform coating having a smooth surface structure and relatively constant thickness, for example, using pneumatic sprayers. Pneumatic sprayers can have a nozzle diameter of from about 0.8 mm to about 2 mm, and can operate at air pressure from about 0.5 to about 3 bar. The spray rate can be adjusted using peristaltic pumps or high pressure tanks. Spraying can be continuous while drying so that the particles do not become too wet (overly wet) and agglomerate. Fluidized bed processes, such as AEROMATIC™, GLATT® with WURSTER HS™ column, are suitable for coating small particles, and are carried out in a closed cylindrical device into which an air stream is introduced from below to liquefy the particles and spray dry the films. Modified coating drums (usually cylindrical, horizontally rotating elements with a perforated wall) can be used to coat fine particles.

The controlled release polymer coated particles may also be formulated into various types of oral dosage forms. As one example, the release-coated particles can be compressed, either alone or in combination with excipients, adjuvants and/or other active ingredients, into pills, tablets, etc. As another example, the release-coated particles can be loaded into either soft gelatin capsules or hard gelatin capsules. As another example, the release-coated particles can be packaged in a pouch with other active or inactive ingredients and dispersed in water in the form of a suspension.

The coating composition may include minor amounts of emulsifiers, wetting agents and stabilizers such as isononylphenylpolyoxyethylene glycol ethers. Minor amounts of talc may also be included in the coating composition, or may then be applied to improve or increase the flow of the coated particles.

Suitable coating thickness may range from about 2 µm to about 15 µm depending on the required diffusion properties. The weight of the coating typically ranges from 2 to 15% of the weight of the phloroglucinol particles.

In another embodiment, release-coated particles can be combined with uncoated particles to provide an orally administered pharmaceutical

- 22 046180 composition having both immediate release and delayed release components. Uncoated particles can typically have substantially the same characteristics as coated ones to provide release of the particle prior to coating. As with release-coated particles, uncoated particles may contain minor amounts of excipients, adjuvants and/or other active ingredients.

Other release coatings may be used, including soluble, insoluble, permeable, impermeable, and biodegradable coatings, in place of water-insoluble, water-permeable, and water-swellable polymer coatings. The polymer coating may be composed of one or more polymers, including copolymers, terpolymers, and other polymers having three or more different monomer units. The polymers may include natural or synthetic polymers. Natural polymers used in sustained release coatings include polypeptides, polysaccharides and alginic acid. Synthetic polymers include aqueous cellulose, hydroxyacylcellulose, cellulose ether, cellulose esters, nitrocellulose, polymers of acrylic and methacrylic acids and their esters, polyamides, polycarbonates, polyalkylenes, polyalkylene glycol, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters ethers, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes and polyurethanes and their copolymers.

Specific polymers for use in a sustained release coating in an immediate release/sustained release formulation include methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose acetate, cellulose propionate (low, medium or high molecular weight), cellulose acetate propionate, cellulose acetate butyrate , cellulose acetate phthalate, carboxymethylcellulose, cellulose triacetate, sodium cellulose sulfate, polymethyl methacrylate, polyethyl methacrylate, polypropyl methacrylate, polybutyl methacrylate, polyisobutyl methacrylate, polyhexomethacrylate, polyisodecyl methacrylate, poly(lauryl methacrylate), poly(phenyl methacrylate), polymetalacrylate, polyisopropylacrylate, polyisobutyl acrylate, polyoctadecyl acrylate, polyethylene (low or high density), polypropoline, polyethylene glycol, polyethylene oxide, polyethylene terephthalate, polyvinyl alcohol, polyvinyl isobutyl ether, polyvinyl acetate, polyvinyl chloride and polyvinyl pyrrolidone. Examples of suitable copolymers include butyl methacrylate/isobutyl methacrylate copolymer, high molecular weight, methyl vinyl ether/maleic acid copolymer, methyl vinyl ether/maleic acid monoethyl ester copolymer, methyl vinyl ether/maleic anhydride copolymer, and vinyl alcohol/vinyl acetate copolymer. Examples of suitable biodegradable polymers include polylactides, polyglycolides, Terathatic polyethylene and polyurethane. Examples of suitable acrylate and methacrylate are polyacrylic and methacrylic polymers, such as those sold under the trade name EUDRAGIT®.

The immediate release/sustained release formulation combination may contain substantially any amount of active ingredient in immediate release form that is effective and non-toxic, and any amount of active ingredient in sustained release form that is therapeutically effective and nontoxic throughout the sustained release period at when used in combination with a selected amount of immediate release active substance.

Uncoated and coated particles can be combined in various oral pharmaceutical dosage forms or formulations, for example, capsules, tablets, pouches, etc. The coated sustained release particles and uncoated particles can be combined with various excipients, adjuvants, etc. and/or other active substances.

In one embodiment, active agent particles that are coated with a water-insoluble, water-permeable, and slightly water-swellable polymer coating provide sustained release with controlled diffusion of the active agent at a highly reproducible, predictable rate. This rate is independent of physiological variations in parameters within and between individuals, such as pH. The particles can be combined with an uncoated active agent, which may be the same or different from the sustained release coated active agent. The resulting immediate-release/sustained-release combination formulation provides greater reproducibility of drug release rates than other sustained-release dosage forms that use conventional enteric delayed-release coating compositions while still providing both immediate and sustained release medicines.

Any of the embodiments described above may be formulated into various types of orally administered pharmaceutical dosage forms, with pills or tablets being typical formulations. The tablets preferably have a hardness of about 11 to about 19 SCU, and most preferably a hardness of about 15 SCU. I prefer tablets

- 23 046180 specifically have an abrasion strength of less than about 0.8% weight reduction after 6 minutes.

Sustained release compositions use pharmaceutically acceptable excipients and adjuvants, for example, excipients and diluents such as lactose, sucrose, dextrose, mannitol, calcium sulfate, dicalcium sulfate, tricalcium sulfate; starches such as rice starch and microcrystalline cellulose; binders including gum arabic, tragacanth, gelatin, sucrose, pregelatinized starch, starch, sodium alginate, calcium ammonium alginate, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, aluminum silicate and polyacrylamide; disintegrants including cross-linked polyvinylpyrrolidone, starch derivatives such as carboxymethylcellulose and cellulose derivatives; lubricants; glidants and anti-adhesives including metal stearates such as magnesium stearate, talc, high melting point waxes and Colordacylica.

In one embodiment, the disintegrant/binder combination includes cross-linked polyvinylpyrrolidone, such as POLYPLASDONE® XL (GAF) or croscarmellose sodium, such as AC-Di-SOL® (FMC Corporation); or microcrystalline cellulose in combination with cross-linked polyvinylpyrrolidone or croscarmellose sodium.

Disintegrants/binders are used in effective amounts, which can be easily determined using known methods.

The active substance can be administered in various dosage forms, for example, solid dosage forms such as tablets, coated tablets, capsules or liquid dosage forms such as syrups or suspensions. A conventional tabletting machine, such as a Manesty Rotary Press, Stokes Rotary Press, etc., can be used to form the tablet at about 15° C. to about 30° C. and at a pressure of about 0.4 ton to about 3.0 ton. .

Desirably, the tablets are provided with a coating to minimize abrasion during processing, both to improve appearance and ease of swallowing, and in a bottle. The examples demonstrate possible tablet coatings, and the coating may have an outer layer of carnauba wax for gloss.

The tablet may have multiple active substance cores with different dissolution properties. The initial and second doses can be administered in the same dosing step. In one embodiment, the initial and second doses are administered in the same dosing step, for example, in a single solid dosage form. Such dosage form may be a single dosage step with an immediate release portion containing an initial dose of active agent and an immediate release portion containing a second dose of active agent. Such a single solid dosage form may be a multilayer tablet, wherein the first immediate release dose is in one layer and the second sustained release dose is in a second layer. The unitary solid dosage form may also be a multiparticulate tablet, wherein the first immediate release dose is contained in one portion of the particulate material, and the second sustained release dose is contained in a second portion of the particulate material, etc.

The composition, for example a tablet, can be designed using additive manufacturing, i.e. three-dimensional printing, as is known in the art, for example, from WO 2014/144512, US patent No. 6471992 and US publications No. 2012/0207929 and 2003-0133975, which describe 3D printed fast disintegrating dosage forms. In this embodiment, the rapidly disintegrating solid dosage form has a 3D printed matrix comprising phloroglucinol, trimethylphloroglucinol, polymer-coated phloroglucinol and/or polymer-coated trimethylphloroglucinol, and at least one excipient, wherein the matrix is formed by applying a printing liquid to the powder and binding powder particles. The matrix is porous with a well-defined overall bulk density, disintegration time in an aqueous liquid, dissolution time in an aqueous liquid, and moisture content. The matrix provides a balance of increased chemical stability, sufficient hardness, low abrasion and extremely fast disintegration time in a small volume of aqueous liquid.

Increasing the content of multiple different types of water-soluble excipients in this embodiment generally results in increased hardness and increased disintegration time. However, increasing the glycerol content increases hardness but reduces disintegration time. Thus, in one embodiment, the printing fluid contains glycerin and at least one pharmaceutically acceptable solvent. The main steps of the method are as follows: (a) applying an incremental layer of active substance-containing powder to the surface, (b) applying a sufficient amount of printing fluid containing glycerin and at least one pharmaceutically acceptable solvent to the incremental layer to bind the particles in the powder, and then repeating steps (a) and (b) to form a tablet or other composition.

Upon administration, the dosage form undergoes very rapid disintegration/disintegration of its solid matrix. The active substance and excipients in the matrix undergo rapid degradation when removed

- 24 046180 are added to a small volume of aqueous liquid such as water, saliva, juice, milk, drink, body fluid, soda water, etc. Typically, degradation overlaps with dissolution and the matrix has a three-dimensional shape that disintegrates over a required period of time upon contact with at least a small volume of aqueous liquid.

An incremental layer of bulk powder of a predetermined thickness is distributed onto the preceding powder layer, and the printing liquid is deposited onto the incremental layer in the form of droplets in accordance with the specified saturation level, printing interval, and flow rate of the printing liquid to bind the particles. This two-step process continues until a matrix is formed with the desired number of incremental layers printed.

The described composition may also contain other therapeutic active substances. The active agents in addition to phloroglucinol and/or trimethylphloroglucinol may be formulated in the same dosage form or may be formulated separately, and the other active agent(s) may be administered simultaneously or sequentially in any order. The dosages may be within the same ranges as for each active agent separately or, when synergistic effects occur, one or more of the combined active agents may be at a lower dose.

One embodiment of the invention relates to an oral formulation of trimethylphloroglucinol that contains both an immediate release form and an extended release form in a single dosage form. One embodiment of the invention relates to an oral phloroglucinol-trimethylphloroglucinol formulation that contains both an immediate release form and an extended release form in a single dosage form. In one embodiment, the immediate release form is phloroglucinol and the extended release form is trimethylphloroglucinol. In one embodiment, the immediate release form is trimethylphloroglucinol and the extended release form is phloroglucinol.

A dosage form of phloroglucinol and/or trimethylphloroglucinol that combines both an immediate release formulation at a dose of 80 mg, ranging from 10 mg to 160 mg, and an extended release formulation at a dose of 160 mg, ranging from 20 mg to 480 mg, provides delivery substances to the patient continuously over a period of approximately 12 hours. This dosage formulation provides action to control intestinal and/or urinary tract spasm for 12 hours with a single dosage in the patient, providing patient convenience and prolonged therapy, for example, the patient can favorably endure a full night sleep, full work day, full leisure time, etc. no symptoms.

Embodiments of the composition of the invention include the following: 100% phloroglucinol, 100% trimethylphloroglucinol, phloroglucinol:trimethylphloroglucinol combinations in any ratios, including but not limited to 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 or 10:90. The composition of the invention contains an immediate release (IR) portion or component and an extended release (XR) portion or component, or combinations thereof. The immediate release portion delivers 100% of the immediate release dose in less than about an hour, and the extended release portion delivers the extended release dose over 12 hours. Any amount or percentage of phloroglucinol and/or trimethylphloroglucinol, including either no phloroglucinol and all trimethylphloroglucinol, or all phloroglucinol and the absence of trimethylphloroglucinol may be present in either the immediate release portion or the extended release portion, thus the composition of the invention is not limited. In one embodiment, both phloroglucinol and trimethylphloroglucinol can be in both immediate release and extended release forms. In this embodiment, both phloroglucinol and trimethylphloroglucinol can be in the same composition or in different compositions.

A typical dissolution profile, also called release profile, of phloroglucinol or trimethylphloroglucinol is shown in FIG. 1. The percentage drug release reaches 100% in one hour or less from the immediate release portion of the delivery system, and approximately 100% in 12 hours or less from the sustained release portion of the delivery system. In fig. 2 is a diagram of simulated phloroglucinol plasma concentrations where the plasma drug concentration from the immediate release portion peaks at approximately twice the concentration at the same time as the drug from the extended release portion reaches a plateau at half the level of the immediate release portion.

To control urinary tract spasms, including renal colic, the oral dose of phloroglucinol and/or trimethylphloroglucinol may be 80 mg six times daily. To control biliary spasticity with moderate abdominal pain, the oral dose of phloroglucinol and/or trimethylphloroglucinol may be 80 mg six times daily.

In one embodiment, an oral dose of 62.2 mg phloroglucinol and 80 mg trimethylphloroglucinol three times daily may be used for patients with IBS. The maximum dose is 80 mg six times a day.

- 25 046180

In one embodiment, the active substance can be administered parenterally. The parenterally administered amount of phloroglucinol and/or trimethylphloroglucinol may be 40 mg twice daily or 40 mg three times daily. Parenteral administration by a healthcare professional in a hospital setting may be suitable.

In one embodiment, the active substance can be administered rectally. The rectally administered amount of the active substance to control spastic conditions of the urinary and biliary tract can be 150 mg three times a day. Rectal administration can be accomplished by means of a suppository formulation. In one embodiment, the composition is administered rectally, for example, by means of a suppository. In one embodiment, the composition is administered parenterally, for example, by intravenous, subcutaneous or intramuscular injection.

The composition may take various forms or delivery systems. The following formulations may be used and are illustrative and non-limiting only. Oral formulations include tablet, capsule, sachet, soft gel, liquid, gel, strip, film, powder, granule, pulsed release coated core, delayed extended release form, coated dosage form, sustained release form, tablet capsule, granule caplet, multilayer tablet, etc., including combinations thereof, for example, capsule tablet, granule caplet, multilayer tablet, etc. with an active substance and at least one pharmaceutically acceptable excipient.

The composition in tablet form is known to one skilled in the art. The tablet may have any shape or size suitable for oral administration, such as round, oval, etc. In one embodiment, the tablet contains 100% of either phloroglucinol or trimethylphloroglucinol, or a mixture as previously described, and may be designed for either immediate release (IR), extended release (XR), or a combination thereof. The tablet may be a two-layer tablet containing IR and XR layers side by side (FIG. 3); a three-layer tablet containing both IR and XR layers separated by a pharmaceutically acceptable buffer layer (FIG. 4); or an XR tablet containing the active substance in a matrix layer and coated with an IR layer with the active substance (Fig. 5).

The composition may also be provided in other delivery forms, for example, in the form of a capsule containing an IR tablet, a stopper and an XR tablet in an osmotic drug delivery system for controlled delivery of the composition over 12 hours (Fig. 6); capsules containing IR spheres and XR spheres mixed in appropriate ratios (Fig. 7); capsules containing IR mini-tablets mixed with XR mini-tablets (Fig. 8); capsules containing IR beads and XR beads coated with sustained release polymers (FIG. 9); capsules containing XR spheres which are coated with an IR layer (Fig. 10), etc. Other forms of delivery of the active substance may be a compressed tablet containing IR granules and coated XR spheres, which are enclosed in the tablet (Fig. 11); a compressed tablet containing an XR tablet enclosed within an IR tablet (FIG. 12); or an XR tablet suspended in a liquid immediate release drug solution in a capsule (FIG. 13).

Another form of delivery is a sachet. The sachet may contain a mixture of IR and XR beads or spheres (Fig. 14) or may contain a mixture of IR effervescent beads and coated XR beads (Fig. 15).

Other immediate, extended or delayed, modified and delayed release systems are described in each of the following references, each of which is incorporated herein by reference in its entirety: US Publications No. 2005/0095295, 2005/0106247 and 2007/0264323 and Patents US No. 6126969 and 8211465. As one example, US Publication No. 2005/0106247 describes a drug (cyclobenzaprine hydrochloride) in sustained release particles such as spheres, beads, granules, etc., having a sustained release coating containing a water-insoluble polymer and/or a water-soluble polymer, and some of the particles are contained in a gelatin capsule. As another example, US Publication No. 2007/0264323 describes drug delivery systems (ADDERALL®), such as spheres in capsules, tablets or sachets, including coating layers, delayed pulse release components, immediate release formulations, intermediate release formulations, sustained release and controlled release capsules. US Pat. No. 6,126,969 describes drug (acetaminophen) delivery systems, such as a combination of coated and uncoated drug particles for an immediate release/sustained release dosage form. US Pat. No. 8,211,465 describes dosage forms for an initial release of a drug (NSAID such as ibuprofen) and a second sustained release of the same drug. The osmotic delivery system is described in Patra et al. Osmotic Drug Delivery Systems: Basis and Design Approaches, Recent Patents on Drug Delivery and Formulation, 7 (2013) 1-12.

The active core of the dosage form may be an inert particle or an alkaline buffer crystal coated with a drug-containing film-forming composition. In one embodiment, the water-soluble film-forming composition forms a

- 26 046180 water-soluble/dispersible particle. Alternatively, the active substance can be prepared by granulating and grinding and/or by extruding and rolling a polymer composition containing the active substance. The amount of active substance in the core depends on the dose required and generally varies from approximately 5% by weight to 60% by weight. The polymer coating of the active agent core is typically from about 4% to 20% by weight of the coated particle, depending on the type of release profile desired and/or the coating polymers and solvents selected. Those skilled in the art will be able to select the appropriate amount of active material to be applied to or included in the core to provide the required dosage. In one embodiment, the inactive core may be a sugar sphere or buffer crystal, or an encapsulated buffer crystal, such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc., which changes the microenvironment of the active substance to facilitate its release.

The drug-containing particle can be coated with an extended release (XR) coating containing a water-insoluble polymer or a combination of a water-insoluble polymer and a water-soluble polymer to form XR spheres. In some embodiments, the water-insoluble polymer and the water-soluble polymer may be present in a weight ratio of 100:0 to 65:35, or about 95:5 to 70:30, or about 85:15 to 75:25. The sustained release coating is applied in the amount necessary to provide the desired release profile. In some embodiments, the sustained release coating comprises from about 1% to 15% by weight of the coated spheres, or from about 7% to 12% by weight of the coated spheres.

A modified release dosage form comprising a mixture of two granule populations can be prepared as follows. The drug-containing core is prepared by coating an inert particle, such as a Non-pareil seed, an acid buffer crystal, or an alkaline buffer crystal, with an active polymeric binder, or by granulation and grinding, or by extrusion/rolling to produce IR granules. The IR bead is coated with a plasticized water-insoluble polymer such as ethylcellulose, alone or in combination with a soluble polymer such as hydroxypropyl methylcellulose to form an XR bead. XR spheres of hard gelatin capsules, alone or in combination with IR spheres, are filled in the required ratio to produce modified release (MR) capsules providing the desired release profile.

IR spheres using the following dissolution technique have been described to release at least about 70%, more specifically at least about 90%, of the active agent within 30 minutes.

USP 2 (50 rpm paddles) is used with the following dissolution medium: 900 ml of 0.1 N HCl (or suitable dissolution medium) at 37° C., with the release of the active substance determined by HPLC.

An aqueous or pharmaceutically acceptable solvent can be used to prepare the active ingredient-containing core particles. The type of film-forming binder used to bind the drug to the inert sugar sphere is not critical, but water-soluble, alcohol-soluble, or acetone/water-soluble binders are typically used. Binders such as polyvinylpyrrolidone (PVP), polyethylene oxide, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polysaccharides such as dextran, corn starch can be used in concentrations of about 0.5 wt% to about 5 wt%, and other concentrations are also used. The active agent may be present in the coating composition in the form of a solution or may be dispersed at a solids content of up to about 35% by weight depending on the viscosity of the coating composition.

The active agent, optionally the PVP binder, the dissolution rate controlling polymer if used, and optionally other pharmaceutically acceptable excipients are mixed in a planetary mixer or high shear granulator such as a FIELDER® and granulated by adding/spraying a granulating fluid such as water or alcohol. The wet mass can be extruded and pelletized into spherical particles (spheres) using an extruder/pelletizer. In these embodiments, the active ingredient loading can be up to 90% by weight based on the total weight of the extruded/rolled core.

Illustrative, but not limiting, examples of water-insoluble polymers suitable for XR coating include ethylcellulose powder or aqueous dispersion (e.g., AQUACOAT® ECD-30), cellulose acetate, polyvinyl acetate (KOLLICOAT® SR 30 D, BASF), neutral-based copolymers ethyl acrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, such as EUDRAGIT® NE, RS and RS30D, RL or RL30D and

- 27 046180

etc. Exemplary, but not limiting, water-soluble polymers include low molecular weight hydroxypropyl methylcellulose (HPMC), methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone and/or polyethylene glycol (PEG) with a molecular weight >3000. The sustained release coating is typically applied at a thickness ranging from about 1 wt.% to 15% by weight depending on the solubility of the active substance in water or the latex suspension-coated formulation used.

Coating compositions used to make membranes are typically plasticized. Illustrative, but not limiting, plasticizers include triacetin, tributyl citrate, triethyl citrate, acetyl tri-n-butyl citrate diethyl phthalate, polyethylene glycol, polypropylene glycol, castor oil, dibutyl sebacate and/or acetylated monoglycerides, etc. The plasticizer may contain from about 3 wt.% to about 30 wt.%, more particularly from about 10 wt.% to about 25 wt.% polymer on a weight basis. The type of plasticizer and its content depends on the polymer or polymers and the nature of the coating system (eg, aqueous or solvent based, solution or dispersion based, and total solids content).

The particle can be initially treated by applying a thin film of hydroxypropyl methylcellulose (HPMC; OPADRY® Clear) before applying a sustained release membrane coating to separate the different layers of the membrane. Typically HPMC is used, but other primary coatings such as hydroxypropyl cellulose (HPC) can also be used.

The membrane coating can be applied to the core using any coating methods used in the pharmaceutical industry. In one embodiment, fluidized bed coating is used.

Multi-dose forms can be used, i.e. products in the form of multiparticulate dosage forms (balls, spheres, granules, minitablets, etc.) or in other forms suitable for oral administration. As used herein, these terms are used interchangeably to refer to multiparticulate dosage forms.

A sustained release dosage form that includes a mixture of two or more granule assemblies can be prepared as follows. An inert particle, such as a Non-pareil seed, an acid buffer crystal or an alkaline buffer crystal, is coated with an active substance and a polymeric binder to obtain an active substance particle, i.e. immediate release (IR) spheres, which may be in unit dosage form serving as a bolus dose. The active particle is coated with a solution or suspension of a water-insoluble polymer or a mixture of water-soluble and water-insoluble polymers to produce an extended-release (XR)-coated active particle. XR spheres of hard gelatin capsules, and optionally in combination with IR spheres in a ratio ranging from 95:5 to 70:30 (XR spheres:IR spheres), are filled to obtain a modified release (MR) capsule exhibiting a desired release profile of the active substance.

In one embodiment, the dosage form has an immediate release portion of the active agent dispersed in an oil or lipid system and another portion that is formulated in a waxy matrix or particulate active agent coated with hydrophilic carriers. At least 15%-50% of the active substance is in the immediate release portion and is in a dosage form suitable for immediate release. The remainder of the tablet-capsule by weight may comprise a sustained release formulation or a portion of a sustained release formulation. The active substance may be formulated in a lipid-based delivery system. Encapsulation or solubilization of lipid excipients can result in increased solubilization and absorption, resulting in increased bioavailability.

Lipid excipients are commercially available. Because lipids influence absorption, it is necessary to know the characteristics of lipid excipients. Factors that determine the selection of excipients for lipid-based formulations include miscibility, solubility, self-dispersing ability and ability to self-disperse the formulation, digestibility and breakdown fate, irritant potential, toxicity, purity, chemical stability, capsule compatibility, melting point , cost, etc.

Edible oils consisting of medium and long chain triglycerides along with various solvents and surfactants are often used to formulate lipid formulations. Many lipids are amphiphilic, i.e. they have a lipophilic part (fatty acids) and a hydrophilic part. The melting point increases as the fatty acid chain length increases, but the melting point decreases as the degree of unsaturation of the fatty acid increases, which also increases sensitivity to oxidation. Solubilizers used in lipid-based formulations are listed in the table below.

- 28 046180

Solubilizing excipients used in commercially available lipid-based oral formulations: Insoluble in water excipients Triglycerides Surfactants Beeswax Long chain triglycerides Polysorbate 20 (TWEEN® 20) Oleic acid Hydrogenated soybean oil Polysorbate 80 (TWEEN® 80) Fatty acid salts Hydrogenated vegetable oil Sorbitan monolaurate (SPAN® 20) D-a-tocopherol (vitamin E) Corn oil D-oc-tocopherol PEG 1000 succinate (TPGS) Corn oil mono-di-triglycerides Olive oil Glyceryl monooleate Mono and diglycerides medium chain (C8/C10) Soybean oil Castor oil polyoxyl 35 diglycerides (CREMOPHOR® EL), Esters of propylene glycol and fatty acids Peanut butter Polyoxyl 40 hydrogenated Castor oil (CREMOPHOR® RH4 0) Sesame oil Polyoxyl 60 hydrogenated Castor oil (CREMOPHOR® RH60) Medium chain triglycerides Oleic glycerides PEG 300 (LABRAFIL® M-1944CS) Capric/capric e Triglycerides derived from coconut oil or palm kernel oil Linoleic glycerides PEG 300 (LABRAFIL® M-2125CS) Caprylic/capric glycerides PEG 4 00 (LABRASOL®) Lauryl glycerides PEG 1500 (GELUCIRE® 44/14)

Vegetable oil triglycerides are the most common lipid excipients. They are completely broken down and absorbed, eliminating safety concerns. Triglycerides are long chain triglycerides (LCT), medium chain triglycerides (MCT) and short chain triglycerides (SCT). Their dissolving power for the active substance is mainly a consequence of the effective concentration of the ester groups. MCTs have higher solubility than LCTs and are less prone to oxidation. Oils from different plant sources have different ratios of fatty acids. The composition of fatty acids in various lipid excipients is presented below.

- 29 046180

Composition of fatty acids present in lipid-based excipients (quantity Common name Melting temperature carbon atoms) (°C) 8 caprylic acid 16.5 10 capric acid 31, 6 12 lauric acid 44.8 14 myristic acid 54.4 16 palmitic acid 62.9 18 stearic acid 70, 1 18 oleic acid 16.0 18 linoleic acid -50 18 γ-linoleic acid -11.0 18 ricinoleic acid 6, 0 20 arachine acid 76.1 22 Behenaceae acid 80, 0

D-a-tocopherol polyethylene glycol 1000 succinate (Vitamin E TPGS) comes from plant tocopherols. It is water soluble and acts as an absorption enhancer for poorly water soluble drugs. Pure triglycerides are present in refined vegetable oils.

Mixed glycerides are obtained by partial hydrolysis of vegetable oils. The triglyceride starting material and the degree of hydrolysis determine the chemical composition of the resulting mixed glycerides. Medium chain mixed glycerides are not sensitive to oxidation, have high solubility and promote emulsification. These polar oil excipients also increase the solvent and dispersibility properties of the formulation. Examples of polar oils include sorbitan trioleate (SPAN® 85) and oleic acid.

Co-solvents such as ethanol, glycerin, propylene glycol, polyethylene glycols (PEG)-400, etc. increase the dissolving capacity of the composition for active substances and promote dispersion of systems that contain a high proportion of water-soluble surfactants. Practical limitations associated with cosolvents include precipitation of the solubilized active substance from the solvent due to reduced solubility after dilution, the inability of some cosolvents to mix with oils, and the incompatibility of low molecular weight solvents with capsule shells.

Water-insoluble surfactants are lipid excipients with an intermediate hydrophilic-lipophilic balance (HLB 8-12) that adsorb to oil-water interfaces. Depending on the degree of ethoxylation, they have a limited solution

- 30 046180 rime in the water. They can form emulsions when subjected to shear and may be referred to as water-dispersible. They can form micelles, but cannot self-emulsify due to their insufficiently hydrophilic nature. Oleate esters such as polyoxyethylene (20) sorbitan trioleate (TWEEN®-85) and polyoxyethylene (20) glyceryl trioleate (TAGOT®-TO) are examples of water-insoluble surfactants with an HLB of 11-11.5. However, a mixture of TWEEN®-80 and SPAN®-80 with an average HLB of 11 is not similar in function to TWEEN®-85. A mixture of TWEEN®-80 and SPAN®-80 has both water-soluble and water-insoluble molecules, but TWEEN®-85 predominantly has water-insoluble molecules.

Water-soluble surfactants are the most common surfactants for formulating self-emulsifying drug delivery systems. Materials with HLB>12 can form micellar solutions at low concentrations by dissolving in pure water above their critical micellar concentration (CMC). Water-soluble surfactants are synthesized from PEG with hydrolyzed vegetable oils, or alternatively, alcohols can be prepared to react with ethylene oxide to produce alkyl ether ethoxylate, a commonly used surfactant (eg, cetostearyl alcohol ethoxylate or CETOMACROGOL™). The reaction of sorbitan esters with ethylene oxide produces polysorbates, predominantly ether ethoxylates.

CREMOPHOR® RH40 and RH60 (ethoxylated hydrogenated castor oil) are examples of this type, obtained by hydrogenating materials from vegetable oils. Also widely used is CREMOPHOR® EL (ethoxylated castor oil), which is not hydrogenated. CREMOPHOR® enhances absorption by inhibiting efflux pumps; While the mechanism of inhibition is uncertain, it may represent a nonspecific conformational change due to penetration of surfactant molecules into the membrane, adsorption to the surface of efflux pumps, or interaction of molecules with intracellular domains of the efflux pump.

Additives can be added to protect the composition from oxidation. Examples thereof include lipid soluble antioxidants such as ascorbyl palmitate, α-tocopherol, β-carotene, propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), etc.

The behavior of lipids during formulation is assessed because lipid excipients have different chemical compositions, which can result in wide melting point ranges. Thermal properties of lipids, such as crystallization temperature, melting point, glass transition temperature and excipient solids content as a function of temperature, are assessed using differential scanning calorimetry (DSC). Lipid organization during heating or cooling is assessed by high temperature microscopy. The crystallinity of the lipid excipient is confirmed by X-ray diffraction (XRD).

High performance liquid chromatography (HPLC) and gas chromatography (GC) can determine the exact composition of ethers, esters and fatty acid distribution. Other chemical indicators include molecular weight of fatty acids, determined by their saponification value, hydrocarbon chain saturation, determined by iodine-based analysis, oxidative changes, determined by quantitation of peroxides, free fatty acids, determined by acid content, and free hydroxyl groups, determined by determining the content of hydroxyl groups.

The FDA-required dissolution test does not correlate with the in vivo behavior of lipid-based formulations. Lipids in the gastrointestinal tract undergo degradation processes in the presence of lipases (gastric and pancreatic), which also affect the emulsification and dispersion properties of lipid excipients, resulting in altered solubilization capacity in vivo. Thus, when choosing lipid-based formulations, the ability of lipid excipients to be degraded must be taken into account. Dissolution testing in a biologically similar environment can evaluate such effects and predict in vivo behavior. The effectiveness of self-emulsifying formulations can be determined by testing dispersibility (emulsifying ability and particle size). Photocorrelation spectroscopy (PCS) or laser diffraction can be used to determine particle size, and visual inspection can help predict emulsification ability.

Lipid-based excipients enhance the oral absorption of drugs by influencing various physiological processes, such as stimulating bile flow and pancreatic juice secretion, prolonging gastric emptying, increasing membrane fluidity, opening tight junctions, stimulating lymphatic transport of drugs, thereby avoiding the metabolism of the former passage, and inhibition of excretory transporters. Various in vitro models are available to evaluate these effects, including intestinal microsomes, Caco-2 cells, everted intestinal sac chamber, and in situ perfusion assays.

- 31 046180

Liposomes can be used; The organization of these spherical bilayer structures resembles that of a cell membrane, and they are mainly amphiphilic phospholipids (a hydrophilic head and a hydrophobic fatty acid tail). In the hydrated state, these phospholipids form spherical bilayer structures with their hydrophobic tails oriented toward the inside of the structure and their hydrophilic heads toward the outside of the structure. Hydrophilic substances can be enclosed in the aqueous interior of the globules, while the hydrophobic active substance can be enclosed in the internal layers of fatty acids.

Solid lipid nanoparticles (SLN) can be used. SLNs can enhance bioavailability along with controlled and specific drug delivery to a given site, such that they are potential carriers for oral lymphatic delivery. SLNs are typically spherical particles ranging in size from 10 nm to 1000 nm with a solid core lipid matrix (stabilized by surfactants) that can solubilize lipophilic molecules. Commonly used lipids include monoglycerides such as glycerol monostearate, diglycerides such as glycerol behenate, triglycerides such as tristearin, fatty acids such as stearic acid, steroids such as cholesterol, and waxes such as cetyl palmitate. The oral bioavailability of a single drug was increased by formulation of an N-carboxymethyl chitosan polymer that coated drug-loaded SLNs using monoglyceride lipid and soy lecithin surfactants and poloxamer 188 (Venishetty et al.).

In spray curing, also called spray cooling, molten lipid is sprayed onto a cooling chamber and upon contact with air it solidifies into spherical solids. Solids are collected from the bottom of the chamber and filled into hard gelatin capsules or compressed into tablets. Ultrasonic atomizers produce particulate matter during the atomization cooling process. The parameters taken into account are the melting point of the excipient, the viscosity of the composition and the temperature of the cooling air inside the chamber to ensure instantaneous solidification of the droplets. It is described that drug granules are prepared by melt granulation using PEG 4000 or poloxamer 188 as a fusible binder and lactose monohydrate as an excipient. Microparticles with a narrow size distribution have been described when stearoylpolyoxyglycerides (GELUCIRE® 50/13) were used as an excipient and significantly increased the solubility of poorly water-soluble drugs (Cavallari et al. Thermal and Fractal Analysis of Diclofenac/Gelucire 50/13 Microparticles Obtained by Ultrasound -Assisted Atomization, J. Pharm. Sci. 94 (2005) 1124-340).

Melt granulation, also called pelletizing, converts the powder mixture of the active substance into granules or beads. Fusible binder (in molten state) is sprayed onto the powder mixture during high shear mixing (spraying method), or fusible binder is mixed into the powder mixture and it melts due to friction of particles (solid/semi-solid) during high shear mixing . The molten binder forms liquid bridges between the powder particles and forms small granules that are converted into spheronized beads under controlled conditions. Depending on the fineness of the powder, 15%-25% lipid based binder can be used. The parameters considered during the process are the particle size of the binder, mixing time, speed of the impeller and the viscosity of the binder in the molten state. The drug dissolution rate was increased by forming melt agglomerates containing solid drug dispersions (Seo et al.). The lactose monohydrate was melt agglomerated with a fusible binder such as PEG 3000 GELUCIRE® 50/13 in a high shear mixer. Polyoxyglycerides, partial glycerides or polysorbates, and lecithins are exemplary lipid components used in the melt granulation process to form self-microemulsifying systems.

In some embodiments, sustained release matrix tablets may be formulated using hydrophobic carriers or fusible binders such as stearic acid, carnauba wax, and beeswax by melt granulation methods rendering the carriers hydrophobic for sustained delivery.

In any of the following examples, both phloroglucinol and trimethylphloroglucinol can be used, provided that one of the phloroglucinol or trimethylphloroglucinol, called the active substance or API, is present.

- 32 046180

Solubility of the active substance (phloroglucinol) in various excipients No. Carrier Solubility (mg/g) 1 KOLLIPHOR® RH 40 45.5 2 PECEOL™ 37.2 3 IMWITOR® 742 82.1 4 PEG 400 82.7 5 TWEEN® 80 43.3 6 LAUROGLYCOL™ 90 71.2 7 Propylene glycol 81.8 8 KOLLIPHOR® EL 26.3 9 LABRAFIL® M1944CS N/A 10 Triglycerides medium chains 6, 3 eleven Oleic acid 0, 1 12 TWEEN® 20 32.4 13 LABRASOL® 82, 9 14 PLUROL® Oleique 25, 3 15 Corn oil 1.5 16 Soybean oil 1.7 17 CAPMUL® PTO 83, 0 18 LABRAFAC™ PG 10, 1 19 MAISINE® 35-1 30, 7

- 33 046180

A lipid-based composition is a composition comprising a lipid in an excipient; Exemplary lipid-based formulations are presented below.

Fl F2 F3 F4 F 5 ( R a t v o R ) Phloroglucinol 8 0 mg 8 0 mg 8 0 mg 8 0 mg 8 0 m g PEG 400 8 2 0 m

- 34 046180

G Soybean oil 4 5 mg 4 5 mg 4 5 mg 4 5 mg Oleic acid 117 mg 117 mg 117 mg 117 mg Medium chain triglycerides 55.8 mg 55.8 mg 55.8 mg 55.8 mg Canola oil 35.76 mg 35.76 mg 35.76 mg 35.76 mg Yellow beeswax 9.99 mg GELUCIRE® 43/01 9.99 mg COMPRITOL® ATO 888 9.99 mg LABRASOL® 9.99 mg Weight content 343.55 mg 343.55 mg 343.55 mg 343.55 mg 9 0 0 m G

Composition Quantity (g) 1 . Phloroglucinol and/or trimethylphloroglucinol 2.38 PECEOL™ 16, 37 CREMOPHOR® RH40 20.77 ACCONON® MC8 10.42 Ascorbyl palmitate 0.6 Total 50.54 2. Phloroglucinol and/or trimethylphloroglucinol 3.33 CAPMUL® MSM 41.25 TWEEN® 20 4.58 Ascorbyl palmitate 0, 1 Total 49.26 3. Phloroglucinol and/or trimethylphloroglucinol 3.48 CAPMUL® MSM 19, 57

- 35 046180

PEG 400 10, 87 ACCONON® MC8 15, 22 Ascorbyl palmitate 0, 1 Total 49, 24 4 . Phloroglucinol and/or trimethylphloroglucinol 3, 08 PEG 400 37, 61 Polyethylene oxide 301 9, 23 Butylated hydroxyanisole (VNA) 0.06 Butylated hydroxytoluene (BIT) 0.02 Total 50, 0

In any of the following embodiments, either phloroglucinol and/or trimethylphloroglucinol can be used, provided that one of the phloroglucinol or trimethylphloroglucinol mentioned as the active substance is present.

In one embodiment, a pulsed release form is used. The pulsed release formulation includes an active core having one or more coatings and is referred to as a coated core formulation. The coated core can also be used in combination with an immediate release amount of the active substance.

In one embodiment, an amount of active substance formulated to be released immediately, in combination with at least a second amount of active substance, either phloroglucinol and/or trimethylphloroglucinol, formulated such that the second amount has a delay before release begins, and the release of the second portion is or may be be extended release is called a delayed extended release formulation. Each of these pulsed release dosage formulations is described below using all percentages by weight unless otherwise indicated.

The coated core composition is an active dosage core that includes an inert particle such as a commercially available Nonpareil sugar sphere. The amount of active substance in the core varies depending on the required dosage to be delivered. In one embodiment, the core contains from about 5% active to about 90% active. In one embodiment, the core contains from about 5% active to about 60% active. The amount of active ingredient is based on the total weight of the core. Those skilled in the art will be able to select the appropriate amount of active material to coat and incorporate into the core to produce the desired dosage form. Typically, the coated core may include about 80 mg, 160 mg, up to about 480 mg of active ingredient. An aqueous or pharmaceutically acceptable solvent may be used to coat the core particles. Any type of pharmaceutically acceptable inert binder may be used to bind the active agent to the inert particle. Water-soluble binders can be used. Alcohol-soluble binders can be used. Binders such as polyvinylpyrrolidone (PVP), carboxyalkylcellulose, polyethylene oxide, polysaccharides such as dextran, corn starch, hydroxypropyl methylcellulose (HPMC or hypromellose), hydroxypropylcellulose, etc. can be used by dispersing them in water at a concentration of from about 0.5 wt.% to 5 wt.%. The active substance may be present in this coating composition in the form of a solution or in the form of a suspension. The concentration of active agent can vary from about 0.1 wt.% to about 20 wt.% depending on the viscosity of the coating composition.

In one embodiment, the active substance core is produced by granulation or by extrusion and rolling. The active agent, a binder such as PVP, an optional rate-controlling polymer such as high viscosity HPMC (hypromellose), and optionally other pharmaceutically acceptable excipients are mixed in a high shear granulator (eg, a FIELDER® granulator), or fluid bed granulator (eg

- 36 046180 measures, GLATT® GPCG granulator) are granulated to obtain agglomerates by adding/spraying a granulating liquid such as water or alcohol and dried. The wet mass is extruded and rolled into spherical particles (spheres) using an extruder. In these embodiments, the drug loading may be 90 wt.% based on the total weight of the extruded or granulated core.

In one embodiment, one layer of the membrane coating on the particle containing the active substance includes a plasticized enteric polymer, and the other layer includes a mixture of a water-insoluble polymer and a plasticized water-dispersible/enteric polymer. The water-insoluble polymer and the water-dispersible polymer are present in a weight ratio of about 10:1 to 1:1, or about 4:1 to 1:1. The total weight of the coatings is from about 15 wt.% to about 80 wt.%, or from about 20 wt.% to about 60 wt.% based on the total weight of the multiparticulate dosage form.

An intermediate acid-containing membrane is optional. If included, the intermediate acid-containing membrane may include an organic acid, for example, fumaric acid, citric acid, succinic acid, tartaric acid, malic acid, maleic acid, etc.; and a binder such as PVP. Typically, water-soluble polymers or alcohol-soluble polymers are used. The weight of this acid-containing membrane ranges from about 5% to about 20% based on the total weight of the coated spheres. The acid in the acid-containing membrane slows the dissolution of the enteric polymer in the inner layer, thereby increasing the retention time as well as reducing the rate of release of the active substance from the coated bead. The composition of the outer layer of the polymer membrane and the individual masses of the inner, intermediate and outer membrane layers are further optimized to achieve pulsed release profiles based on predicted in vitro/in vivo correlations. Thus, the pulse release dosage formulation is optimized to release an amount of active substance after a predetermined period of time and/or at a specific point in time in the digestive tract of the individual to whom the formulation is administered.

Examples of enteric polymers include, but are not limited to, the following compounds or composition, either alone or in combination: esters of cellulose and its derivatives (cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate), polyvinyl acetate phthalate, pH-sensitive copolymers methacrylic acid -methacrylate, and shellac. These polymers can be used as a dry powder or an aqueous dispersion. Methacrylic acid copolymers EUDRAGIT® L100, S100, L30D (Rohm Pharma), cellulose acetate phthalate CELLACEFATE® (Eastman Chemical Co.), cellulose acetate phthalate aqueous dispersion AQUATERIC® (FMC Corp.) and hydroxypropyl methylcellulose acetate succinate aqueous dispersion AQOAT® (Shin Etsu K.K.) are available.

Examples of water-insoluble polymers include, but are not limited to, the following compounds or composition, either alone or in combination: cellulose derivatives (eg, ethylcellulose), polyvinyl acetate (KOLLICOAT® SR 30 D, BASF), neutral ethyl acrylate copolymers and methyl methacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, such as EUDRAGIT® NE, RS or RS30D, RL or RL30D, etc.

Membrane coatings can be applied to the core using any pharmaceutical coating method known in the art. For example, fluidized bed coating can be used.

The pulsed release dosage formulation can be prepared by: (i) coating an inert particle, for example a Non-pareil seed (sugar sphere), with the active substance and a polymeric binder, or producing a particle containing the active substance by granulation and/or extrusion/rolling to obtain active particle; (ii) coating the active substance particle with a plasticized enteric coating, forming a plasticized enteric coating-coated active substance particle; and (iii) coating the active substance particle coated with a plasticized enteric coating with a mixture of a water-insoluble polymer and an enteric polymer. The release characteristics can be modulated by interchanging parts (ii) and (iii). An organic acid, as described previously, can be added to the membrane between parts (ii) and (iii) to further modulate the lag time and release profile of the active substance from the particle.

In one embodiment, a single particle form may be used in the formulation to provide a time-controlled pulsed release of the active agent several hours after oral administration or to target specific sites of absorption. In one embodiment, dosage forms comprising active ingredient-containing particles with multiple coating layers are combined into a compound dosage formulation with some immediate release active ingredient, for example, in a gelatin or solid form.

- 37 046180 gelatin or soft gelatin capsule. This embodiment provides a compound dosage form having both an immediate release portion and a time controlled pulse release portion.

Each of the optional immediate release portion and the coated core active may include about 10 mg, 20 mg, 40 mg, 80 mg, etc. active agent, the coated core dosage form of the present invention may contain from about 10 to 800 mg of active agent.

In one embodiment, a delayed extended release form is used.

In one embodiment, the dosage form may provide at least a bimodal profile of the active substance in the blood, such as the profile shown in FIG. 2. In this embodiment, the dosage form contains at least a first amount of active substance for immediate release and a second amount of active substance for delayed extended release. For example, the first portion of the active substance is released immediately within the first hour after administration from the dosage form of the invention. There is a period of time when the active substance is substantially not released and/or is unable to enter the bloodstream, and/or is bioavailable from the second portion of the administered active substance. Then after another period of time, for example several hours, the additional active substance is released, and the release of this second part occurs over an extended period of time, for example up to 12 hours after the initial administration or even longer. This release of the second portion typically occurs after a delay period during which the active substance is not released, so that dosage forms that exhibit a delay before the release of some of the active substance are called delayed extended release dosage forms. Such dosage form may be administered alone or may be administered in combination with other dosage forms.

It is desirable that the level of the active substance in the blood increases, with the concentration in the blood corresponding to the amount of the substance that is bioavailable after immediate release within the first hour after administration. After a period of time, the levels of the active substance in the blood decrease to levels that are less than desirable or therapeutic levels. The second part can enter the bloodstream after release from the immediate release part of the active substance. In some embodiments, once blood levels of the active agent begin to decrease, it is desirable for the amount of the formulation to increase and/or maintain blood levels at or approximately the desired concentration without the need to administer a second dose of the active agent.

The example below illustrates one embodiment. The first part of the immediate release of the active substance has an initial pharmacokinetic profile. Fillers, excipients, etc. may correspond to a final percentage by mass.

Delayed sustained or extended release formulations are as follows. Each sustained release composition includes an amount of active agent formulated to release the active agent over a period of 4 hours to 12 hours, typically 6 to 12 hours.

Polyalcohols such as mannitol, coagulants such as POLYOX®, coagulants and lubricants such as stearic acid are added to provide granulation which can provide delayed and extended release of the active formulation. Caplets, tablets, or other sustained release dosage forms of the formulation are prepared using techniques known in the art, including encapsulation techniques. Such dosage forms, neither more nor less, generally exhibit sustained release profiles in the blood, i.e. dosage forms usually release the active substance immediately after swallowing and continue to release the active substance over time. These compositions may also be formulated in dosage form and may exhibit sustained release profiles, releasing the active agent over a period of several hours up to 12 hours after ingestion.

In one embodiment, the dosage forms formed from the compositions may optionally be a base coated to isolate the tablets for subsequent processing. Sealants include, for example, HPMC, (poly)ethylene glycol (PEG), etc.

In one embodiment, the dosage form has a stripe structure, wherein one or more stripes are formed by one or more polymeric materials, as described below and illustrated in FIG. 16. One or more annular or other types of strips of polymeric material are used, for example, a relatively insoluble polymeric material that only minimally erodes or degrades or does not erode or degrade during the distribution period. Exemplary insoluble polymers include the water-insoluble polymers described above. The number of stripes, the position or spacing of the stripes, and the thickness of the stripes can control the rate of release of the active substance. For example, if you use a set of

- 38 046180 los, the distance between stripes can be 0.5 mm, 1.0 mm, 1.5 mm, 2.0 mm, 2.5 mm or 3.0 mm. For example, each strip may have a width of 0.5 mm, 1.0 mm, 1.5 mm, or 2.0 mm and have a thickness of from about 0.1 μm to 100 μm, or from 0.1 μm to 50 μm, or from 0.1 µm to 20 µm. As shown in FIG. 16, in one embodiment, the caplet has annular polymer strips, with each of the strips 20 and 30 having a width of approximately 1 mm and a distance 40 between them of approximately 2 mm. The striped composition slows down the release of the active substance and prolongs the period of time during which the active substance can be released and/or enter the bloodstream, i.e. become bioavailable. In some embodiments, the strip(s) delay the onset of release of the active agent such that there is a delay time, also referred to as delayed onset of release or delayed release, during which the active agent is not released. The delay in onset of release may be from 0 hour to 4 hours, or it may be from 0 hour to 3 hours, or it may be from 0.5 hour to 4 hours, or it may be from 1 hour to 2 hours after administration.

In one embodiment, the striped dosage form may optionally be coated with a suitable enteric coating known in the art, for example, EUDRAGIT® L30D-55 and PEG, and/or polymers, examples of which are presented in the table below.

Polymer Type Level (%) EUDRAGIT® Acrylate polymers methacrylate RSPO Insoluble, high permeability 10 RLPO Insoluble, low permeability 10, 15, 30 NE30D-suspension* Insoluble, permeable 20 CARBOPOL® Cross-linked polymers polyacrylic acid 971Р Low cross-linking, slow release in SGF 10, 15 934Р High cross-linking, release throughout the entire gastrointestinal tract 10 974Р Tight cross-linking, rapid drug release in SGF 10, 20 METHOCEL™ Water soluble HPMC K4M* Viscosity: 4000 millipascal second 15, 18, 30 METHOCEL™: AVICEL® Soluble in water: insoluble MSS 10, 14, 14.5, 15, 16.5, 18, 30

- 39 046180

K4M Viscosity: 4000 millipascal second 5 K10 0M Viscosity: 100000 millipascal second 10 K15M Viscosity: 15000 millipascal second 7, 10, 12 K4M* POLYOX™ Water soluble polymer poly(ethylene oxide) Coagulant MM: 5000000 5, 8, 9, 9.5, 10, 20 WSRN301 MM: 4000000 10, 12.5, 15, 20 WSRN60K MM: 2000000 20, 30, 40 KELTONE® Alginate HVCR High Viscosity 10 Ethylcellulose Water-insoluble ethylcellulose ETHOCEL™ 100FP With particle size 40 micrometers 5-15 KOLLIDON® SR 80% polyvinyl acetate and 19% povidone, partially water soluble 20

*can be added by wet granulation.

The enteric coating may also include other excipients or fillers, such as talc, lactose, dicalcium phosphate, lubricants such as magnesium stearate, etc.

The striped dosage form can be coated at a level of from about 2 μg/cm ² to 10 μg/cm ² , typically about 7 μg/cm ² . The enteric coating delays the onset of action of the active substance so that there is a period of time after administration of the dosage form during which the active substance is not released. Typically, after application of the enteric coating, the delay in the onset of release of the active substance from the coated dosage form with a striped structure (e.g., enteric-coated caplet) can be from 0.5 hour to 4 hours, typically from 1 hour to 2 hours.

In one embodiment, the immediate release dose of active agent described above is combined with an enteric coated striped caplet using methods known in the art to form a single compound dosage form, for example, in a single gelatin capsule. The composition can be tailored to provide a specific desired blood profile.

In some embodiments, the compositions include at least an immediate release formulation and a sustained release formulation described below. Sustained release formulations generally do not demonstrate a delayed onset of release of the active substance. A sustained release formulation typically does not exhibit a significant period of time during which the drug is not bioavailable from the dosage form following administration.

In one embodiment, a capsule tablet is a capsule containing a first portion of the active substance in tablet form that is formulated for immediate release upon ingestion or administration, and at least a second portion of the active substance in tablet form that is formulated for sustained release, i.e. e. the second part continues to release some active substance for up to 6-12 hours after ingestion. At least 15%50% of the active substance is an immediate release formulation and is in tablet form and is suitable for immediate release. The rest of the tablet-capsule is

- 40 046180 mass may include an immediate release of the active substance or a part of the delayed release of the active substance. A tablet containing an immediate release formulation and a tablet containing a sustained release formulation can be combined into a single dosage form, for example a gelatin capsule, using methods known in the art.

In one embodiment, the granulated caplet is a capsule or caplet containing a first part of the active substance granulate that is formulated for immediate release and at least a second part of the active substance that is in tablet form that is formulated for sustained release. At least 15%-50% of the active substance is an immediate release formulation and may be in the form of granules as opposed to a tablet. In one embodiment, at least about 80% of the granule capsule includes an immediate release active ingredient composition in the form of granules, typically contained in a separate caplet. The remainder of the granular caplet by weight may comprise a sustained release active ingredient formulation, or the granular caplet may include a sustained release portion of the active ingredient formulation. A caplet containing an immediate release formulation and a caplet containing a sustained release formulation can be combined in a single dosage form, for example a gelatin capsule, using methods known in the art.

In one embodiment, a multilayer tablet comprises a tablet having two or more active agent layers that are formulated for immediate release and an active agent layer that is formulated for sustained release. The multilayer tablet contains an amount of active substance for immediate release upon swallowing and at least a second part of the active substance, which can provide the amount of active substance in a sustained manner for up to 6 hours to 12 hours after swallowing the multilayer tablet. At least 15%-50% of the active substance is an immediate release formulation. In one embodiment, at least about 80% of the multilayer tablet is an immediate release active ingredient composition. The remainder of the multilayer tablet by weight may include a sustained release formulation or may include a portion of a sustained release formulation. The formulations can be combined in a conventional manner, for example in a tablet press, such that, after processing, the final tablet dosage form has two or more layers: at least a first layer containing the immediate release formulation and a second layer containing the sustained release formulation.

In one embodiment, 100% of the active substance is in an immediate release dosage form and is not combined with a dosage form suitable for sustained release. The active substance may be dispersed in a lipid-based formulation, for example, in an oil or lipid system, as described above.

In one embodiment, the active ingredient constitutes at least 20% to 30%, 30% to 60%, or 70% by weight of the sustained release composition, the remainder of the composition being excipients, such as fillers, lubricants, polymers and etc. In one embodiment, the polymer may be present in an amount from 5% to 20% by weight of the sustained release composition, and in one embodiment, it may be present in an amount from 7% to 10% by weight of the sustained release composition, and in one embodiment it may be present in an amount from 10% to 16.5% by weight of the sustained release composition. In one embodiment, the polymer is a cellulosic polymer, such as METHOCEL™ K4M, and is present in an amount of approximately 10% by weight. The sustained release formulation can be prepared by direct compression or wet granulation.

The formulation may be compressed into tablets or may be included directly in food. Such compositions must contain at least 0.1% active compound. The percentage in compositions and preparations may vary, for example, from about 2% to about 60% by weight of the unit.

Excipients include, but are not limited to, one or more of a pharmaceutically acceptable inert diluent; digestible food carrier; a disintegrant to facilitate disintegration of, for example, modified cellulose derivatives, modified starch derivatives, etc., given that one skilled in the art will appreciate that other ingredients, including binders and lubricants, may also affect the dissolution profile of the dosage form; hard or soft gelatin capsule; dicalcium phosphate; a binder such as gum tragacanth, gum arabic, corn starch or gelatin; a leavening agent such as corn starch, potato starch, alginic acid, etc.; a lubricant such as magnesium stearate; a sweetener such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen, cherry flavor; one or more surfactants, such as ionic, non-ionic surfactants and/or surfactants

- 41 046180 active substances based on bile salts, wherein anionic surfactants include sodium alkyl sulfate (sodium lauryl sulfate) and sulfosuccinate derivatives such as docusate sodium, non-ionic surfactants including polyoxyethylene sorbitan fatty acid esters (polysorbates), such as TWEEN® 20, TWEEN® 80, TWEEN® 40, SPAN® 20, polyethylene glycol fatty acid esters such as GELUCIRE® 44/14, GELUCIRE® 50/13, saturated polyglycolysed (including mono, di or tri)glycerides , medium chain monoglycerides (6-10 carbons) such as glyceryl monocaprylate (IMWITOR® 308), glyceryl monocaproate (CAPMUL® MSM C-8), glyceryl caprylate/caprate (CAPMUL® MSM), polyoxyethylene glyceryl caprylate and polyoxyethylene glyceryl caproate (LABRASOL®), medium chain fatty acid esters such as glyceryl tricaprate and glyceryl tricaprylate (MIGLYOL® 612), ethylene oxide and propylene oxide block polymers, polyoxyethylene-polyoxypropylene block copolymers such as poloxamer 188 (PLURONIC® F-68), poloxamer 237 (PLURONIC® F -87), poloxamer 338 (PLURONIC® F-108), poloxamer 407 (PLURONIC® F-127), poloxamer 124 (PLURONIC® L-44), polyoxystearate-polyethoxylated (40) stearic acid (MYRJ™ 52), ethoxylated castor polyethoxylated (60) hydrogenated castor oil (CREMOPHOR® EL), ethoxylated hydrostearic acid polyethylene glycol 660 hydroxystearate (SOLUTOL® HS 15), polyoxyethylene alkyl ethers (12-18 carbons) such as polyoxy 20 cetostearyl ether (ATLAS™ G- 3713), polyoxy 10 oleyl ether (BRIJ™ 96, BRIJ™ 97, Oleth 10), polyethylene glycol ether surfactants (TRITON™ X-100, TRITON™ X-114, TRITON™ X-405, TRITON™ N -101) and lecithins such as phospholipids (dimyristoyl DL-alpha-phosphatidylcholine), bile salt surfactants including deoxycholic acid, sodium deoxycholate, cholic acid, sodium taurocholate, etc. The capsule dosage form may also contain a liquid carrier. Other materials may be present as coatings or to otherwise modify the physical form of the dosage form, for example, tablets, pills or capsules may be coated with shellac and/or sugar. The syrup or elixir may contain the active substance, sucrose as a sweetener, methyl and propylparabens as preservatives, a coloring agent and a flavoring agent.

In some embodiments, other active agents may be included in the composition.

In one embodiment, the dosage forms are a liquid-filled soft gelatin capsule containing excipients that include lipids, surfactants and solvents. Capsules may contain immediate release, delayed release, sustained release, or controlled release formulations.

The composition may contain excipients such as one or more fatty acids. The method involves dissolving, melting or suspending a low water-soluble active substance in one or more fatty acids, conjugated fatty acids, (semi-)solid surfactants having a high HLB value, and/or hydrophilic polymers. Suitable fatty acids include C _1o -C ₁₈ fatty acids, preferably C16-C18 fatty acids. Suitable conjugated fatty acids include C _1o -C ₁₈ fatty acids, preferably C 16 -C 18 fatty acids conjugated to glycerol (eg monoglycerides), monosaccharides and/or polyethylene glycol (PEG). Suitable hydrophilic polymers include poloxamers and poloxamines.

Suitable fatty acids include C10-C18 fatty acids, more preferably C16-C18 fatty acids. Exemplary fatty acids include, but are not limited to, dodecanoic (lauric) acid, tetradecanoic (myristic) acid, hexadecanic (palmitic) acid, heptadecanic (margaric) acid, octadecanoic (stearic) acid, eicosanoic (arachidic) acid, docosanoic (behenic) acid, tetracosanoic (lignoceric) acid, hexacosanoic (cerotinic) acid, heptacosanoic (carboceric) acid, octacosanoic (montanic) acid, triacontanoic (melissic) acid, dotriacontanoic (laceric) acid, tritriacontanoic (ceromelicic) acid, tetratriacontanoic (heddic) acid and pentatriacontanoic (ceroplastinic) acid. The fatty acids may be saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, or combinations thereof.

Oils, for example vegetable oils such as soybean oil, can be used alone or in combination with the coating materials listed above. Soybean oil contains 14.4% saturated fatty acids, 23.3% monounsaturated fatty acids such as oleic acid, and 57.9% polyunsaturated fatty acids such as linoleic acid and alpha-linoleic acid.

In one embodiment, the fatty acid is covalently linked to glycerol, a monosaccharide such as sorbitol or sorbitan, a polyalkylene oxide such as polyethylene glycol and polypropylene glycol, or combinations thereof. These materials are called conjugated fatty acids. Suitable conjugated fatty acids include, but are not limited to, polyethylene glycol fatty acid esters, such as the esters commercially available under the trade name

- 42 046180 under the name GELUCIRE®, sorbitan fatty acid esters, such as sorbitan monostearate, glycerol esters of the fatty acids mentioned above, such as glycerol behenate and glyceryl monostearate, and combinations thereof.

The range of fatty acid concentrations is from about 1 to about 20% by weight of the composition, preferably from about 5 to about 15% by weight of the composition (microparticles and carrier).

The water-insoluble active substance may be coated with one or more surfactants, alone or in combination with one or more fatty acids or conjugated fatty acids, and/or one or more hydrophilic polymers. In one embodiment, the surfactant has an HLB value of greater than about 10, greater than about 12, greater than about 14, or greater than about 16 (on a scale of 1-18). Surfactants having the required HLB value are known in the art. The surfactant may be anionic, cationic or nonionic. In one embodiment, the surfactant is a nonionic surfactant.

Examples of such surfactants include, but are not limited to, polysorbate 20, 40 and 80 (marketed as TWEEN®), polyoxyethylene monostearate, certain sugar esters such as sucrose monolaurate, ethoxylated nonylphenols, alpha olefin sulfonates, ethoxylated tallow amines, ethylene oxide/propylene oxide block copolymers, ethoxylated soy amines, fatty acids and alcohols, polyethoxylated castor oil, polysorbates, polyoxyethylene alkyl ethers and polyoxyethylene stearates.

In one embodiment, the surfactant is a high HLB surfactant containing a fatty acid chain. Suitable surfactants include, but are not limited to, polyethoxylated castor oil, polysorbates, polyoxyethylene alkyl ethers and polyoxyethylene stearates.

Polyoxyethylene castor oil derivatives contain mainly ricinoleylglycerol, ethoxylated with 30-50 molecules of ethylene oxide. Polysorbates or polyoxyethylene sorbitan fatty acid esters are a series of partial fatty acid esters of sorbitol and its anhydrides copolymerized with approximately 20, 5 or 4 moles of ethylene oxide for each mole of sorbitol and its anhydrides. The resulting product is a mixture of molecules having a wide range of molecular weights. Polyoxyethylene alkyl ethers are a series of polyoxyethylene glycol ethers of linear fatty alcohols (n-alcohols) such as lauryl, myristyl, cetyl and stearyl alcohols. Polyoxyethylene stearates are produced by polyethoxylation of stearic acid.

Without being bound by any theory, it is believed that the hydrophilic portion of the surfactant increases the compatibility of the active substance with the aqueous dissolution medium in vitro or in vivo and that the fatty acid side chain enhances absorption through fatty acid oxidation. During fatty acid oxidation, intracellular Ca ²⁺ is consumed, which leads to widening of gap junctions, allowing the passage of the active substance between cells, in addition, such coated particles can be more stable than the drug alone, for example, by preventing oxidation of the active substance.

The surfactant concentration is from about 1 to about 50%, preferably from about 5 to about 15% by weight of the composition (microparticles and carrier).

Suitable hydrophilic polymers include, but are not limited to, poloxamers, poloxamines, polyethylene glycols, polyvinyl alcohols, polyvinylpyrrolidone, poly(vinyl alcohol), cellulosic materials such as hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, gelatin, carboxymethylcellulose, and polypeptides.

The concentration of hydrophilic polymer is from about 1 to about 50% by weight of the composition, more preferably from about 5 to about 15% by weight of the composition. If the hydrophilic polymer is polyethylene glycol, the concentration is from about 1 to about 80% by weight of the composition, from about 30 to about 60%, from about 35% to about 60%, or from about 40% to about 60% by weight of the composition (microparticles and carrier).

In one embodiment, the microparticles are formed by adding a mixture of drug and coating material(s) to a pharmaceutically acceptable carrier. In one embodiment, the carrier is a hydrophilic or lipophilic carrier. The resulting particles are suspended in a carrier. The carrier may be a single component or a mixture of components. The carrier may include solvents, surfactants or other excipients. Carrier materials can alter or modify the rate of drug release from the microparticles and/or the rate of drug dissolution. Compositions can

- 43 046180 exhibit a biphasic release profile due to the controlled release properties of the microparticles and the controlled release properties of the carrier. Varying the qualitative and quantitative composition of the carrier materials may allow modulation of the release profile of the active substance. The carrier may contain one or more rate-controlling excipients that control the release of the active substance. Exemplary rate-controlling excipients include, but are not limited to, glyceryl behenate, GELUCIRE®, Cremophor, hydrogenated vegetable oil, beeswax, cellulose polymers such as hypromellose, alginates, CARBOPOL®, and combinations thereof.

In one embodiment, the carrier is a hydrophilic carrier containing a surfactant having an HLB value of greater than about 10, greater than about 12, greater than about 14, or greater than about 16, and/or is water soluble. Exemplary hydrophilic carriers include, but are not limited to, polyethylene glycols, polyoxyethylene 32 lauryl glycerides (available from Abitech under the trade name ACCONON® M-44), polyoxyethylene 8 caprylic/capric glycerides (available from Abitech under the trade name ACCONON® MC-8) and glycofurol The hydrophilic carrier may further contain one or more miscible solvents such as glycerol, ethanol, glycofurol and caprylocaproyl macrogol-8 (available from Gattefosse S.A., Saint Priest, France, under the trade name LABRASOL®).

In one embodiment, the hydrophilic carrier is water or alcohol. In another embodiment, the carrier is a mixture of hydrophilic carriers containing polyethylene glycol, and optionally one or more surfactants and/or water. In a specific embodiment, the hydrophilic carrier is a mixture of PEG 400 (eg, 57% by weight of the composition), water (eg, 8% by weight of the composition) and TWEEN® 20 (eg, 10% by weight of the composition). The hydrophilic carrier may also contain CREMOPHOR® RH 40. The concentration of the hydrophilic carrier is typically from about 50% to about 85% by weight of the composition (microparticles and carrier), preferably from about 70% to about 80% by weight of the composition.

In another embodiment, the carrier is a lipophilic carrier. In a preferred embodiment, the lipophilic carrier has an HLB value of less than about 10 and/or is oil soluble. Exemplary lipophilic oil carriers include, but are not limited to, vegetable oils, medium chain mono-, di- and triglycerides, glyceryl stearates (available from Sasol under the trade name IMWITOR®), polyoxyethylated oleic glycerides (available from Gattefosse, S.A., Saint Priest, France , under the trade name LABRAFIL®), mineral oil, mono- and diglyceride emulsifiers such as glyceryl monooleate, glyceryl monocaprate, glyceryl monocaprylate, propylene glycol monocaprylate, and propylene glycol monolaurate (available from Abitec Corp., Columbus, Ohio, under the trade name CAPMUL®), and dimethylpolysiloxanes, such as simethicone.

The concentration of the lipophilic carrier is typically from about 10% to about 50% by weight of the composition (microparticles and carrier), preferably from about 5 to about 35% by weight of the composition.

The described compositions may contain one or more pharmaceutically acceptable excipients that are considered safe and effective and can be administered to an individual without causing undesirable biological side effects or unwanted interactions.

Exemplary additives include, but are not limited to, solvents, suspending agents, dispersing agents, buffers, pH modifying agents, tonicity modifying agents, preservatives, antimicrobial agents, and combinations thereof.

Suitable additives for inclusion in the compositions described herein include, but are not limited to, antioxidants (eg, alpha-tocopherols such as vitamin E acetate, ascorbic acid, butylated hydroxyanisole, and butylated hydroxytoluene); polar solvents (eg water, propylene glycol and glycerin); hydrophobic solvents (eg, corn oil, castor oil, soybean oil, olive oil, fish oil, peanut oil, peppermint oil, safflower oil, sesame oil, medium chain triglycerides, caprylic triglycerides, capric triglycerides from coconut oil or palm kernel oil); and viscosity enhancers (eg, gelatin, glycerin, carrageenan, colloidal silica, hydrogenated vegetable oil; povidone and propylene glycol alginate).

The microparticle compositions described herein are typically formulated for oral or parenteral administration. Suitable oral dosage forms include capsules, such as hard or soft gelatin or non-gelatin capsules, or oral suspensions or syrups. Suitable parenteral formulations include suspensions.

In one embodiment, the microparticle compositions (microparticles suspended in a hydrophilic or lipophilic carrier) are encapsulated in a capsule, such as a hard or soft capsule

- 44 046180 capsule. Capsules can be prepared from natural and/or synthetic film-forming polymers. Suitable natural film-forming materials include, but are not limited to, gelatin. Non-gelatin capsules include, but are not limited to, capsules made from carrageenan, shellac, alginates, pectin and zeins. Suitable synthetic film-forming polymers include, but are not limited to, methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, and acrylates such as polymethacrylate.

The compositions may also be encapsulated in an enteric capsule, where the capsule is coated with an enteric coating or the capsule shell contains an enteric polymer, as described in WO 2004/030658, Banner Pharmacaps, Inc.

Hard shell capsules are typically made by forming two capsule halves, filling one of the halves with a filling solution, and then closing the capsule halves together to form a finished capsule. Soft gelatin capsules are typically produced using a rotary die encapsulation process. Such processes are known in the art.

The capsule shell may contain one or more additives. Suitable coating additives include plasticizers, opacifiers, colorants, humectants, preservatives, flavoring agents and buffering salts and acids, and combinations thereof.

Plasticizers are chemicals added to gelatin to make the material softer and more elastic. Suitable plasticizers include, but are not limited to, glycerin, sorbitol solutions, which are mixtures of sorbitol and sorbitan, and other polyhydric alcohols such as propylene glycol and maltitol or combinations thereof.

Opacifiers are used to opacify the capsule shell when the encapsulated active substances are light sensitive. Suitable opacifiers include titanium dioxide, zinc oxide, calcium carbonate, and combinations thereof.

Dyes can be used for marketing purposes and product identification/distinction. Suitable dyes include synthetic and natural dyes, and combinations thereof.

Humectants can be used to suppress the water activity of the soft gel. Suitable humectants include glycerin and sorbitol, which are often components of plasticizer compositions. Due to the low water activity of dried, properly stored soft gels, the greatest risk from microorganisms is from mold and yeast. For this reason, preservatives may be included in the capsule shell. Suitable preservatives include alkyl esters of p-hydroxybenzoic acid such as methyl, ethyl, propyl, butyl and heptyl esters (collectively known as parabens) or combinations thereof.

Flavoring additives can be used to mask the unpleasant odors and tastes of filler formulations. Suitable flavoring agents include synthetic and natural flavoring agents. The use of flavorings can be problematic due to the presence of aldehydes, which can cross-link gelatin. As a result, buffer salts and acids can be used in conjunction with flavoring agents that contain aldehydes to inhibit gelatin cross-linking.

Medium chain triglycerides can also be used. As used herein, medium chain triglycerides mean C6-C12 ester chains formed by the esterification of glycerol and fatty acids. Sources of medium chain triglycerides can be varied, such as coconut oil, palm kernel oil, etc. Fractionated coconut oils are the most commonly used sources of medium chain triglycerides. Examples of commercially available medium chain triglycerides may include MIGLYOL® 810, 812 or 881, produced by Sasol Germany GMBH, CAPTEX® 300, 355 or 810D, produced by Abitec Corporation, NEOBEE® M5 from Stepan Company, CRODAMOL® GTC/C, produced by Croda Inc, and LABRAFAC® Lipophile WL 1349, produced by Gattesfosse Group. In one illustrative embodiment, the medium chain triglyceride may comprise CARTEX® 355, which is a caprylic (C8)/capric (C10) acid triglyceride.

Various amounts of medium chain triglycerides may be included in the pharmaceutical formulation. In one or more embodiments, the pharmaceutical composition may contain from about 50 to about 95 wt.% medium chain triglycerides, or from about 85 to about 95 wt.% medium chain triglycerides. Moreover, in illustrative embodiments, the pharmaceutical composition may include from about 100 to about 300 mg, or about 200 to 300 mg by weight, medium chain triglycerides, or about 225 to 275 mg by weight, medium chain triglycerides, or about 250 mg by weight mass of medium chain triglycerides.

Similar to medium chain triglycerides, medium chain monoglycerides and medium chain diglycerides are C6-C12 ester chains formed by the esterification of glycerol with one fatty acid or two fatty acids, respectively. Examples of commercially available medium chain mono/diglycerides may include CAPMUL® products manufactured by Abitec.

- 45 046180

The use of medium chain mono/diglyceride compounds, which also include medium chain triglycerides, such as the commercially available IMWITOR® compositions produced by Sasol, is also contemplated.

In illustrative embodiments, the medium chain mono/diglycerides may include CAPMUL® MCM, which includes medium chain mono/diglycerides based on caprylic (C8)/capric (C10) acid. While all categories of the CAPMUL® MCM product line are suitable for use within the scope of the present invention, for example the National Formulary (NF) category or CAPMUL® MCM EP, it may be desirable to use the EP category since it includes 3% glycerol , while the NF category includes 7% glycerin.

In accordance with one or more embodiments, the pharmaceutical composition may contain from about 5% to about 25 wt.% medium chain mono/diglycerides, or from about 5% to about 15 wt.% medium chain mono/diglycerides. In illustrative embodiments, the pharmaceutical composition may include from about 20 mg to 50 mg by weight of medium chain mono/diglycerides, or from about 25 mg to 30 mg by weight of medium chain mono/diglycerides, or about 25 mg by weight of medium chain mono/diglycerides .

Without being bound by theory, the mixture of medium chain triglycerides and medium chain mono/diglycerides is important for the bioavailability of the active substance within the liquid-filled hard gelatin capsule formulation. While a soft gelatin capsule may include only medium chain mono/diglycerides, a hard gelatin capsule with only medium chain mono/diglycerides may not provide the required physical stability of the finished dosage forms. A mixture of medium chain triglycerides and medium chain mono/diglycerides within a hard gelatin capsule can achieve the required stability, solubility and bioavailability of the active ingredient of the product. Therefore, the ratio by weight of medium chain triglycerides to medium chain mono/diglycerides contributes to the solubility and stability of the active substance in the non-emulsified mixture before and after adding the mixture to the capsule. Medium chain triglycerides and medium chain mono/diglycerides may be present in a weight ratio of from about 10:1 to about 5:1, or from about 10:1 to about 7:1.

The invention may include other excipients known to one skilled in the art, for example, excipients in the oral composition may be selected from diluents, binders, lubricants, disintegrants, flavoring agents, coloring agents, stabilizers, glidants, plasticizers, preservatives, sweeteners and etc.

Diluents may include liquid diluents such as any long chain triglyceride (peanut oil, almond oil, peanut butter, palm oil, palm kernel oil, black currant seed oil, rice hull oil, soybean oil, canola oil, corn oil, coconut oil, cottonseed oil, castor oil, olive oil, magnolia (neem) oil, sesame oil, primrose oil, vegetable oil, LIPEX® 108 (Abitec), wheat germ oil, fish oil, canola oil, sunflower oil and safflower oil. it is contemplated that other diluents may be used, for example diluents selected from calcium aluminosilicates (SIPERNAT® 106PQ), calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dexrates, dextrose, fructose, lactitol, lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol, sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose, maltodextrin, maltitol, silicon dioxide, HPMC and combinations thereof.

Formulation includes route of administration, type of drug, inactive ingredients that release the active substance, stability, scale-up, new processes for obtaining the active substance, new formulation processes.

In vivo efficacy evaluation includes pharmacokinetic data such as pK/pD such as Tmax, Cmax, plasma concentration curve, efficacy, side effects, etc.

The active substance includes all forms of the active substance and, in addition to the trimethyl form, includes, but is not limited to, intermediates, metabolites, enantiomers, polymorphs, crystal structures, hydrates, stereoisomers, salts, bases, complexes, carriers, and derivatives and conjugates.

Other release profiles include, but are not limited to, controlled, enteric, sustained, rapid, multiphasic, etc.

The invention covers other known and future uses of the phloroglucinol and trimethylphloroglucinol compositions of the invention.

Aspects of.

Aspect 1. A pharmaceutical composition containing a phloroglucinol and/or trimethylphloroglucinol composition and at least one excipient, wherein at least one of phloroglucinol or

- 46 046180 trimethylphloroglucinol is available in both immediate release (IR) and extended release formulations.

Aspect 2. The composition according to aspect 1 containing 100% phloroglucinol.

Aspect 3. The composition according to aspect 1 containing 100% trimethylphloroglucinol.

Aspect 4. The composition according to aspect 1, containing phloroglucinol:trimethylphloroglucinol in a ratio selected from the group consisting of 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20 :80 and 10:90.

Aspect 5. A dosage form of phloroglucinol and/or trimethylphloroglucinol, the dosage form comprising an immediate release (IR) dose portion and an extended release (XR) dose portion.

Aspect 6. The dosage form according to aspect 5, wherein the IR portion delivers 100% of the dose in less than one hour.

Aspect 7. The dosage form according to aspect 5, wherein the XR portion delivers the dose over a period of 12 hours.

Aspect 8. The dosage form according to aspect 5, selected from the group consisting of a two-layer tablet containing IR and XR layers, a three-layer tablet containing IR, XR layers and a buffer layer between the IR and XR layers, an XR tablet containing PG or TMP in a matrix layer and IR-coated PG or TMP, capsule containing IR tablet, stopper and XR tablet in an osmotic system that delivers the drug over 12 hours capsules containing IR spheres and XR spheres mixed in appropriate ratio, capsules containing mini-tablets IR mixed with XR mini-tablets, capsules containing IR and XR granules coated with sustained release polymers, capsules containing coated XR spheres which are coated with a layer of IR as a top coating, compressed tablet containing IR granules and coated XR spheres enclosed in a tablet , a compressed tablet containing an XR tablet enclosed in an IR tablet, an XR tablet suspended in a liquid drug solution in a capsule, a sachet containing a mixture of IR and XR granules or spheres, a sachet containing a mixture of effervescent IR granules and coated XR granules, orally disintegrating a tablet containing coated particles, spheres or granules of a delayed/extended release drug, a capsule containing a drug solution and coated particles, spheres or granules of a delayed/extended release drug, a soft gel containing a drug solution and particles, spheres or granules of a drug delayed/extended release agents, and liquid carrier coated delayed/extended release drug particles, spheres or granules.

Aspect 9. A pharmaceutical composition comprising a first plurality of first active agent spheres and a second plurality of second active agent spheres, the composition providing dual pulse substantially simultaneous delivery of each of the first active agent and the second active agent to a patient to whom the composition is orally administered.

Aspect 10. A pharmaceutical composition for delivering one or more salts of an active substance, the composition comprising:

(a) one or more pharmaceutically active salts coated with an immediate release coating; and (b) one or more pharmaceutically active salts coated with an enteric coating that provides a delayed pulse release in the intestine, wherein the enteric coating releases substantially all of the one or more enteric coated active salts within about 60 minutes after the start of the delayed pulse release in the intestines.

Aspect 11. A pharmaceutical composition for delivering a mixture of active salts effective for treating a patient, the composition comprising an immediate release dosage form that provides immediate release of the active substance upon oral administration of the composition to the patient, a delayed release dosage form in the intestine that provides delayed release of the active substance when orally administering the composition to a patient, and a pharmaceutically acceptable carrier.

Aspect 12. A pharmaceutical composition comprising a lipid-based composition of phloroglucinol and/or trimethylphloroglucinol and at least one excipient, wherein at least one of the phloroglucinol or trimethylphloroglucinol is in an immediate release (IR) formulation.

Aspect 13. The composition according to aspect 12 containing 100% phloroglucinol.

- 47 046180

Aspect 14. The composition according to aspect 12 containing 100% trimethylphloroglucinol.

Aspect 15. The composition according to aspect 12 containing phloroglucinol:trimethylphloroglucinol in a ratio selected from the group consisting of 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20 :80 and 10:90.

Aspect 16. A dosage form of phloroglucinol and/or trimethylphloroglucinol, wherein the dosage form contains an immediate release (IR) formulation.

The following examples are provided to illustrate some of the ideas described herein. While each example is intended to provide specific individual embodiments of the composition, methods of preparation and use, none of the examples should be considered limiting to the more general embodiments described herein.

In the examples below, efforts have been made to ensure the accuracy of the numbers used (e.g. quantities, temperatures, etc.), however some experimental error and variation must be taken into account. Unless otherwise indicated, temperatures are in degrees C and pressures are at or near atmospheric.

Examples

Example 1.

An example of a modified release phloroglucinol formulation is presented below.

Phloroglucinol, capsules 200 mg Composition %wt./wt. Amount per 200 mg dosage (mg/capsule) Phloroglucinol anhydrous 42, 6 200, 0 Cellulose microcrystalline PH200 NF/EP 21.3 100, 0 ACRYL-EZE 93F19255 14.9 70, 0 Povidone KZO 10 50 Pullulan capsule, size 0 20.2 95, 0 Theoretical general quantity 100.0 470.0

Method for obtaining spheres.

Extrusion.

A wet mass containing a mixture of phloroglucinol and microcrystalline cellulose PH200 (MCC) is prepared in a 1:1 ratio using a top drive mixer. A mixture of 500 g of phloroglucinol and 500 g of MCC is dry stirred for 5 minutes. While stirring, add 900 ml of water over 5 minutes. The wet mass is extruded through a 1.0 mm sieve and formed into spheres using a rolling element using 2.0 mm grid plates. The spheres are dried in an oven for 2 hours at 65°C.

Application of enteric coating.

The spheres were coated with ACRYL-EZE Clear 93F1925 in a fluidized bed using a Wurster column. The coating solution is applied through a 1 mm nozzle at a speed of 10 g/min. Apply sufficient coating solution to maintain a theoretical weight gain of approximately 35%. The release profile from coated and uncoated spheres is analyzed using a dissolution test; see, for example, Fig. 21, which shows drug release at various times.

Each of the following references is incorporated herein by reference in its entirety:

Chang and Robinson, chapter 4: Sustained Drug Release from Tablets and Particles Through Coating, Pharmaceutical Dosage Forms: Tablets, vol. 3, Eds. Lieberman, Lachman and Schwartz, Marcel Dekker, Inc., 1991,

Campbell and Sackett, chapter 3: Film coating, Pharmaceutical Unit Operations: Coating, edited by Avis, Shukla, and Chang, Interpharm Press, Inc., 1999.

The embodiments presented and described in the specification are only specific embodiments described by the inventors, who are experts in the field, and they are not non-limiting in any way. Thus, various isms

Claims (13)

Changes, modifications or deviations from these embodiments may be made without departing from the spirit of the invention within the scope of the claims appended below. The cited references are expressly incorporated herein by reference in their entirety. CLAIM 1. An oral dosage unit containing an immediate release composition containing a plurality of immediate release spheres, each immediate release sphere containing a core which is in the form of an immediate release composition containing: (i) phloroglucinol, trimethylphloroglucinol or a pharmaceutically acceptable salt thereof, (ii) microcrystalline cellulose or (iii) hydroxypropyl methylcellulose, wherein at least about 90% by weight of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, based on the weight of the immediate release formulation, is released from the dosage unit in about 1 hour when determined by the USP 2 paddle method at approximately 50 rpm in approximately 750 ml of an aqueous solution containing approximately 0.1 N HCl at approximately 37°C; and a modified release composition comprising a plurality of modified release spheres, each modified release sphere comprising a core containing phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, and an enteric coating of the core containing: (i) a methacrylic acid-ethyl acrylate copolymer or (ii) a polymer of a polyvinyl acetate phthalate base, wherein the coating releases phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof in at least about 2 hours when determined by the USP 2 paddle method at about 50 rpm in about 1000 ml of an aqueous solution containing about 0.1 N HCl and approximately 20 mM tribasic sodium phosphate at a pH of approximately 6.8 at approximately 37°C. 2. The oral dosage unit of claim 1, wherein one or both of the immediate release formulation or the modified release formulation contains phloroglucinol or a pharmaceutically acceptable salt thereof. 3. The oral dosage unit of claim 1, wherein one or both of the immediate release formulation or the modified release formulation contains trimethylphloroglucinol or a pharmaceutically acceptable salt thereof. 4. The oral dosage unit of claim 1, wherein the immediate release formulation and the modified release formulation comprise phloroglucinol or a pharmaceutically acceptable salt thereof and trimethylphloroglucinol or a pharmaceutically acceptable salt thereof. 5. The oral dosage unit of claim 3, wherein the ratio of phloroglucinol to trimethylphloroglucinol is from about 90:10 to about 10:90, such as about 80:20, about 70:30, about 60:40, about 50:50 , approximately 40:60, approximately 30:70 or approximately 20:80. 6. The oral dosage unit of any one of the preceding claims, wherein at least 90% by weight of the modified release formulation of phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof is released from the modified release formulation after approximately 12 hours. 7. The oral dosage unit of claim 1, comprising from about 10 to about 50 weight percent of the modified release formulation, based on the weight of the oral dosage unit. 8. The oral dosage unit of any one of the preceding claims, further comprising a second modified release formulation. 9. The oral dosage unit of claim 8, wherein at least about 90% by weight of the phloroglucinol, trimethylphloroglucinol, or a pharmaceutically acceptable salt thereof, based on the weight of the second modified release formulation, is released from the dosage unit within about 4 to about 6 h, when determined by the USP 2 paddle method at approximately 50 rpm in approximately 1000 ml of an aqueous solution containing approximately 0.1 N HCl and approximately 20 mM tribasic sodium phosphate at a pH of approximately 6.8 at approximately 37°C. 10. The oral dosage unit of claim 1, wherein the enteric polymer is a copolymer of methacrylic acid and ethyl acrylate. 11. The oral dosage unit of claim 1, wherein the enteric polymer is ACRYL-EZE® polymer. 12. The oral dosage unit of claim 1, wherein the enteric polymer is a polyvinyl acetate phthalate polymer, such as Sureteric® polymer. 13. An oral dosage unit according to any of the preceding claims, which is -