# US 9,750,698 B2 · Controlled release compositions of agents that reduce circulating levels of platelets and methods therefor

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- Number: US 9,750,698 B2
- Document ID: US9750698B2
- Status: Granted
- Kind: B2
- Application number: 15/169,345
- Filed: 2016-05-31
- Published: 2017-04-27
- Granted: 2017-09-05
- Earliest claimed: 2008-06-16
- Assignees: BioVascular, Inc.
- Applicants: BioVascular, Inc.
- Inventors: Paul F. Glidden; Alison J. Pilgrim; Stephen R. Hanson
- Web page: https://patentgrep.com/patent/US9750698B2

## CPC

- A61K 9/1676: {having a drug-free core with discrete complete coating layer containing drug (adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921)}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/1617: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2081: {with microcapsules or coated microparticles according to A61K9/50}
- A61K 9/4808: {characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release (capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084)}
- A61K 9/4858: {Organic compounds}
- A61K 9/4866: {Organic macromolecular compounds}
- A61K 9/5078: {with drug-free core}
- A61K 31/00: Medicinal preparations containing organic active ingredients
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61L 27/025: {Other specific inorganic materials not covered by A61L27/04 - A61L27/12}
- A61L 27/20: Polysaccharides
- A61L 27/227: {Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24}
- A61L 27/34: Macromolecular materials
- A61L 27/54: Biologically active materials, e.g. therapeutic substances {(A61L27/227 takes precedence)}
- A61L 27/56: Porous materials, {e.g. foams or sponges}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 3/14: for calcium homeostasis (vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04)
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/08: Vasodilators for multiple indications
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 37/02: Immunomodulators
- A61P 39/02: Antidotes
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 239/72: Quinazolines; Hydrogenated quinazolines
- C07D 487/04: Ortho-condensed systems
- A61L 2300/42: Anti-thrombotic agents, anticoagulants, anti-platelet agents
- A61L 2300/602: Type of release, e.g. controlled, sustained, slow
- A61L 2300/608: having two or more layers
- A61L 2300/622: Microcapsules
- A61L 2300/63: Crystals
- A61L 2420/08: Coatings comprising two or more layers
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Provided are prophylactic and therapeutic methods of treatment of subjects for the purpose of inhibiting vaso-occlusive events, including embolism, by administering agents, including anagrelide and anagrelide derivatives, which reduce the number of circulating platelets to low normal or to below normal levels. Methods and pharmaceutical preparations comprising such agents are provided.

## Claims

### Claim 1

A pharmaceutical composition in unit dosage form comprising:
(a) a solid support core comprising a plurality of non-pareil sugar spheres at a size range of about 700 microns to about 850 microns (20-25 mesh sieve);
(b) a substrate layer comprising hydroxypropyl methylcellulose and microparticles of anagrelide hydrochloride monohydrate in hydrated crystal form in an amount that is equivalent to from about 100 μg to about 1000 μg of anagrelide free base, wherein at least 90% of the microparticles are 25 microns or less, and the hydroxypropyl methylcellulose in the substrate layer is present at about 2-4% by weight of the composition;
(c) a seal coat layer comprising hydroxypropyl methylcellulose, wherein the seal coat layer is present at about at about 2-4% by weight of the composition; and
(d) a release control component comprising ethyl cellulose and hydroxypropyl methyl cellulose at a ratio of about 3:1 and triethyl citrate, wherein the release control component is present at about 1-5% by weight of the composition,
wherein the seal coat layer is disposed between the substrate layer and the release control component and reduces chemical interaction between the anagrelide hydrochloride monohydrate in the substrate layer and the triethyl citrate in the release control component.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the hydroxypropyl methylcellulose in the substrate layer is present at about 2%, 2.05%, 2.1%, 2.15%, 2.2%, 2.25%, 2.3%, 2.35%, 2.4%, 2.45%, or 2.5% by weight of the composition.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the hydroxypropyl methyl cellulose in the seal coat present at about 3%, 3.05%, 3.1%, 3.15%, 3.2%, 3.25%, 3.3%, 3.35%, 3.4%, 3.45%, 3.5%, 3.55%, 3.6%, 3.65%, 3.7%, 3.75%, 3.8%, 3.85%, 3.9%, 3.95%, 4% by weight of the composition.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the release control component is present at about 2.0-4.0% by weight.

### Claim 5 (depends on 1)

The composition of claim 1, wherein the unit dosage form is a tablet or capsule.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the anagrelide hydrochloride monohydrate is present in an amount that is equivalent to about 500 μg of anagrelide free base.

### Claim 7 (depends on 1)

A method for treating a myeloproliferative disease in a subject having a platelet count exceeding 600×103 per μl of blood, the method comprising administering the composition of claim 1 in an amount effective to reduce the circulating platelet count in the subject.

### Claim 8 (depends on 7)

The method of claim 7, wherein the circulating platelet count in the subject is reduced by at least 20%.

### Claim 9 (depends on 7)

The method of claim 7, wherein the circulating platelet count in the subject is reduced by at least 30%.

### Claim 10 (depends on 7)

The method of claim 7, wherein the circulating platelet count in the subject is reduced by at least 50%.

### Claim 11 (depends on 7)

The method of claim 7, wherein the circulating platelet count in the subject is reduced to below about 450×103 per μl of blood.

### Claim 12 (depends on 7)

The method of claim 7, wherein the composition comprises about anagrelide hydrochloride monohydrate in an amount that is equivalent to about 500 μg of anagrelide free base.

### Claim 13 (depends on 7)

The method of claim 7, wherein the composition is administered orally at least once daily.

### Claim 14 (depends on 7)

The method of claim 7, wherein the composition is administered at a dosage of anagrelide hydrochloride monohydrate in an amount that is equivalent to about 1000 μg of anagrelide free base per day.

### Claim 15 (depends on 7)

The method of claim 7, wherein the myeloproliferative disease is essential thrombocythemia.

### Claim 16 (depends on 15)

The method of claim 15, wherein the subject is intolerant to previous therapy for essential thrombocythemia or whose elevated platelet counts are not reduced to an acceptable level by previous therapy.

### Claim 17

A method of treating essential thrombocythemia in a subject having a circulating platelet count exceeding 600×103 per μl of blood, the method comprising orally administering anagrelide hydrochloride to the subject in a unit dosage at least once daily, wherein the unit dosage form comprises:
(a) a solid support core comprising a plurality of non-pareil sugar spheres at a size range of about 700 microns to about 850 microns (20-25 mesh sieve);
(b) a substrate layer comprising hydroxypropyl methylcellulose and microparticles of anagrelide hydrochloride monohydrate in hydrated crystal form in an amount that is equivalent to about 500 μg of anagrelide free base, wherein at least 90% of the microparticles are 25 microns or less, and the hydroxypropyl methylcellulose in the substrate layer is present at about 2-4% by weight of the composition;
(c) a seal coat layer comprising hydroxypropyl methylcellulose, wherein the seal coat layer is present at about at about 2-4% by weight of the composition; and
(d) a release control component comprising ethyl cellulose and hydroxypropyl methyl cellulose at a ratio of about 3:1 and triethyl citrate, wherein the release control component is present at about 1-5% by weight of the composition;
wherein the seal coat layer is disposed between the substrate layer and the release control component and reduces chemical interaction between the anagrelide hydrochloride monohydrate in the substrate layer and the triethyl citrate in the release control component.

### Claim 18 (depends on 17)

The method of claim 17, wherein the circulating platelet count in the subject is reduced to below about 450×103 per μl of blood.

### Claim 19 (depends on 17)

The method of claim 17, wherein the subject is intolerant to previous therapy for essential thrombocythemia.

### Claim 20 (depends on 19)

The method of claim 19, wherein the previous therapy was hydroxycarbamide.