# US 7,612,073 B2 · Methods of administering tetrahydrobiopterin, associated compositions, and methods of measuring

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 7,612,073 B2
- Document ID: US7612073B2
- Status: Granted
- Kind: B2
- Application number: 12/329,838
- Filed: 2008-12-08
- Published: 2009-03-19
- Granted: 2009-11-03
- Earliest claimed: 2007-04-11
- Assignees: Biomarin Pharmaceutical Inc.
- Inventors: Daniel I. Oppenheimer; Alejandro Dorenbaum
- Web page: https://patentgrep.com/patent/US7612073B2

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/0065: {Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus}
- A61K 9/0095: {Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches (A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006)}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 9/2027: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- 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 9/4891: {Coated capsules; Multilayered drug free capsule shells (with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/02: Nutrients, e.g. vitamins, minerals
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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 25/00: Drugs for disorders of the nervous system
- A61P 25/06: Antimigraine agents
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07B 63/00: Purification; Separation (separation of optically-active compounds C07B57/00); Stabilisation; Use of additives
- C07D 487/04: Ortho-condensed systems
- G01N 33/6848: {Methods of protein analysis involving mass spectrometry}
- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- A61K 9/2086: {Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat (active cores with a complete drug-free outer coat A61K9/28)}
- G01N 30/7233: {interfaced to liquid or supercritical fluid chromatograph (interfaces in general for introducing or extracting samples to be analysed with specially adapted mass spectrometer, see H01J49/04)}
- H01J 49/004: {Combinations of spectrometers, tandem spectrometers, e.g. MS/MS, MSn}
- Y10T 436/147777: Plural nitrogen in the same ring [e.g., barbituates, creatinine, etc.]
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- H01J: ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS (spark-gaps H01T; electric arc lamps H05B31/00; particle accelerators H05H)
- Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION

## Abstract

The present invention is directed to treatment methods of administering tetrahydrobiopterin, including in oral dosage forms, in intravenous formulations, and with food. Also disclosed herein are biopterin assays for measuring the amount of biopterin and metabolites of biopterin in a sample.

## Claims

### Claim 1

A method of treating hyperphenylalaninemia (HPA) comprising orally administering to a patient diagnosed with HPA a therapeutically effective amount of tetrahydrobiopterin (BH4) or a pharmaceutically acceptable salt thereof, at a daily dose of 5 to 20 mg/kg and for a duration of at least 3 weeks or longer, wherein said administering comprises (i) dissolving a tablet or capsule of said BH4 or pharmaceutically acceptable salt thereof in liquid, and separately (ii) taking the dissolved BH4 or pharmaceutically acceptable salt thereof orally with food, at the same time as the food or within approximately 30 minutes after the food.

### Claim 2 (depends on 1)

The method of claim 1 further comprising informing said human that absorption of said BH4 or pharmaceutically acceptable salt thereof is increased when it is ingested with food.

### Claim 3 (depends on 1)

The method of claim 1, further comprising informing the human that both the mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of BH4 are increased when the BH4 or pharmaceutically acceptable salt thereof is administered with a high-fat, high-calorie meal, compared to when the BH4 or pharmaceutically acceptable salt thereof is administered under fasted conditions.

### Claim 4 (depends on 3)

The method of claim 3, wherein the increases in Cmax and AUC are increases of at least 30%.

### Claim 5 (depends on 1)

The method of claim 1, wherein said BH4 is a crystalline polymorph, as a hydrochloride salt, that exhibits an X-ray powder diffraction pattern with the following characteristic peaks expressed in d-values (Å): 8.7 (vs), 5.63 (m), 4.76 (m), 4.40 (m), 4.00 (s), 3.23 (s), 3.11 (vs), preferably 8.7 (vs), 6.9 (w), 5.90 (vw), 5.63 (m), 5.07 (m), 4.76 (m), 4.40 (m), 4.15 (w), 4.00 (s), 3.95 (m), 3.52 (m), 3.44 (w), 3.32 (m), 3.23 (s), 3.17 (w), 3.11 (vs), 3.06 (w), 2.99 (w), 2.96 (w), 2.94 (m), 2.87 (w), 2.84 (s), 2.82 (m), 2.69 (w), 2.59 (w), and 2.44 (w).

### Claim 6 (depends on 1)

The method of claim 1, wherein the human has been diagnosed with HPA due to BH4-responsive phenylketonuria (PKU).

### Claim 7 (depends on 1)

The method of claim 1, wherein the human has been diagnosed with HPA due to BH4 deficiency.

### Claim 8 (depends on 1)

The method of claim 1, wherein the frequency of administering the BH4 or pharmaceutically acceptable salt thereof consists of once daily administration.

### Claim 9

A method of increasing absorption of tetrahydrobiopterin (BH4), comprising orally administering to a human in need thereof a therapeutically effective amount of BH4 or a pharmaceutically acceptable salt thereof dissolved in a liquid, at the same time as or within approximately 30 minutes after a high fat, high calorie meal, to increase absorption of BH4.

### Claim 10 (depends on 9)

The method of claim 9, wherein the increase in absorption of said BH4 is characterized by increases in mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of at least about 30%.

### Claim 11

A method of treating hyperphenylalaninemia (HPA) comprising orally administering to a patient diagnosed with HPA a daily dose of 5 to 20 mg/kg of tetrahydrobiopterin (BH4) or a pharmaceutically acceptable salt thereof, wherein said administering comprises (i) dissolving a tablet or capsule of said BH4 or pharmaceutically acceptable salt thereof in liquid, and separately (ii) taking the dissolved BH4 or pharmaceutically acceptable salt thereof orally, at the same time as or within approximately 30 minutes after a high fat, high calorie meal.