# US 10,117,834 B2 · Formulations and methods for lyophilization and lyophilates provided thereby

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- Number: US 10,117,834 B2
- Document ID: US10117834B2
- Status: Granted
- Kind: B2
- Application number: 14/508,488
- Filed: 2014-10-07
- Published: 2015-05-21
- Granted: 2018-11-06
- Earliest claimed: 2007-12-04
- Assignees: Biogen Chesapeake LLC
- Applicants: Biogen Chesapeake LLC
- Inventors: Sven Jacobson
- Web page: https://patentgrep.com/patent/US10117834B2

## CPC

- A61K 9/1682: {Processes}
- 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 9/1611: {Inorganic compounds}
- A61K 9/1623: {Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 31/175: having the group [IMAGE cpc-sch-A61K-0950.gif] , >N—C(O)—N=N— or[IMAGE cpc-sch-A61K-0951.gif] , e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
- A61K 31/451: having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
- A61K 31/64: Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/10: Antioedematous agents; Diuretics
- 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 9/12: Antihypertensives
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- A61P 31/04: Antibacterial agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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

## Abstract

The present invention provides compositions, methods for lyophilizing compounds and making pharmaceutical compositions, and kits providing solutions and lyophilized formulations of compounds. The compositions, methods, and kits are particularly useful in pharmaceutical applications involving therapeutic agents that have low solubility at low pH and medium pH values. Certain embodiments provide methods for lyophilizing compounds in liquid solutions, which include the steps of: a) preparing aqueous solutions of a compound of interest in the absence of buffer; b) adjusting the pH to high values of pH in order to increase the solubility of the compound of interest; and c) freeze-drying the solution to provide a lyophilized solid composition. Aqueous solutions including buffer are also disclosed. Lyophilized formulations, including micronized and non-micronized powders, are provided.

## Claims

### Claim 1

A lyophilized pharmaceutical composition, comprising:
a) glibenclamide or a pharmaceutically acceptable salt thereof,
b) at least one substantially pharmaceutically inert compound selected from the group consisting of glucose, fructose, mannose, galactose, mannitol, sorbitol, lactose, trehalose, sucrose, sodium chloride and potassium chloride, and
c) one or more alkali bases,
wherein the lyophilized pharmaceutical composition contains said one or more alkali bases in an amount sufficient such that when said lyophilized pharmaceutical composition is reconstituted in deionized water at a concentration of about 0.2 mg/mL to about 1.0 mg/mL, its pH is greater than 8, and
wherein the lyophilized pharmaceutical composition is stable for at least 3 months at 25° C. and 60% relative humidity.

### Claim 2 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein the weight of the one or more of glucose, fructose, mannose, galactose, mannitol, sorbitol, lactose, trehalose, sucrose, sodium chloride, and potassium chloride comprises at least about 10 times the weight of glibenclamide or a pharmaceutically acceptable salt thereof in the lyophilized pharmaceutical composition.

### Claim 3 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein the lyophilized pharmaceutical composition is a powder.

### Claim 4 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein the at least one substantially pharmaceutically inert compound comprises mannitol.

### Claim 5 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein the one or more alkali bases comprise sodium hydroxide or potassium hydroxide.

### Claim 6 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein the at least one substantially pharmaceutically inert compound comprises mannitol and the one or more alkali bases comprise sodium hydroxide.

### Claim 7 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein the lyophilized pharmaceutical composition contains said one or more alkali bases in an amount sufficient such that when said lyophilized pharmaceutical composition is reconstituted in deionized water at a concentration of about 0.2 mg/mL to about 1.0 mg/mL, its pH is greater than 10.

### Claim 8 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein the composition further includes a buffer and a second pharmaceutically active compound.

### Claim 9

A method for preparing a pharmaceutically acceptable injection solution having increased solubility of glibenclamide or a pharmaceutically acceptable salt thereof therein by lyophilizing glibenclamide in a liquid solution, comprising:
a) preparing an aqueous solution comprising glibenclamide or a pharmaceutically acceptable salt thereof and a substantially pharmaceutically inert compound,
b) adjusting the pH of the aqueous solution to a value greater than pH 10 to increase the solubility of the glibenclamide,
c) adding at least one pharmaceutically substantially inert compound selected from the group consisting of glucose, fructose, mannose, galactose, mannitol, sorbitol, lactose, trehalose, sucrose, sodium chloride and potassium chloride before, during or after steps a) or b),
d) freeze-drying the solution to provide a lyophilized solid composition,
e) reconstituting the lyophilized solid composition in an aqueous solution to form a reconstituted glibenclamide solution having a pH less than 10, and
f) diluting the reconstituted glibenclamide solution with an aqueous solution to form a diluted glibenclamide solution having glibenclamide or a pharmaceutically acceptable salt thereof at a concentration of about 1.0 mg/mL and a pH of about 6 to about 8,
wherein organic solvents are not used in said method.

### Claim 10 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein glibenclamide is in the form of a pharmaceutically acceptable salt.

### Claim 11 (depends on 1)

The lyophilized pharmaceutical composition of claim 1, wherein the composition contains less than 0.1% w/w of agents that enhance the solubility of glibenclamide.

### Claim 12 (depends on 11)

The lyophilized pharmaceutical composition of claim 11, wherein the composition contains less than 0.01% w/w of agents that enhance the solubility of glibenclamide.

### Claim 13 (depends on 12)

The lyophilized pharmaceutical composition of claim 12 wherein the composition is substantially free of agents that enhance the solubility of glibenclamide.

### Claim 14 (depends on 9)

The method of claim 9, wherein the weight of the at least one substantially pharmaceutically inert compound comprises at least about 10 times the weight of glibenclamide or a pharmaceutically acceptable salt thereof in the lyophilized solid composition.

### Claim 15 (depends on 9)

The method of claim 9, wherein the lyophilized solid composition is a powder.

### Claim 16 (depends on 9)

The method of claim 9, wherein the at least one substantially pharmaceutically inert compound comprises mannitol.

### Claim 17 (depends on 9)

The method of claim 9, wherein the adjusting of the pH comprises adding sodium hydroxide or potassium hydroxide.