# US 10,869,835 B2 · Formulations and methods for lyophilization and lyophilates provided thereby

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- Number: US 10,869,835 B2
- Document ID: US10869835B2
- Status: Granted
- Kind: B2
- Application number: 16/585,255
- Filed: 2019-09-27
- Published: 2020-03-26
- Granted: 2020-12-22
- Earliest claimed: 2007-12-04
- Assignees: Biogen Chesapeake LLC
- Applicants: Biogen Chesapeake LLC
- Inventors: Sven Martin Jacobson
- Web page: https://patentgrep.com/patent/US10869835B2

## 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 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 method of forming a reconstituted pharmaceutical formulation, the method comprising reconstituting a lyophilized composition that comprises:
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,
in deionized water at a concentration of about 0.2 mg/mL to about 1.0 mg/mL of the glibenclamide or a pharmaceutically acceptable salt thereof, and forming said reconstituted pharmaceutical formulation having a pH greater than 8,
wherein the lyophilized composition is stable for at least 3 months at 25° C. and 60% relative humidity.

### Claim 2 (depends on 1)

The method 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 is at least about 10 times the weight of glibenclamide or a pharmaceutically acceptable salt thereof in the lyophilized composition.

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

The method of claim 1, wherein the at least one substantially pharmaceutically inert compound is mannitol.

### Claim 5 (depends on 1)

The method of claim 1, wherein the one or more alkali bases is sodium hydroxide or potassium hydroxide.

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 1)

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

### Claim 10 (depends on 1)

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

### Claim 11 (depends on 1)

The method of claim 1, wherein said reconstituted pharmaceutical formulation comprises glibenclamide or a pharmaceutically acceptable salt thereof at a concentration of about 1 mg/ml.

### Claim 12 (depends on 1)

The method of claim 1, wherein said reconstituted pharmaceutical formulation comprises glibenclamide or a pharmaceutically acceptable salt thereof, mannitol, sodium hydroxide, and water, and has an osmolality of 200 mOsm to 400 mOsm.

### Claim 13 (depends on 1)

The method of claim 1, wherein said reconstituted pharmaceutical formulation is suitable for intravenous administration.

### Claim 14 (depends on 1)

The method of claim 1, wherein said reconstituted pharmaceutical formulation is suitable for administration as a bolus injection.

### Claim 15 (depends on 1)

The method of claim 1, wherein said reconstituted pharmaceutical formulation is suitable for administration as an intravenous infusion.

### Claim 16

A container containing a reconstituted pharmaceutical formulation comprising a lyophilized composition that comprises:
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,
reconstituted in deionized water at a concentration of about 0.2 mg/mL to about 1.0 mg/mL of the glibenclamide or a pharmaceutically acceptable salt thereof, said reconstituted pharmaceutical formulation having a pH greater than 8,
wherein the lyophilized composition is stable for at least 3 months at 25° C. and 60% relative humidity.

### Claim 17 (depends on 16)

The container of claim 16, wherein the at least one substantially pharmaceutically inert compound is mannitol.

### Claim 18 (depends on 16)

The container of claim 16, wherein the one or more alkali bases is sodium hydroxide or potassium hydroxide.

### Claim 19 (depends on 16)

The container of claim 16, wherein the at least one substantially pharmaceutically inert compound is mannitol and the one or more alkali bases comprise sodium hydroxide.

### Claim 20 (depends on 16)

The container of claim 16, wherein glibenclamide is in the form of a pharmaceutically acceptable salt.

### Claim 21 (depends on 16)

The container of claim 16, wherein the lyophilized composition contains less than 0.1% w/w of agents that enhance the solubility of glibenclamide.

### Claim 22 (depends on 16)

The container of claim 16, wherein said reconstituted pharmaceutical formulation comprises glibenclamide or a pharmaceutically acceptable salt thereof at a concentration of about 1 mg/ml.

### Claim 23 (depends on 16)

The container of claim 16, wherein said reconstituted pharmaceutical formulation comprises glibenclamide or a pharmaceutically acceptable salt thereof, mannitol, sodium hydroxide, and water, and has an osmolality of 200 mOsm to 400 mOsm.