IP Verse

Pharmaceutical Formulations Comprising 4-{(1R)-2-[(6-{2-[(2,6-Dichlorobenzyl)Oxy]Ethoxy}Hexyl)Amino]-1-Hydroxyethyl}-2-(Hydroxymethyl) Phenol

Patent No. US11116721 (titled "Pharmaceutical Formulations Comprising 4-{(1R)-2-[(6-{2-[(2,6-Dichlorobenzyl)Oxy]Ethoxy}Hexyl)Amino]-1-Hydroxyethyl}-2-(Hydroxymethyl) Phenol") was filed by Glaxo Group Ltd on Feb 26, 2009.

What is this patent about?

’721 is related to the field of pharmaceutical formulations, specifically those designed for inhalation to treat respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD). The background involves the use of beta-2 adrenoreceptor agonists for bronchodilation and corticosteroids for inflammation, often requiring separate treatments. The goal is to provide a convenient and effective combination therapy.

The underlying idea behind ’721 is to create a stable and effective dry powder formulation containing both a long-acting beta-2 agonist, specifically 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol (Compound I), and a corticosteroid, 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester (Compound II), for simultaneous delivery to the lungs. The formulation aims to improve patient compliance and therapeutic outcomes by combining bronchodilation and anti-inflammatory effects in a single inhaler.

The claims of ’721 focus on a pharmaceutical product comprising two dry powder formulations. One formulation contains a micronized form of Compound I, or a pharmaceutically acceptable salt thereof such as the triphenylacetate salt, in specific doses (12.5, 25, or 50 mcg), mixed with lactose and a defined percentage (0.6 to 2% w/w) of magnesium stearate . The other formulation contains Compound II, a corticosteroid, mixed with lactose, at various doses such as 100 mcg or 200 mcg.

In practice, the invention involves carefully blending the active pharmaceutical ingredients (APIs) with excipients to achieve a homogeneous mixture with the desired particle size distribution for effective inhalation. The magnesium stearate acts as a ternary agent , improving the flow properties of the powder and ensuring consistent dosing. The lactose serves as a carrier, increasing the bulk of the formulation and aiding in the dispersion of the micronized drug particles within the inhaler device.

The differentiation from prior approaches lies in the specific combination of Compound I and Compound II in a dry powder formulation that includes magnesium stearate. This ternary mixture enhances the stability and dispersibility of the formulation, leading to improved drug delivery to the lungs. The defined ratios of the components, particularly the magnesium stearate content, are crucial for achieving optimal performance and consistent dosing, addressing limitations of earlier formulations that may have suffered from poor flowability or inconsistent drug delivery.

How does this patent fit in bigger picture?

Technical landscape at the time

In the late 2000s when ’721 was filed, inhaled medications for respiratory diseases were typically delivered using dry powder inhalers or metered-dose inhalers. At a time when combination therapies were becoming more common, systems commonly relied on combining a bronchodilator with a corticosteroid to address both bronchoconstriction and inflammation. When hardware or software constraints made precise control of particle size and formulation stability non-trivial, achieving consistent drug delivery to the lungs was a key engineering challenge.

Novelty and Inventive Step

The examiner allowed the claims because the applicant provided data showing unexpected results for a fluticasone furoate/vilanterol combination compared to a fluticasone propionate/salmeterol combination. Specifically, clinical trials demonstrated a statistically significant improvement in 24-hour lung function favoring the claimed combination. The examiner also withdrew rejections based on double patenting because the cited references did not teach or suggest the specific dry powder formulation with defined doses of the two compounds, lactose, and magnesium stearate.

Claims

This patent contains 67 claims, with independent claims numbered 1, 12, 20, 49, 50, and 51. The independent claims are directed to pharmaceutical products containing dry powder formulations of two compounds for respiratory treatment. The dependent claims generally specify details of the formulations, methods of administration, and diseases treated using the pharmaceutical products.

Key Claim Terms New

Definitions of key terms used in the patent claims.

Term (Source)Support for SpecificationInterpretation
4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol
(Claim 1, Claim 12, Claim 20, Claim 49, Claim 50, Claim 51)		“To date, 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol (and salts thereof) has been extensively tested in animal and human studies and has been found to demonstrate sustained bronchodilation over a 24 hour period in conjunction with a favourable safety profile and thus has the potential for once-daily administration. In a first aspect the present invention provides a novel formulation comprising 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol: or a pharmaceutically acceptable salt thereof (Compound I), a carrier such as lactose and a ternary agent such as magnesium stearate.”A selective beta-2 adrenoreceptor agonist, also referred to as Compound (I), used in the treatment of respiratory diseases.
6α, 9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester
(Claim 1, Claim 12, Claim 20, Claim 49, Claim 50, Claim 51)		“Compound (II) has also been the subject of extensive studies in animal models and humans and has been found to be a long acting inhaled glucocorticosteroid which has potential for once-daily administration to the lungs. Compound (II) is considered to have potential in the treatment of respiratory tract disease such as chronic obstructive pulmonary disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema and allergic rhinitis. Compound (II) may be presented as a formulation for inhalation, for example as described in WO02/12265.”A long acting inhaled glucocorticosteroid, also referred to as Compound (II), used in combination with Compound (I) for the treatment of respiratory diseases.
Dry powder formulation
(Claim 1, Claim 12, Claim 20, Claim 49, Claim 50, Claim 51)		“Said formulation is suitable for topical delivery to the lung by inhalation, and may be administered by inhalation via the nose or mouth. Formulations of Compound (I) with lactose and magnesium stearate have been found to demonstrate good levels of physical and chemical stability of the product, including at lower product strengths. Said formulation may be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing the active ingredient into association with said carrier and ternary agent.”A formulation in powder form suitable for inhalation, comprising the active pharmaceutical ingredient(s) and excipients such as lactose and magnesium stearate.
Magnesium stearate
(Claim 1, Claim 12, Claim 20, Claim 49, Claim 50, Claim 51)		“Magnesium stearate is generally present in an amount of 0.2 to 2%, e.g. 0.6 to 2%%, e.g. 0.75%, 1%, 1.25% or 1.5%. The magnesium stearate will typically have a particle size in the range 1 to 50 μm, and more particularly 1-20 μm, e.g. 1-10 μm. As is well known in the art stearic acid may comprise a mixture of stearic and palmitic acids; small amounts of other acids, e.g., lauric acid, myristic acid and/or arachic acid may also be present.”A ternary agent present in the dry powder formulation, typically in an amount of 0.6 to 2% w/w, used in combination with lactose and Compound (I).
Micronized form
(Claim 1, Claim 12, Claim 20, Claim 49, Claim 50, Claim 51)		“Medicaments for administration by inhalation desirably have a controlled particle size. The optimum particle size for inhalation into the bronchial system is usually 1-10 μm, preferably 2-5 μm. Particles having a size above 20 μm are generally too large when inhaled to reach the small airways. To achieve these particle sizes the particles of the active ingredient as produced may be size reduced by conventional means e.g. by micronization.”The physical state of Compound (I) in the dry powder formulation, having a particle size suitable for inhalation.

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US11116721

GLAXO GROUP LTD
Application Number
US13148982
Filing Date
Feb 26, 2009
Status
Granted
Expiry Date
Feb 26, 2029
External Links
Slate, USPTO, Google Patents