Hydrocortisone acetate suppository formulation for treatment of disease
Inventors
Davagian, Jennifer J. • Devarajan, Raj
Assignees
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Publication Number
US-12115253-B2
Publication Date
2024-10-15
Expiration Date
Abstract
The present invention relates, in various embodiments, to formulations comprising hydrocortisone and silicon dioxide. In additional embodiments, the invention relates to suppositories comprising hydrocortisone and silicon dioxide. The formulations of the present invention are useful for administration to patients who have gastrointestinal diseases and disorders such as, for example, inflammatory bowel disease.
Core Innovation
The disclosure relates to rectal formulations comprising hydrocortisone acetate and colloidal silicon dioxide, optionally with an oleaginous triglyceride base, and further optionally with butylated hydroxytoluene (BHT). The formulations are directed to gastrointestinal diseases, including ulcerative colitis and ulcerative proctitis, and are described as hydrocortisone acetate rectal suppository formulations containing hydrocortisone acetate and colloidal silicon dioxide within specified weight ranges.
The problem addressed is providing a hydrocortisone acetate rectal formulation with improved dissolution/release performance and better retention, while reducing absorption variability and reducing dependence on melting. The disclosure emphasizes achieving a dissolution profile in which at least about 80% release is obtained at about 180 minutes in buffered 5% w/v sodium lauryl sulfate (SLS) at about pH 6.8 to 7.0, together with stability performance for impurities and assay.
A further aspect of the invention concerns manufacturing and formulation structure, including multiple rectal drug-component geometries and an insertion applicator concept for targeted placement at the anal-rectal line. The disclosure describes lead formulation selection based on melting, dissolution, and impurity/assay stability, including an exemplary suppository with hydrocortisone acetate and colloidal silicon dioxide in the presence of a specified base, and alternative geometries such as ring, tree, filaments, medicated film, fabric, sponge, and water-soluble shell.
Claims Coverage
The provided independent claims cover five inventive features for making a hydrocortisone acetate formulation comprising hydrocortisone acetate, colloidal silicon dioxide, and a semi-synthetic glyceride base comprising saturated C8-C18 triglyceride fatty acids and lecithin, with specified formulation weight ranges.
Melting semi-synthetic glyceride base, adding hydrating colloidal silicon dioxide, and adding hydrocortisone acetate
A method of making a formulation by melting a semi-synthetic glyceride base comprising saturated C8-C18 triglyceride fatty acids and lecithin, adding colloidal silicon dioxide to the melted base to produce a batch by mixing the colloidal silicon dioxide with the base to hydrate the colloidal silicon dioxide, and adding hydrocortisone acetate to thereby produce a formulation wherein the formulation comprises about 0.5% to about 5% by weight hydrocortisone acetate and about 0.1% to about 5% by weight colloidal silicon dioxide.
Melting using hot stir plate and water bath and hydrating colloidal silicon dioxide
A method where the semi-synthetic glyceride base comprising saturated C8-C18 triglyceride fatty acids and lecithin is melted using a hot stir plate and water bath; colloidal silicon dioxide is added to the melted base to produce a batch by mixing the colloidal silicon dioxide with the base to hydrate the colloidal silicon dioxide; and hydrocortisone acetate is added to produce a formulation comprising about 0.5% to about 5% by weight hydrocortisone acetate and about 0.1% to about 5% by weight colloidal silicon dioxide.
Low shear sweep or side scrape mixing for melting and hydrating colloidal silicon dioxide
A method where the semi-synthetic glyceride base comprising saturated C8-C18 triglyceride fatty acids and lecithin is melted using low shear sweep or side scrape mixing, or a combination thereof; colloidal silicon dioxide is added to the melted base to produce a batch by mixing the colloidal silicon dioxide with the base to hydrate the colloidal silicon dioxide; and hydrocortisone acetate is added to produce a formulation comprising about 0.5% to about 5% by weight hydrocortisone acetate and about 0.1% to about 5% by weight colloidal silicon dioxide.
Mesh to hydrate colloidal silicon dioxide during addition
A method where a semi-synthetic glyceride base comprising saturated C8-C18 triglyceride fatty acids and lecithin is melted; colloidal silicon dioxide is added to the melted base to produce a batch, wherein adding the colloidal silicon dioxide comprises mixing the colloidal silicon dioxide with the base using a mesh to hydrate the colloidal silicon dioxide; and hydrocortisone acetate is added to produce a formulation comprising about 0.5% to about 5% by weight hydrocortisone acetate and about 0.1% to about 5% by weight colloidal silicon dioxide.
Homogenizer mixing to add hydrocortisone acetate after hydrating colloidal silicon dioxide
A method where a semi-synthetic glyceride base comprising saturated C8-C18 triglyceride fatty acids and lecithin is melted; colloidal silicon dioxide is added to the melted base to produce a batch by mixing the colloidal silicon dioxide with the base to hydrate the colloidal silicon dioxide; and hydrocortisone acetate is added to the batch by mixing using a homogenizer, thereby producing a formulation comprising about 0.5% to about 5% by weight hydrocortisone acetate and about 0.1% to about 5% by weight colloidal silicon dioxide.
Overall, the independent claims define a formulation-making sequence in which a semi-synthetic glyceride base with saturated C8-C18 triglyceride fatty acids and lecithin is melted, colloidal silicon dioxide is incorporated to hydrate it, and hydrocortisone acetate is added to yield a formulation with specified hydrocortisone acetate and colloidal silicon dioxide weight ranges; the claims distinguish themselves by the melting and incorporation approach and, in one independent claim, by requiring mixing using a homogenizer when adding hydrocortisone acetate.
Stated Advantages
Improved retention and reduced absorption variability.
Less dependence on melting.
At least about 80% release at about 180 minutes in buffered 5% w/v SLS (pH about 6.8 to 7.0).
Stability for impurities and assay.
Documented Applications
Rectal suppository formulations for gastrointestinal diseases including ulcerative colitis and ulcerative proctitis.
Use in inflammatory bowel disease (IBD), including ulcerative colitis and ulcerative proctitis, and including Crohn's disease as stated in the disclosure.
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