Intestinal alkaline phosphatase formulations
Inventors
Bristol, Andrew • STAPLETON, Ray • Kaleko, Michael • FURLAN FREGUIA, Christian • Hubert, Steven • FREIRE, Cristina • GUBBINS, James
Assignees
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Publication Number
US-11638699-B2
Publication Date
2023-05-02
Expiration Date
Abstract
The present invention provides for a formulation comprising an active alkaline phosphatase (AP)-based agent and an enteric agent, wherein the formulation is suitable for releasing a substantial amount of the active AP-based agent in the intestines.
Core Innovation
A formulation is provided in the form of a tablet that comprises an intestinal alkaline phosphatase (AP)-based agent, wherein the AP-based agent comprises an amino acid sequence of at least 95% sequence identity with the amino acid sequence set forth in SEQ ID NOs: 2, 3, 5, 6 or 7. The tablet further comprises sugar, buffer salts, and magnesium stearate, and maintains intestinal alkaline phosphatase activity at least at 60% until 36 weeks of storage.
The formulation is designed to provide an enteric, pH-dependent release in the intestines, including small intestine and large intestine. Enteric-coating materials include EUDRAGIT-type polymers, including EUDRAGIT L 30 D 55, and an optional two-layer coating arrangement including an HPC subcoat and an enteric coat.
The invention also covers AP-based agent variants and sources in which the intestinal alkaline phosphatase activity is maintained through processing and storage, including forms where the AP-based agent is selected from hIAP, cIAP, bIAP isozymes and sequence-identical variants. The formulation is further described with processing and composition choices intended to preserve enzymatic activity, and example tablets are disclosed with dissolution and release profiles under pH conditions.
Claims Coverage
The provided independent claim defines a tablet formulation with four main inventive elements: a high-sequence-identity intestinal AP-based agent, a storage activity retention threshold, and specific weight ranges for sugar, buffer salts, and magnesium stearate. The dependent claims refine these features with specific AP sequence selection, specific sugar and buffer-salt selections, enteric or two-layer coatings, and defined release constraints at specified pH and time.
Tablet formulation with high-sequence-identity intestinal AP-based agent
A formulation in the form of a tablet comprising 42-48% by weight intestinal alkaline phosphatase (AP)-based agent, wherein the AP-based agent comprises an amino acid sequence of at least 95% sequence identity with the amino acid sequence set forth in SEQ ID NOs: 2, 3, 5, 6 or 7.
Maintained intestinal alkaline phosphatase activity during storage
The tablet maintains activity of the intestinal alkaline phosphatase at least at 60% until 36 weeks of storage.
Defined sugar content
The tablet comprises 42-48% by weight sugar.
Defined buffer salts content
The tablet comprises 7-13% by weight buffer salts.
Magnesium stearate content range
The tablet comprises 0.5-1.5% by weight magnesium stearate.
High release within a defined time at defined pH
The formulation releases at least 75% of the AP-based agent within 15 minutes at pH 4-5.
AP-based agent limited to SEQ ID NO: 2 at ≥95% identity
The formulation is one in which the AP-based agent includes an amino acid sequence having at least 95% sequence identity with the sequence in SEQ ID NO: 2.
Sugar selected as lactose
The formulation is one in which the sugar is lactose.
Buffer salts selected from Tris, MgCl2, and ZnSO4
The formulation is one in which the buffer salts are selected from Tris, MgCl2, and ZnSO4.
Two-layer coating with HPC subcoat and enteric coating
The formulation includes a first coating with an HPC subcoat and a second coating with an enteric coating.
Across the independent claim and cited refinements, the core coverage centers on a tablet formulation with a high-sequence-identity intestinal AP-based agent and a storage activity retention requirement, combined with specified weight ranges for sugar, buffer salts, and magnesium stearate. Dependent refinements further narrow sequence identity to specific SEQ ID selection, specify sugar and buffer-salt identities, add enteric or two-layer coating configurations, and impose quantitative release performance at defined pH and time.
Stated Advantages
Maintains intestinal alkaline phosphatase activity at least at 60% until 36 weeks of storage.
Documented Applications
Therapeutic use for GI disorders associated with HIV/AIDS.
Use for cystic fibrosis (CF) GI dysfunction associated with CFTR mutations.
Prevention and/or treatment of necrotizing enterocolitis (NEC) in neonates, including premature and low birth weight, with staging per Bell et al.
Use for radiation-induced enteropathy/colitis/proctitis.
Use for metabolic diseases including metabolic syndrome, obesity, and diabetes (type 1/type 2; glucose intolerance) and related hypoglycemia/hyperglycemia.
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