Alkaline phosphatase formulations and uses thereof
The present invention provides, in part, formulations comprising an alkaline phosphatase. Particularly, modified-release formulations comprising an alkaline phosphatase are provided, which release a substantial amount of the alkaline phosphatase in the intestines. Therapeutic uses of the alkaline phosphatase formulations are also provided.
1 . A modified-release formulation comprising at least one modified-release pellet comprising an alkaline phosphatase (AP)-based agent contained in a capsule, wherein the modified-release formulation comprises:
about 5-15% by weight AP-based agent;
about 35-45% by weight sucrose sphere;
about 15-25% by weight hydroxypropylcellulose;
about 0.1-1% by weight of buffer salt;
about 20-30% by weight enteric polymer; and
about 1-10% by weight coating system additive, wherein the coating system additive is a mixture of glyceryl monostearate, polysorbate-80, and triethyl citrate, wherein the formulation maintains at least 80% AP-based agent activity when stored at 2-8° C. for at least 6 months.
2 . The modified-release formulation of claim 1 , wherein the modified-release formulation comprises:
about 10% by weight AP-based agent;
about 39% by weight sucrose sphere;
about 20% by weight hydroxypropylcellulose;
about 0.5% by weight of buffer salt; and
about 26% by weight enteric polymer.
3 . The modified-release formulation of claim 1 , wherein the modified-release formulation comprises:
about 10.0% by weight AP-based agent;
about 38.9% by weight sucrose sphere;
about 20.0% by weight hydroxypropylcellulose;
about 0.3% by weight of buffer salt; and
about 26.3% by weight enteric polymer.
4 . The modified-release formulation of claim 1 , wherein the capsule comprises about 15 mg or 5 mg of AP-based agent.
5 . The modified-release formulation of claim 1 , wherein the capsule comprises gelatin or hydroxypropyl methylcellulose.
6 . The modified-release formulation of claim 1 , wherein the AP-based agent comprises an amino acid sequence having at least 90% identity with any one of SEQ ID NOs: 1-17 and 39.
7 . The modified-release formulation of claim 1 , wherein the AP-based agent is substantially released in the small intestine, or in the large intestine.
8 . The modified-release formulation of claim 1 , wherein the formulation comprises a core particle and a base coat over the core particle, wherein the base coat comprises the AP-based agent.
9 . The modified-release formulation of claim 1 , wherein the formulation further comprises a modified-release coating that is substantially stable in gastric fluid.
10 . The modified-release formulation of claim 1 , wherein the formulation comprises a modified-release coating that is degraded by a microbial enzyme present in the gut flora.
11 . The modified-release formulation of claim 1 , wherein the formulation comprises a modified-release coating having a solubility that is pH-dependent.
12 . The modified-release formulation of claim 1 , wherein the formulation comprises a modified-release coating having a time-dependent erosion profile.
13 . The modified-release formulation of claim 1 , wherein the formulation further comprises an additional therapeutic agent.
14 . The modified-release formulation of claim 1 , wherein the buffer salt is selected from a Tris base, magnesium chloride, magnesium sulfate, zinc chloride and zinc sulfate.
15 . The modified-release formulation of claim 1 , wherein the enteric polymer is selected from poly(methacrylic acid-ethyl acrylate copolymer) 1:1, FS 30D, L 100-55, L 100, L 12,5, L 12,5 P, RL 30 D, RL PO, RL 100, RL 12,5, RS 30 D, RS PO, RS 100, RS 12,5, NE 30 D, NE 40 D, NM 30 D, S 100, S 12,5, and S 12,5 P.
16 . The modified-release formulation of claim 1 , wherein the modified-release formulation comprises:
10.0% by weight AP-based agent;
38.9% by weight sucrose sphere;
20.0% by weight hydroxypropylcellulose;
0.3% by weight of buffer salt;
26.3% by weight enteric polymer; and
4.5% by weight coating system additive, wherein the coating system additive is a combination of glyceryl monostearate, polysorbate-80, and triethyl citrate;
wherein the capsule comprises about 15 mg or 5 mg of AP-based agent; and
wherein the AP-based agent comprises an amino acid sequence having at least 90% identity with any one of SEQ ID NOs: 1-17 and 39.
17 . A method of treating or preventing a radiation-induced disorder in a subject in need thereof comprising, administering to the subject a formulation of claim 1 .
18 . The method of claim 17 , wherein the radiation-induced disorder is selected from enterocolitis due to radiation therapy for cancer, radiation-induced enteropathy, colitis, proctitis, bowel toxicity, mucosal atrophy, vascular sclerosis, progressive intestinal wall fibrosis, and a side effect of radiotherapy.
19 . The method of claim 17 , wherein the radiation comprises ionizing radiation, optionally wherein the radiation comprises one or more of X-rays, gamma rays, and charged particles.