Claims for Patent: 10,683,335

Summary for Patent: 10,683,335

Title:	Freeze-dried preparation containing high-purity PTH and method for producing same
Abstract:	Provided herein are freeze-dried preparations comprising a high-purity parathyroid hormone (PTH) peptide and one or more PTH analogs, and methods for the production thereof. Also provided is a test method for detecting PTH analogs to confirm the purity of a freeze-dried preparation containing PTH peptide, and the like.
Inventor(s):	Nishio; Fumihide (Tokyo, JP), Maejima; Takuji (Tokyo, JP), Mitome; Yoshiro (Tokyo, JP)
Assignee:	ASAHI KASEI PHARMA CORPORATION (Tokyo, JP)
Application Number:	15/991,485
Patent Claims:	1. A method for producing a freeze-dried preparation containing human parathyroid hormone (PTH) (1-34), wherein the method is conducted in a pharmaceutical production facility, the method comprising: (a) preparing a solution comprising the human PTH (1-34); (b) loading the solution comprising the human PTH (1-34) into a freeze-drying apparatus; (c) producing a freeze-dried preparation comprising the human PTH (1-34) from the solution; and (d) controlling contact of the human PTH (1-34) with ozone in the air in a Grade A zone of the facility at least during (b) to produce the freeze-dried preparation comprising human PTH (1-34) in which (i) a ratio of an amount of any one human PTH (1-34) analog to the sum of the total amount of human PTH (1-34) and the total amount of human PTH (1-34) analogs in the freeze-dried preparation is 1.0% or less, and (ii) a ratio of the total amount of the human PTH (1-34) analogs to the sum of the total amount of human PTH (1-34) and the total amount of human PTH (1-34) analogs in the freeze-dried preparation is 5.0% or less; wherein the ozone in the air is present in an amount of from 0.02-0.1 ppm. 2. The method of claim 1, wherein the air comprises formaldehyde. 3. The method of claim 1, wherein the freeze-dried preparation is sterile. 4. The method of claim 1, wherein the human PTH analogs are selected from one or more of the group consisting of: a) analog 1 comprising an oxide of the human PTH (1-34) having a molecular weight 64 Daltons (Da) greater than the molecular weight of the human PTH (1-34), wherein a trypsin digestion of the analog 1 produces digestion products corresponding to fragments (1-a) to (1-c), wherein (1-a) comprises the amino acid sequence Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys (SEQ ID NO: 1) having a molecular weight of about 1472 Da, (1-b) comprises the amino acid sequence His-Leu-Asn-Ser-Met-Glu-Arg (SEQ ID NO: 2) having a molecular weight of about 902 Da, and (1-c) comprises the amino acid sequence Val-Glu-Trp-Leu-Arg (SEQ ID NO: 3) having a molecular weight of about 706 Da; b) analog 2 comprising an oxide of the human PTH (1-34) having a molecular weight 36 Da greater than the molecular weight of the human PTH (1-34), wherein a trypsin digestion of the analog 2 produces digestion products corresponding to the fragments (1-a) to (1-c); c) analog 3 comprising an oxide of the human PTH (1-34) having a molecular weight 32 Da greater than the molecular weight of the human PTH (1-34), wherein a trypsin digestion of the analog 3 produces digestion products corresponding to the fragments (1-a) and (1-b); d) analog 4 comprising an oxide of the human PTH (1-34) having a molecular weight 48 Da greater than the molecular weight of the human PTH (1-34), wherein a trypsin digestion of the analog 4 produces digestion products corresponding to the fragments (1-a) and (1-c); e) analog 5 comprising an oxide of the human PTH (1-34) having a molecular weight 48 Da greater than the molecular weight of the human PTH (1-34), wherein a trypsin digestion of the analog 5 produces digestion products corresponding to the fragments (1-b) and (1-c); f) analog 6 comprising an oxide of the human PTH (1-34) having a molecular weight 20 Da greater than the molecular weight of the human PTH (1-34), wherein a trypsin digestion of the analog 6 produces digestion products corresponding to the fragments (1-b) and (1-c); g) analog 9 comprising an oxide of the human PTH (1-34) having a molecular weight 32 Da greater than the molecular weight of the human PTH (1-34), wherein a trypsin digestion of the analog 9 produces a digestion product corresponding to the fragment (1-c); h) analog 10 comprising an oxide of the human PTH (1-34) having a molecular weight 16 Da greater than the molecular weight of the human PTH (1-34), wherein a trypsin digestion of the analog 10 produces a digestion product corresponding to a fragment (1-d) comprises the amino acid sequence of SEQ ID NO: 3 and having a molecular weight of about 718 Da; i) analog 11 comprising an oxide of the human PTH (1-34) having a molecular weight 4 Da greater than the molecular weight of the human PTH (1-34), wherein a trypsin digestion of the analog 11 produces a digestion product corresponding to the fragment (1-c); j) analog 7 comprising an oxide of the human PTH (1-34) having a molecular weight 16 Da greater than the molecular weight of the human PTH (1-34), wherein a trypsin digestion of the analog 7 produces a digestion product corresponding to the fragment (1-a); and k) analog 8 comprising an oxide of the human PTH (1-34) having a molecular weight 16 Da greater than the molecular weight of the human PTH (1-34), wherein a trypsin digestion of the analog 7 produces a digestion product corresponding to the fragment (1-b). 5. The method of claim 1, wherein the human PTH analogs are selected from one or more of the group consisting of: a) analog 1' an oxide of the human PTH (1-34) in which residues corresponding to position 8 and position 18 methionine of the human PTH (1-34) are methionine sulfoxide residues and residue corresponding to a position 23 tryptophan is a residue of formula (a); b) analog 2' an oxide of the human PTH (1-34) in which the residues corresponding to the position 8 and position 18 methionine of the human PTH (1-34) are methionine sulfoxide residues and the residue corresponding to the position 23 tryptophan is a residue of formula (b); c) analog 3' an oxide of the human PTH (1-34) in which the residues corresponding to the position 8 and position 18 methionine of the human PTH (1-34) are methionine sulfoxide residues; d) analog 4' an oxide of the human PTH (1-34) in which the residue corresponding to the position 8 methionine of the human PTH (1-34) is a methionine sulfoxide residue and the residue corresponding to the position 23 tryptophan is the residue of formula (a); e) analog 5' an oxide of the human PTH (1-34) in which the residue corresponding to the position 18 methionine of the human PTH (1-34) is a methionine sulfoxide residue and the residue corresponding to the position 23 tryptophan is the residue of formula (a); f) analog 6' an oxide of the human PTH (1-34) in which the residue corresponding to the position 18 methionine of the human PTH (1-34) is a methionine sulfoxide residue and the residue corresponding to the position 23 tryptophan is the residue of formula (b); g) analog 9' an oxide of the human PTH (1-34) in which the residue corresponding to the position 23 tryptophan of the human PTH (1-34) is the residue of formula (a); h) analog 10' an oxide of the human PTH (1-34) in which the residue corresponding to the position 23 tryptophan of the human PTH (1-34) is a tryptophan monoxide residue of formula (c-1) or (c-2) below ##STR00007## i) analog 11' an oxide of the human PTH (1-34) in which the residue corresponding to the position 23 tryptophan of the human PTH (1-34) is the residue of formula (b); j) analog 7' an oxide of the human PTH (1-34) in which the residue corresponding to the position 8 methionine of the human PTH (1-34) is a methionine sulfoxide residue; and k) analog 8' an oxide of the human PTH (1-34) in which the residue corresponding to the position 18 methionine of the human PTH (1-34) is a methionine sulfoxide residue, wherein formula (a) is ##STR00008## and formula (b) is ##STR00009## 6. The method of claim 1, wherein (a) comprises dispensing the solution into one or more containers. 7. The method of claim 1, wherein the loading at (b) is carried out for a period of time of three or more hours. 8. The method of claim 6, wherein the containers are purged with an inert gas in advance of dispensing the solution or the freeze-drying apparatus is purged with an inert gas when loading the containers. 9. The method of claim 6, wherein the containers are glass vials. 10. The method of claim 1, wherein the freeze-drying apparatus comprises a freeze-drying chamber having an easily openable and closable sub-door provided in an opening created in a small door unit configured to be opened when the containers are loaded into or are unloaded from the chamber, and an inflow of the air within the pharmaceutical production facility into the freeze-drying apparatus is controlled by a process comprising opening the sub-door only during the loading and quickly closing the sub-door after the loading. 11. The method of claim 1, wherein the freeze-drying apparatus comprises a freeze-drying chamber having an opening created in a small door unit configured to be opened when the containers are loaded into or are unloaded from the chamber, and an inflow of air within the pharmaceutical production facility into the freeze-drying apparatus is controlled by a process comprising directing air flow within the pharmaceutical production facility away from the opening to the inside of the chamber by means of an airflow-adjusting cover configured to alter the air flow away from the opening of the chamber. 12. The method of claim 1, wherein the ratio of the amount of any one human PTH (1-34) analog to the sum of the total amount of human PTH (1-34) and the total amount of human PTH (1-34) analogs in the freeze-dried preparation is 0.6% or less. 13. The method of claim 1, wherein the ratio of the total amount of the human PT (1-34) analogs to the sum of the total amount of human PTH (1-34) and the total amount of human PTH (1-34) analogs in the freeze-dried preparation is 3.0% or less. 14. The method of claim 7, wherein the amount of the analog 1 in the preparation is 0.04% or less, the amount of the analog 3 and the analog 4 in the preparation is 0.11% or less, the amount of the analog 5 in the preparation is 0.26% or less; the amount of the analog 7 in the preparation is 0.33% or less; the amount of the analog 8 in the preparation is from 0.21-1.00%; and the amount of the analog 9 in the preparation is 0.68% or less.

Details for Patent 10,683,335

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2031-06-07