US20030225000A1 - Stabilized teriparatide solutions - Google Patents
Stabilized teriparatide solutions Download PDFInfo
- Publication number
- US20030225000A1 US20030225000A1 US10/427,259 US42725903A US2003225000A1 US 20030225000 A1 US20030225000 A1 US 20030225000A1 US 42725903 A US42725903 A US 42725903A US 2003225000 A1 US2003225000 A1 US 2003225000A1
- Authority
- US
- United States
- Prior art keywords
- pth
- solution
- hormone
- composition
- acetate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 150000001896 cresols Chemical class 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- -1 for example Chemical class 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 1
- 108010050848 glycylleucine Proteins 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000001184 hypocalcaemic effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 108010044348 lysyl-glutamyl-aspartic acid Proteins 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- FJQXCDYVZAHXNS-UHFFFAOYSA-N methadone hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 FJQXCDYVZAHXNS-UHFFFAOYSA-N 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 210000002990 parathyroid gland Anatomy 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 208000006078 pseudohypoparathyroidism Diseases 0.000 description 1
- 230000000541 pulsatile effect Effects 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
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- 150000003839 salts Chemical class 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Definitions
- This invention relates to pharmaceutical compositions containing a parathyroid hormone. More particularly the invention relates to teriparatide, PTH(1-34), stabilized solution formulations
- Parathyroid hormone is a secreted. 84 amino acid product of the mammalian parathyroid gland that controls serum calcium levels through its action on various tissues, including bone. Studies in humans with certain forms of PTH have demonstrated an anabolic effect on bone, and have prompted significant interest in its use for the treatment of osteoporosis and related bone disorders.
- PTH preparations have been reconstituted from fresh or lyophilized hormone, and incorporate various forms of carrier, excipient and vehicle. Most are prepared in water-based vehicles such as saline, or water acidified typically with acetic acid to solubilize the hormone. The majority of reported formulations also incorporate albumin as a stabilizer (see for example Reeve at al., Br. Med. J., 1980, 280:6228; Reeve at al., Lancet, 1976. 1:1035; Reeve at al., Calcif. Tissue Res., 1976, 21:469; Hodsman et al., Bone Miner: 1990, 9(2):137; Tsai et al., J. Clin.
- Formulations representative of those employed for human studies include a human PTH(1-34) (SEQ ID NO: 2) preparation consisting, upon reconstitution, of mannitol, heat inactivated human serum albumin, and caproic acid (a protease inhibitor) as absorption enhancer (see Reeve at al., 1976, Calcif. Tissue Res., 21, Suppl., 469-477); a human PTH(1-38) preparation reconstituted into a saline vehicle (see Hodsman et al., 1991, 14(1), 67-83); and a bovine PTH(1-34) preparation in aqueous vehicle pH adjusted with acetic acid and containing albumin.
- parathyroid hormone requires the development of a formulation that is acceptable in terms of storage stability and ease of preparation. Because it is a protein and thus far more labile than the traditionally small molecular weight drugs, however, the formulation of parathyroid hormone presents challenges not commonly encountered by the pharmaceutical industry. Furthermore, like other proteins that have been formulated successfully, PTH is particularly sensitive to oxidation, deamidation and hydrolysis, and requires that its N-terminal and C-terminal sequences remain intact in order to preserve bioactivity.
- the present invention provides a pharmaceutical composition in the form of a stabilized solution containing a parathyroid hormone (PTH) in a therapeutically effective amount.
- the solution is storage stable and in sterile form, may be stored in vials or cartridges ready for parenteral administration in human patients.
- the advantages of the present solution is the elimination of the need for lyophilization.
- the present invention is a parathyroid hormone solution including:
- This solution may, if desired, undergo lyophilization to form a freeze-dried powder containing not more than 2% water by weight.
- Another aspect of the present invention is a parathyroid hormone solution including:
- a buffering agent in an amount sufficient to maintain the pH of the composition within a range of about 3-7 and selected from an acetate or tartrate source;
- Still another aspect of the present invention is a pharmaceutical composition in the form of a freeze-dried powder prior to reconstitution including:
- the invention relates to parathyroid hormone solutions that exhibit storage stability in terms of hormone composition and activity.
- the composition or solution may incorporate the full length, 84 amino acid form of parathyroid hormone, particularly the human form, hPTH (1-814) (SEQ ID NO: 1), obtained either recombinantly, by peptide synthesis or by extraction from human fluid. See, for example, U.S. Pat. No. 5,208,041, incorporated herein by reference.
- the amino acid sequence for hPTH (1-84) is reported by Kimura et al. in Biochem. Biophys. Res. Comm., 114(2):493 (SEQ ID NO: 1).
- composition or solution may also incorporate as active ingredient fragments or variants of fragments of human PTH or of rat, porcine or bovine PTH that have human PTH activity as determined in the ovarectomized rat model of 15, osteoporosis reported by Kimmel et al., Endocrinology, 1993, 32(4):1577.
- the parathyroid hormone fragments desirably incorporate at least the first 34 N-terminal residues, such as PTH(1-34) (SEQ ID NO: 2), PTH(1-37), PTH(1-38) and PTH(1-41).
- Alternatives in the form of PTH variants incorporate from 1 to 5 amino acid substitutions that improve PTH stability and half-life, such as the replacement of methionine residues at positions 8 and/or 18 with leucine or other hydrophobic amino acid that improves PTH stability against oxidation and the replacement of amino acids in the 25-27 region with trypsin-insensitive amino acids such as histidine or other amino acid that improves PTH stability against protease.
- thyroid hormone as used generically herein.
- the preferred hormone is human PTH(1-34) (SEQ ID NO: 2) also known as teriparatide.
- the hormones may be obtained by known recombinant or synthetic methods, such as described in U.S. Pat. No. 4,086,196, incorporated herein by reference.
- the stabilizing agent incorporated into the solution or composition includes a polyol which includes a saccharide, preferably a monosaccharide or disaccharide, e.g., glucose, trehalose, raffinose, or sucrose; a sugar alcohol such as, for example, mannitol, sorbitol or inositol, and a polyhydric alcohol such as glycerine or propylene glycol or mixtures thereof.
- a preferred polyol is mannitol or propylene glycol.
- the concentration of polyol may range from about 1 to about 20 wt-%, preferably about 3 to 10 wt-% of the total solution.
- the buffering agent employed in the solution or composition of the present invention may be any acid or salt combination which is pharmaceutically acceptable and capable of maintaining the aqueous solution at a pH range of 3 to 7, preferably 3-6.
- Useful buffering systems are, for example, acetate, tartrate or citrate sources.
- Preferred buffer systems are acetate or tartrate sources most preferred is an acetate source.
- the concentration of buffer may be in the range of about 2 mM to about 500 mM, preferably about 2 mM to 100 mM.
- the stabilized solution or composition of the present invention may also include a parenterally acceptable preservative.
- preservatives include, for example, cresols, benzyl alcohol, phenol benzalkonium chloride, benzethonium chloride, chlorobutanol, phenylethyl alcohol, methyl paraben, propyl paraben, thimerosal and phenylmercuric nitrate and acetate.
- a preferred preservative is m-cresol or benzyl alcohol; most preferred is m-cresol.
- the amount of preservative employed may range from about 0.1 to about 2 wt-%, preferably about 0.3 to about 1.0 wt-% of the total solution.
- the present invention has provided, for example, a stabilized teriparatide solution containing mannitol acetate and m-cresol with a predicted shelf-life of over 15 months at 5° C.
- the parathyroid hormone compositions of the present invention may, if desired, be provided in a powder form containing not more than 2% water by weight, that results from the freeze-drying of a sterile, aqueous hormone solution prepared by mixing the selected parathyroid hormone, a buffering agent and a stabilizing agent as above described.
- a buffering agent when preparing lyophilized powders is a tartrate source.
- Particularly useful stabilizing agents include glycine, mannitol, sucrose, trehalose, raffinose or a mixture thereof.
- the PTH solution and composition of the present invention incorporate PTH in a medically effective amount, a term used with reference to amounts useful either therapeutically or in medical diagnosis.
- the particular amount of parathyroid hormone incorporated in the preparation can be pre-determined based on the type of PTH selected and on the intended end-use of the preparation. In one application, the preparations are exploited for therapeutic purposes, and particularly for the treatment of osteoporosis.
- Osteoporosis therapy entails administration of the reconstituted preparation by injection, desirably subcutaneous injection, in unit doses that reflect the prescribed treatment regimen but are, by way of example, for human PTH(1-34) (SEQ ID NO: 2), within the range from 25 ⁇ g PTH/mL of injected solution to 1000 ⁇ g/mL of injected solution per patient, with injection volumes being desirably from 0.02 to 1.3 mL.
- the purified PTH is desirably incorporated with the buffering agent and-excipient to form an aqueous solution containing PTH in a concentration range from 25 ⁇ g/mL to 1000 ⁇ g/mL, preferably 100 ⁇ g/mL to 500 ⁇ g/mL, which is then sterile-filtered and filled into a vial or cartridge for use.
- the preparation is obtained as an aqueous solution containing desired amounts and concentrations of the buffering agent, excipient and PTH, individual vials are filled with the solution to the desired volume.
- the advantage of the present invention is that the above solution may be prepared with sterile water without the need to undergo a freeze-drying process.
- the preparations are provided in a form that yields a unit container of 100-500 ⁇ g human PTH(1-34) (SEQ ID NO: 2) upon reconstitution into about 1 mL (0.8-1.2 mL) of the reconstitution vehicle, and the vials are accordingly loaded with about 1 mL of the aqueous PTH preparation, for subsequent freeze-drying.
- the PTH preparation subjected to freeze-drying comprises from 25 to 1000 ⁇ g/mL of human PTH(1-34) (SEQ ID NO: 2), from 2 to 8% by weight of mannitol, and a tartrate source in an amount capable of buffering the preparation to within the range from 3.0 to 6.5 upon reconstitution in sterile water.
- the tartrate buffering agent is incorporated in an amount sufficient to buffer the pH to 3.5 to 5.5.
- the present PTH composition can be formulated and administered to aid in medical diagnosis, and particularly to assist in establishing the diagnosis of hypoparathyroidism and pseudohypoparathyroidism in hypocalcemic patients. Except for the dose of PTH, the composition of the PTH preparation will remain as described herein for therapeutic use.
- An intravenously infused, single dose of human PTH(1-34) (SEQ ID NO: 2) that is equal to 200 International Units of PTH activity is appropriate for this diagnostic purpose. Diagnosis is then made by determining the effect of administered PTH or urinary cAMP levels, with cAMP elevation being indicative of the hypoparathyroidism condition, rather than its pseudoform.
- rhPTH (1-34) (SEQ ID NO: 2)
- 50 mg mannitol, 2.5 mg m-cresol, 0.52 mg acetic acid and 0.12 mg sodium acetate were mixed into a solution with 1 ml of distilled water.
- a control solution and solutions for samples A through O were prepared as previously described with the ingredients and concentrations shown in Table 3. The solutions were then freeze-dried and the resulting lyophilized powder formulations were stored at 40° C. for a one month period. The amount of PTH(1-34) remaining in each sample was then measured by HPLC. The results are shown in Table 3. TABLE 3 Stability of PTH(1-34) Lyophilized Formulations at 40° C. for One Month PTH Bulking Buffer % PTH (1-34) Bulking Agent Conc. Conc.
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Abstract
A stabilized pharmaceutical composition in the form of a solution for parenteral administration of a parathyroid hormone is described wherein the therapeutically active ingredient is stabilized with a buffer and a polyol. Preferred preparations contain in an aqueous solution human PTH(1-34), mannitol, an acetate or tartrate buffering agent and m-cresol or benzyl alcohol as a preservative.
Description
- This invention relates to pharmaceutical compositions containing a parathyroid hormone. More particularly the invention relates to teriparatide, PTH(1-34), stabilized solution formulations
- Parathyroid hormone (PTH) is a secreted. 84 amino acid product of the mammalian parathyroid gland that controls serum calcium levels through its action on various tissues, including bone. Studies in humans with certain forms of PTH have demonstrated an anabolic effect on bone, and have prompted significant interest in its use for the treatment of osteoporosis and related bone disorders.
- Using the N-terminal 34 amino acids of the bovine and human hormone for example, which by all published accounts are deemed biologically equivalent to the full length hormone, it has been demonstrated in humans that parathyroid hormone enhances bone growth particularly when administered in pulsatile fashion by the subcutaneous route. A slightly different form of PTH, human PTH(1-38) has shown similar results.
- PTH preparations have been reconstituted from fresh or lyophilized hormone, and incorporate various forms of carrier, excipient and vehicle. Most are prepared in water-based vehicles such as saline, or water acidified typically with acetic acid to solubilize the hormone. The majority of reported formulations also incorporate albumin as a stabilizer (see for example Reeve at al., Br. Med. J., 1980, 280:6228; Reeve at al., Lancet, 1976. 1:1035; Reeve at al., Calcif. Tissue Res., 1976, 21:469; Hodsman et al., Bone Miner: 1990, 9(2):137; Tsai et al., J. Clin. Endocrinol Metab., 1989, 69(5):1024; Isaac et al., Horm. Metab. Res. 1980, 12(9):487; Law et al., J. Clin Invest. 1983, 72(3):1106; and Hulter, J. Clin Hypertens, 1986, 2(4):360). Other reported formulations have incorporated an excipient such as mannitol, which is present either with the lyophilized hormone or in the reconstitution vehicle. Formulations representative of those employed for human studies include a human PTH(1-34) (SEQ ID NO: 2) preparation consisting, upon reconstitution, of mannitol, heat inactivated human serum albumin, and caproic acid (a protease inhibitor) as absorption enhancer (see Reeve at al., 1976, Calcif. Tissue Res., 21, Suppl., 469-477); a human PTH(1-38) preparation reconstituted into a saline vehicle (see Hodsman et al., 1991, 14(1), 67-83); and a bovine PTH(1-34) preparation in aqueous vehicle pH adjusted with acetic acid and containing albumin. There is also an International Reference preparation which for human PTH (1-84) (SEQ ID NO: 1) consists of 100 ng of hormone ampouled with 250 μg human serum albumin and 1.25 mg lactose (1981), and for bovine PTH (1-84) consists of 10 μg lyophilized hormone in 0.01M acetic acid and 0.1% w/v mannitol (see Martindale, The Extra Pharmacoepia, The Pharmaceutical Press. London, 29th Edition, 1989 at p. 1338).
- A recent attempt at improving the stability for the lyophilized preparation of h-PTH(1-34) (SEQ ID NO: 2) is reported in EP 619 119 with a combination of sugar and sodium chloride. Also U.S. Pat. No. 5,496,801 describes a freeze-dried composition for the natural hormnone, PTH(1-84), containing mannitol as an excipient and a citrate source as a non-volatile buffering agent.
- Commercial exploitation of parathyroid hormone requires the development of a formulation that is acceptable in terms of storage stability and ease of preparation. Because it is a protein and thus far more labile than the traditionally small molecular weight drugs, however, the formulation of parathyroid hormone presents challenges not commonly encountered by the pharmaceutical industry. Furthermore, like other proteins that have been formulated successfully, PTH is particularly sensitive to oxidation, deamidation and hydrolysis, and requires that its N-terminal and C-terminal sequences remain intact in order to preserve bioactivity.
- It is an object of the present invention to provide a pharmaceutically useful PTH preparation, particularly one comprising, as active ingredient, teriparatide, PTH(1-34) (SEQ ID NO: 2).
- The present invention provides a pharmaceutical composition in the form of a stabilized solution containing a parathyroid hormone (PTH) in a therapeutically effective amount. The solution is storage stable and in sterile form, may be stored in vials or cartridges ready for parenteral administration in human patients. The advantages of the present solution is the elimination of the need for lyophilization.
- Accordingly, the present invention is a parathyroid hormone solution including:
- (a) a therapeutically effective amount of a parathyroid hormone;
- (b) an effective amount of a stabilizing agent;
- (c) a buffering agent in an amount sufficient to maintain the pH of the composition within a range of about 3-7; and
- (d) the balance being water.
- This solution may, if desired, undergo lyophilization to form a freeze-dried powder containing not more than 2% water by weight.
- Another aspect of the present invention is a parathyroid hormone solution including:
- (a) a therapeutically effective amount of a parathyroid hormone;
- (b) from about 1 to 20 wt-% of a stabilizing agent;
- (c) a buffering agent in an amount sufficient to maintain the pH of the composition within a range of about 3-7 and selected from an acetate or tartrate source;
- (d) from about 0.1 to 2 wt-% of a parenterally acceptable preservative; and
- (e) the balance being water.
- Still another aspect of the present invention is a pharmaceutical composition in the form of a freeze-dried powder prior to reconstitution including:
- (a) a therapeutically effective amount of a fragmented parathyroid hormone selected from the group consisting of PTH (1-34), PTH (1-37), PTH (1-38), and PTH (1-41);
- (b) an effective amount of a stabilizing agent;
- (c) a buffering agent in an amount sufficient to maintain the pH of the composition within a range of about 3-7; and
- (d) less than 2% water by weight.
- The invention relates to parathyroid hormone solutions that exhibit storage stability in terms of hormone composition and activity.
- As active ingredient, the composition or solution may incorporate the full length, 84 amino acid form of parathyroid hormone, particularly the human form, hPTH (1-814) (SEQ ID NO: 1), obtained either recombinantly, by peptide synthesis or by extraction from human fluid. See, for example, U.S. Pat. No. 5,208,041, incorporated herein by reference. The amino acid sequence for hPTH (1-84) is reported by Kimura et al. in Biochem. Biophys. Res. Comm., 114(2):493 (SEQ ID NO: 1).
- The composition or solution may also incorporate as active ingredient fragments or variants of fragments of human PTH or of rat, porcine or bovine PTH that have human PTH activity as determined in the ovarectomized rat model of 15, osteoporosis reported by Kimmel et al., Endocrinology, 1993, 32(4):1577.
- The parathyroid hormone fragments desirably incorporate at least the first 34 N-terminal residues, such as PTH(1-34) (SEQ ID NO: 2), PTH(1-37), PTH(1-38) and PTH(1-41). Alternatives in the form of PTH variants incorporate from 1 to 5 amino acid substitutions that improve PTH stability and half-life, such as the replacement of methionine residues at positions 8 and/or 18 with leucine or other hydrophobic amino acid that improves PTH stability against oxidation and the replacement of amino acids in the 25-27 region with trypsin-insensitive amino acids such as histidine or other amino acid that improves PTH stability against protease. These forms of PTH are embraced by the term “parathyroid hormone” as used generically herein. The preferred hormone is human PTH(1-34) (SEQ ID NO: 2) also known as teriparatide. The hormones may be obtained by known recombinant or synthetic methods, such as described in U.S. Pat. No. 4,086,196, incorporated herein by reference.
- The stabilizing agent incorporated into the solution or composition includes a polyol which includes a saccharide, preferably a monosaccharide or disaccharide, e.g., glucose, trehalose, raffinose, or sucrose; a sugar alcohol such as, for example, mannitol, sorbitol or inositol, and a polyhydric alcohol such as glycerine or propylene glycol or mixtures thereof. A preferred polyol is mannitol or propylene glycol. The concentration of polyol may range from about 1 to about 20 wt-%, preferably about 3 to 10 wt-% of the total solution.
- The buffering agent employed in the solution or composition of the present invention may be any acid or salt combination which is pharmaceutically acceptable and capable of maintaining the aqueous solution at a pH range of 3 to 7, preferably 3-6. Useful buffering systems are, for example, acetate, tartrate or citrate sources. Preferred buffer systems are acetate or tartrate sources most preferred is an acetate source. The concentration of buffer may be in the range of about 2 mM to about 500 mM, preferably about 2 mM to 100 mM.
- The stabilized solution or composition of the present invention may also include a parenterally acceptable preservative. Such preservatives include, for example, cresols, benzyl alcohol, phenol benzalkonium chloride, benzethonium chloride, chlorobutanol, phenylethyl alcohol, methyl paraben, propyl paraben, thimerosal and phenylmercuric nitrate and acetate. A preferred preservative is m-cresol or benzyl alcohol; most preferred is m-cresol. The amount of preservative employed may range from about 0.1 to about 2 wt-%, preferably about 0.3 to about 1.0 wt-% of the total solution.
- Thus the present invention has provided, for example, a stabilized teriparatide solution containing mannitol acetate and m-cresol with a predicted shelf-life of over 15 months at 5° C.
- The parathyroid hormone compositions of the present invention may, if desired, be provided in a powder form containing not more than 2% water by weight, that results from the freeze-drying of a sterile, aqueous hormone solution prepared by mixing the selected parathyroid hormone, a buffering agent and a stabilizing agent as above described. Especially useful as a buffering agent when preparing lyophilized powders is a tartrate source. Particularly useful stabilizing agents include glycine, mannitol, sucrose, trehalose, raffinose or a mixture thereof.
- The PTH solution and composition of the present invention incorporate PTH in a medically effective amount, a term used with reference to amounts useful either therapeutically or in medical diagnosis. The particular amount of parathyroid hormone incorporated in the preparation can be pre-determined based on the type of PTH selected and on the intended end-use of the preparation. In one application, the preparations are exploited for therapeutic purposes, and particularly for the treatment of osteoporosis. Osteoporosis therapy entails administration of the reconstituted preparation by injection, desirably subcutaneous injection, in unit doses that reflect the prescribed treatment regimen but are, by way of example, for human PTH(1-34) (SEQ ID NO: 2), within the range from 25 μg PTH/mL of injected solution to 1000 μg/mL of injected solution per patient, with injection volumes being desirably from 0.02 to 1.3 mL. Accordingly, the purified PTH is desirably incorporated with the buffering agent and-excipient to form an aqueous solution containing PTH in a concentration range from 25 μg/mL to 1000 μg/mL, preferably 100 μg/mL to 500 μg/mL, which is then sterile-filtered and filled into a vial or cartridge for use.
- Once the preparation is obtained as an aqueous solution containing desired amounts and concentrations of the buffering agent, excipient and PTH, individual vials are filled with the solution to the desired volume. The advantage of the present invention is that the above solution may be prepared with sterile water without the need to undergo a freeze-drying process.
- In an alternative embodiment of the invention, the preparations are provided in a form that yields a unit container of 100-500 μg human PTH(1-34) (SEQ ID NO: 2) upon reconstitution into about 1 mL (0.8-1.2 mL) of the reconstitution vehicle, and the vials are accordingly loaded with about 1 mL of the aqueous PTH preparation, for subsequent freeze-drying.
- In a preferred alternative embodiment of the invention, the PTH preparation subjected to freeze-drying comprises from 25 to 1000 μg/mL of human PTH(1-34) (SEQ ID NO: 2), from 2 to 8% by weight of mannitol, and a tartrate source in an amount capable of buffering the preparation to within the range from 3.0 to 6.5 upon reconstitution in sterile water. In specific embodiments of the invention, the tartrate buffering agent is incorporated in an amount sufficient to buffer the pH to 3.5 to 5.5.
- In addition to their therapeutic use, the present PTH composition can be formulated and administered to aid in medical diagnosis, and particularly to assist in establishing the diagnosis of hypoparathyroidism and pseudohypoparathyroidism in hypocalcemic patients. Except for the dose of PTH, the composition of the PTH preparation will remain as described herein for therapeutic use. An intravenously infused, single dose of human PTH(1-34) (SEQ ID NO: 2) that is equal to 200 International Units of PTH activity is appropriate for this diagnostic purpose. Diagnosis is then made by determining the effect of administered PTH or urinary cAMP levels, with cAMP elevation being indicative of the hypoparathyroidism condition, rather than its pseudoform.
- The examples which follow are illustrative of the invention and are not intended to be limiting.
-
- 0.25 mg rhPTH (1-34) (SEQ ID NO: 2), 45.4 mg mannitol, 3 mg m-cresol, 0.41 mg acetic acid and 0.1 mg sodium acetate were mixed into a solution with 1 ml of distilled water.
- The formulations of the present invention, Examples 1 and 2 were compared to solutions containing no stabilizer, 0.9% NaCl, 20 mM acetate and 10 mM acetate as primary stabilizer. The stability was measured by determining the amount in % of rhPTH (1-34) (SEQ ID NO: 2) remaining after a certain time. The measurement was made by HPLC. The results are shown in Tables 1 and 2.
TABLE 1 Effect of Primary Stabilizer on Chemical Stability of rhPTH (1-34) at 50° C. % Remaining Time, days Water 0.9% NaCl 20 mM acetate 10 mM acetate Initial 100 100 100 100 7 74 81 84 80 14 55 58 67 71 -
TABLE 2 Comparison of Stability of rhPTH (1-34) at 30° C. % Remaining Time, days 20 mM acetate 10 mM acetate Example 1 Example 2 Initial 100 100 100 100 7 96 94 100 — 14 94 92 96 100 21 90 93 97 — 30 — 81 96 96 - The following experiment was carried out to show that lyophilized powder formulations prepared from stabilized solutions of the present invention are more stable than a control which was prepared from PTH(1-34) and mannitol alone.
- A control solution and solutions for samples A through O were prepared as previously described with the ingredients and concentrations shown in Table 3. The solutions were then freeze-dried and the resulting lyophilized powder formulations were stored at 40° C. for a one month period. The amount of PTH(1-34) remaining in each sample was then measured by HPLC. The results are shown in Table 3.
TABLE 3 Stability of PTH(1-34) Lyophilized Formulations at 40° C. for One Month PTH Bulking Buffer % PTH (1-34) Bulking Agent Conc. Conc. Re- Sample mg/mL Agent mg/mL Buffer mM maining Control 0.2 mannitol 40 — — 78 A 0.5 mannitol 30 acetate 5 90 B 0.5 glycine 30 acetate 5 98 C 0.5 sucrose 30 acetate 5 98 D 0.5 trehalose 30 acetate 5 97 E 0.5 raffinose 30 acetate 5 99 F 0.75 mannitol 30 tartrate 15 95 G 1.5 sucrose & 5/25 tartrate 5 99 mannitol H 0.75 sucrose & 5/25 tartrate 15 99 mannitol I 1.5 mannitol 30 tartrate 5 96 J 1.5 sucrose 30 tartrate 15 100 K 1.5 mannitol 30 tartrate 15 99 L 0.75 sucrose 30 tartrate 15 100 M 0.75 sucrose 30 tartrate 5 100 N 1.5 sucrose & 5/25 tarirate 15 99 mannitol O 1.5 sucrose & 5/25 acetate 5 91* mannitol -
-
1 2 1 84 PRT homo sapiens 1 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45 Gln Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60 Lys Ser Leu Gly Glu Ala Asp Lys Ala Asn Val Asp Val Leu Thr Lys 65 70 75 80 Ala Lys Ser Gln 2 34 PRT homo sapiens 2 Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn 1 5 10 15 Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His 20 25 30 Asn Phe
Claims (25)
1. A parathyroid hormone solution comprising:
(a) a therapeutically effective amount of a parathyroid hormone;
(b) an effective amount of a stabilizing agent;
(c) a buffering agent in an amount sufficient to maintain the pH of the composition within a range of about 3-7; and
(d) the balance being water.
2. The solution of claim 1 , wherein the hormone is a fragmented hormone selected from the group consisting of PTH(1-34), PTH(1-37), PTH(1-38), and PTH(141).
3. The solution of claim 1 , wherein the hormone is human PTH(1-34) (SEQ ID NO: 2).
4. The solution of claim 1 , wherein the hormone is human PTH(1-84) (SEQ ID NO: 1).
5. The solution of claim 1 , wherein the stabilizing agent is a polyol.
6. The solution of claim 5 , wherein the polyol is mannitol.
7. The solution of claim 5 , wherein the polyol is propylene glycol.
8. The solution of claim 1 , wherein the buffering agent is an acetate or tartrate source.
9. The solution of claim 8 , wherein the buffering agent is acetate.
10. The solution of claim 1 , which further comprises a parenterally acceptable preservative.
11. The solution of claim 10 , wherein the preservative is m-cresol or benzyl alcohol.
12. The solution of claim 11 , wherein the preservative is m-cresol.
13. A composition according to claim 1 , in the form of a freeze-dried powder containing less than 2% water by weight.
14. A parathyroid hormone solution comprising:
(a) a therapeutically effective amount of a parathyroid hormone;
(b) from about 1 to 20 wt-% of a stabilizing agent;
(c) a buffering agent in an amount sufficient to maintain the pH of the composition within a range of about 3-7 and selected from an acetate or tartrate source;
(d) from about 0.1 to 2 wt-% of a parenterally acceptable preservative; and
(e) the balance being water.
15. The solution of claim 14 , wherein the hormone is PTH(1-84).
16. The solution of claim 14 , wherein the hormone is selected from the group consisting of PTH(1-34), PTH(1-37), PTH(1-38), and PTH(1-41).
17. The solution of claim 16 , wherein the hormone is human PTH(1-34) (SEQ ID NO: 2).
18. The solution of claim 14 , wherein the stabilizing agent is a polyol in an amount of about 3 to about 10 wt-%.
19. The solution of claim 14 , wherein the preservative is m-cresol or benzylalcohol in an amount of about 0.3 to about 1.0 wt-%.
20. A pharmaceutical composition in the form of a freeze-dried powder comprising:
(a) a therapeutically effective amount of a fragmented parathyroid hormone selected from the group consisting of PTH(1-34), PTH(1-37), PTH(1-38), and PTH(1-41);
(b) an effective amount of a stabilizing agent;
(c) a buffering agent in an amount sufficient to maintain the pH of the composition within a range of about 3-7; and
(d) less than 2 wt-% water by weight.
21. The composition of claim 20 , wherein the hormone is human PTH(1-34) (SEQ ID NO: 2).
22. The composition of claim 20 , wherein the stabilizing agent is selected from the group consisting of glycine, mannitol, sucrose, trehalose, raffinose and a mixture thereof.
23. The composition of claim 20 , wherein the buffering agent is an acetate or tartrate source.
24. The composition of claim 23 , wherein the buffering agent is a tartrate source.
25. The composition of claim 20 , wherein the stabilizing agent is in an amount of about 1 to about 20 wt-%.
Priority Applications (1)
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US10/427,259 US20030225000A1 (en) | 1997-12-09 | 2003-04-30 | Stabilized teriparatide solutions |
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US6907597P | 1997-12-09 | 1997-12-09 | |
US09/555,476 US6770623B1 (en) | 1997-12-09 | 1998-12-08 | Stabilized teriparatide solutions |
US10/427,259 US20030225000A1 (en) | 1997-12-09 | 2003-04-30 | Stabilized teriparatide solutions |
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PCT/US1998/026043 Division WO1999029337A1 (en) | 1997-12-09 | 1998-12-08 | Stabilized teriparatide solutions |
US09/555,476 Division US6770623B1 (en) | 1997-12-09 | 1998-12-08 | Stabilized teriparatide solutions |
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US10/055,509 Expired - Lifetime US7144861B2 (en) | 1997-12-09 | 2002-01-23 | Stabilized teriparatide solutions |
US10/427,259 Abandoned US20030225000A1 (en) | 1997-12-09 | 2003-04-30 | Stabilized teriparatide solutions |
US11/541,862 Expired - Fee Related US7550434B2 (en) | 1997-12-09 | 2006-10-02 | Stabilized teriparatide solutions |
US11/541,863 Abandoned US20070021344A1 (en) | 1997-12-09 | 2006-10-02 | Stabilized teriparatide solutions |
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US10/055,509 Expired - Lifetime US7144861B2 (en) | 1997-12-09 | 2002-01-23 | Stabilized teriparatide solutions |
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US11/541,863 Abandoned US20070021344A1 (en) | 1997-12-09 | 2006-10-02 | Stabilized teriparatide solutions |
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Also Published As
Publication number | Publication date |
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US20070021343A1 (en) | 2007-01-25 |
US20070021344A1 (en) | 2007-01-25 |
US6770623B1 (en) | 2004-08-03 |
US7144861B2 (en) | 2006-12-05 |
US7550434B2 (en) | 2009-06-23 |
US20020107200A1 (en) | 2002-08-08 |
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