US20070021344A1 - Stabilized teriparatide solutions - Google Patents
Stabilized teriparatide solutions Download PDFInfo
- Publication number
- US20070021344A1 US20070021344A1 US11/541,863 US54186306A US2007021344A1 US 20070021344 A1 US20070021344 A1 US 20070021344A1 US 54186306 A US54186306 A US 54186306A US 2007021344 A1 US2007021344 A1 US 2007021344A1
- Authority
- US
- United States
- Prior art keywords
- solution
- pth
- acetate
- stabilizing agent
- hormone
- 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
Links
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Classifications
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- 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
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- 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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
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- 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
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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(I1-34), 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, dearnidation and hydrolysis, and requires that its N-terminal and C-terminal sequences remain intact in order to preserve bioactivity.
- 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.
- 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.
- parathyroid hormone solution including:
- 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 (1-84) (SEQ ID NO: 1), obtained either recombinantly, by peptide synthesis or by extraction from human fluid. Sec, 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 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.
- trypsin-insensitive amino acids such as histidine or other amino acid that improves PTH stability against protease.
- 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 ) 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.
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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(I1-34), 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., Horn. 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 Iyophilized 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 0.01 M 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 hormone, 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, dearnidation 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 (1-84) (SEQ ID NO: 1), obtained either recombinantly, by peptide synthesis or by extraction from human fluid. Sec, 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 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 ) 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.
- 0.1 mg 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.
- 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. Water 0.9% NaCl 20 mM acetate 10 mM acetate Time, days % Remaining 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. 20 mM acetate 10 mM acetate Example 1 Example 2 Time, days % Remaining 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 Bulking Buff- Agent er % PTH PTH(1-34) Bulking Conc. Conc. Remain- Sample mg/mL Agent mg/mL Buffer mM ing 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 tartrate 15 99 mannitol O 1.5 sucrose & 5/25 acetate 5 91* mannitol
*the stability at 2 months was 96%
-
Claims (27)
1-25. (canceled)
26. A method for treating osteoporosis in a patient comprising: administering via subcutaneous injection into the patient a medically effective amount of a solution, wherein the solution is from a vial or cartridge; the solution in the vial or the cartridge is sterile; and the solution in the vial or the cartridge comprises human parathyroid hormone, at least one stabilizing agent, a buffer; and has a pH from 3 to 7.
27. The method of claim 26 , wherein said at least one stabilizing agent includes at least one polyol.
28. The method of claim 27 , wherein said solution has a pH from 3 to 6.
29. The method of claim 28 , wherein said solution contains the human parathyroid hormone in the range from 100 μg/ml to 500 μg/ml.
30. The method of claim 29 , wherein the concentration of said buffer is about 2 mM to 100 mM.
31. The method of claim 30 , wherein said solution further comprises a parenterally acceptable preservative in a concentration of about 0.1 to about 2 wt-% of the total solution.
32. The method of claim 31 , wherein said human parathyroid hormone is hPTH(1-34).
33. The method of claim 31 , wherein said human parathyroid hormone is hPTH(1-84).
34. The method of claim 32 wherein said buffer is citrate, tartarate, or acetate.
35. The method of claim 33 wherein said buffer is citrate, tartarate, or acetate.
36. The method of claim 32 wherein said parenterally acceptable preservative is selected from cresols, benzyl alcohol, phenol, benzalkonium chloride, benzethonium chloride, chlorobutanol, phenylethyl alcohol, methyl paraben, propyl paraben, thimerosal, phenylmercuric nitrate and phenylmercuric acetate.
37. The method of claim 33 wherein said parenterally acceptable preservative is selected from cresols, benzyl alcohol, phenol, benzalkonium chloride, benzethonium chloride, chlorobutanol, phenylethyl alcohol, methyl paraben, propyl paraben, thimerosal, phenylmercuric nitrate and phenylmercuric acetate.
38. The method of claim 36 wherein said at least one stabilizing agent is a saccharide, a sugar alcohol, a polyhydric alcohol, or a mixture thereof.
39. The method of claim 37 wherein said at least one stabilizing agent is a saccharide, a sugar alcohol, a polyhydric alcohol, or a mixture thereof.
40. The method of claim 38 wherein said buffer is acetate.
41. The method of claim 38 wherein said parenterally acceptable preservative is m-cresol or benzyl alcohol.
42. The method of claim 40 wherein said at least one stabilizing agent is mannitol, glycine, sucrose, trehalose, raffinose, sucrose or a mixture thereof.
43. The method of claim 42 wherein said parenterally acceptable preservative is m-cresol or benzyl alcohol.
44. The method of claim 45 wherein said at least one stabilizing agent is selected from mannitol, glycine, sucrose, trehalose, raffinose, sucrose or a mixture thereof.
45. The method of claim 46 wherein said parenterally acceptable preservative is m-cresol and said stabilizing agent is mannitol.
46. The method of claim 27 comprising administering the therapeutically effective amount in a pulsatile fashion.
47. The method of claim 29 comprising administering a therapeutically effective amount of said solution in a pulsatile fashion.
48. The method of claim 29 comprising administering the solution from a pre-filled vial.
49. The method of claim 29 wherein said hormone has been in said solution for at least 14 days prior to the subcutaneous administration to the patient.
50. The method of claim 30 wherein said hormone has been in said solution for at least 21 days prior to the subcutaneous administration to the patient.
51. The method of claim 31 wherein said hormone has been in said solution for at least 30 days prior to the subcutaneous administration to the patient.
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US09/555,476 US6770623B1 (en) | 1997-12-09 | 1998-12-08 | Stabilized teriparatide solutions |
US10/055,509 US7144861B2 (en) | 1997-12-09 | 2002-01-23 | Stabilized teriparatide solutions |
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Application Number | Title | Priority Date | Filing Date |
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US09/555,476 Expired - Lifetime US6770623B1 (en) | 1997-12-09 | 1998-12-08 | Stabilized teriparatide solutions |
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 |
Family Applications Before (4)
Application Number | Title | Priority Date | Filing Date |
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US09/555,476 Expired - Lifetime US6770623B1 (en) | 1997-12-09 | 1998-12-08 | Stabilized teriparatide solutions |
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 |
Country Status (1)
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US (5) | US6770623B1 (en) |
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Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4698328A (en) * | 1985-04-04 | 1987-10-06 | The General Hospital Corporation | Method of increasing bone mass |
US4833125A (en) * | 1986-12-05 | 1989-05-23 | The General Hospital Corporation | Method of increasing bone mass |
US5208041A (en) * | 1991-05-23 | 1993-05-04 | Allelix Biopharmaceuticals Inc. | Essentially pure human parathyroid hormone |
US5496801A (en) * | 1993-12-23 | 1996-03-05 | Allelix Biopharmaceuticals Inc. | Parathyroid hormone formulation |
US5563122A (en) * | 1991-12-09 | 1996-10-08 | Asahi Kasei Kogyo Kabushiki Kaisha | Stabilized parathyroid hormone composition |
US5607915A (en) * | 1992-09-29 | 1997-03-04 | Inhale Therapeutic Systems | Pulmonary delivery of active fragments of parathyroid hormone |
US5616560A (en) * | 1991-12-17 | 1997-04-01 | The Procter & Gamble Company | Methods for the treatment of osteoporosis using bisphosphonates and parathyroid hormone |
US5891086A (en) * | 1993-07-31 | 1999-04-06 | Weston Medical Limited | Needle-less injector |
US6454746B1 (en) * | 1997-06-04 | 2002-09-24 | Eli Lilly And Company | Medication delivery apparatus |
US6770623B1 (en) * | 1997-12-09 | 2004-08-03 | Eli Lilly And Company | Stabilized teriparatide solutions |
US6977077B1 (en) * | 1998-08-19 | 2005-12-20 | Eli Lilly And Company | Method of increasing bone toughness and stiffness and reducing fractures |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6360940A (en) | 1986-09-01 | 1988-03-17 | Toyo Jozo Co Ltd | Preventive or remedy for cataract |
JP2505812B2 (en) | 1987-07-10 | 1996-06-12 | 旭化成工業株式会社 | Freeze-dried composition of h-PTH (1-34) |
US5059587A (en) | 1987-08-03 | 1991-10-22 | Toyo Jozo Company, Ltd. | Physiologically active peptide composition for nasal administration |
DE3935738A1 (en) | 1989-10-27 | 1991-05-08 | Forssmann Wolf Georg | DRUGS CONTAINING THE HUMAN PARATHORMONE FRAGMENT (1-37) AS AN ACTIVE AGENT |
GB9020544D0 (en) | 1990-09-20 | 1990-10-31 | Sandoz Ltd | Improvements in or relating to organic compounds |
US6582728B1 (en) * | 1992-07-08 | 2003-06-24 | Inhale Therapeutic Systems, Inc. | Spray drying of macromolecules to produce inhaleable dry powders |
IT1255723B (en) * | 1992-10-09 | 1995-11-13 | USE OF PARATORMONE, ITS BIOLOGICALLY ACTIVE FRAGMENTS AND RELATED PEPTIDES, FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS USEFUL IN THE PREVENTION AND THERAPY OF ABORTION AND PRETERMONE BIRTH AND IN GENERAL FOR THE TREATMENT OF GESTATION | |
CA2178894A1 (en) * | 1995-06-15 | 1996-12-16 | Tsunehiko Fukuda | Parathyroid hormone derivatives and their use |
DE19538687A1 (en) * | 1995-10-17 | 1997-04-24 | Boehringer Mannheim Gmbh | Stable pharmaceutical dosage forms containing parathyroid hormone |
US6545746B1 (en) * | 1996-03-04 | 2003-04-08 | Nikon Corporation | Projection exposure apparatus |
JPH1147069A (en) | 1997-07-23 | 1999-02-23 | Minnesota Mining & Mfg Co <3M> | Tufted mat |
SE9801495D0 (en) | 1998-04-28 | 1998-04-28 | Astra Ab | Protein formulation |
-
1998
- 1998-12-08 US US09/555,476 patent/US6770623B1/en not_active Expired - Lifetime
-
2002
- 2002-01-23 US US10/055,509 patent/US7144861B2/en not_active Expired - Lifetime
-
2003
- 2003-04-30 US US10/427,259 patent/US20030225000A1/en not_active Abandoned
-
2006
- 2006-10-02 US US11/541,862 patent/US7550434B2/en not_active Expired - Fee Related
- 2006-10-02 US US11/541,863 patent/US20070021344A1/en not_active Abandoned
Patent Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4698328A (en) * | 1985-04-04 | 1987-10-06 | The General Hospital Corporation | Method of increasing bone mass |
US4833125A (en) * | 1986-12-05 | 1989-05-23 | The General Hospital Corporation | Method of increasing bone mass |
US5208041A (en) * | 1991-05-23 | 1993-05-04 | Allelix Biopharmaceuticals Inc. | Essentially pure human parathyroid hormone |
US5563122A (en) * | 1991-12-09 | 1996-10-08 | Asahi Kasei Kogyo Kabushiki Kaisha | Stabilized parathyroid hormone composition |
US5616560A (en) * | 1991-12-17 | 1997-04-01 | The Procter & Gamble Company | Methods for the treatment of osteoporosis using bisphosphonates and parathyroid hormone |
US5607915A (en) * | 1992-09-29 | 1997-03-04 | Inhale Therapeutic Systems | Pulmonary delivery of active fragments of parathyroid hormone |
US5891086A (en) * | 1993-07-31 | 1999-04-06 | Weston Medical Limited | Needle-less injector |
US5496801A (en) * | 1993-12-23 | 1996-03-05 | Allelix Biopharmaceuticals Inc. | Parathyroid hormone formulation |
US6454746B1 (en) * | 1997-06-04 | 2002-09-24 | Eli Lilly And Company | Medication delivery apparatus |
US6770623B1 (en) * | 1997-12-09 | 2004-08-03 | Eli Lilly And Company | Stabilized teriparatide solutions |
US7144861B2 (en) * | 1997-12-09 | 2006-12-05 | Eli Lilly And Company | Stabilized teriparatide solutions |
US6977077B1 (en) * | 1998-08-19 | 2005-12-20 | Eli Lilly And Company | Method of increasing bone toughness and stiffness and reducing fractures |
US7163684B2 (en) * | 1998-08-19 | 2007-01-16 | Eli Lilly And Company | Method of increasing bone toughness and stiffness and reducing fractures |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090227503A1 (en) * | 2008-02-07 | 2009-09-10 | University Of Rochester | Parathyroid hormone treatment for enhanced allograft and tissue-engineered reconstruction of bone defects |
US20170015844A1 (en) * | 2015-07-16 | 2017-01-19 | United States Mineral Products Company | Water Repellent Spray Applied Fire Resistive Materials |
Also Published As
Publication number | Publication date |
---|---|
US20070021343A1 (en) | 2007-01-25 |
US20030225000A1 (en) | 2003-12-04 |
US6770623B1 (en) | 2004-08-03 |
US7144861B2 (en) | 2006-12-05 |
US7550434B2 (en) | 2009-06-23 |
US20020107200A1 (en) | 2002-08-08 |
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Legal Events
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STCB | Information on status: application discontinuation |
Free format text: EXPRESSLY ABANDONED -- DURING EXAMINATION |