• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Stable pharmaceutical compositions in the form of parenteral administration solutions of parathyroid hormones are disclosed wherein the therapeutically active ingredient is stabilized with a buffer and a polyol. Preferred formulations include m-cresol or benzyl alcohol as human PTH (1-34), mannitol, acetate or tartrate buffer and preservative in aqueous solution.
    公开号:KR20010032881A
    申请号:KR1020007006211
    申请日:1998-12-08
    公开日:2001-04-25
    发明作者:진-밍 장；헨리 에이. 하벨
    申请人:피터 지. 스트링거；일라이 릴리 앤드 캄파니；
    IPC主号:
    专利说明:

    Stabilized Teriparatide Solutions
    [2] Parathyroid hormone (PTH), an 84-amino acid product that acts on bone and other tissues to regulate serum calcium content, is secreted by the mammalian parathyroid gland. Studies of several types of PTH in humans have demonstrated the effect of bone synthesis and sparked considerable interest in the use of PTH in the treatment of osteoporosis and related bone diseases.
    [3] For example, if the parathyroid hormone is administered in a pulsating manner by the subcutaneous route, using 34 amino acids of the N-terminus of bovine and human hormones that are considered biologically equivalent to the full-length hormone through all published reports, In particular, it has been shown to enhance bone growth. A slightly different form of PTH, human PTH (1-38), showed similar results.
    [4] PTH preparations have been formulated from fresh or lyophilized hormones in admixture with various forms of carriers, excipients and vehicles. Most are prepared using water normally acidified with acetic acid to dissolve an aqueous vehicle or hormone, such as saline. In addition, most of the reported formulations include albumin as a stabilizer (see Reeve et al., Br. Med. J., 1980, 280: 6228, Reeve et al., Lancet, 1976, 1: 1035, Reeve et al., Calcif. Tissue Res., 1976, 21: 469, Hodsman et al., Bon 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 formulations have been reported, including excipients such as mannitol, in combination with lyophilized hormone or in dilution vehicles. Representative formulations for use in human studies include, after thawing, a human PTH (1-34) (SEQ ID NO: 2) formulation consisting of mannitol, heat inactivated human serum albumin and caproic acid (protease inhibitor) as absorption enhancer [ Reeve et al., 1976, Calcif. Tissue Res., 21, Suppl., 469-477], human PTH (1-38) preparations dissolved in saline vehicles [Hodsman et al., 1991, 14 (1), 67-83]. And bovine PTH (1-34) preparations in albumin-containing aqueous vehicles adjusted to pH with acetic acid. In addition, the international reference formulation is formulated with 100 ng hormone ampoules containing 250 μg human serum albumin and 1.25 mg lactose for human PTH (1-84) (SEQ ID NO: 1) and bovine PTH (1- 1). 84) is formulated with 10 μg of lyophilized hormone in 0.01 M acetic acid and 0.1% (w / v) mannitol (Martindale, The Extra Pharmacoepia, The Pharmaceutical Press, London, 29th Edition, 1989 at p. 1338]].
    [5] A recent attempt to improve the stability of h-PTH (1-34) (SEQ ID NO: 2) lyophilized formulations is a combination of sugar and sodium chloride is disclosed in European Patent No. 619 119. U. S. Patent No. 5,496, 801 also discloses a lyophilized composition of natural hormone PTH (1-84) comprising mannitol as excipient and citrate source as non-volatile buffer.
    [6] Commercial use of parathyroid hormones requires the development of acceptable formulations in terms of storage stability and ease of preparation. However, since proteins are much more unstable than conventional low molecular weight drugs, parathyroid hormone formulations cause problems that are not encountered in the pharmaceutical industry. In addition, like other proteins successfully formulated, PTH is very sensitive to oxidation, deamidation and hydrolysis, and the N-terminal and C-terminal sequences must be intact in order to maintain bioactivity.
    [7] It is an object of the present invention to provide pharmaceutically useful PTH preparations, in particular preparations comprising teriparatide, PTH (1-34) (SEQ ID NO: 2) as active ingredients.
    [8] <Summary of invention>
    [9] The present invention provides a pharmaceutical composition in the form of a stable solution containing a therapeutically effective amount of parathyroid hormone (PTH). The solution can be stored in sterile form in vials or cartridges which are storage stable and which are intended for parenteral administration to human patients. The advantage of the solution of the invention is that it does not need to be lyophilized.
    [10] Thus, the present invention relates to a parathyroid hormone solution comprising a therapeutically effective amount of parathyroid hormone, an effective amount of stabilizer, an amount of buffer sufficient to maintain the pH of the composition in a range of about 3 to about 7, and water as the remainder will be.
    [11] If desired, this solution may be lyophilized to produce lyophilized powders with a moisture content of up to 2% by weight.
    [12] Another aspect of the invention is selected from a source of acetate or tartrate, in a therapeutically effective amount of a parathyroid hormone, in a stabilizer of from about 1 to 20% by weight, in an amount sufficient to maintain a pH of the composition in a range from about 3 to about 7. A parathyroid hormone solution comprising buffer, ⒟ parenterally acceptable about 0.1 to 2% by weight of preservative, and ⒠ water as the remainder.
    [13] Another aspect of the invention is a therapeutically effective amount of a parathyroid hormone fragment selected from the group consisting of PTH (1-34), PTH (1-37), PTH (1-38) and PTH (1-41), ⒝ effective amount Stabilizer,, a sufficient amount of buffer to maintain the pH of the composition in the range of about 3 to 7 and ⒟ less than 2% by weight of water, to a pharmaceutical composition in the form of a lyophilized powder before dissolving.
    [1] The present invention relates to a parathyroid hormone containing pharmaceutical composition. More specifically, the present invention relates to a stable solution formulation of teriparatide, ie PTH (1-34).
    [14] The present invention relates to a parathyroid hormone solution that exhibits storage stability in terms of hormone composition and activity.
    [15] The composition or solution of the present invention is a parathyroid hormone in the form of 84 amino acids in full length, in particular humanoid hPTH (1-84) (SEQ ID NO, obtained by recombinant peptide synthesis or extraction from human body fluids with the active ingredient. It may include: 1). See, eg, US Pat. No. 5,208,041, which is incorporated herein by reference. The amino acid sequence of hPTH (1-84) is described by Kimura et al., Biochem. Biophys. Res. Comm., 114 (2): 493] (SEQ ID NO: 1).
    [16] As measured by an ovarian isolated osteoporosis rat model disclosed in Kimmel et al., Endocrinology, 1993, 32 (4): 1577, the composition or solution of the present invention has human PTH activity as an active ingredient. Fragments or variants of human PTH or rat, porcine or bovine PTH.
    [17] Parathyroid hormone fragments contain the first 34 or more N-terminal residues, such as PTH (1-34) (SEQ ID NO: 2), PTH (1-37), PTH (1-38) and PTH (1-41). It is preferable to include. Hormonal fragments in the form of PTH variants include 1-5 amino acid substituents that improve PTH stability and half-life, for example, positions 8 and / or 18 with leucine or other hydrophobic amino acids that improve the stability of PTH to oxidation Replacing amino acids in regions 25-27 with trypsin-insensitive amino acids such as histidine or other amino acids that replace the methionine residues of and improve the stability of PTH to proteases. This form of PTH is included in the term "parathyroid hormone" as used herein collectively. Preferred hormones are human PTH (1-34) (SEQ ID NO: 2), also known as teriparatide. This hormone can be obtained by known recombinant or synthetic methods, for example the method disclosed in US Pat. No. 4,086,196, which is incorporated herein by reference.
    [18] Stabilizers to be mixed in the solution or composition include saccharides, preferably monosaccharides or disaccharides such as glucose, trehalose, raffinose or sucrose, and sugar alcohols such as mannitol, sorbitol or inositol And polyols including polyhydric alcohols such as glycerin or propylene glycol or mixtures thereof. Preferred polyols are mannitol or propylene glycol. The concentration of the polyol is in the range of about 1 to about 20% by weight of the total solution, preferably from about 3 to 10% by weight.
    [19] The buffer used in the solution or composition of the present invention may be any acid or salt combination that is pharmaceutically acceptable and capable of maintaining the aqueous solution in the range of pH 3-7, preferably in the range of 3-6. Useful buffer systems for example are acetate, tartrate or citrate sources. Preferred buffer systems are acetate or tartrate sources, and most preferred buffer systems are acetate sources. The concentration of the buffer may range from about 2 mM to about 500 mM, preferably from about 2 mM to 100 mM.
    [20] In addition, stable solutions or compositions of the present invention may include parenterally acceptable preservatives. For example, these preservatives include cresol, benzyl alcohol, phenol, benzalkonium chloride, benzetonium chloride, chlorobutanol, phenylethyl alcohol, methyl paraben, propyl paraben, thimerosal, phenyl mercury nitrate and phenyl mercury acetate. Preferred preservatives are m-cresol or benzyl alcohol and most preferred preservatives are m-cresol. The amount of preservative used is about 0.1 to about 2 wt% in the total solution, and preferably about 0.3 to about 1.0 wt%.
    [21] Thus, the present invention provides a stable terryparatide solution containing mannitol, acetate and m-cresol having an expected shelf life of 15 months, for example at 5 ° C.
    [22] If desired, the parathyroid hormone composition of the present invention may be provided in powder form with a moisture content of 2% by weight or less through lyophilization of an aqueous solution of sterile hormone prepared by mixing the specific parathyroid hormone, buffer and stabilizer described above. Tartrate sources are especially useful as buffers when preparing lyophilized powders. Particularly useful stabilizers include glycine, mannitol, sucrose, trehalose, raffinose or mixtures thereof.
    [23] PTH solutions and compositions of the present invention include the term used in reference to amounts useful for treatment or medical examination, ie, medically effective amounts of PTH. The particular amount included in the preparation of parathyroid hormone can be determined in advance depending on the selected type of PTH and the desired end use of the preparation. In one example, the agent is used for therapeutic purposes, in particular for the treatment of osteoporosis. Osteoporosis therapies range from 25 μg PTH / mL to 1000 μg / mL per patient, depending on the treatment regimen prescribed, for example for human PTH (1-34) (SEQ ID NO: 2), preferably Preferably, it consists of administering a formulation dissolved in an injection, preferably subcutaneous injection, in a single dose with an injection volume of 0.02 to 1.3 mL. Thus, preferably, purified PTH is mixed with buffers and excipients to prepare PTH-containing aqueous solutions in a concentration range of 25 μg / mL to 1000 μg / mL, preferably in the range of 100 μg / mL to 500 μg / mL. Afterwards, sterile-filtered for use and filled into vials or cartridges.
    [24] Once the formulation is obtained with the desired amount and concentration of buffer, excipient and PTH-containing aqueous solution, each vial is filled up to the desired volume. An advantage of the present invention is that the solution can be prepared in sterile water without the need for performing a freeze drying process.
    [25] In another embodiment of the invention, it is dissolved in about 1 mL (0.8-1.2 mL) of dilution vehicle and then in a form of providing a one-time container of 100-500 μg human PTH (1-34) (SEQ ID NO: 2). The formulation is prepared and, for later freeze drying, the vial is then filled with about 1 mL of aqueous PTH formulation.
    [26] In another preferred embodiment of the invention, the lyophilized PTH formulation is 25 to 1000 μg / mL of human PTH (1-34) (SEQ ID NO: 2), 2 to 8% by weight of mannitol when dissolved in sterile water, and Tartrate source in an amount capable of buffering the formulation within the range of pH 3.0 to 6.5. In a specific embodiment of the present invention, the tartrate buffer is included in an amount sufficient to buffer the pH from 3.5 to 5.5.
    [27] In addition to the therapeutic use, the PTH composition of the present invention may be formulated and administered to aid the medical examination, and in particular, may be used to diagnose hypothyroidism and hypothyroidism in patients with hypocalcemia. The composition of the PTH formulation will be as described herein for therapeutic use, with the exception of the PTH dosage. A single dose of human PTH (1-34) (SEQ ID NO: 2), which is injected intravenously, equivalent to PTH activity of 200 I.U., is suitable for this diagnostic purpose. Thereafter, it can be diagnosed by measuring the action of urinary PTH or the content of urinary cAMP, and the increase in cAMP indicates a state of hypothyroidism rather than hypothyroidism.
    [28] The following examples are illustrative of the invention but are not limited thereto.
    [29] <Example 1>
    [30] One solution was prepared by mixing 0.1 mg of rhPTH (1-34) (SEQ ID NO: 2), 50 mg of mannitol, 2.5 mg of m-cresol, 0.52 mg of acetic acid and 0.12 mg of sodium acetate with 1 ml of distilled water.
    [31] <Example 2>
    [32] One solution was prepared by mixing 0.25 mg of rhPTH (1-34) (SEQ ID NO: 2), 45.4 mg of mannitol, 3 mg of m-cresol, 0.41 mg of acetic acid and 0.1 mg of sodium acetate with 1 ml of distilled water.
    [33] The formulations of Examples 1 and 2 of the present invention were compared with stabilizer-free solutions, 0.9% NaCl containing solution as main stabilizer, 20 mM acetate containing solution and 10 mM acetate containing solution. After a predetermined time, the stability was determined by measuring the amount (%) of remaining rhPTH (1-34) (SEQ ID NO: 2). Measured by HPLC. The results are shown in Tables 1 and 2.
    [34] Effect of Main Stabilizer on Chemical Stability of rhPTH (1-34) at 50 ° Cwater0.9% NaCl20 mM acetate10 mM acetate Hours (days)Residual amount (%) Initial value100100100100 774818480 1455586771
    [35] Comparison of Stability of rhPTH (1-34) at 30 ° C20 mM acetate10 mM acetateExample 1Example 2 Hours (days)Residual amount (%) Initial value100100100100 79694100- 14949296100 21909397- 30-819696
    [36] <Example 3>
    [37] The following experiment was performed to find that the lyophilized powder formulations prepared from the stable solutions of the present invention were more stable than the controls prepared with PTH (1-34) and mannitol alone.
    [38] A solution of the control solution and samples A to O was prepared as described above with the components and concentrations shown in Table 3. Thereafter, the solution was lyophilized and the resulting lyophilized powder formulation was stored at 40 ° C. for 1 month period. Thereafter, the residual amount of PTH (1-34) in each sample was determined by HPLC. The results are shown in Table 3.
    [39] Stability of PTH (1-34) Freeze Dried Formulation at 40 ° C. for 1 Month SamplePTH (1-34) mg / mLExcipientExcipient Concentration mg / mLBufferBuffer concentration mMPTH residue (%) Control0.2Mannitol40--78 A0.5Mannitol30acetate590 B0.5Glycine30acetate598 C0.5Sucrose30acetate598 D0.5Trehalose30acetate597 E0.5Raffinos30acetate599 F0.75Mannitol30Tartrate1595 G1.5Sucrose and mannitol5/25Tartrate599 H0.75Sucrose and mannitol5/25Tartrate1599 I1.5Mannitol30Tartrate596 J1.5Sucrose30Tartrate15100 K1.5Mannitol30Tartrate1599 L0.75Sucrose30Tartrate15100 M0.75Sucrose30Tartrate5100 N1.5Sucrose and mannitol5/25Tartrate1599 O1.5Sucrose and mannitol5/25acetate591 * * Stability was 96% at 2 months.
    〈110〉 Eli Lilly and Company
    〈120〉 STABILIZED TERIPARATIDE SOLUTIONS
    <130> 3797.16WO01
    〈140〉 NEW FILING
    <141> 1998-12-08
    〈150〉 60 / 069,075
    (151) 1997-12-09
    〈160〉 2
    <170> Patent In Ver. 2.0
    〈210〉 1
    <211> 84
    <212> PRT
    〈213〉 Homo sapiens
    <400> 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
    〈210〉 2
    <211> 34
    <212> PRT
    〈213〉 Homo sapiens
    <400> 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
    权利要求:
    Claims (25)
    [1" claim-type="Currently amended] A parathyroid hormone solution comprising a therapeutically effective amount of parathyroid hormone, an effective amount of stabilizer, an amount of buffer sufficient to maintain the pH of the composition in the range of about 3 to about 7, and water as the remainder.
    [2" claim-type="Currently amended] The solution of claim 1 wherein the hormone is a hormone fragment selected from the group consisting of PTH (1-34), PTH (1-37), PTH (1-38) and PTH (1-41).
    [3" claim-type="Currently amended] The solution of claim 1 wherein the hormone is human PTH (1-34) (SEQ ID NO: 2).
    [4" claim-type="Currently amended] The solution of claim 1 wherein the hormone is human PTH (1-84) (SEQ ID NO: 1).
    [5" claim-type="Currently amended] The solution of claim 1 wherein the stabilizer is a polyol.
    [6" claim-type="Currently amended] The solution of claim 5 wherein the polyol is mannitol.
    [7" claim-type="Currently amended] The solution of claim 5 wherein the polyol is propylene glycol.
    [8" claim-type="Currently amended] The solution of claim 1 wherein the buffer is an acetate or tartrate source.
    [9" claim-type="Currently amended] The solution of claim 8 wherein the buffer is an acetate source.
    [10" claim-type="Currently amended] The solution of claim 1 further comprising a parenterally acceptable preservative.
    [11" claim-type="Currently amended] The solution of claim 10 wherein the preservative is m-cresol or benzyl alcohol.
    [12" claim-type="Currently amended] The solution of claim 11 wherein the preservative is m-cresol.
    [13" claim-type="Currently amended] The composition according to claim 1, in the form of a lyophilized powder with a moisture content of up to 2% by weight.
    [14" claim-type="Currently amended] ⒜ a therapeutically effective amount of parathyroid hormone, ⒝ about 1-20% by weight stabilizer, 양 an amount sufficient to maintain the pH of the composition in the range of about 3 to about 7, and a buffer selected from an acetate or tartrate source, ⒟ parenterally acceptable Parathyroid hormone solution comprising about 0.1 to 2% by weight of a preservative and water to the rest.
    [15" claim-type="Currently amended] The solution of claim 14 wherein the hormone is PTH (1-84).
    [16" claim-type="Currently amended] 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" claim-type="Currently amended] The solution of claim 16 wherein the hormone is human PTH (1-34) (SEQ ID NO: 2).
    [18" claim-type="Currently amended] The solution of claim 14 wherein the stabilizer is polyol in an amount from about 3 to about 10 weight percent.
    [19" claim-type="Currently amended] The solution of claim 14 wherein the preservative is m-cresol or benzyl alcohol in an amount from about 0.3 to about 1.0 wt%.
    [20" claim-type="Currently amended] 치료 a therapeutically effective amount of a parathyroid hormone fragment selected from the group consisting of PTH (1-34), PTH (1-37), PTH (1-38), and PTH (1-41), ⒝ an effective amount of a stabilizer, ⒞ the pH of the composition A pharmaceutical composition in the form of a lyophilized powder comprising a sufficient amount of buffer to maintain in the range of about 3 to about 7 and up to 2% by weight of water.
    [21" claim-type="Currently amended] The composition of claim 20, wherein the hormone is human PTH (1-34) (SEQ ID NO: 2).
    [22" claim-type="Currently amended] The composition of claim 20, wherein the stabilizer is selected from the group consisting of glycine, mannitol, sucrose, trehalose, raffinose, and mixtures thereof.
    [23" claim-type="Currently amended] The composition of claim 20, wherein the buffer is an acetate or tartrate source.
    [24" claim-type="Currently amended] The composition of claim 23 wherein the buffer is a tartrate source.
    [25" claim-type="Currently amended] The composition of claim 20, wherein the stabilizer is in an amount of about 1 to about 20 weight percent.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1997-12-09|Priority to US6907597P
    1997-12-09|Priority to US60/069,075
    1998-12-08|Application filed by 피터 지. 스트링거, 일라이 릴리 앤드 캄파니
    1998-12-08|Priority to PCT/US1998/026043
    2001-04-25|Publication of KR20010032881A
    2004-11-25|First worldwide family litigation filed
    2005-04-14|Publication of KR100482703B1
    2005-04-14|Application granted
    优先权:
    申请号 | 申请日 | 专利标题
    US6907597P| true| 1997-12-09|1997-12-09|
    US60/069,075|1997-12-09|
    PCT/US1998/026043|WO1999029337A1|1997-12-09|1998-12-08|Stabilized teriparatide solutions|
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