US20140194356A1 - Aqueous formulation comprising at least a neutral salt and a biopharmaceutical protein - Google Patents

Aqueous formulation comprising at least a neutral salt and a biopharmaceutical protein Download PDF

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Publication number
US20140194356A1
US20140194356A1 US14/234,652 US201214234652A US2014194356A1 US 20140194356 A1 US20140194356 A1 US 20140194356A1 US 201214234652 A US201214234652 A US 201214234652A US 2014194356 A1 US2014194356 A1 US 2014194356A1
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Prior art keywords
formulation according
formulation
neutral salt
biopharmaceutical protein
group
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US14/234,652
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Inventor
Bernt Pragl
Sabine Fuertinger
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Sandoz AG
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Sandoz AG
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Assigned to SANDOZ AG reassignment SANDOZ AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FUERTINGER, SABINE, Pragl, Bernt
Publication of US20140194356A1 publication Critical patent/US20140194356A1/en
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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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system

Definitions

  • biopharmaceutical drugs have entered the market, particularly protein drugs, both isolated from biological resources and/or produced with recombinant means.
  • biopharmaceuticals as therapeutics requires the preservation of their biological activity in all steps of development including storage and delivery.
  • proteins pose additional challenges in preserving their activity because they are much larger, contain relatively labile groups, possess fragile three-dimensional structures, and can furthermore be subject of metabolic processes, e.g. by microorganismic contaminations.
  • Degradation may occur in different ways, including aggregation of molecules, denaturation of tertiary structure and deamidation of amino acid residues, e.g. asparagine and glutamine with their amide-containing side chains. Generally, all these processes of degradation are accelerated under suboptimal storage conditions, e.g., raised temperature, exposure to light and/or high relative humidity.
  • Aggregation can take place in form of visible aggregates and sub visible aggregates. Once formed, however, the latter can act as aggregation seeds for the formation of larger (then visible) aggregations.
  • biopharmaceutical drugs are often produced to stock, and are thus subject to relatively long periods of storage times and/or have to undergo long transportation routes before they reach the point of care. This situation is even worsened by the fact that in many cases it cannot be guaranteed that the cooling chain remains unbroken during storage and/or transport.
  • biopharmaceutics reach the point of care in a state of advanced degradation, and can thus need to be discarded, which involves substantial financial losses, e.g., for the healthcare sponsoring institutions, due to the relatively high market prices for biopharmaceutics, and may, in the worst case, isolate a patient from an essential treatment.
  • a pharmaceutically acceptable aqueous formulation comprising at least a neutral salt and a biopharmaceutical protein, wherein the concentration ratio between the biopharmaceutical protein and the neutral salt is in the range of ⁇ 0.7 and ⁇ 5.
  • biopharmaceutical protein relates to physiologically active proteins both isolated from biological resources and/or produced with recombinant means.
  • concentration refers to the weight of a given substance per volume, i.e., to weight concentration.
  • concentration of a biopharmaceutic is provided in a concentration of mg ml ⁇ 1.
  • the weight of the biopharmaceutical protein refers to weight of the protein alone, i.e, to the one or more amino acid chain which constitute the protein, plus, if applicable, the one or more glycosylation patterns.
  • the weight does not include said modifications, which can add substantial additional weight.
  • concentration ratio refers to the dimensionless ratio of the concentrations of at least two substances.
  • the biopharmaceutic is provided in a concentration of 10 mg ml ⁇ 1 and the neutral salt is provided in a concentration of 7.07 mg ml ⁇ 1
  • the inventors have for the first time shown in an aqueous formulation comprising a biopharmaceutical aggregations, particularly sub-visible aggregations can be reduced in case said particular concentration ratio between the biopharmaceutic and the neutral salt is provided.
  • said concentration ratio is 0.7; 0.8; 0.9; 1.0; 1.1; 1,.2; 1.3; 1.4; 1.5; 1.6; 1.7; 1,8; 1.9; 2.0; 2.1; 2.2; 2.3; 2.4; 2.5; 2.6; 2.7; 2.8; 2.9; 3.0; 3.1; 3.32; 3.3; 3.4; 3.5; 3.6; 3.7; 3,8; 3,9; 4; 4.1; 4.2; 4.3; 4.4; 4.5; 4.6; 4.7; 4.8 4.9; or 5.0.
  • the biopharmaceutical protein has between ⁇ 150 and ⁇ 220 amino acid residues and/or a molecular weight between ⁇ 15 and ⁇ 26 kDaltons.
  • the protein has 150; 151; 152; 153; 154; 155; 156; 157; 158; 159; 160; 1641; 162; 163; 164; 165; 166; 167; 168; 169; 170; 171; 172; 173; 174; 175; 176; 177; 178; 179; 180; 181; 182; 183; 184; 185; 186; 187; 188; 189; 190; 191; 192; 193; 194; 195; 196; 197; 198; 199; 200; 201; 202; 203; 204; 205; 206; 207; 208; 209; 210; 211; 212; 213; 214; 215; 216; 217; 218; 219 or 220 amino acid residues; and/or a molecular weight of 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25 or 26 k
  • the biopharmaceutical protein is human growth hormone (hGH).
  • Human Growth Hormone hGH is a protein-based peptide hormone which stimulates growth, cell reproduction and regeneration in humans and other animals.
  • hGH is a single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior pituitary gland.
  • hGH is primarily used to treat children's growth disorders and adult growth hormone deficiency.
  • growth hormone was extracted from human pituitary glands (Cadaver growth hormone, also referred to as NPA growth hormone).
  • hGH is primarily produced with recombinant DNA technology (rhGH, also referred to as somatropin).
  • rhGH has, typically, 191 amino acid residues.
  • the amino acid sequence is available in the UniProt Database under accession No. P01241.
  • met-GH methionyl-growth hormone
  • methionyl-growth hormone has the same amino acid sequence as hGH, with an extra N-terminal methionine.
  • human growth hormone encompasses all the above mentioned variants.
  • the formulation further comprises at least one agent selected from the group consisting of
  • said buffer is selected from the group consisting of:
  • said non-ionic surfactant is selected from the group consisting of:
  • tonifier relates to an osmotically active substance which can be used to affect the osmolarity of a pharmaceutical formulation.
  • said tonifier is selected from the group consisting of:
  • said preservative is selected from the group consisting of:
  • Suitable concentrations for the buffers, non-ionic surfactants, tonifiers, and/or preservatives are for example shown in Table 2.
  • human growth hormone is present in a concentration ranging between ⁇ 3 and ⁇ 20 mg ml ⁇ 1 .
  • hGH is present in a concentration of 3; 3.33; 4; 5; 6; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18; 19 or 20 mg ml ⁇ 1 .
  • Particularly preferred concentrations for hGH are for example shown in Table 2.
  • said neutral salt is selected from the group consisting of:
  • said neutral salt is present in a concentration ranging between ⁇ 2 and ⁇ 100 mg ml ⁇ 1 .
  • said neutral salt is present in a concentration of 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30; 31; 32; 33; 34; 35; 36; 37; 38; 39; 40; 41; 42; 43; 44; 45; 46; 47; 48; 49; 50; 51; 52; 53; 54; 55; 56; 57; 58; 59; 60; 61; 62; 63; 64; 65; 66; 67; 68; 69; 70; 71; 72; 73; 74; 75; 76; 77; 78; 79; 80; 81; 82; 83; 84; 85; 86; 87; 88; 89; 90; 91; 92;
  • concentrations for the neutral salt are for example shown in Table 2.
  • the pH of said formulation is in a range between ⁇ 5,8 and ⁇ 6.2.
  • said pH is 5,8; 5,9; 6; 6,1 or 6,2.
  • Particularly preferred pH values are for example shown in Table 2.
  • the formulation according to the invention has an optimized stability. Said optimized stability results, e.g., in reduced formation of visible and subvisible aggregates, reduced formation of precipitates, reduced tendency to develop turbidity, particularly after long storage or storage under suboptimal conditions.
  • This feature is particularly beneficial under conditions where it cannot be guaranteed that the cooling chain remains unbroken, as its can for example be the case in emerging markets and/or developing countries.
  • aggregates can for example be analyzed with light obscuration Particle Counting, Size exclusion HPLC (SE-HPLC)and/or Dynamic light scattering (DLS).
  • SE-HPLC Size exclusion HPLC
  • DLS Dynamic light scattering
  • Light obscuration Particle Counting is a method that helps to detect and count particles.
  • the nature of particle counting is based upon either light scattering or light obscuration.
  • a high energy light source is used to illuminate the particle as it passes through the detection chamber.
  • the particle passes through the light source (typically a laser) and if light scattering is used, then the redirected light is detected by a photo detector, while, if light obscuration is used, the loss of light is detected. The amplitude of the light scattered or light blocked.
  • SE-HPLC Size exclusion HPLC
  • Dynamic light scattering is a technique in physics, which can be used to determine the size distribution profile of small particles in suspension or polymers in solution. It can also be used to probe the behavior of complex fluids such as concentrated polymer solutions.
  • a method of increasing the stability of a pharmaceutically acceptable aqueous formulation comprising a biopharmaceutical protein comprises providing the biopharmaceutical protein and the neutral salt in a final concentration ratio in the range of ⁇ 0.7 and ⁇ 5.
  • the biopharmaceutical protein is human growth hormone (hGH).
  • a primary packaging comprising the formulation according to the invention.
  • Said primary packaging is preferably a vial, a pre-filled syringe, a carpule, a bottle, or a cartridge.
  • Table 3 shows other aqueous formulations from the prior art comprising human growth hormone, but without a neutral salt.
  • FIG. 1 Particle distribution of samples stored at 5° C. in the first tonifier screening experiment (example 1, “intended storage condition”), as determined with light obscuration Particle Counting.
  • sample 1 “intended storage condition”
  • sub-visible particle levels were high at the initial time point and shows elevated levels for formulations containing no tonifier, Glycine, Mannitol and Sorbitol. NaCl containing formulations showed the lowest sub-visible particle levels.
  • FIG. 2 Particle distribution of samples stored at 25° C. in the first tonifier screening experiment (example 1, “accelerated storage condition”), as determined with light obscuration Particle Counting.
  • sample 1 “accelerated storage condition”
  • sub-visible particle levels were high at the initial time point but stayed at elevated levels for formulations containing no tonifier, Glycine and Sorbitol. NaCl containing formulations showed the lowest sub-visible particle levels.
  • FIG. 3 Particle distribution of samples stored at 40° C. in the first tonifier screening experiment (example 1, “stressed storage conditions”), as determined with light obscuration Particle Counting.
  • sample 1 stressed storage conditions
  • sub-visible particle levels were highest at the initial time point. All formulations stored for 1 week and 2 weeks at 40° C. showed a significant decrease in sub-visible particle levels.
  • FIG. 4 Particle distribution of samples stored at 5° C. in the second tonifier screening experiment (example 3, “intended storage condition”), as determined with light obscuration Particle Counting.
  • sample 3 “intended storage condition”
  • sub-visible particles progressively increase for formulations containing no tonifier and Glycine and pronounced for formulations containing Sorbitol and Mannitol. NaCl containing formulations showed the lowest sub-visible particle levels.
  • FIG. 5 Particle distribution of samples stored at 25° C. in the second tonifier screening experiment (example 3, “accelerated storage condition”), as determined with light obscuration Particle Counting.
  • sample 3 “accelerated storage condition”
  • sub-visible particles stayed at elevated levels for formulations containing no tonifier, Glycine, Sorbitol and Mannitol. NaCl containing formulations showed the lowest sub-visible particle levels.
  • FIG. 6 Particle distribution of samples stored at 40° C. in the second tonifier screening experiment (example 3, “stressed storage condition”), as determined with light obscuration Particle Counting.
  • sample 3 stressed storage condition
  • sub-visible particle levels were highest at the end of storage after 2 weeks at 40° C.
  • Sub-visible particles were at elevated levels for formulations containing no tonifier, Glycine, Sorbitol and Mannitol. NaCl containing formulations showed the lowest sub-visible particle levels.
  • FIG. 7 Particle distribution of samples stored at 5° C. in the optimization of neutral salt concentration experiment (example 2, “intended storage condition”), as determined with light obscuration Particle Counting. Sub-visible particle levels were elevated for all batches except for formulations containing 3.5 mg/ml, 7.07 mg/ml and 14 mg/ml NaCl during storage at 5° C. This finding is further backed by DLS data (data not shown).
  • FIG. 8 Particle distribution of samples stored at 25° C. in the optimization of neutral salt concentration experiment (example 2, “accelerated condition”), as determined with light obscuration Particle Counting. Sub-visible particle levels were elevated for all batches except for formulations containing 3.5 mg/ml, 7.07 mg/ml and 14 mg/ml NaCl during storage at 25° C. This finding is further backed by DLS data (data not shown).

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  • Proteomics, Peptides & Aminoacids (AREA)
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US14/234,652 2011-07-25 2012-07-25 Aqueous formulation comprising at least a neutral salt and a biopharmaceutical protein Abandoned US20140194356A1 (en)

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US14/234,652 US20140194356A1 (en) 2011-07-25 2012-07-25 Aqueous formulation comprising at least a neutral salt and a biopharmaceutical protein

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US201161511168P 2011-07-25 2011-07-25
PCT/EP2012/064613 WO2013014196A1 (en) 2011-07-25 2012-07-25 Aqueous formulation comprising at least a neutral salt and a biopharmaceutical protein
US14/234,652 US20140194356A1 (en) 2011-07-25 2012-07-25 Aqueous formulation comprising at least a neutral salt and a biopharmaceutical protein

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US15/913,550 Active 2033-03-08 US11446381B2 (en) 2011-07-25 2018-03-06 Stable aqueous formulation for growth hormone

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EP (1) EP2736490A1 (pt)
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WO (1) WO2013014196A1 (pt)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112494638A (zh) * 2020-12-22 2021-03-16 深圳科兴药业有限公司 一种人生长激素注射剂组合物及其制备方法
US11738068B2 (en) 2018-06-25 2023-08-29 Jcr Pharmaceuticals Co., Ltd. Protein-containing aqueous liquid formulation

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US6448225B2 (en) * 1988-04-15 2002-09-10 Genentech, Inc. Human growth hormone aqueous formulation
US6593296B1 (en) * 1996-02-12 2003-07-15 Csl Limited Stabilized growth hormone formulation and method of preparation thereof
US8071544B2 (en) * 2006-12-18 2011-12-06 Althea Technologies, Inc. Crystallized recombinant human growth factor formulations

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DE69329651T3 (de) * 1992-07-31 2008-10-30 Genentech, Inc., South San Francisco Wässrige arzneizusammensetzung, welche das menschliche wachstumshormon enthält
JP3723857B2 (ja) * 1998-02-04 2005-12-07 日本ケミカルリサーチ株式会社 ヒト成長ホルモン含有水性医薬組成物
CN1360506A (zh) 1999-07-12 2002-07-24 格兰迪斯生物技术有限公司 生长激素配方
EP1536835A1 (en) * 2002-07-09 2005-06-08 Sandoz AG Liquid formulations with high concentration of human growth hormone (hgh) comprising phenol
EP1603588A2 (en) * 2003-03-18 2005-12-14 Ares Trading S.A. Stabilisation of growth hormones in solution
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EA010626B1 (ru) * 2004-04-07 2008-10-30 Арес Трейдинг С.А. Жидкий состав гормона роста
RU2558821C2 (ru) * 2009-11-17 2015-08-10 Ипсен Фарма С.А.С. ЛЕКАРСТВЕННАЯ ФОРМА ДЛЯ КОМБИНАЦИИ hGH И rhIGF-1

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US6448225B2 (en) * 1988-04-15 2002-09-10 Genentech, Inc. Human growth hormone aqueous formulation
US6593296B1 (en) * 1996-02-12 2003-07-15 Csl Limited Stabilized growth hormone formulation and method of preparation thereof
US8071544B2 (en) * 2006-12-18 2011-12-06 Althea Technologies, Inc. Crystallized recombinant human growth factor formulations

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11738068B2 (en) 2018-06-25 2023-08-29 Jcr Pharmaceuticals Co., Ltd. Protein-containing aqueous liquid formulation
CN112494638A (zh) * 2020-12-22 2021-03-16 深圳科兴药业有限公司 一种人生长激素注射剂组合物及其制备方法

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WO2013014196A1 (en) 2013-01-31
JP2014528919A (ja) 2014-10-30
BR112014001921B1 (pt) 2022-05-10
BR112014001921A2 (pt) 2019-04-02
US11446381B2 (en) 2022-09-20
EP2736490A1 (en) 2014-06-04
JP6363949B2 (ja) 2018-07-25
US20180256722A1 (en) 2018-09-13

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