WO2015050160A1 - Composition pharmaceutique anti-âge pour muscle contenant en tant que principe actif une hormone parathyroïde ou un dérivé de celle-ci - Google Patents

Composition pharmaceutique anti-âge pour muscle contenant en tant que principe actif une hormone parathyroïde ou un dérivé de celle-ci Download PDF

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WO2015050160A1
WO2015050160A1 PCT/JP2014/076289 JP2014076289W WO2015050160A1 WO 2015050160 A1 WO2015050160 A1 WO 2015050160A1 JP 2014076289 W JP2014076289 W JP 2014076289W WO 2015050160 A1 WO2015050160 A1 WO 2015050160A1
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muscle
parathyroid hormone
group
pharmaceutical composition
teriparatide
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PCT/JP2014/076289
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English (en)
Japanese (ja)
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圭祐 萩原
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国立大学法人大阪大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/635—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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • the present invention relates to a pharmaceutical composition for preventing muscle aging, which comprises parathyroid hormone or a derivative thereof as an active ingredient.
  • Non-Patent Documents 1 and 2 the most effective means for prevention and treatment of sarcopenia is strength training (Non-Patent Documents 1 and 2), but there are complications such as joints and circulatory organs, and body movement is already restricted. If so, it is difficult to exercise with sufficient intensity.
  • Clinical studies on essential amino acids, hormonal agents (testosterone, estrogen, growth hormone) and ACE inhibitors have been conducted, but amino acids have no therapeutic effect (Non-patent Document 3), and hormonal agents such as breast cancer and prostate cancer It has been reported that the risk increases and ACE inhibitors have few cases and do not lead to evidence construction (Non-patent Document 4). In other words, at present, sufficient measures have not been taken against sarcopenia, and there is no drug approved as a therapeutic drug.
  • Locomotive syndrome refers to a condition in which the mobility function has deteriorated due to a disorder of the musculoskelet. More specifically, one or more of the musculoskeletal organs such as muscle, bone, joint, cartilage, and intervertebral disc have failed. This refers to a state where some obstacles are caused to walking and daily life. As the locomotive syndrome progresses, the risk of needing care increases, so it is considered important to prevent locomotive syndrome and extend healthy life expectancy. Sarcopenia is considered one of the most important factors causing locomotive syndrome, therefore preventing sarcopenia and improving muscle weakness and loss of muscle slows the progression of locomotive syndrome and prevents locomotive syndrome And greatly contribute to improvement.
  • PTH parathyroid hormone
  • teriparatide an osteoporosis therapeutic agent
  • Non-patent Document 5 Non-patent Document 5
  • An object of the present invention is to provide a pharmaceutical composition useful for preventing muscle aging, particularly a pharmaceutical composition useful for preventing or treating sarcopenia and locomotive syndrome by suppressing the decrease in muscle strength accompanying aging.
  • the present invention includes the following inventions in order to solve the above problems.
  • a pharmaceutical composition for preventing muscle aging which contains parathyroid hormone, a parathyroid hormone derivative or a salt thereof as an active ingredient.
  • a method for preventing muscle aging comprising administering an effective amount of a parathyroid hormone, a parathyroid hormone derivative or a salt thereof to a mammal.
  • a method for suppressing muscle weakness comprising administering an effective amount of a parathyroid hormone, a parathyroid hormone derivative or a salt thereof to a mammal.
  • a method for preventing and / or treating sarcopenia comprising administering an effective amount of parathyroid hormone, a parathyroid hormone derivative or a salt thereof to a mammal.
  • a method for preventing and / or treating locomotive syndrome comprising administering an effective amount of parathyroid hormone, a parathyroid hormone derivative or a salt thereof to a mammal.
  • parathyroid hormone, a parathyroid hormone derivative or a salt thereof for producing a pharmaceutical composition for preventing muscle aging.
  • Use of a parathyroid hormone, a parathyroid hormone derivative or a salt thereof for producing a pharmaceutical composition for preventing and / or treating sarcopenia Use of a parathyroid hormone, a parathyroid hormone derivative or a salt thereof for producing a pharmaceutical composition for preventing and / or treating locomotive syndrome.
  • a pharmaceutical composition useful for preventing muscle aging can be provided.
  • the pharmaceutical composition of the present invention can suppress a decrease in muscle strength associated with aging, and is very useful as a pharmaceutical for preventing or treating sarcopenia and a pharmaceutical for preventing or treating locomotive syndrome.
  • teriparatide administration test using an aging promoting model mouse it is a figure showing the results of bone mass measurement by 2D-CT of representative individuals in each group at the age of 30 weeks.
  • a teriparatide administration test using an aging promoting model mouse it is a figure showing the average bone mass of each group at the age of 30 weeks.
  • a teriparatide administration test using an aging promoting model mouse it is a figure showing the average grip strength of each group at the age of 20 weeks.
  • a teriparatide administration test using an aging promoting model mouse it is a figure showing the average grip strength of each group at the age of 30 weeks.
  • the present invention provides a pharmaceutical composition for preventing muscle aging, which contains parathyroid hormone (hereinafter referred to as “PTH”), a parathyroid hormone derivative (hereinafter referred to as “PTH derivative”) or a salt thereof as an active ingredient.
  • PTH parathyroid hormone
  • PTH derivative parathyroid hormone derivative
  • the origin of PTH used as an active ingredient in the present invention is not particularly limited, and PTH derived from various organisms can be used. Preferred is PTH derived from a mammal. Examples of mammals include, but are not limited to, humans, mice, rats, cows, pigs and the like. Among these, it is particularly preferable to use human PTH.
  • human PTH natural human PTH, synthetic human PTH, recombinant human PTH and the like can be suitably used.
  • Human PTH has the amino acid sequence shown in SEQ ID NO: 1.
  • PTH derivatives used as active ingredients in the present invention include PTH fragments, mutations in which 1 to several amino acids are deleted, substituted or added in the amino acid sequence of wild-type PTH, but exhibit biological activity of PTH And mutants in which 1 to several amino acids are conservatively substituted in the amino acid sequence of wild-type PTH.
  • it is a variant of human PTH.
  • a variant of human PTH a fragment of human PTH, a variant in which 1 to several amino acids are deleted, substituted or added in the amino acid sequence of human PTH (SEQ ID NO: 1), but exhibiting the biological activity of PTH
  • Examples include a variant in which one to several amino acids are conservatively substituted in the amino acid sequence of human PTH (SEQ ID NO: 1).
  • the human PTH fragment may be any fragment as long as it exhibits the biological activity of PTH, but is preferably a fragment containing 34 amino acids on the N-terminal side of human PTH, more preferably the N-terminal of human PTH. It is a fragment (teriparatide) consisting of 34 amino acids (SEQ ID NO: 2) on the side. As long as the fragment of human PTH shows the biological activity of PTH, the amino acid may be conservatively substituted.
  • PTH derivatives include those having a modified carboxy terminus.
  • the modified carboxy terminus include carboxylate (—COO ⁇ ), amide (—CONH 2 ), ester (—COOR) and the like.
  • R in the ester is, for example, a C1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl or n-butyl, for example, a C3-8 cycloalkyl group such as cyclopentyl, cyclohexyl, etc., for example, phenyl, ⁇ -naphthyl, etc.
  • C7-14 aralkyl groups such as phenyl-C1-2 alkyl groups such as benzyl and phenethyl or ⁇ -naphthyl-C1-2 alkyl groups such as ⁇ -naphthylmethyl, and the like Examples include pivaloyloxymethyl group, which is widely used as an ester.
  • PTH derivatives include those in which the side chain of the constituent amino acid is modified with an arbitrary substituent.
  • a substituent is not specifically limited, For example, a fluorine atom, a chlorine atom, a cyano group, a hydroxyl group, a nitro group, an alkyl group, a cycloalkyl group, an alkoxy group, an amino group etc. are mentioned.
  • substituents on the side chain of amino acids in the molecule for example, —OH, —SH, amino group, imidazole group, indole group, guanidino group, etc.
  • protecting groups for example, formyl group, acetyl, etc.
  • C those protected with a C 1-6 acyl group such as a 2-6 alkanoyl group.
  • the PTH or PTH derivative used as an active ingredient in the present invention may form a salt.
  • examples thereof include salts with inorganic acids such as hydrochloric acid and sulfuric acid, and salts with organic acids such as acetic acid, tartaric acid, succinic acid, and malic acid.
  • Acetate is preferred, and teriparatide acetate (acetate teriparatide) is particularly preferred.
  • a PTH or PTH derivative is expressed as a recombinant protein by constructing a recombinant expression vector into which a gene encoding PTH or a fragment thereof is inserted in a suitable host cell, for example, by a known genetic engineering technique. And can be produced by purification.
  • the base sequence of the gene encoding PTH can be obtained from a known data base (DDBJ / GenBank / EMBL, etc.).
  • the base sequence of the gene encoding human PTH for example, the base sequence shown in SEQ ID NO: 3 (ACCESSION: NM_000315) can be used.
  • PTH or a PTH derivative can be manufactured using, for example, an in vitro transcription / translation system.
  • PTH or a PTH derivative can be produced by a solid phase synthesis method (Fmoc method, Boc method) or a liquid phase synthesis method according to a known general peptide synthesis protocol.
  • the pharmaceutical composition of the present invention can effectively prevent muscle aging.
  • it is very useful as a pharmaceutical for preventing and / or treating sarcopenia.
  • the pharmaceutical composition of the present invention is very useful as a medicament for preventing and / or treating locomotive syndrome.
  • the muscle that is subject to aging prevention is not particularly limited, but skeletal muscle is preferred.
  • Examples of skeletal muscles include the sternocleidomastoid muscle, the great pectoral muscle, the small pectoral muscle, the anterior sawnous muscle, the subclavian muscle, the rectus abdominis muscle, the external oblique muscle, the internal oblique muscle, the transverse abdominal muscle, the lumbar muscle, the monk.
  • Cap muscle latissimus dorsi, spine standing muscle, levator scapula, rhomboid, triangular muscle, small circular muscle, supraspinatus, subspinous muscle, subscapular muscle, great circular muscle, incisor arm, biceps , Brachial muscles, brachial muscles, triceps, elbows, circular rotator muscles, rectangular rotator muscles, supination muscles, ulnar carpal flexors, radial carpal flexors, long palmar muscles, superficial finger flexors, deep Finger flexor, long thumb flexor, long lateral carpal extensor, short lateral carpal extensor, ulnar carpal extensor, finger extensor, index finger extensor, little finger extensor, long thumb extensor, short thumb extensor Muscles, long thumb abductors, medial muscles (4 muscles), palmar interosseous muscles (3 muscles), dorsal interosseous
  • the pharmaceutical composition of the present invention can be formulated by appropriately blending a pharmaceutically acceptable carrier and an additive with PTH, a PTH derivative or a salt thereof.
  • oral preparations such as tablets, coated tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions; parenterals such as injections, infusions, suppositories, ointments, patches, etc. can do.
  • What is necessary is just to set suitably about the mixture ratio of a carrier or an additive based on the range normally employ
  • Carriers or additives that can be blended are not particularly limited.
  • various carriers such as water, physiological saline, other aqueous solvents, aqueous or oily bases; excipients, binders, pH adjusters, disintegrants, absorption
  • Various additives such as an accelerator, a lubricant, a colorant, a corrigent, and a fragrance are included.
  • Additives that can be mixed into tablets, capsules and the like include binders such as gelatin, corn starch, tragacanth, gum arabic, excipients such as crystalline cellulose, corn starch, gelatin, alginic acid and the like. Leavening agents, lubricants such as magnesium stearate, sweeteners such as sucrose, lactose or saccharin, flavorings such as peppermint, red oil and cherry.
  • a liquid carrier such as fats and oils can be further contained in the above type of material.
  • Sterile compositions for injection can be prepared according to normal pharmaceutical practice (for example, dissolving or suspending an active ingredient in a solvent such as water for injection or natural vegetable oil).
  • aqueous liquid for injection for example, isotonic solutions containing physiological saline, glucose and other adjuvants (for example, D-sorbitol, D-mannitol, sodium chloride, etc.) are used.
  • alcohol eg, ethanol
  • polyalcohol eg, propylene glycol, polyethylene glycol
  • nonionic surfactant eg, polysorbate 80 TM , HCO-50
  • oily liquid for example, sesame oil, soybean oil and the like are used, and they may be used in combination with solubilizing agents such as benzyl benzoate and benzyl alcohol.
  • Buffers eg, phosphate buffer, sodium acetate buffer
  • soothing agents eg, benzalkonium chloride, procaine, etc.
  • stabilizers eg, human serum albumin, polyethylene glycol, etc.
  • storage You may mix
  • the pharmaceutical composition of the present invention can be used in humans and other mammals (for example, rats, mice, rabbits, sheep, pigs, cows, cats). , Dogs, monkeys, etc.).
  • the daily dose of the pharmaceutical composition of the present invention is not particularly limited as long as it is an amount effective for preventing muscle aging and has few side effects.
  • the daily dose of the pharmaceutical composition of the present invention is preferably set according to the daily dose of a commercially available osteoporosis therapeutic agent.
  • Example 1 Effect of teriparatide on muscle strength of senescence accelerated model mice
  • Animals Used SAMP8 (7 weeks old, male) which is an aging promoting model mouse and SAMR1 (7 weeks old, male) which is a normal aging mouse were obtained from SLC Japan.
  • the teriparatide dosing solution was prepared by dissolving 0.5 mg / vial teriparatide in 37.5 ml of solvent in a safety cabinet to prepare 1.2 ⁇ g / 90 ⁇ l teriparatide dosing solution. About 1.5 ml was dispensed, frozen at ⁇ 30 ° C. and thawed before use.
  • mice were euthanized, and the lower limbs (including the femur and tibia) were removed.
  • the femur and tibia were subjected to tissue preparation.
  • the soleus and rectus femoris were removed, immediately frozen in liquid nitrogen, and then stored at ⁇ 80 ° C.
  • Cryopreserved soleus and rectus femoris were thawed at a later date, homogenized, and subjected to Western blotting.
  • the paravertebral column standing muscle was excised, the thoracic vertebrae to the coccyx were removed, and the bone mass of the first lumbar vertebra was measured.
  • tissue specimens of the tibia were prepared according to a conventional method.
  • anti-SERCA1 antibody Anti-SERCA1 ATPase Rabbit monoclonal Ab, Abcam (ab133275)
  • SERCA1 fast-twitch skeletal muscle sarcoplasmic reticulum Ca (2+) ATPase
  • anti-UCP-3 antibody Anti-UCP-3 Rabbit polyclonal Ab, abcam (ab3477)
  • GE horseradish peroxidase labeled secondary antibody
  • UCP-3 UCP (Uncoupling protein) is a mitochondrial inner membrane protein, and UCP-3 is often present in muscle tissues such as skeletal muscle. Are known. Therefore, the expression level of UCP-3 in the muscle of each group of mice was analyzed by Western blotting. The results are shown in FIG. In the SAMP8 solvent administration group, the expression level of UCP-3 was decreased, but in the SAMP8 teriparatide administration group, the decrease in the expression level was suppressed.

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Abstract

La présente invention concerne une composition pharmaceutique anti-âge pour muscle contenant en tant que principe actif une hormone parathyroïde ou un dérivé d'hormone parathyroïde, ou un sel de celui-ci. De préférence, le dérivé d'hormone parathyroïde est le tériparatide. La composition pharmaceutique anti-âge est capable de prévenir la réduction de la force musculaire associée à l'âge et de prévenir ou traiter la sarcopénie et le syndrome locomoteur.
PCT/JP2014/076289 2013-10-03 2014-10-01 Composition pharmaceutique anti-âge pour muscle contenant en tant que principe actif une hormone parathyroïde ou un dérivé de celle-ci WO2015050160A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2015064585A1 (ja) * 2013-10-29 2017-03-09 国立大学法人 熊本大学 筋疾患の治療または予防のための医薬組成物
CN115768430A (zh) * 2020-06-30 2023-03-07 东丽株式会社 伴随代谢异常的疾病或综合征中的肌力下降症状的改善剂或预防剂

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WO2005027915A1 (fr) * 2003-09-19 2005-03-31 Pfizer Products Inc. Compositions pharmaceutiques et methodes de traitement consistant en des associations d'un derive de la 2-alkylidene-19-nor-vitamine d et de l'hormone parathyroidienne
JP2013519869A (ja) * 2010-02-10 2013-05-30 ノバルティス アーゲー 筋肉成長のための方法および化合物
WO2014162925A1 (fr) * 2013-04-01 2014-10-09 国立大学法人大阪大学 Composition pour la prévention du vieillissement articulaire

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2005027915A1 (fr) * 2003-09-19 2005-03-31 Pfizer Products Inc. Compositions pharmaceutiques et methodes de traitement consistant en des associations d'un derive de la 2-alkylidene-19-nor-vitamine d et de l'hormone parathyroidienne
JP2013519869A (ja) * 2010-02-10 2013-05-30 ノバルティス アーゲー 筋肉成長のための方法および化合物
WO2014162925A1 (fr) * 2013-04-01 2014-10-09 国立大学法人大阪大学 Composition pour la prévention du vieillissement articulaire

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Title
KAJI, H. ET AL.: "Insulin-like growth factor-I mediates osteoclast-like cell formation stimulated by parathyroid hormone", J. CELL. PHYSIOL., vol. 172, no. 1, 1997, pages 55 - 62, XP002917107, DOI: doi:10.1002/(SICI)1097-4652(199707)172:1<55::AID-JCP6>3.0.CO;2-C *
MASAYUKI YAMAGUCHI ET AL.: "Fuku Kojosen Hormone (PTH 1-34) no Kotsu Doka Sayo ni Okeru IGF-I/IRS-1 Signal no Kan'yo", THE ANNUAL MEETING OF THE JAPANESE SOCIETY FOR BONE AND MINERAL RESEARCH: PROGRAM & ABSTRACTS, vol. 22 ND, 2005, pages 204, P-068 *
MASAYUKI YAMAGUCHI ET AL.: "PTH no Kotsu Doka Sayo ni Okeru IGF-I/IRS-1 Signal no Kan'yo", THE JOURNAL OF THE JAPANESE ORTHOPAEDIC ASSOCIATION, vol. 78, no. 8, 2004, pages S1016 *
SHOTA KAGAWA ET AL.: "Goshajinkigan wa insulin/IGF1 Signal o Kaishite SAMP8 Mouse no Sarcopenia o Kaizen suru", J. TRADITIONAL MEDICINES, vol. 30, 29 July 2013 (2013-07-29), pages 62, O-10 *
TAKESHI MIYAZAKI ET AL.: "Recent advances in basic and clinical research of osteoporosis", JAPANESE JOURNAL OF GERIATRICS, vol. 50, no. 2, 25 March 2013 (2013-03-25), pages 130 - 134 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2015064585A1 (ja) * 2013-10-29 2017-03-09 国立大学法人 熊本大学 筋疾患の治療または予防のための医薬組成物
CN115768430A (zh) * 2020-06-30 2023-03-07 东丽株式会社 伴随代谢异常的疾病或综合征中的肌力下降症状的改善剂或预防剂

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