TW303299B - - Google Patents
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- TW303299B TW303299B TW082106163A TW82106163A TW303299B TW 303299 B TW303299 B TW 303299B TW 082106163 A TW082106163 A TW 082106163A TW 82106163 A TW82106163 A TW 82106163A TW 303299 B TW303299 B TW 303299B
- Authority
- TW
- Taiwan
- Prior art keywords
- bone
- parathyroid hormone
- effective dose
- medicine
- bone loss
- Prior art date
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- 210000000988 bone and bone Anatomy 0.000 claims abstract description 39
- 206010065687 Bone loss Diseases 0.000 claims abstract description 21
- 238000011282 treatment Methods 0.000 claims abstract description 19
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 239000000199 parathyroid hormone Substances 0.000 claims description 41
- 102000003982 Parathyroid hormone Human genes 0.000 claims description 40
- 108090000445 Parathyroid hormone Proteins 0.000 claims description 40
- 229960001319 parathyroid hormone Drugs 0.000 claims description 40
- 239000003814 drug Substances 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 229940088597 hormone Drugs 0.000 claims description 7
- 239000005556 hormone Substances 0.000 claims description 7
- 210000002990 parathyroid gland Anatomy 0.000 claims description 4
- 235000002791 Panax Nutrition 0.000 claims 3
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- 238000000034 method Methods 0.000 abstract description 9
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 abstract description 5
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- 101000845188 Homo sapiens Tetratricopeptide repeat protein 4 Proteins 0.000 description 1
- 101000598103 Homo sapiens Tuberoinfundibular peptide of 39 residues Proteins 0.000 description 1
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- 108090001060 Lipase Proteins 0.000 description 1
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- 239000004367 Lipase Substances 0.000 description 1
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- 208000034578 Multiple myelomas Diseases 0.000 description 1
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- 229910019142 PO4 Inorganic materials 0.000 description 1
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- 102100031279 Tetratricopeptide repeat protein 4 Human genes 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- 102100036964 Tuberoinfundibular peptide of 39 residues Human genes 0.000 description 1
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
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- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
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- 210000004705 lumbosacral region Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
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- 230000000399 orthopedic effect Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
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- 108090000765 processed proteins & peptides Proteins 0.000 description 1
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- BKXVVCILCIUCLG-UHFFFAOYSA-N raloxifene hydrochloride Chemical compound [H+].[Cl-].C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 BKXVVCILCIUCLG-UHFFFAOYSA-N 0.000 description 1
- 235000012950 rattan cane Nutrition 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 description 1
- 229960005460 teriparatide Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
-
- 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
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Physical Education & Sports Medicine (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Zoology (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
A6 _B6_I_ 五、發明説明(1 ) 發明節圈 本發明係關於作為增加骨質量之甲吠旁腺激素當和熱洛 昔夫恩一起使用時之使用方法,此治療上之混合治療法導 致促進骨生成速率及骨質量增加。 链明背吾 亞當等、美國專利案號第5, 118,667號·揭示骨質生長 因子和骨質耗損抑制劑,兩者混合為一同時或次第的投藥 ,以促進骨骼生成。 斯洛維克(Slovik)等(J. Bone & Min Res. 1:377-381 ,1986)發表藉由甲狀旁腺激素刺激骨骼生長。 美國專利案號第4,418,068號介紹熱洛昔夫恩,1992, 7,28日建檔(X-7949)之美國專利申請序列案號第 07/920,933號,併人本文供參考,其揭示熱洛昔夫恩對抑 制或防止骨質流失是有效的。熱洛昔夫恩具下列之结構: (諳先W讀背面之注意事項再填寫本頁)
適用中ΚΛ1孓彳(CNS)甲4規格(210 X 297公货) 82.6. 40,000 經濟部中央標準局貝工消費合作杜印¾ Α6 Β6 五、發明説明(2 ) 發明摘沭 本發明係闞藉由甲狀旁腺激素及熱洛昔夫恩之投藥Μ增 加生物個體#質量之方法。 本發明另一観點是一種藉由甲狀旁腺激素及熱洛昔夫恩 之投藥Μ治療生物個體骨質流失的方法。 本發明另提供一種增加生物個體骨質量之甲狀旁腺激素 及熱洛昔夫恩之姐合物。 本發明另一觀點是一種治療生物個體骨質流失之甲狀旁 腺激素及熱洛昔夫恩之組合物。 發明詳沭 當提及熱洛昔夫恩時須知它是包含其鹽類及其媒合物, 當提及甲狀旁腺激素時,它不僅包含完整的人體激素|也 包含負責促進骨骼生畏的部分激素,如ΡΤΗ1-34 ,及在胺 基酸序列上稍為修改但仍保留促進骨骼生長的特性之類似 物,如 PTH-RP 。 術語”骨質耗損之抑制”係指防止骨質流失、特別是抑制 現存之骨姐織從礦物質態及/或有機基質態二者之一 *經 由破骨细胞生成或代謝代用直接或間接的改變之方式移除 。因此,本_文使用的術語”骨質再吸收抑制劑”係指藉由破 骨细胞生成或代謝作用之改變Μ防止骨質流失之藥劑。 術語”骨質生成有效性”係指影W骨質生成及分化的量, 在本文中使用,骨質生成有效的劑量亦即”醫藥上有效性 ,’ 0 本文所用術語"個體”係指一個需要治療1也就是需要骨 β ?.嗖通用中节卫(C\S)甲4規烙(210 X 297*公釐) 82.6. 40,000 --Τ-Ι----------------------^-----ΊΪΤ------線 (靖先閲讀背面之注意事項再堉寫本頁) 經濟部中央標準局員工消f合作杜印¾ A6 _ B6_'_ 五、發明説明(3 ) 質修復或補充的活生生奇椎動物如某種哺乳類或鳥_。若 發生骨祈,接合不全,骨骼缺陷、彌補物植人,諸如此類 等會產生此種需要,若發生全身骨骼疾病,如骨骼疏鬆症 •费闞節炎,Paget氐病、軟骨病,骨質耗損、多發性骨 髓瘤及其它型式之癌症,K及和年舲有關之骨質量流失也 會發生此種需要。 本文所用術語”治療”應該指Π)對個體給與一種足以產 生預防作用以防止一種變弱的和/或不健康的狀態的適量 之某物質;或(2 )給與個體一種足量的某物質Μ期能夠減 輕或消除某種疾病狀態及/或某種疾病之症狀· Μ及某種 變弱的及/或不健康的狀態。 熱洛昔夫恩可藉由如美國專利案號第4,418.068號所詳 述的那些已證明的步驟來製造,甲狀旁腺激素可以藉由已 證明的步驟合成的或複合地製造,Ρ ΤΗ卜3 4可以從加州托 倫斯(Torrence)之Bachem公司購得。 防止骨質流失,及/或補充流失骨質及/或增加骨質量 之藥物可以在卵巢摘除鼠體内予Μ測量,此種動物模式在 技藝中已充分證明(例如參考Wronski ,等(1985)
Calcif Tissue Int 37:324-328; Kimmel 等( 1990)
Calcif Tissue Int 46:101-110;及 Durbridge ,等 (1990) Calcif Tissue Int 47:383-387 ;在此將這些參 考文獻全部併列本文供參考)Wr〇nSki ,等(1985)
Calcif Tissue Int 43:179-183)介紹卵巢摘除鼠體内骨 質流失與骨質重新分配之關連,霍克(Hock)等也介紹未成 -5- ' { 《 .HT---------------------裝-----ΙΤΓ------.% (請先閱讀背面之注意事項再填寫本頁) 通用中 Μ (CNS)甲 4 規格(210 X 297 公;$ ) 82.Γ,. 40,000 303299 經濟部中央標準曷貝工消費合作社印¾ A6 _B6___ 五、發明説明(4 ) 热鼠之使用((1988) Endocrinology, v〇l. 122, PP. 2899-2904) 〇 甲吠旁腺激素和熱洛昔夫恩可Μ依序地’共同地或同時 混合在一起成單一姐成投藥予個賴,假如依序地投槩,甲 狀旁腺激素及熱洛昔夫恩的投藥時間間隔典型地將為一遇 至一年,而最適當的時間間隔為一週至六個月,在一個較 佳的投槩計創内,在甲狀旁腺激素投槩後’加或不加熱洛 昔夫恩,此涸體將在停止甲狀旁腺激素投藥後再投予熱洛 昔夫恩。 關於供投藥含甲狀旁腺激素及/或熱洛昔夫恩之本發明 之豁藥學調配物通常包含促進骨骼生長的贵質生長因子之 骨生成有效量,另外也包含皤藥上可接受之賦型劑,合逋 的賦型劑包含大多數的已經過核准非經腸道投藥之載體, 包括水、食鹽水、林格氐溶液、Hank氏溶液、及葡萄糖、 乳糖、右旋葡萄糖、乙酵、甘油、白蛋白等類之溶液,這 些姐合物的成份可随意的包含穩定劑,抗氧化劑,殺菌劑 ,防腐酬,緩衝劑,表面活性劑及其它輔助添加劑等。甲 狀旁腺激素及/或熱洛昔夫恩也可Μ電離子透入貼錠 (Iontophor_etic patch)输内,有闞腸道外投藥之合適的 和藥物之完整的討論可在E. W. Martin所.著 tf Remington fs Pharmaceutical Sciences,, (Mack Pub. Co.,目前所用版本有關輔藥和槩物及其開處方的許多章節 等在此和參考文獻一併參看可明白此點)一書中找到,此 種調配物為熟知此技藝者普遍週和而且用於全身性的投藥 (請先閲讀背面之注意事項再塡寫本頁) 裝. 訂· •線. -6 - t 通用中甲 4 現格(210 X 297 公货) 經濟部中央標準局工消費合作社印製 A6 ______B6_._ 五、發明説明(5 ) >乂作全身性的治療。 假如將甲狀旁腺激素及熱洛昔夫恩兩者混合在一起配成 單一姐合物來投藥•甲狀旁腺激素對熱洛昔夫恩的莫可比 率約為1 〇 : 1到1 : 1 〇,較好是5 : 1到1 : 5,最佳是1 : 1 ,此外 ,假如以單一組合物來投藥,此單一姐合物可κ是酒別的 成份,或其也可W是個別的成份互相结合成份。 必要的正確劑量將視年龄、體型、性別及個體之狀況, 所要B治的疾病之特性與嚴重程度等而有所差別,因此, 一個正確有效的劑量無法更進一步做介定,而將由腌予看 _者決定•然而,可M 由以ΐί (物模式所做的例行的實驗 而決定適當的劑量,大體上來說,一涸對全身性治療有效 之甲吠旁腺激素劑量將從約每天0.001微克/公斤體重到 約丨0毫克/公斤體重,熱洛昔夫恩之有效劑量是從約 〇 . 〇 0 1毫克/公斤體重到1 0毫克/公斤體重,每天。 本發明之方法及姐合物對治療骨折、骨骼缺陷、及因骨 異常導致脅骼變弱如骨質疏鬆症、骨關節炎、Paget氏 病、骨質耗損、軟骨病、多發生骨髓瘤専致的骨質流失及 其它型式之癌症,其它藥物治療(如類脂酵)之副作用所導 致的骨質流朱,Μ及與年龄有闞之骨質最流失是有效的。 根據懕用中的一個方法’甲狀旁腺激素及熱洛昔夫恩可 Μ經由口服及/或不經由腸道’包含皮下或靜脈注射及/ 或經由鼻内的给予全身性的投藥。 根據應用中之另一個方法’甲狀旁腺激素可以局部地對 特定需要骨骼生長或修復之區域投藥’和熱洛昔夫恩一起 -7- (^^1 n >^i n n i —^ I 111 I n I - It - - In κ I n » (請先«·讀背面之注意事項再填寫本頁) 衣*人张义度通用中國國家標·準(CNS)甲4规格(打〇 X 297公釐) 82·6· 40,〇〇〇 五 '發明説明(6 ) A6
經濟部中央標準局DK工消費合作社印5i 投藥在此部位•或熱洛昔夫恩配合各自的和槩物給予 ,或者,熱洛昔夫恩和甲狀旁腺激素配合各自的和藥 部地投藥。因此,甲吠旁腺激素及/或熱洛昔夫恩可^® 接植入需要治療之部位,例如,以注射或外科手術植人$ 式植入此部位。合適的載體包括水乳膠體,調控的-或# 鑛的-釋放装置等(例如,一種Alzet®»微幫浦)’聚乳 酸,及膠原基質等,現行的較軎好採用的載體等是由含· W 特別的磷酸鈣確物成份的不完全肽膠原(atelopeptide collagen)之調配物,如相似的或相異的Uenographie:» 微嫩維的(fibri丨Ur)不完全'呔膠原(例如Zyderm*®)^原 棺入物,可瞒自膠原公司,Palo Alto ,加州)和碟酸S 氧碟灰石三耗(hydroxyapatitetricalcium phosphate)(HA-TCP ,購自Zimmer, Inc., Warsaw, I η .)之化合。 牙科及矯形外科植入物可在外面包覆甲狀旁腺'激素& $ 洛昔夫恩兩者組合成的姐合物* Μ增加對骨植入物之附著 ,Μ下二者可任擇其一,甲狀旁腺激素可用於包覆植入物 ,而熱洛昔夫恩可共同地或依序地以和藥物的方式1纟合.予S 藥,反之亦_同。 通常,植入物可Μ用甲狀旁腺激素及/或熱洛昔夫恩包 覆如下,甲狀旁腺激素(及熱洛昔夫恩,假若需要的話) 溶在含有2毫克/毫升血清白蛋白,濃度範圍在0.01微克 /毫升到2 00毫克/毫升之間的磷酸鹽-鑀衝溶液中’植 入物之多孔的一端浸在如上之溶液中,且薄其在空氣中乾 -8 - (請先闇讀背ώ之.;i意事項舟項寫本茛) •装· 訂. %· ’r '哽通用中因/·::家彳京(CNS)甲4規格(210 X 297公釐) 82.6. 40,000
嫌(或冷凍乾嫌)或者立即植入骨骼之位置*假如需要的話 ,包覆溶液可賴由添加玻尿酸a至〇.1毫克/ ¾升到1〇〇 毫克/毫升的最後濃度或»由添加蕖學上可接受的輔蕖而 使其黏度增加,以下二者可任擇其一,含有甲狀旁腺«[素 (及f洛昔夫恩,假若霈要的話)的溶液和膠原凝膠或人» 膠原(如,Zyder·®謬原植入物,膠原公司,Polo Alto ,加州)以配成最後膠原濃度2奄克/奄升到100 «克/ 奄升的糊齎或凝膠,然後用於包覆植入物多孔的一蟠,已 包覆好的植入物立即植入脅賂位置或在空氣中乾嫌而在植 入前再Μ磷酸鹽-嫒街溶液浸潤,以達到在植入物内使增 加新骨生成至最大效能之目的而減少植入物部位内軟姐雄 之向內生長。 奮俐 下列實例係為攞供箱此技藝之人士《於如何使用本發明 之姐合物及方法的完全掲示與描述,而非限制本發明之範 圔° 老鼠在四通歲時摘除卵巢(0VX)且單獨地給予SC媒劑 (V)或單獮絵予8激克/100公克/日hPTH 1-34 (Ρ)或者 搭Ssc热洛昔夫恩0.3毫克/100公克/日給予,如下所 示:V 24d; R 24d; P 24d; P&R 24d; P 12d 然後 V 12d; ;P 12d然後R 12d; V 12d然後R 12d,老it在第24日被 殺死,且收集血液、大腿骨、腰椎及腎臓等*測量下半截 大腿骨骨質量的鈣含董及乾重(DV),將琦椎處理K做姐纖 型態測鼉。 f請先聞碛背面之注意事項再填寫本頁) •裝· •打· •線· 甲 4 (210X297 Y 发) Ά 1'29 修ih if- Η |3 »_μ. Λ-A;· t. 29 補无 A6 B6 最終 «I籯 五、發明説明( 當投予热洛昔夫恩之卵巢摘除鼠的最终腰重小於卵巢摘 除氟或完整»時•所得的數據K每100公克艚重做校正· 卵巢摘除鼠其下半截大藤骨鈣含ft及乾重較對照組老思減 少15%,投蕖熱洛昔夫恩(R2 4d)者之骨霣量壜加接近25% 而投蕖PTH2 4d者增加接近42%。停藥後(P12dV12d>,甲狀 旁腺激素對合成代謝作用的效懕消失。當热洛昔夫恩 和甲狀旁胨激素併行投予時,可得到相加的效果(和卵巢 摘除鼠控制姐比較•增加65% ),在所有的姐別中,其大 _骨長度、血清鈣及腎臓鈣值係可相比的。 大嫌骨 長度
Sham- 載劑
OVX-載劑 OVX-PTH ovx-ralox ovx-?TH&rs cvx PT>: CVX ?ΤΗ OVX ralox (12d) 載劑 (12d) 201 土 4 28.5 ± 0,4 (12d) 教酬 (12d) 2 41 5a 28.8 ± 0.3 (12d) PTH (12d) 241 丄 4ac 23,8 土 C.2 (12d) raicx (12d) 139 土 5b 2S . 5 z. 0 ·2 (12d) ?TH&Raiox(12i) 150 土 4b 28.8 ΐ 0*2 (12d) 戧劑 (12d) 245 4. 4a 29.5 i 0.3 (12d) ralox ilZd) 203 25c 30.C * 1.2 (12d) nm I12d) 20Θ ± 6bc 29.0 ± C · 3 每姐Α隻老»所得到之數據Μ平均值±平均檷準誤差來表 示。 顯著差異,Ρ<0.05 · a和對照姐媒劑對照比較,c和卵巢 摘除投莆热洛昔夫恩(12 + 1 2d)姐對照比較。 老鼠在四通歲時摘除卵巢在約十遇歲時殺死,所秤得的 «重較同舲的完整款為重,甲狀旁腺激索不影響》重之增 加。热洛昔夫恩投蕖對卵巢摘除R而言,不管有無甲狀旁 腺激素存在,皆會防止體重增加,給槩热洛昔夫恩12天然 -1 0 甲 4(210X297 公发) : { < ......................................................装.......................h......打..............................綠 {請先閲讀背面之注意事項再填寫本页) 303299 乂女:· A6 B6 五、發明説明( 後再給予媒劑12天,老鼠》重增加較卵巢摘除鼠控制姐為 少•但是較持續給予热洛昔夫恩者為多。 對大雎#長度沒有影響*對長骨生長的測量表示嫌重的 改變不代表骨賂的生長(老鼠僅變得較瘦而巳)。 遠端大胜#骨質量之乾重 - 1-Ί2 i - 2 «i 全数#骼 DW/lOOr? PW 全数骨骼. r» 全數骨骼 nw 1. V V 18.5 土 C , 5a.b ' 9.0 ± 0 . 4c〇3 37 . L = Λ .Sab 2. CVX V V 15.8 士 C , 5abcd S . 3 ± 0.5a.b 3S.4 1 .l&b 3. OVX R R 19.: 士 0 . 5ib 5 . 6 ± 0 , 4 a.b 37.1 • Λ .2&b 4, CVX P ? :2.i = 0.4b 12 , 2 土 0 54.2 土 1 • Ί 5. CVX PtH PiR 26.1 z 0.9a 丄 6 = C .4 4? .5 士 2 .0 6, OVX P V 15.7 *. 0.3abc 9.9 i 0.3 ab 41.C Λ, 1 7 . OVX P R 17 . a 1 0 .^iabcd 10 . 0 r: 0 .7ab 37.1 4· 二 .Oab 8 . OVX V R . 16 . S 4> 0 5,0 ± 0.5ab 34.9 ± 1. 〇Ab p < 0.05, δ vb ?TH; b va ?ΤΗ〇λ ν =始劑 R =熱洛昔夫恩 P =甲吠旁腺激素
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ν· ralcx; d vs OVX 逭端大越骨的全部骨質量 (請先閑讀背面之注意事項再填穽本頁) .装· 各方法間增加% 2! -3¾ -3% j . 3% 0% ^ . 31¾ 41% 5. 25% 29% 5, 6% 7% T / « 7% -3% β 4 -3% -i% _訂· 全數骨骼=骨皮質及小梁骨的總和
埔繡士臃優之優g最 小斑優 CA 3W •綠·
Sham v R P&P、 P-V ?-R R.-V 2 DW •…土 o.s 土 ο 土 ο ^ 0.3 ± 1.0 5a 4 5b S·5 ±0.5 15.5 * 0.3 9.7 . Ό.Ξ :2.4 - 1.C6 10.8 - 0.4 3.1 ± 0.5 3.5 ^ Q.5 36 3 0 22 i 1 土 1 土: 2-1 3 二 C 為 4 5a 9 45 甲 4(210Χ 29?公;¥) -11- A6 B6 m 五、發明説明() P<0. 05 a ,b和所有其他姐別對照比較•顯示在小梁骨及 骨皮質之增加相同。 因此,Μ甲狀旁胨激素治療的卵巢摘除鼠等致骨生成增 加。然而此種增加薄由和热洛昔夫恩合併投蕖治療而更形 顯者。 (請先閲讀背面之注意事項再填寫本頁) •装. •^· •線· 甲 4(21〇Χ 297公发)
第82106163號專利申請案 中文補充説明書(85年10月) Μ簡單説明 圖1單獨投予媒劑(V)、甲狀旁腺激素(Ρ)及熱洛昔夫恩⑻或其各種 組合後所測大腿骨頸斷裂載量。 圖2經摘除卵巢之年輕雌鼠歷經12天各種激素每日處理一次後之最終 體重。 圖3經摘除卵巢之年輕雌鼠歷經〗2天各種激素每日處理—次後每百克 體重之遠端大腿骨骨質增加量。 圖4經摘除卵巢之年輕雌鼠歷經12天各種激素每日處理一次後之大腿 骨頸強度。 0184G. DOC/sh 8 昏 1¾ 1 ♦ 補充 第82106163號專利申請案 83年1月補充説明書修正頁(85年10月) 茲測試單獨投予媒劑(V)、甲狀旁腺激素(P)及熱洛昔夫恩(汉)或其 各種組合後之大腿骨頸強度。結果示於圖1。如圖清楚所示者,當甲狀 旁腺激素與熱洛昔夫恩併用於24天療法,與任何其他療法相較,可大 幅改善大腿骨輯職量。基於該等數據,·㈣雜敖素與熱洛 印夫心〈..且。確具有利(處,其係非可預期者,且大幅優於單獨使用 各藥物。 0184G. DOC/sh 修jl 補充 —I _ 第82106163號專利申請案 0年10月中文補充説明書修正頁(85年1〇月) 在三項實驗中測試經摘除卵巢之年輕雌鼠單獨投予媒劑或甲狀旁腺 激素(PTH)或與熱洛昔夫恩、雌激素、泰目昔夫恩(tamoxifen)或普維拉 (provera)併用之作用。結果示於圖2、圖3及圖4 在圖2中,基準相當於第〇天之體重,因此,沒有任何一組落於最初 起始體重之下。然而,熱洛昔夫恩、雌激素和泰目昔夫恩會避免伴隨 卵巢摘除而來之體重增加。 在圖3中,數據係顯示高於控制组之遠端大腿骨骨質增加量。因爲 重量之增加量不同,乃將數據調整爲每100克體重之增加量。不像雌激 素或熱洛者夫恩,泰目昔夫恩抑制PTH之同化作用,且與PTH單獨和 PTH和雌激素顯著不同,當投予雌激素或熱洛昔夫恩時,PTH之同化 作用無顯著不同。 圖4顯示出對大腿骨頸斷裂之抗性,頃發現,在圖中,單獨以泰目 昔夫恩處理會減低PTH對大腿骨強度之保護作用。雌激素或熱洛昔夫 恩則均不會顯著影響pTH對大腿骨頸之加強作用。 0184G. DOC/sh
Claims (1)
- 85. 年 ^ 1 〇修正 A8 B8 C8 D8 第82106163號專利申請第 中文由請專利範阈修正本(85年7月) 六、申請專利範圍 1. 一種增加個體骨質量之醫藥姐合物,其包含在一種齧藥 上可接受的賦型劑中醫藥上有效劑量之甲狀旁腺激累 (Ρ Τ Η )及翳藥上有效劑量之熱洛昔夫恩(r a U X i f e n e ), 其係在一種翳藥上可接受的陚型劑中,其中甲狀旁腺激 素對熱洛昔夫恩之冥耳比率為1 0 : 1到1 : 1 0。 2. —種治療個體骨質流失之豁藥姐合物,其包含在一種醫 藥上可接受的賦型劑中翳藥上有效劑量的甲狀旁腺激素 及翳藥上有效劑量之熱洛昔夫恩,其係在一種醫藥上可 接受的賦型劑中*其中甲吠旁腺激素對熱洛昔夫恩之莫 百比率為1 0 : 1到1 : 1 0。 3. —種具有治療已接受甲狀旁腺激素治療之人體骨質流失 之增進功效之翳藥姐合物,其含醫藥上有效劑量之熱洛 昔夫恩,其係在一挿醫藥上可接受的賦型劑中。 4. 一榑具有治療正接受甲狀旁腺激素治療之人體骨質流失 之增進功效之醫藥姐合物,其含翳藥上有效劑量之熱洛 昔夫恩,其係在一種翳藥上可接受的賦型劑中。 5. 一種具有治療將接受甲吠旁腺激素治療之人f|骨質流失 之增進功效之睜藥组合物,其含翳藥上有效劑量之熱洛 昔夫恩,其係在一種翳藥上可接受的賦型劑中。 --r------j I裝------訂-----f ·線 (請先閔讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 本纸乐尺度適用中國國家標準(CNS ) A4規格(210X297公釐)
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- 1994-07-21 HU HU9402157A patent/HU219382B/hu not_active IP Right Cessation
- 1994-07-22 MY MYPI94001920A patent/MY124311A/en unknown
-
1995
- 1995-03-06 US US08/400,436 patent/US5510370A/en not_active Expired - Fee Related
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1998
- 1998-12-23 HK HK98115198A patent/HK1013800A1/xx not_active IP Right Cessation
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2000
- 2000-05-24 GR GR20000401189T patent/GR3033492T3/el not_active IP Right Cessation
- 2000-08-02 CY CY0000034A patent/CY2192B1/xx unknown
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