EP0825872A1 - Paeathormon pharmazeutische darreichungsform mit einer wirkstofffreisetzungsperiode von zwei bis sechs stunden - Google Patents
Paeathormon pharmazeutische darreichungsform mit einer wirkstofffreisetzungsperiode von zwei bis sechs stundenInfo
- Publication number
- EP0825872A1 EP0825872A1 EP96919738A EP96919738A EP0825872A1 EP 0825872 A1 EP0825872 A1 EP 0825872A1 EP 96919738 A EP96919738 A EP 96919738A EP 96919738 A EP96919738 A EP 96919738A EP 0825872 A1 EP0825872 A1 EP 0825872A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- hours
- parathyroid hormone
- administration form
- active ingredient
- quart
- 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.)
- Withdrawn
Links
- 108090000445 Parathyroid hormone Proteins 0.000 title claims abstract description 56
- 102000003982 Parathyroid hormone Human genes 0.000 title claims abstract description 26
- 239000000199 parathyroid hormone Substances 0.000 title claims abstract description 26
- 229960001319 parathyroid hormone Drugs 0.000 title claims abstract description 26
- 239000004480 active ingredient Substances 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 12
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 7
- 238000001802 infusion Methods 0.000 claims description 30
- 210000000988 bone and bone Anatomy 0.000 claims description 15
- 101001135770 Homo sapiens Parathyroid hormone Proteins 0.000 claims description 4
- 101001135995 Homo sapiens Probable peptidyl-tRNA hydrolase Proteins 0.000 claims description 4
- 238000013475 authorization Methods 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 102000058004 human PTH Human genes 0.000 claims description 4
- 238000012360 testing method Methods 0.000 claims description 4
- 229920000891 common polymer Polymers 0.000 claims description 3
- 239000003978 infusion fluid Substances 0.000 claims description 3
- 239000002502 liposome Substances 0.000 claims description 3
- 239000004005 microsphere Substances 0.000 claims description 3
- 229940088597 hormone Drugs 0.000 claims 1
- 239000005556 hormone Substances 0.000 claims 1
- 210000004898 n-terminal fragment Anatomy 0.000 claims 1
- 102100036893 Parathyroid hormone Human genes 0.000 description 30
- 238000001990 intravenous administration Methods 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 239000011575 calcium Substances 0.000 description 8
- 239000007924 injection Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000012634 fragment Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 230000000541 pulsatile effect Effects 0.000 description 3
- 239000000654 additive Substances 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- JLESVLCTIOAHPT-UHFFFAOYSA-N mmai Chemical compound C1=C(C)C(OC)=CC2=C1CC(N)C2 JLESVLCTIOAHPT-UHFFFAOYSA-N 0.000 description 2
- -1 poly(ethylene oxide) Polymers 0.000 description 2
- 230000008092 positive effect Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000000689 upper leg Anatomy 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000001195 anabolic effect Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 229920006158 high molecular weight polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000004824 osteo-anabolic effect Effects 0.000 description 1
- 230000001009 osteoporotic effect Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
Classifications
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
-
- 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
- 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
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- 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
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- 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
Definitions
- the present invention is directed to a pharmaceutical administration form of parathyroid hormone or parathyroid hormone derivatives having an active ingredient release period of from two to six hours, the use of parathyroid hormone in the treatment of osteoporosis by applying said pharmaceutical administration form, and a method for the treatment of osteoporosis in the human body.
- Parathyroid hormone and N-terminal parathyroid hormone fragments are known to have osteogenous activity which has been observed in animal experimental studies on rats as well as in clinical studies on osteoporotic patients and has been described in technical literature (Selye, Endocrinology 16 (1932), 547-558; Hefti et al., Clin. Sci. 62 (1982), 389-396; Gunnes-Hey et al., Metab. Bone Dis. Relat. Res. 5 (1984), 177-181; Reeve et al., Br. Med. J. 280 (1980), 1340-1344; Slovik et al., J. Bone Miner. Res. 1 (1986), 377- 381, EP 0,197,514).
- the invention is directed to a pharmaceutical administration form of PTH or derivatives thereof having an active ingredient release period of from two to six hours, and preferably of four hours.
- the pharmaceutical administration form may be an infusion solution or a transdermic or enteric pharmaceutical system having an active ingredient release period of up to six hours.
- the transdermic or enteric application of PTH offers the decisive advantage of retarded active ingredient release. Abrupt PTH pulses and the associated substantial disturbance of the patient's well-being due to the necessary injection can be dismissed.
- the pharmaceutical administration form contains biologically active parathyroid hormone or parathyroid hormone derivatives, particularly human PTH(l-84) or an N-terminal human PTH fragment having the sequences 1-29 to
- PT ⁇ - analogous peptides, variants or modifications of parathyroid hormone (PTH agonists) resulting from the replacement of single or multiple amino acids in the amino acid se ⁇ quence of unmodified parathyroid hormone may also be employed.
- PTH fragments appropriately abridged at the N terminus and/or the C terminus are also possible within the meaning of the invention. Such fragments have been described in WO 90/10067, EP 0,301,484 or EP 0,301,485, for example.
- PTH peptides are effected in such a manner that release of the pharmacologically active substance in the body within a period of from 2 to 6 hours is ensured. Such release may be obtained in different ways.
- One method is to administer the required amount of PTH intravenously over the appropriate period of time.
- Another method involves transdermic application, releasing the active ingredient within the desired period of time. This may be effected using a patch which is applied to the skin for the desired period of time. By adding permeation accelerators, release of the active ingredient through the skin as regularly as possible can be ensured so that during appli ⁇ cation of the patch to the skin, continuous release of the active ingredient and permeation through the skin take place.
- Another way of transdermic application involves ion ⁇ tophoresis. To this end. an appropriate dosage unit (iontophoretic patch) is applied to the skin, and release of the active ingredient through the skin within the desired period of time is controlled by applying an electrical potential.
- loaded liposomes Preferably, loaded liposomes.
- PTH or a PTH fragment may be administered in the form of a continuous infusion preferably over two to six hours, particularly about four hours.
- a tendency to higher anabolic activity can be observed following an infusion of about four hours compared to a one hour infusion or subcutaneous bolus administration.
- An exceedingly good osteogenous activity was observed following a four hour intravenous infusion of hPTH(l-34) on five working days within two successive weeks.
- water is used as injection medium, containing additives common with injection solutions, such as stabilizers, solubilizers and buffers.
- additives are. e.g., tartrate and citrate buffers, ethanol, complexing agents such as ethylenediaminetetra- acetic acid and non-toxic salts thereof, high molecular weight polymers such as liquid poly(ethylene oxide) for viscosity control.
- Liquid carrier substances must be sterile and are preferably filled into ampoules.
- the dosage may depend on various factors such as mode of application, species, age or individual condition. Usually, from 30 to 50 ⁇ g/kg/day are administered.
- the invention relates to the use of parathyroid hormone or a parathyroid hormone derivative in the treatment of osteoporosis by application in the form of a continuous infusion for two to six hours or a transdermic or enteric administration form having an active ingredient release period of from two to six hours.
- Such examinations relating to the use of PTH or PTH fragments, according to the invention will be subject to protection, particularly within the scope of clinical tests for the purpose of authorization according to the drug law.
- the corresponding petitioned authorization according to the drug law relates to the treatment of calcium-metabolic dis ⁇ eases in general and to the treatment of osteoporosis, in particular.
- the invention is directed to a method for osteoporosis treatment of the human body wherein, in order to increase the bone matter, a therapeutically effective amount of parathyroid hormone or parathyroid hormone derivative is applied in the form of a continuous infusion for two to six hours or a transdermic or enteric administration form having an active ingredient release period of from two to six hours.
- a therapeutically effective amount of parathyroid hormone or parathyroid hormone derivative is applied in the form of a continuous infusion for two to six hours or a transdermic or enteric administration form having an active ingredient release period of from two to six hours.
- the method according to the invention is conducted within the scope of clinical tests for the purpose of authorization according to the drug law.
- a venous permanent catheter was implanted in male Wistar rats weighing about 230-250 g.
- the animals were assigned to 5 different groups of treatment of 6 animals each, which were treated as follows:
- the compa- rison comprises intravenous infusion of 40 ⁇ g/kg and 80 ⁇ g/kg over four and eight hours, respectively, as well as subcutaneous injection of 40 ⁇ g/kg and intravenous bolus injection of 80 ⁇ g/kg.
- Group 1 4 hours iv; 40 ⁇ g/kg/day
- Group 2 8 hours iv; 80 ⁇ g/kg/day
- a pilot experiment on transdermic application by iontophoresis was conducted on two rabbits. The animals were trimmed in the flanks, and the skin was cleaned with ethanol. A filter paper soaked with hPTH(l-34) solution was placed on the skin and fixated with a chlorinated silver electrode. Iontophoresis was carried out over a time period of 90 and 105 minutes, respectively, under the following conditions: current intensity: 5-7 mA, current density: 0.44-0.62 mA/cm , current pulses: 8 ms at 2 ms intervals. During the experiment, blood was taken from the ear artery at various times (see table below), and the serum obtained was deep frozen. Using the Nichols RIA INS-PTH, the PTH concentration in the serum samples was measured. Result: In both animals, a significant level of hPTH(l-34) could be detected after a period of 1 to 1.5 hours.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Endocrinology (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Nutrition Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19517430 | 1995-05-12 | ||
| DE19517430A DE19517430A1 (de) | 1995-05-12 | 1995-05-12 | Pharmazeutische Darreichungsform von Parathormon mit einer zwei- bis sechsstündigen Wirkstoff-Freisetzungsperiode |
| PCT/EP1996/001962 WO1996035447A1 (en) | 1995-05-12 | 1996-05-09 | Pharmaceutical administration form of parathyroid hormone having an active ingredient release period of from two to six hours |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0825872A1 true EP0825872A1 (de) | 1998-03-04 |
Family
ID=7761731
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP96919738A Withdrawn EP0825872A1 (de) | 1995-05-12 | 1996-05-09 | Paeathormon pharmazeutische darreichungsform mit einer wirkstofffreisetzungsperiode von zwei bis sechs stunden |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0825872A1 (de) |
| JP (1) | JPH11505222A (de) |
| AU (1) | AU5816596A (de) |
| DE (1) | DE19517430A1 (de) |
| IL (1) | IL118202A0 (de) |
| WO (1) | WO1996035447A1 (de) |
| ZA (1) | ZA963714B (de) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0922467A3 (de) | 1997-12-12 | 2000-05-24 | Takeda Chemical Industries, Ltd. | Iontophoretische Verabreichung von Medikamenten |
| US8088734B2 (en) | 2003-01-21 | 2012-01-03 | Unigene Laboratories Inc. | Oral delivery of peptides |
| WO2007059470A2 (en) | 2005-11-10 | 2007-05-24 | Board Of Control Of Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
| JP2013512688A (ja) | 2009-12-07 | 2013-04-18 | ミシガン テクノロジカル ユニバーシティ | クロクマの副甲状腺ホルモン及びクロクマの副甲状腺ホルモンを使用する方法 |
| MX342898B (es) | 2010-05-12 | 2016-10-18 | Radius Health Inc * | Regimen terapéutico de la sal de diclorhidrato del (r) -6-(2-(etil (4-2(etilamino) etil) bencil) amino)-4-metoxifenil)-5, 6,7,8-tetrahidronaftaleno-2-ol. |
| ES2550319T3 (es) | 2010-09-28 | 2015-11-06 | Radius Health, Inc | Moduladores selectivos del receptor de andrógenos |
| AU2016256470B2 (en) | 2015-04-29 | 2020-10-15 | Radius Pharmaceuticals, Inc. | Methods of treating cancer |
| LT3474841T (lt) | 2016-06-22 | 2022-06-10 | Ellipses Pharma Ltd | Ar+ krūties vėžio gydymo būdai |
| LT3565542T (lt) | 2017-01-05 | 2024-07-10 | Radius Pharmaceuticals, Inc. | Polimorfinės rad1901-2hcl formos |
| CN112423844B (zh) | 2018-07-04 | 2024-08-13 | 雷迪厄斯制药公司 | Rad1901-2hcl的多晶型形式 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4692433A (en) * | 1983-10-12 | 1987-09-08 | The Regents Of The University Of California | Method and composition for regulating serum calcium levels of mammals |
| DE3935738A1 (de) * | 1989-10-27 | 1991-05-08 | Forssmann Wolf Georg | Arzneimittel, enthaltend das humane parathormon-fragment (1-37) als aktiven wirkstoff |
| DE69429603T2 (de) * | 1993-09-22 | 2002-08-14 | Hisamitsu Pharmaceutical Co., Inc. | Iontophoresematrix |
-
1995
- 1995-05-12 DE DE19517430A patent/DE19517430A1/de not_active Withdrawn
-
1996
- 1996-05-09 WO PCT/EP1996/001962 patent/WO1996035447A1/en not_active Application Discontinuation
- 1996-05-09 EP EP96919738A patent/EP0825872A1/de not_active Withdrawn
- 1996-05-09 AU AU58165/96A patent/AU5816596A/en not_active Abandoned
- 1996-05-09 IL IL11820296A patent/IL118202A0/xx unknown
- 1996-05-09 JP JP8533762A patent/JPH11505222A/ja active Pending
- 1996-05-10 ZA ZA9603714A patent/ZA963714B/xx unknown
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9635447A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| IL118202A0 (en) | 1996-09-12 |
| AU5816596A (en) | 1996-11-29 |
| ZA963714B (en) | 1997-11-10 |
| JPH11505222A (ja) | 1999-05-18 |
| DE19517430A1 (de) | 1996-11-14 |
| WO1996035447A1 (en) | 1996-11-14 |
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| STAA | Information on the status of an ep patent application or granted ep patent |
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| 18D | Application deemed to be withdrawn |
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