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.

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• 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)

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• 1995
  • 1995-05-12 DE DE19517430A patent/DE19517430A1/de not_active Withdrawn
• 1996
  • 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 JP JP8533762A patent/JPH11505222A/ja active Pending
  • 1996-05-09 IL IL11820296A patent/IL118202A0/xx unknown
  • 1996-05-09 WO PCT/EP1996/001962 patent/WO1996035447A1/en not_active Application Discontinuation
  • 1996-05-10 ZA ZA9603714A patent/ZA963714B/xx unknown

Non-Patent Citations (1)

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