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Therapeutic perparation for inhalation containing parathyroid hormone, PTH

A parathyroid hormone and therapeutic agent technology, applied to medical preparations containing active ingredients, medical preparations with non-active ingredients, metabolic diseases, etc., can solve problems such as platform phenomena

Inactive Publication Date: 2004-10-13
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In contrast, a plateau in serum following IT application of intact PTH (PTH84) did not significantly disappear during the 90-minute experiment

Method used

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  • Therapeutic perparation for inhalation containing parathyroid hormone, PTH
  • Therapeutic perparation for inhalation containing parathyroid hormone, PTH

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] 1.1 Therapeutic Agents of PTH 1-84 for Inhalation

[0035] Prepare an aqueous solution of the following composition:

[0036] Human PTH 1-84 41mg

[0037] Citric acid, monohydrate 57mg

[0038] Sodium citrate 113mg

[0039] Lactose 3888mg

[0040] Water about 53ml

[0041] Adjust the pH to 5.0. The solution was concentrated by evaporation for about one day at 37°C. The resulting solid cake was crushed and passed through a 0.5 mm sieve, and the resulting powder was micronized by a jet mill to particles of 2 microns in diameter.

[0042] 1.2 Therapeutic Agents of PTH 1-34 for Inhalation

[0043] Prepare an aqueous solution with the following composition:

[0044] Human PTH 1-34 11.2mg

[0045] Citric acid, monohydrate 66mg

[0046] Sodium citrate 131mg

[0047] Lactose 4589mg

[0048] Water about 52ml

[0049] This solution was worked up as described above in Example 1.1.

[0050] 1.3 Therapeutic PTH preparations containing enhancers

[0051] Prepare an aqu...

Embodiment 2

[0060] Pharmacokinetic experiment

[0061] 2.1 Powder formulations and inhalation systems

[0062] Human PTH 1-84 or PTH 1-34 were prepared according to Examples 1.1 and 1.3, respectively. The powder formulation was compressed in a dust container and continuously produced as a dry powder aerosol by a Wright Dust Feed (WDF). This aerosol is generated by wiping the tablet in a dust collector. The material flow rate through the WDF was 8.0 liters / minute.

[0063] Inhaled dose (ID) was determined by measuring tidal volume (ITV) and PTH concentration during inhalation.

[0064] 2.2 Treatment

[0065] English Beagle dogs (n=5, each formulation) were fasted for 16 hours prior to inhalation, and experiments were performed in the morning. with Plegecil  and Penthotal  Dogs were anesthetized, intubated and exposed to PTH1-34 or PTH1-84 for approximately 10 minutes.

[0066] PTH concentrations were determined in venous blood samples collected from the jugular vein into heparini...

Embodiment 3

[0069] bone effect

[0070] Bone response was measured as the mineral density (weight / volume) of the distal femur in ovariectomized osteoporotic rats after 4 weeks of dosing (dosing started 6 weeks after ovariectomy). The results obtained indicate that inhalation of full-length PTH has a significant effect on femur formation.

[0071] Table 1

[0072]

[0073] S.E. = standard error of the mean

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Abstract

The present invention relates to compositions and methods for pulmonary administration of full-length parathyroid hormone to mammalian hosts for the treatment of osteoporosis. Thus there is provided a therapeutic, dry powder preparation suitable for inhalation comprising (i) as an active substance, a parathyroid hormone having an amino acid sequence which is at least 90% homologous to the sequence shown as SEQ ID NO: 1 in the Sequence Listing having the biological activities of the full-length parathyroid hormone; (ii) a pharmaceutically acceptable carrier consisting of coarse particles; and, optionally, (iii) as an active substance, a substance which enhances the absorption of parathyroid hormone in the lower respiratory tract; wherein an ordered mixture is formed between said active compound(s) and the carrier; in which at least 50% of the total mass of the active substance parathyroid hormone consists of (a) particles having a diameter of up to 10 microns; or (b) agglomerates of such particles.

Description

technical field [0001] The present invention relates to compositions and methods for pulmonary administration of parathyroid hormone (parathyroid hormone, PTH) to a mammalian patient for the treatment of osteoporosis. Background technique [0002] Human parathyroid hormone is an 84 amino acid protein (SEQ ID NO: 1) that is involved in calcium and phosphorus homeostasis and controls bone growth and density. Human PTH can be obtained by peptide synthesis or from genetically engineered yeast, bacterial or mammalian cell hosts. Human PTH is also commercially available from Bachem Inc., Bubendorf, Switzerland land. The preparation of recombinant human parathyroid hormone is disclosed in EP-B-0383751. [0003] In mammals, the balance between bone formation associated with osteoblast activity on the one hand and bone loss associated with osteoclasts on the other is disturbed in several bone-affecting diseases such as osteoporosis. Parathyroid hormone has a potential therapeutic ...

Claims

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Application Information

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IPC IPC(8): A61K9/14A61K9/00A61K9/72A61K38/22A61K38/29A61K47/12A61P19/10A61P43/00
CPCA61K38/29Y10S514/826A61K47/12A61K9/0075A61P19/10A61P3/14A61P43/00
Inventor K·贝克斯特兰B·威尔马克
Owner ASTRAZENECA AB
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