DE19517430A1 - Pharmaceutical dosage form of parathyroid hormone with a two to six hour drug release period - Google Patents

Abstract

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 for the preparation of such pharmaceutical administration forms, and to a method for treating osteoporosis in the human body.

Description

The present invention relates to a pharmaceutical dosage form of Parathyroid hormone or parathyroid hormone derivatives with a two to six hour active ingredient Release period, the use of parathyroid hormone in osteoporosis treatment by applying this pharmaceutical dosage form and a method for Osteoporosis treatment of the human body.

It is known that parathyroid hormone or N-terminal parathyroid hormone fragments a have anabolic effect. This was in animal experiments on advice observed in clinical studies on osteoporotic patients and in of the technical literature (Selye, Endocrinology 16 (1932), 547-558; Hefti et al., Clin. Sci. 62: 389-396 (1982); 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: 377-381 (1986); EP 0197514).

There is agreement among experts regarding the fact that the bone-anabolic Wir PTH is linked to a pulsatile or intermittent application. The pulsatile application of PTH led in animal and clinical studies Patients to an increase in bone mass (Tam et al., Endocrinology 110 (2) (1982), 506-512; Podbesek et al., Endocrinology 112 (3) (1983), 1000-1006; Hock et al., J. Bone Miner. Res. 7 (1) (1992), 65-72; Reeve et al., Br. Med. J. 280 (1980), 1340- 1344; Slovik et al., J. Bone Miner. Res. 1 (1986), 377-381).

With continuous infusion of PTH an animal was admitted increase in bone remodeling rate was observed without, however, a net increase in Lead bone mass (Tam et al., Endocrinology 110 (2) (1982), 506-512; Malluche et al., Am. J. Physiol. 242 (2) (1982), F197-F201; Hock et al., J. Bone Miner. Res. 7 (1) (1992), 65-72; Podbesek et al., Endocrinology 112 (3) (1983), 1000-1006).

Surprisingly, it has now been found that a continuous application of PTH or whose derivatives definitely lead to a net increase in bone mass if they are up to remains limited to six hours.

The invention therefore relates to a pharmaceutical dosage form of PTH or its derivatives with a two to six hours, preferably four hours Drug release period. The pharmaceutical dosage form can be a Solution for infusion or a transdermal or enteral pharmaceutical system with one Drug release period can be up to six hours. Opposite the pulsatile app likation, which in all known animal experimental and clinical studies as daily subcutaneous injection, transdermal or enteral application of PTH the decisive advantage of delayed drug release. The sharp PTH Impulses and the associated significant impairment of the wellbeing of the Patients due to the need for injection can be eliminated.

According to the present invention, the pharmaceutical dosage form contains bio logically active parathyroid hormone or parathyroid hormone derivatives, especially human PTH (1- 84) or an N-terminal human PTH fragment with the sequences zen 1-29 to 1-41, preferably the sequences 1-34, 1-35, 1-36, 1-37 or 1-38. Further can also use PTH-analogous peptides, variants or modifications of the parathyroid hormone (PTH agonists) are used by exchanging one or more Amino acids result in the amino acid sequence of the unmodified parathyroid hormone. In addition, according to the invention, the corresponding N-terminal and / or C-terminal truncated PTH fragments in question. Such fragments are, for example described in WO 90/10067, EP 0 301 484 or EP 0 301 485.

The PTH peptides are applied in such a way that the pharmacolo active substance in the body within a period of 2 to 6 hours is accomplished. This release can be accomplished in a number of ways. A method is that the required amount of PTH is given intravenously via the appropriate period. Another method is that a transdermal application takes place, the active ingredient within the desired time span ne releases. This can be done in the form of a patch that lasts for the desired length of time is applied to the skin. By adding permeation accelerators ensure that the active ingredient is released as evenly as possible is guaranteed by the skin, so that during the application of the patch on the  Skin a continuous release of the active ingredient and permeation through the skin takes place. Another option for transdermal application is ion tophorese. For this purpose, a corresponding dosing device (iontophoresis patch) attached to the skin and the release by applying an electrical voltage the active ingredient is controlled by the skin for the desired period of time.

The enteral pharmaceutical system used is preferably loaded liposomes, Microspheres from common polymers or proteinoid complexes in question, the one Active substance absorption in the small intestine over a corresponding period of time guarantee.

According to the invention, PTH or a PTH fragment can preferably be in the form of a two- up to six hours, especially about four hours of continuous infusion. After an infusion period of approximately four hours, this tends to be stronger anabolic effect recognizable as after an hour's infusion or s.c. Bolus. A very good bone anabolic effect was seen after four hours of intravenous infusion of hPTH (1-34) or hPTH (1-37) on five working days of two consecutive weeks observed.

Further studies using PTH (1-37) showed that over 8 hours maintained levels at 80 µg / kg IV, d. H. with the same infusion rate as with 40 µg / kg IV over 4 hours, lead to serious negative effects on the bone, while at 40 µg / kg i.v. PTH (1-37) over 4 hours is a clearly osteoanabolic effect occurred. Intravenous bolus injection of 80 µg / kg PTH (1-37) within approximately one Minute, however, did not lead to negative, but to positive effects on the relative X-ray density and the Ca content. The therapeutic usability is comparatively high However, intravenous PTH doses as a bolus dose are due to the expected gravie render circulatory effects not considered advantageous.

Water is preferably used as the injection medium, as is the case with Injek usual solutions such as stabilizers, solubilizers and buffers contains. Such additives are e.g. B. tartrate and citrate buffers, ethanol, complexing agents such as ethylenediaminetetraacetic acid and its non-toxic salts, high molecular weight poly mere like liquid polyethylene oxide for viscosity regulation. Liquid carriers for Injection solutions must be sterile and are preferably filled into ampoules.  

The dosage can depend on various factors, such as the mode of administration, species and age or individual condition. Usually 30 to 50 µg / kg / day are appli graces.

The invention further relates to the use of parathyroid hormone or a parate hormone derivative in the treatment of osteoporosis by application in the form of a two to six hours of continuous infusion or a transdermal or enteral darrei form with a two to six hour drug release period. Such Investigations regarding the use of PTH or PTH- Fragments are used especially in clinical trials for the purpose of drug approval carried out. The corresponding aimed drug approval usually refers to the treatment of Cal cium metabolic diseases in general, and in particular on treatment of osteoporosis.

The invention also relates to a method for treating osteoporosis human body in which to increase bone mass has a therapeutic effect same amount of parathyroid hormone or parathyroid hormone derivative in the form of a two to six hour period continuous infusion or a transdermal or enteral dosage form with a two to six hours of drug release period is applied. The invention The appropriate method is preferably used in clinical trials for the purpose of drug approval of the pharmaceutical form.

The invention will be explained in more detail below on the basis of exemplary embodiments will.

example 1 Infusion of PTH over different times

Male Wistar rats weighing approximately 230-250 g underwent venous surgery in a previous operation Permanent catheter implanted. The animals were treated in 5 different treatment groups of 6 Associated with animals treated as follows:

• 1. Rinse the catheter with solvent for 5 consecutive working days Weeks = negative control.
• 2. Intravenous infusion of hPTH (1-34), 40 µg / kg / day within one hour on 5 Working days of two consecutive weeks.
• 3. Intravenous infusion of hPTH (1-34), 40 µg / kg / day within four hours on 5 Working days of two consecutive weeks.
• 4. Intravenous infusion of hPTH (1-34), 40 µg / kg / day within eight hours on 5 Working days of two consecutive weeks.
• 5. Subcutaneous bolus injection of hPTH (1-34), 40 µg / kg / day on 5 working days two consecutive weeks = positive control.
• 6. In another experiment, PTH (1-37) was used under different conditions tested. The comparison includes the infusion of 40 µg / kg and 80 µg / kg intravenously over four or eight hours, as well as the subcutaneous injection of 40 µg / kg and the intravenous bolus injection of 80 µg / kg.

On the third day after the last treatment, the animals and the femora were sacrificed taken for the subsequent analysis of femur weight, volume, dry weight, ash weight and calcium content.

The results for PTH (1-34) are summarized in Table 1 below and show that in treatment groups 1 (1 hour infusion), 2 (4 hour infusion) and 4 (SC bolus) there was a significant increase in bone mass, while in group 3 (8 hour infusion) there were no differences from the control group surrendered.  

Table 1

In a series of tests by PTH (1-37) the influence of the time was identical Infusion rate of 10 µg / kg / h (40 µg / kg i.v. over four hours; 80 µg / kg i.v. over eight Hours). It was found that at 40 µg / kg i.v. PTH (1-37) over four Hours a significant osteoanabolic effect occurred during the double infusion period of eight hours with a total of 80 µg / kg i.v. to drastic negatives Effects on bone balance. In contrast, the repeated affected intravenous bolus injection of 80 µg / kg within approx. one minute Bone balance positive. The therapeutic usability is comparatively high However, intravenous PTH doses as a bolus are given because of the relatively minor effect and especially because of the expected serious circulation effects as not assessed as advantageous.

The results for PTH (1-37) are summarized in Table 2.  

Table 2

Example 2 Iontophoretic application of PTH

A pilot experiment for transdermal application using ion was carried out on two rabbits tophoresis performed. The animals were shorn in the flanks and the skin with Ethanol cleaned. A filter paper soaked with hPTH (1-34) solution was placed on the Skin placed and fixed with a chlorinated silver electrode. Iontophoresis was  over a period of 90 or 105 minutes under the following conditions leads: current: 5-7 mA; Current density: 0.44-0.62 mA / cm² Current pulses: 8 ms with 2 ms interruption. During the experiment, at different times (see Table below) blood is taken from the ear artery and the serum obtained frozen. The PTH- was determined in the serum samples using the Nichols HA INS-PTH Concentration measured.

Result

A clear level was seen in both animals after a time of 1 to 1.5 hours hPTH (1-34) can be determined.

hPTH (1-34) [pg / ml]

Claims (15)

1. Pharmaceutical dosage form containing parathyroid hormone (PTH) as active ingredient or a parathyroid hormone derivative with a two to six hour drug release set period. 2. Dosage form according to claim 1 comprising an infusion solution for two to six hour, preferably four hour, continuous infusion. 3. Dosage form according to claim 1 comprising a transdermal pharmaceutical cal system, preferably a patch or an iontophoretic system. 4. Dosage form according to claim 1 comprising an enteral pharmaceutical System, preferably loaded liposomes or microspheres from usual Polymers or proteinoid complexes. 5. Dosage form according to one of claims 1 to 4 containing human PTH (1- 84). 6. Dosage form according to one of claims 1 to 4 containing the N-terminal Fragments of human PTH comprising sequences 1-29 to 1-41 preferably 1-34, 1-35, 1-36, 1-37 and 1-38. 7. Use of parathyroid hormone or parathyroid hormone derivatives to produce a pharmaceutical dosage form with a two to six hour active ingredient Release period. 8. Use according to claim 7 for the preparation of an infusion solution for the two- up to six hours, preferably four hours, of continuous infusion. 9. Use according to claim 7 for the production of a transdermal or entera len pharmaceutical form. 10. A method of treating calcium metabolic diseases, in particular the osteoporosis treatment of the human body in which to increase the  Bone mass a therapeutically effective amount of parathyroid hormone or Parathormone derivative in the form of a two to six hour long infusion or egg ner transdermal or enteral dosage form with a two to six hours the active substance release period is applied. 11. The method according to claim 10, which is used in clinical trials for the purpose approval of the pharmaceutical form is carried out. 12. The method according to claim 10 or 11, in which as therapeutically effective Amount 10 to 100 µg / kg / day, especially 30 to 50 µg / kg / day parathyroid hormone or Parathormone derivative can be used. 13. The method according to any one of claims 10 to 12, in which the continuous infusion on 5 Working days of two consecutive weeks. 14. The method according to any one of claims 10 to 12, in which the transdermal appli cation by means of a patch which may contain permeation accelerators, or by iontophoresis. 15. The method according to any one of claims 10 to 12, in which the enteral application using loaded liposomes, microspheres made of common polymers or protein oid complexes.