WO1996035447A1

WO1996035447A1 - Pharmaceutical administration form of parathyroid hormone having an active ingredient release period of from two to six hours

Info

Publication number: WO1996035447A1
Application number: PCT/EP1996/001962
Authority: WO
Inventors: Peter-Paul Ochlich; Bernd MÜLLER-BECKMANN
Original assignee: Boehringer Mannheim Gmbh
Priority date: 1995-05-12
Filing date: 1996-05-09
Publication date: 1996-11-14
Also published as: JPH11505222A; ZA963714B; AU5816596A; EP0825872A1; DE19517430A1; IL118202A0

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

Pharmaceutical Administration Form of Parathyroid Hormone

Having an Active Ingredient Release Period of from Two to Six Hours

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).

There is general agreement in the art about the fact that the osteogenous activity of PTH is bound to a pulsatile or intermittent application. Pulsatile application of PTH in animal experimental as well as in clinical studies on patients resulted in an increase of bone matter (Tarn et al., Endocrinology 110(2) (1982), 506-512; Podbesek et al., Endo¬ crinology 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).

While in animal experiments an increased bone transformation rate was observed with continuous infusion of PTH, this, however, did not result in a net gain of bone matter (Tarn 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; Podbe- sek et al.. Endocrinology 1 12(3) ( 1983), 1000-1006).

Surprisingly, it has now been found that continuous application of PTH or derivatives thereof certainly results in a net gain of bone matter, when limited to up to six hours.

Therefore, 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. Here, 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. Compared to pulsatile application which in all hitherto known animal experimental and clinical studies has been effected as a daily subcutaneous injection, 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.

According to the present invention, 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

1-41, preferably the sequences 1-34, 1-35, 1-36, 1-37, or 1-38. Furthermore, PTΗ- 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. In addition, 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.

Application of the PTH peptides is 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.

Preferably, loaded liposomes. microspheres made of common polymers, or proteinoid complexes ensuring resorption of the active ingredient in the small intestine over an ap¬ propriate period of time are possible as enteric pharmaceutical systems.

According to the invention, 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. Here, 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.

Further examinations using PTH(l-37) showed that levels maintained for 8 hours at 80 μg/kg iv, i.e., at the same infusion rate as 40 μg/kg iv over 4 hours, give rise to severe adverse effects on the bones, while at 40 μg/kg PTH(l-37) iv over 4 hours a distinct osteoanabolic effect occurs. In contrast, intravenous bolus injection of 80 μg/kg PTH(l-37) within about one minute does not result in negative but positive effects with respect to the relative X-ray density and the Ca content. However, the therapeutic utility of comparably high intravenous PTH doses in the form of a bolus administration is not deemed advantageous due to severe circulatory effects to be expected. Preferably, water is used as injection medium, containing additives common with injection solutions, such as stabilizers, solubilizers and buffers. Such 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 μg/kg/day are administered.

In addition, 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. As a rule, 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.

Likewise, 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. Preferably, the method according to the invention is conducted within the scope of clinical tests for the purpose of authorization according to the drug law.

In the following, the invention will be illustrated in more detail by way of embodiments. Example 1

Infusion of PTH for various periods of time

In a pre-operation, 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:

1. Rinsing the catheter with solvent on 5 working days within two successive weeks = negative control.

2. Intravenous infusion of hPTH(l-34), 40 μg/kg/day within one hour on 5 working days within two successive weeks.

3. Intravenous infusion of hPTH(l-34), 40 μg/kg/day within four hours on 5 working days within two successive weeks.

4. Intravenous infusion of hPTH(l-34), 40 μg/kg/day within eight hours on 5 working days within two successive weeks.

5. Subcutaneous bolus injection of hPTH(l-34), 40 μg/kg/day on 5 working days within two successive weeks = positive control.

6. In another experiment, PTH(l-37) was tested under various conditions. The compa- rison comprises intravenous infusion of 40 μg/kg and 80 μg/kg over four and eight hours, respectively, as well as subcutaneous injection of 40 μg/kg and intravenous bolus injection of 80 μg/kg.

On the third day following the last treatment, the animals were sacrificed and the femora were removed for subsequent analysis of femur weight, volume, dry weight, ash weight, and calcium content. The results for PTHd-34) are summarized in the following Table 1. showing that a significant increase of bone matter was observed in the Treatment Groups 1 (1 hour infu¬ sion), 2 (4 hours infusion) and 4 (sc bolus), while no differences compared to the control group occurred in Group 3 (8 hours infusion).

Table 1

Continuous infusion of PTH(l-34) on rats (Wistar) Duration of treatment: Continuous infusion for 1 hour (Group 1), 4 hours (Group 2), 8 hours (Group 3) once per day iv, and once per day subcutaneous (sc) (Group 4). Dose: 40 μg PTH(l-34)/kg/day n = 5 - 6

Group 1 Group 2 Group 3 Group 4

Duration of infusion Control 1 hour iv 4 hours iv 8 hours iv sc

Lene h (mm)

Median 34 34 34 34 34

1st quart. 34 34 34 33 34

3rd quart. 34 35 34 34 34

Volume (μl)

Median 645 648 672 680 639

1st quart. 628 639 645 642 627

3rd quart. 675 670 679 683 668

Drv weieht (mg)

Median 458 499 520 471 512

1st quart. 445 479 518 458 493

3rd quart. 473 517 539 503 522

Ash weieht (me)

Median 278 308 328 280 316

1st quart. 270 296 323 278 306

3rd quart. 288 320 337 308 321 Group 1 Group 2 Group 3 Group 4 hour iv 4 hours iv

Duration of infusion Control 1 8 hours iv sc

Ca content (me)

Median 100 1 13 123 102 115

1st quart. 98 109 115 99 115

3rd quart. 106 116 131 112 116

Drv Weieht/Volume

(mg/ml)

Median 707 758 794 710 786

1st quart. 682 747 773 671 776

3rd quart. 715 784 820 740 795

Ash Weieht/Volume

(me/ml)

Median 428 468 497 - 433 488

1st quart. 412 459 481 401 479

3rd quart. 438 485 519 453 490

Ca Content/Volume

(me/ml)

Median 155 171 192 155 175

1st quart. 152 170 171 145 171

3rd quart. 158 176 193 164 180

In one test series of PTH(l-37) the influence of duration at an identical infusion rate (40 μg/kg iv over four hours; 80 μg/kg iv over eight hours) was examined. Here, it appeared that a significant osteoanabohc effect occurred at 40 μg/kg PTΗ(l-37) iv over four hours, while the double infusion time period of eight hours at an overall amount of 80 μg/kg iv resulted in dramatic negative effects on the bone balance. In contrast, repeated intravenous bolus injection of 80 μg/kg within about one minute had a positive effect on the bone balance. However, the therapeutic utility of comparably high intravenous PTH doses in the form of a bolus administration is not deemed advantageous due to the relatively small effect and, in particular, due to severe circulatory effects to be expected. The results for PTH(l-37) are summarized in Table 2.

Table 2

a) Effect of PTH(l-37) by intravenous infusion on rats Duration of treatment: 10 working days, once per day

Dose: 40 (4 hours) and 80 (8 hours) μg/kg/day, respectively

Infusion rate: 10 μg/kg/hour

Group 1 : 4 hours iv; 40 μg/kg/day

Group 2: 8 hours iv; 80 μg/kg/day

Group 3 : subcutaneous (sc); 40 μg/kg/day n = 7 - 10

Group 1 Group 2 Group 3

Duration of infusion Control 4 hours iv 8 hours iv sc

Relative X-Rav Densitv (mmAI)

Median 1.5 2.0 1.5 1.8

1st quart. 1.3 2.0 1.3 1.7

3rd quart. 1.6 2.2 1.7 1.8

Lenεth (mm)

Median 36 35 34 36

1st quart. 35 35 34 36

3rd quart. 36 36 35 36

Volume (ul)

Median 709 786 737 775

1st quart. 659 752 692 710

3rd quart. 735 803 831 814 Group 1 Group 2 Group 3

Control 4 hours iv 8 hours iv

Duration of infusion sc

Drv Weieht (me)

Median 515 600 424 599

1st quart. 476 581 420 570

3rd quart. 535 608 500 633

Ash Weieht (me)

Median 329 381 262 384

1st quart. 308 377 256 357

3rd quart. 336 388 330 398

Ca Content (me)

Median 119 138 95 140

1st quart. 111 137 93 132

3rd quart. 120 140 1 19 145

Drv Weieht/Volume (me/ml)

Median 716 770 593 768

1st quart. 709 756 533 743

3rd quart. 736 785 618 779

Ash Weieht Volume (me/ml)

Median 460 490 356 484

1st quart. 450 480 319 467

3rd quart. 474 506 384 487

Ca Content/Volume (me/ml)

Median 167 177 134 177

1st quart. 164 174 116 170

3rd quart. 172 181 158 179 b) Effect of PTH( 1 -37) by intravenous bolus administration on rats Duration of treatment: 10 working days, once per day

Dose: 80 μg/kg/day

Infusion rate: 10 μg ^'kg/hour

Group 4: intravenous bolus administration n = 7 - 10

Group 4

Control Bolus iv

Relative X-Rav Densitv (mmAI)

Median 1.0 1.3

1st quart. 0.9 1.2

3rd quart. 1.0 1.3

Leneth (mm)

Median 35 35

1st quart. 35 34

3rd quart. 35 36

Volume (ul)

Median 562 635

1st quart. 522 624

3rd quart. 641 714

Drv Weieht (me)

Median 449 517

1st quart. 426 487

3rd quart. 466 548

Ash Weieht (me)

Median 299 348

1st quart. 293 329

3rd quart. 313 366

Ca Content (me)

Median 102 119

1st quart. 101 114

3rd quart. 106 126 Group 4

Control Bolus iv

Drv Weieht/Volume (me/ml)

Median 771 800

1st quart. 726 754

3rd quart. 817 829

Ash Weieht/Volume (me/ml)

Median 513 527

1st quart. 483 507

3rd quart. 561 549

Ca Content Volume (me/ml)

Median 175 182

1st quart. 165 176

3rd quart. 191 189

Example 2

Iontophoretic application of PTH

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.

hPTH(l-34) [pg/ml]

Time [min]

0 20 30 45 60 90 105 120

Animal 1 36 112 123 1834

Animal 2 52 107 112 391 915 1420 1315

Claims

C L A I M S :

1. A pharmaceutical administration form, containing parathyroid hormone (PTH) or a parathyroid hormone derivative as the active ingredient, with an active ingredient release period of from two to six hours.

2 The administration form according to claim 1, comprising an infusion solution for continuous infusion of from two to six hours and preferably, four hours.

3. The administration form according to claim 1, comprising a transdermic pharmaceu¬ tical system, preferably a patch or an iontophoretic system.

4. The administration form according to claim 1, comprising an enteric pharmaceutical system, preferably loaded liposomes. or microspheres made of common polymers, or proteinoid complexes.

5. The administration form according to one of claims 1 to 4, containing human PTH(l-84).

6. The administration form according to one of claims 1 to 4. containing the N-terminal fragments of human PTH comprising the sequences 1-29 through 1-41, preferably 1-34, 1-35, 1-36, 1-37, and 1-38.

7. Use of parathyroid hormone or parathyroid hormone derivatives for the preparation of an administration form having an active ingredient release period of from two to six hours.

8. The use according to claim 7 for the preparation of an infusion solution for continuous infusion of from two to six hours and preferably, four hours.

9. The use according to claim 7 for the preparation of a transdermic or enteric administration form.

10. 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.

1 1. The method according to claim 10, conducted within the scope of clinical tests for the purpose of authorization according to the drug law.

12. The method according to claim 10 or 1 1, wherein from 30 to 50 μg/kg/day parathy¬ roid hormone or parathyroid hormone derivative is used as therapeutically effective amount.

13. The method according to one of claims 10 to 12, wherein said continuous infusion is effected on 5 working days within two successive weeks.

14. The method according to one of claims 10 to 12, wherein said transdermic applica¬ tion is effected using a patch optionally containing permeation accelerators, or by iontophoresis.

15. The method according to one of claims 10 to 12, wherein said enteric application is effected using loaded liposomes, microspheres made of common polymers, or pro- teinoid complexes.