Oral formulations comprising bone morphogenetic proteins for treating metabolic bone diseases
A morphogenic protein and preparation technology, which is applied in the field of oral administration of therapeutic protein preparations, can solve the problems that clinical programs have not been developed or approved
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Embodiment 1
[0118] Example 1. Dose Response and Efficacy of Bone Morphogenetic Protein-6 (BMP-6) Administered Intravenously in Ovariectomized Aged Rats
[0119] The study showed that intravenous administration of BMP-6 was effective in promoting bone growth in a rat model of osteoporosis.
[0120] Materials and methods
[0121] Animals and research protocol. One hundred and sixty (160) 4 month old Sprague-Dawley female rats were used in this study. Animals weigh about 300 grams. Rats were maintained in standard conditions (24°C and 12h / 12h light / dark cycle) in cages of 20 x 32 x 20 cm during the study. All animals were given free access to water and pelleted commercial chow (Harlan Teklad, Borchen, Germany) containing 1.00% calcium, 0.65% phosphorus and 2.40 KIU vitamin D3 per kg. Estradiol is administered as an estrogen. Recombinant BMP-6 was prepared from transfected CHO cells according to standard procedures.
[0122] On days 14 and 4, animals received a calcein green labeling ...
Embodiment 2
[0154] Example 2. Effect of lower doses of BMP-6 on bone in ovariectomized aged rats
[0155] As above, 7 month old Sprague-Dawley rats were ovariectomized (OVX) and allowed to lose bone mineral density (BMD) for approximately 20 months. Therefore, treatment was started at 72 weeks post-ovariectomy at an age of 2 years and 1 month and continued for 3 months until slaughter for analysis. Divide the animals into the following groups:
[0156] Group 1 SHAM (n=8)
[0157] Group 2 OVX control (n=8)
[0158] Group 3 OVX treated with BMP, 10 μg / kg, 3×weeks (n=8)
[0159] Group 4 OVX treated with BMP, 10 μg / kg, 1×week (n=12)
[0160] Group 5 OVX treated with BMP, 1 μg / kg, 3×weeks (n=12)
[0161] in vivoBMD . In vivo BMD was monitored every 6 weeks. At 6 weeks after treatment initiation, all BMP-6 treated animals exhibited statistically significantly higher hindlimb BMD values than OVX control animals, and even higher BMD than sham animals. There were no statistically signi...
Embodiment 3
[0164] Example 3. Duodenal absorption and biodistribution of BMP-6 labeled with 99m technetium
[0165] This study demonstrates that the potency of orally administered BMP-6 to induce bone formation in an individual is dependent on the age of the individual. In particular, bone morphogenetic proteins are degraded under the influence of gastric enzymes known to be present in adults but generally not in infants. Therefore, this study was performed to compare the amount of orally (peroral) and duodenally administered BMP absorbed in infant and adult subjects. Specifically, the uptake of labeled BMP-6 in 3-day-old, 15-day-old, 45-day-old and 75-day-old rats was compared.
[0166] BMP-6 marker . Mature BMP-6 was chelated with mercaptoacetylthreeglycin (MAG3). The BMP-6-MAG3 complex was labeled with radioactive 99m technetium-pertechnetate (99mTc). Chromatography showed that more than 97% of the 99mTc was bound to the complex.
[0167] Animals and Treatment Protocols . Ani...
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