Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2002-02-01
2004-08-03
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C523S114000, C523S115000
Reexamination Certificate
active
06770289
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the medical field and more particularly to pharmaceutical compositions containing ibandronaic acids or salts thereof and method for treating osseous diseases and disorders in the calcium metabolism. The invention also provides methods for obtaining the compositions.
2. Description of the Prior Art
An increasing number of individuals affected by diseases related to the loss of osseous mass has been a concern in the last years. Many of these affections are related to endocrine pathologies or cancer, to treatments based in the use of pharmaceuticals and menopause. In this latter case the process is characterized by a high osseous disorder affecting to the 25% of post-menopause women. When forms not so severe like the osteopenia are considered, the incidence is considerably increased. All these osseous affections could be encircled within the osseous diseases, particularly within those diseases having disorders in the calcium metabolism.
During the last years it has been progressed in the knowledge, diagnostic and treating of the senile involutional osteoporosis which, differing from the above mentioned affections, it is characterized by a little osseous renewal thus causing the traditional therapeutic focusing to be modified.
At present there are more reviewing over the osteoporosis question, its prevention and treatment in the different clinic situations (Eastell, R. New England Journal of Medicine, 338: 736-746, 1998 and Lane, J. M. “Osteoporosis-Medical Prevention and Treatment”. Spine, 22: 32-37, 1997).
It is considered that supplementing calcium is a necessary condition for treating osteopenia/osteoporosis, but this is not enough for obtaining the desired results. Administering calcium and vitamin D is the first treatment option in post-menopause women.
Other types of treatments include: hormonal replacing therapy, partial estrogenic agonists (SERM), agents for stimulating the osseous synthesis and agents for inhibiting the osseous resorption. Within the group including the agents for inhibiting the osseous resorption, the bisphosphonates are in a relevant position.
Bisphosphonates are analogous to pyrophosphate, and include a phosphorous-carbon-phosphorous column in its chemical composition and the bisphosphonates are bonded to the surface of hydroxyapatite crystals, particularly in the sites of the bone for active re-modeling.
There are several bisphosphonate generations. Within a first generation the etidronate is compressed and it is employed in prevention and treating methods by administering doses of 400 mg in three month cycles, together with supplementing of about 800 to about 1250 mg/day of calcium during a break period. The alendronate is another medicament that has shown effectiveness when orally administered together with calcium and, eventually, with vitamin D. This compound is useful either in prevention as well as in treating procedures, remarkably increasing the mineral osseous density at a long term, and reducing the incidence of bone fractures in patients with osteoporosis. For prevention purposes the dose is 5 mg/day administered in fasting. For treatment purposes, 10 mg/day fasting doses are administered. However, the alendronate is related to many side effects, particularly irritations in the esophagus and gastritis. For preventing this gastric irritations and oesophagitis, this pharmaceutical product must be administered in fasting with the patient in a stand up position and by drinking a lot of water.
The above mentioned drawbacks make this product to be very cumbersome for administration, particularly when the patient must be subject to a treatment for general osteoporosis and, more particularly, when the patient is undergoing a treatment of involutional osteoporosis because the same is found in elderly individuals. Due to this inconveniences, the product must be administered in doses below 10 mg. Other bisphosphonates are: pamidonate, risedronate, zolendronate and ibandronate.
The modern non halogenated bisphosphonates (amino-bisphosphonates) actuate via several mechanisms such as, competing for the osteoplastic action site at the level of free osseous surfaces, reducing the osteoplastic recruiting and incrementing the apoptosis of osteoplasts.
Ibandronate is employed in the treatment of osseous metastasis and neoplastic hypercalcaemias, in the form of injectable solutions. The ibandronate is administered via intravenous application at a rate of about 1 mg to about 5 mg each 1 to 6 months, but it maybe also orally administered at doses of 0.5 mg to 5 mg per tablet according to the particular indications.
U.S. Pat. No. 6,143,326 to Mockel et al. discloses a method of treating a bone disease by administering to the patient a pharmaceutical formulation comprising a tablet core containing about 0.1 mg to 100 mg of ibandronate. It is well known in the art that all the treatments by early administering ibandronate are specially complex and cumbersome because of the poor gastric absorption as well as of the side effects produced by the ibandronate. Among these effects is to be remarked the esophageal irritation. These ibandronate compounds in solid tablets to be orally administered must be ingested under certain conditions to diminish the irritating effects.
It would be therefore very desired in the art to have a new form of a pharmaceutical compound containing ibandronate to be administered to the patients in need thereof without the above mentioned side effects and drawbacks.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide a pharmaceutical composition containing ibandronaic acid or the salts thereof which are manufactured in none parenteral pharmaceutical forms which represents a significant therapeutic development and which leads to an easy administration thereof without the side effects produced by typical pharmaceutical forms such as the gastric intolerance, the invented composition providing a rapid absorption with excellent results in connection to the osseous synthesis and re-absorption biochemical markers.
It is still another object of the present invention to provide a liquid pharmaceutical composition for use in the treating of bone diseases, the composition being an aqueous solution comprising about 0.05% to about 35% by weight of ibandronaic acid or salts thereof; about 0.1% to about 5% by weight of a pH regulating agent; about 1% to about 15% by weight of a co-solvent; about 0.005% to about 1.5% by weight of a conserving agent; about 1% to about 90% by weight of a de-ionized water; and excipients and pharmaceutically acceptable stabilizers, wherein the composition has a pH of about 2 to 7. The pH regulating agent being acetates, phosphates, citrates, ascorbates, or bases and acids thereof, with the citric acid or the sodium salt thereof being the preferred ones. The co-solvent being glycol, glycerol or mixtures of same, with the preferred co-solvent being propylene glycol, and the conserving agent is nipagin or nipasol.
It is even another object of the present invention to provide a method of making the immediately above disclosed composition, comprising the steps of:
a) dissolving the pH regulating agent in de-ionized water to form a solution;
b) adding the ibandronate to the solution of step a) and agitating the solution until obtaining a complete dissolution;
c) adding the co-solvent while maintaining said agitation;
d) adding de-ionized water for bringing the solution to a final weight and sterilizing the solution by passing it through 0.22 &mgr;m filter. If necessary, an step of measuring the pH of the solution and bringing the pH to about 2 to about 3 is carried out before step d).
It is a further object of the present invention to provide a liquid pharmaceutical composition for use in the treating of bone diseases, the composition being an aqueous solution comprising, per each 100 g of solution, about 2 g to about 35 g of sodium ibandronate; about 0.8 g to about 1.5 g of monohydrate citric acid; about 15 g to about 25 g
Azpuru Carlos A.
Darby & Darby
Riderway Corporation
LandOfFree
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