MXPA00002394A - Method of increasing bone volume using non-naturally-occurring fp selective agonists - Google Patents
Method of increasing bone volume using non-naturally-occurring fp selective agonistsInfo
- Publication number
- MXPA00002394A MXPA00002394A MXPA/A/2000/002394A MXPA00002394A MXPA00002394A MX PA00002394 A MXPA00002394 A MX PA00002394A MX PA00002394 A MXPA00002394 A MX PA00002394A MX PA00002394 A MXPA00002394 A MX PA00002394A
- Authority
- MX
- Mexico
- Prior art keywords
- agonist
- use according
- bone
- unnatural
- selective
- Prior art date
Links
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Abstract
The present invention relates to novel methods of increasing bone volume comprising the administration of a non-naturally-occurring selective FP agonist to a subject in need of such treatment. This invention further relates to a method of treating or preventing bone disorders comprising the administration of a non-naturally-occurring selective FP agonist to a subject in need of such treatment.
Description
METHOD TO INCREASE BONE VOLUME USING SELECTING AGENTS OF PROSTANOID F NON-NATURAL
TECHNICAL FIELD OF THE INVENTION
The present invention relates to novel methods for increasing bone volume consisting of the administration of a non-natural selective FP agonist to a subject in need of such treatment. This invention further relates to a method for treating or preventing bone disorders comprising the administration of a non-natural selective FP agonist to a subject in need of such treatment.
BACKGROUND OF THE INVENTION
In subjects suffering from osteoporosis an imbalance develops in the process of bone remodeling in which the bone is reabsorbed faster than it is formed. Although this imbalance occurs to a certain degree in most individuals, both male and female, as they age, is much more severe and occurs at an earlier age in subjects who appear to be osteoporosis, particularly those who are that develop the postmenopausal form of the condition. Accelerated bone loss can also be caused by the administration of medications, such as corticosteroids; prolonged bed rest; lack of use of a member; and microgravity. A consequence of this bone loss is the complete elimination of trabeculae and a deterioration of the bone structure such that the hardness of the rest of the bone decreases disproportionately. It is thought that to completely return the bone to its normal hardness, new trabeculae must be formed to restore the structure and increase bone mass. Also, it is thought that when the restoration of normal structure is related not only to an increase in hardness, but also a return to normal stiffness and ability to absorb impacts, the bone is less likely to fracture. Subjects suffering from other bone disorders such as osteoarthritis, Paget's disease, periodontal disease, and fractures may also benefit from treatments that restore bone mass and normal bone structure. There have been many attempts to treat bone disorders with a variety of pharmacological agents with the goal of either delaying greater bone loss or producing a net gain in bone mass. There are anti-resorptive agents, such as bisphosphonates, which retard further bone loss, and there are anabolic agents, such as PTH, fluoride, and prostaglandins, which make up the bone. But none of these agents form bone that is substantially similar, that is, structurally, to the type of bone lost.
It is known that PTH and prostaglandins, especially prostaglandins of the E series (example PGE2), are potent stimulators of resorption and bone formation. The acceleration in turnover that is seen with these known bone anabolic agents can be harmful to an already osteoporotic skeleton because the increased reabsorption can cause perforation and loss of trabeculae, or it can weaken the existing trabecular structure. In addition, increased resorption may occur in the cortex. These effects can in turn lead to an increased incidence of fracture in some places. It has also been shown that PGF2a is a stimulator of bone resorption, but it is not as potent as PGE2. It has been suggested that some of the effects of PGF2a on resorption, bone formation and self-reproduction of cells can be mediated by an increase in the production of endogenous PGE2. Likewise, in vitro data with FP agonists have shown a decrease in the synthesis of collagen in the osteoblastic cell lines, suggesting that FP agonists would not be effective in increasing bone mass in vivo. Tamura, et al., J. Bone Min. Rsch., Supp. Vol. 5189, T352 (1997). Likewise, prostaglandins have serious drawbacks that limit the convenience of their systemic administration. For exampleAlthough prostaglandins are characterized by their activity in a particular prostaglandin receptor, their activity is not limited to any prostaglandin receptor. Therefore, it is known that systemic administration of prostaglandins causes side effects such as inflammation, as well as surface irritation, smooth muscle contraction, bronchoconstriction and vasoconstriction. Also, systemic administration of nonselective prostaglandin analogues can cause side effects. Therefore, there is a continuing need to develop methods for replacing bones that result in bone that is substantially structurally similar to the type of bone lost.
BRIEF DESCRIPTION OF THE INVENTION
It has surprisingly been found that systemic administration of non-natural selective FP agonists results in an anabolic effect of bone. It has also been surprisingly found that the bone quality formed by the administration of non-natural selective FP agonists is superior to that formed by the administration of other bone anabolic agents, including prostaglandins of the E series. Accordingly, the present invention is directed to methods for increasing bone volume by administering to a subject a safe and effective amount of a non-natural selective FP agonist. Particularly preferred non-natural FP agonists are selective for the FP receptor on other excitatory prostaglandin receptors in a ratio of at least about 1: 10, preferably at least about 1: 20, and preferably at least about 1 :fifty. The non-natural FP agonists that are even more preferred are selective for FP receptors on all other prostanoid receptors in a ratio of at least about 1: 10, preferably at least about 1: 20, and preferably at least minus approximately 1:50. It has also been found that non-natural selective FP agonists increase the trabecular number (by forming new trabeculae), increase bone volume and mass while maintaining a normal bone turnover rate, and increase endosteal surface formation. without removing bone from the resistant bark. Accordingly, the present invention is directed to methods for increasing the trabecular number by administering to a subject a safe and effective amount of a non-natural selective FP agonist. Similarly, it has been found that non-natural selective FP agonists are useful for treating bone disorders. Accordingly, the present invention is directed to methods of treating bone disorders by administering to a subject a safe and effective amount of a non-natural selective FP agonist.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to methods for increasing bone volume, methods for increasing the trabecular number, and methods for treating bone disorders by administering to a subject a safe and effective amount of a non-natural selective FP agonist.
Definitions and use of terms As used herein, "bone disorder" means the need for repair and replacement of bones. Conditions in which the need for bone repair or replacement may arise include: osteoporosis (including postmenopausal osteoporosis, male and female senile osteoporosis and corticosteroid-induced osteoporosis), osteoarthritis, Paget's disease, osteomalacia, multiple myeloma and other forms of cancer , prolonged bed rest, lack of chronic limb use, anorexia, microgravity, exogenous gonadal insufficiency and endogenous fracture of bones, lack of union in fragments of fractured bones, defect, implantation of prosthesis and the like. As used herein, "bone turnover index" means the amount of bone resorption and bone formation per unit of time measured or estimated using fluorescent tag incorporation in bone, fluorescent and bright field microscopy, and histomorphometric techniques or by measurement of markers of bone metabolism. For example, a subject can reabsorb and replace (replace) approximately 3% of their skeleton in a period of 3 months. A more in-depth description of histomorphometric techniques can be found in Bone Histomorphometry, 1994, by Eriksen et al., Raven Press. As used herein, "bone volume" refers to the percentage of bone occupied by a mineralized matrix. The measurement or estimation of the mineralized matrix volume can be carried out using histomorphometry, computer tomography or magnetic resonance imaging. Two-dimensional measurements can be used to estimate three-dimensional volume. A more in-depth description of histomorphometric techniques can be found in Bone Histomorphometry, 1994, by Eriksen et al., Raven Press. As used herein, "excitatory prostaglandin receptor" means prostanoid receptors that can cause smooth muscle contraction or release of internal calcium deposits. Such receivers include but are not limited to FP, EP-i, EP3, TPi and TP2. As used herein, "FP" is an abbreviation of prostanoid F. As used herein, "FP agonist" means a compound with affinity to the FP receptor that results in a measurable biological activity (including but not limited to a elevation in intracellular calcium or smooth muscle contraction) in cells, tissues, or organisms that contain the FP receptor. Cell, tissue and whole organism analyzes demonstrating FP activity of compounds are well known in the art. A particularly useful analysis is the R-SAT ™ Analysis described by Brann, et al. in J. Biomole, Screen, Vol. 1, Number 1, 1996. As used herein, "FP receptor" means known human FP receptors, their binding variants, and undescribed receptors that preferentially bind PGF2a. A human FP receptor is described in PCT publication WO 95/00551. As used herein, "measurable" means that the biological effect is both reproducible and significantly different from the variability of the baseline of the analysis. As used herein, "non-natural" means an agent that is not derived biologically from mammals. As used herein, "prostaglandin analog" refers to a non-natural compound that is structurally similar to a prostaglandin. As used herein, "prostaglandin receptor" or "prostanoid receptor" means a natural protein that binds prostaglandins, which when bound together alters the function of a cell. Prostaglandin receptors can be classified as either excitatory or relaxing. Such receivers include but are not limited to FP, EP ^ EP2, EP3, EP4, DP, IP, TPi and TP2. These receptors are described in more detail by Coleman et al., In Pharmacological Reviews, 1994, Volume 6, No. 2, pages 205-229. As used herein, "selective" means having an activation preference for a specific receptor over other receptors which can be quantified based on cell, tissue or whole organism analysis demonstrating receptor activity, such as the R-SAT Analysis ™ described above. The selectivity of a compound is determined from a comparison of its EC50 (or ED50 if an organism analysis is used) in the relevant receptors. For example, a compound having an EC50 of 8nM in the FP receptor and an EC50 of 80 nM in the EP-i receptor has a selectivity ratio for the FP receptor over the EP receptor! of 1: 10. As used herein, "trabecular number" refers to the number of individual bone trabeculae per unit volume of cancellous bone measured or estimated from a two-dimensional representation or a three-dimensional specimen using histomorphometry, computer tomography, or magnetic resonance imaging. As used herein, "subject" means a living vertebrate animal such as a mammal (especially human) in need of treatment.
Compounds The compounds useful in the present invention are selective non-natural FP agonists. Particularly preferred non-natural FP agonists are selective for the FP receptor on other excitatory prostaglandin receptors in a ratio of at least about 1: 10, preferably at least about 1: 20, and preferably at least about 1 :fifty. The non-natural FP agonists that are even more preferred are selective for FP receptors on all other prostanoid receptors in a ratio of at least about 1: 10, preferably at least about 1: 20, and preferably at least minus approximately 1:50. Particularly useful non-natural selective FP agonists are prostaglandin analogues. Examples of said compounds are protaglandin analogs having the following general structure:
wherein: R1 is CO2H, C (O) NHOH, CO2R2, CH2OH, S (0) 2R2, C (O) NHR2, C (0) NHS (0) 2R2, or tetrazole; wherein R2 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, aromatic ring or heteroaromatic ring; X is (CH2) n, where n is 0 to 3, NH, S, or O; and Y is a cycloalkyl or aromatic portion, whether substituted or unsubstituted. Prostaglandin analogs of the above structure include: cloprostenol (Estrumate®), fluprostenol (Equimate®), tiaprost, alphaprostol, delprostenate, froxiprost, latanoprost, 13, 14-dihydro-16 - ((3-trifluoromethyl) phenoxy) -16- tetranor-prostaglandin F-? a, 17 - ((3-trifluoromethyl) phenyl) -17-trinor-prostaglandin F2a, 13, 14-dihydro-18-thienyl-18-dinor-prostaglandin F-ia and their analogues. Other prostaglandin analogs of the present invention include 9-alpha-11-alpha-15-alpha-trihydroxy-16- (3-chlorophenoxy) -omega-tetranor-prosta-4-cis-13-trans-dienoic acid and its analogs . Additional protaglandin analogues are also described in CRC Handbook of Eicosanoids: Protaqlandins and Related Lipids, Volume I. Chemical and Biochemical Aspects, Part B. Ed. By Anthony L. Willis, CRC Press (Boca Raton, 1987) Table 4 pp. 80-97 (included here by reference), and references therein.
Methods of use The compounds described above are useful for increasing bone volume, increasing the trabecular number by forming new trabeculae, increasing bone mass without increasing the rate of bone turnover, and increasing endosteum surface formation without removing bone. of the resistant bark. In addition, bone quality formed by the administration of these compounds is superior to that formed by the administration of other anabolic bone agents, including prostaglandins of the E series. Bone quality refers to the combination of bone matrix (inorganic and organic), bone mass or volume, and bone structure which gives the bone general hardness and fracture resistance. Accordingly, these compounds are also useful in the treatment and prevention of a variety of bone disorders. Preferred routes of administration for increasing bone volume and treating bone disorders are transdermal and subcutaneous, e.g. injection or injectable tablet. Other preferred routes of administration include oral, sublingual and intranasal. The dose range for systemic administration of the non-natural FP agonists of the present invention is from about 0.01 to about 1000 μg / kg of body weight per day, preferably from about 0.05 to about 100 μg / kg of body weight per day. day, preferably from about 0.1 to about 50 μg / kg of body weight per day. The plasma levels are expected to be in the range of about 0.01 to about 500 ng / ml, preferably about 0.05 to 100 ng / ml, and preferably about 0.1 to 50 ng / ml. Although this dose is based on a daily administration rate, cumulative weekly or monthly doses can also be used to calculate clinical requirements. The non-natural FP agonists of the present invention can be administered, based on a weekly dose, more often than once a day. The non-natural FP agonists of the present invention can also be administered on a weekly basis less frequently than once a day. Therefore, the weekly dose can be divided into 3, 4, 5, 6 or 7 daily doses, preferably 5, 6 or 7 daily doses. Doses can be varied based on the patient being treated, the condition being treated, the severity of the condition being treated, and the route of administration to achieve the desired effect. It has also been discovered that the prolonged provision (also called "prolonged administration") of the unnatural FP agonist unexpectedly results in an improved dose separation between the side effects and the desired bone effect. That is, as used herein, "prolonged provision" or "prolonged administration" means that the total daily dose is provided in the circulation of the subject in a period of at least about 6 hours and up to 24 hours. The preferred extended-time periods are for at least about 12 hours and up to 24 hours. Examples of prolonged provision include administration of the unnatural FP agonist via a transdermal patch or a subcutaneous pump that provides the total daily dose over a period of 24 hours. It is believed that the flattening of the plasma concentration curve resulting from prolonged provision mitigates side effects while maintaining bone efficiency. It is also believed that the administration of non-natural FP agonists with extended half-lives will likewise result in a flattening of the plasma concentration curve without prolonging administration.
The following non-limiting examples serve to further illustrate the use of the agents of the present invention.
EXAMPLE I
The FP agonist, fluprostenol, is given to a 65-year-old woman who has reduced bone mass and whose doctor has diagnosed osteoporosis. He is treated daily with a transdermal patch that provides 10 μg / kg of fluprostenol in a 24-hour period. This treatment continues for 24 months at which time, the vertebral bone mass increases considerably compared to its vertebral bone mass at the beginning of therapy as measured by dual-energy X-ray absorptiometry (DXA).
EXAMPLE II
The FP agonist, fluprostenol, is given to a 63-year-old woman who has reduced bone mass and whose doctor has diagnosed osteoporosis. You are treated with an implantable subcutaneous pump that provides 10 μg / kg of fluprostenol in a 24-hour period. This treatment continues for 12 months, at which time, the vertebral bone mass increases considerably compared to its vertebral bone mass at the beginning of therapy as measured by dual-energy X-ray absorptiometry (DXA).
Pharmaceutical Formulations The pharmaceutical formulations of the present invention comprise a safe and effective amount of an unnatural FP agonist and a pharmaceutically acceptable carrier. The phrase "safe and effective amount" as used herein means an amount of a compound or composition high enough to positively and significantly modify the symptoms and / or condition to be treated, but low enough to avoid serious side effects (to a reasonable benefit / risk ratio), within the scope of the correct medical criteria. The safe and effective amount of an agent to be used in the method of the present invention will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of the concurrent therapy, the particular agent that is being used, the excipients acceptable from the particular pharmaceutical point of view used, and similar factors within the knowledge and experience of the attending physician. In addition to the compound, the compositions of the present invention contain a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier", as used herein, means one or more liquid or solid filler diluents or compatible encapsulating substances that are suitable for administration to a subject. The term "compatible", as used herein, means that the components of the composition can be mixed with the compound, and with each other, in a manner such that there is no interaction that would significantly reduce the pharmaceutical efficacy of the composition under use situations. ordinary. The pharmaceutically acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the subject being treated. Some examples of substances that can serve as pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate; powdered tragacanth; malt; jelly; talcum powder; solid lubricants, such as stearic acid, magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as Tweens®; wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents; excipients; tabletting agents; stabilizers; antioxidants; condoms; pyrogen-free water; isotonic saline solution and pH-regulated phosphate solutions. The choice of a pharmaceutically acceptable carrier to be used in conjunction with a compound is basically determined by the manner in which the compound is to be administered. The non-natural FP agonist of the present invention can be administered systemically, including transdermally, orally and / or parenterally, including subcutaneous or intravenous injection, and / or intranasally. The appropriate amount of the agent, preferably unnatural FP agonist, to be used can be determined by routine experimentation with animal models. Said model includes, but is not limited to, osteoporosis models of intact or ovariectomized rats, models of osteoporosis of ferrets, canines, and non-human primates, as well as models of osteoporosis in disuse. A preferred method for administering non-natural FP agonists is via transdermal delivery. Preferred transdermal dosage forms include transdermal patches, creams, ointments, gels and the like. Another method for administering non-natural FP agonists is via subcutaneous injection in a unit dose form. Preferred unit dose forms for injection include sterile water solutions, physiological saline, or mixtures thereof. The pH of these solutions should be adjusted to approximately 7.4.
Other preferred dosage forms include nasal, rectal, sublingual, and oral. Suitable vehicles for injection or surgical implants include hydrogels, controlled-or-sustained-discharge devices, polylactic acid, and collagen matrices. The implant devices can be coated with the unnatural FP agonist. The unnatural prostaglandin FP agonist can be dissolved in a pH regulator and mixed with a collagen gel which is then coated on the porous end of the implant device. Preferred oral forms include, for example, liposomes, lipid emulsions, proteinaceous cells and pharmaceutically acceptable excipients. The term "pharmaceutically acceptable excipients" as used herein includes any physiologically inert, pharmacologically inactive material known to one skilled in the art, which is compatible with the physical and chemical characteristics of the particular active ingredient selected for use. Pharmaceutically acceptable excipients include, but are not limited to, polymers, resins, plasticizers, fillers, lubricants, binders, disintegrants, solvents, cosolvents, pH regulator systems, surfactants, preservatives, sweetening agents, agents. flavorings, dyes and pharmaceutical grade pigments. The following non-limiting examples illustrate formulations of the present invention.
EXAMPLE III
The pharmaceutical formulations (compositions) in the form of tablets are prepared by conventional methods, such as mixing and direct compression, formulated in the following manner.
Ingredient Amount (mq per tablet) Fluprostenol 5 Microcrystalline Cellulose 100 Sodium starch glycolate 30 Magnesium stearate 3
The previous tablet administered orally once a day for six months considerably increases the bone volume of a patient suffering from osteoporosis.
EXAMPLE IV
A pharmaceutical composition in liquid form is prepared by conventional methods, formulated in the following manner:
Ingredient Amount Cloprostenol 5 mg Physiological saline pH regulated with phosphate 10 ml Methylparaben 0.05 ml
1. 0 ml of the above composition administered subcutaneously once a day for six months considerably increases the bone volume of a patient suffering from osteoporosis. Although particular embodiments of the present invention have been described, it would be obvious to those skilled in the art that various changes and modifications can be made to the compositions described herein without departing from the spirit and scope of the invention.
Claims (22)
1. The use of a non-natural selective FP agonist in the manufacture of a medicament for increasing bone volume in a subject.
2. The use of a non-natural selective FP agonist in the manufacture of a medicament for increasing the trabecular number in a subject.
3. The use of a non-natural selective FP agonist in the manufacture of a medicament for treating a bone disorder in a subject.
4. The use according to claim 1, 2 or 3 wherein the unnatural FP agonist is selective for the FP receptor on other excitatory prostaglandin receptors in a ratio of at least 1: 10.
5. The use according to claim 4, wherein the unnatural FP agonist is selective for the FP receptor on all other prostanoid receptors in a ratio of at least 1: 10.
6. The use according to claim 5, wherein the unnatural FP agonist is also selective for the FP receptor on other excitatory prostaglandin receptors in a ratio of at least 1: 20.
7. The use according to claim 6, wherein the unnatural FP agonist is also selective for the FP receptor on all other prostanoid receptors in a ratio of at least 1: 20.
8. The use according to claim 7, wherein the unnatural FP agonist is also selective for the FP receptor on other excitatory prostaglandin receptors in a ratio of at least 1: 50.
9. The use according to claim 8, wherein the unnatural FP agonist is also selective for the FP receptor on all other prostanoid receptors in a ratio of at least 1: 50.
10. The use according to claim 9, wherein the unnatural FP agonist is a prostaglandin analogue.
11. The use according to claim 10, wherein the medicament allows the transdermal provision of the unnatural FP agonist.
12. The use according to claim 10, wherein the prostaglandin analog has the general formula: wherein: Ri is C02H, C (0) NHOH, CO2R2, CH2OH, S (0) 2R2, C (0) NHR2, C (O) NHS (O) 2R2, or tetrazole; wherein R2 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, aromatic ring, or heteroaromatic ring; X is (CH2) n, where n is 0 to 3, NH, S, or O; and Y is a cycloalkyl or aromatic portion, either substituted or unsubstituted.
13. The use according to claim 10, wherein the prostaglandin analogue is fluprostenol.
14. The use according to claim 13, wherein the medicament allows the transdermal provision of fluprostenol.
15. The use according to claim 7, wherein the unnatural FP agonist is selected from the group consisting of cloprostenol (Estrumate®), fluprostenol (Equimate®), tiaprost, alphaprostol, delprostenate, froxiprost, acid 9- alpha-11-alpha-15-alpha-trihydroxy-16- (3-chlorophenoxy) -omega-tetranor-prosta-4-cis-13-trans-dienoic, 17 - ((3-trifluoromethyl) phenyl-17-trinor- prostaglandin F2a, 13,14-dihydro-18-thienyl-18-dinor prostaglandin Fia, 13,14-dihydro-16 - ((3-trifluoromethyl) phenoxy) -16-tetranor prostaglandin Fia, latanoprost, and their analogues.
16. The use according to claim 3, wherein the bone disorder is selected from the group consisting of: osteoporosis, osteoarthritis, Paget's disease, osteomalacia, and bone fracture.
17. The use according to claim 3, wherein the bone disorder is osteoporosis.
18. The use according to claim 17, wherein the unnatural FP agonist is fluprostenol.
19. The use according to claim 17, wherein the bone disorder is postmenopausal osteoporosis.
20. The use according to claim 1, 2 or 3, wherein the medicament allows prolonged administration of the unnatural FP agonist.
21. The use according to claim 20, wherein the medicament allows the provision of the unnatural FP agonist in a period of at least twelve hours.
22. The use according to claim 1, 2, or 3, wherein the medicament does not considerably increase bone turnover of a subject. APPENDIX SHEET SUMMARY OF THE INVENTION The present invention relates to novel methods for increasing bone volume consisting of the administration of a non-natural selective FP agonist to a subject in need of such treatment; this invention also relates to a method for treating or preventing bone disorders consisting in the administration of a non-natural selective FP agonist to a subject in need of such treatment. P00 / 290F
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US60/058,306 | 1997-09-09 |
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