Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
  • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
  • A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention provides novel methods of increasing bone volume comprising the administration of a non-naturally-occurring FP selective agonist and an antiresorptive compound to a subject in need of such treatment.
• This invention further provides methods of treating or preventing bone disorders comprising the administration of a non-naturally-occurring FP selective agonist and an antiresorptive compound to a subject in need of such treatment.
• Osteoporosis can be generally defined as a reduction in the quantity of bone, or as the atrophy of skeletal tissue. In general, there are two types of osteoporosis: primary and secondary. "Secondary osteoporosis" is the result of an identifiable disease process or agent. However, approximately 90% of all osteoporosis cases is “primary osteoporosis.” Primary osteoporosis includes post menopausal osteoporosis, age-associated osteoporosis (affecting a majority of individuals over the age of 70 to 80), and idiopathic osteoporosis affecting middle-aged and younger men and women.
• Bone fractures often occur, for example, in the hip and spine of women suffering from post menopausal osteoporosis. Kyphosis (abnormally increased curvature of the thoracic spine) may also result.
• Bone remodeling occurs throughout life, renewing the skeleton and maintaining the strength of bone. This remodeling involves the erosion and filling of discrete sites on the surface of bone by an organized group of cells called “basic multicellular units" or "BMUs.” BMUs primarily consist of osteoclasts and osteoblasts and their cellular precursors. In the remodeling cycle, bone is resorbed at the site of an "activated" BMU by an osteoclast, forming a resorption cavity. This cavity is then filled with bone by osteoblasts. In osteoporotics an imbalance in the bone remodeling process develops in which bone is resorbed at a rate faster than it is being made resulting in bone loss.
• the use of bisphosphonates for the treatment of osteoporosis, and other disorders involving abnormal calcium and phosphate metabolism, is also described in U.S. Patent 3,683,080, Francis, issued August 8, 1972; U.S. Patent 4,330,537, Francis, issued October 28, 1980; U.S.
• estrogen is also used as a means to prevent osteoporosis in post menopausal women.
• This therapy typically involves daily administration of from about 0.625 milligrams to about 1.25 milligrams of conjugated estrogens, or equivalent amounts of other estrogenic hormones.
• Estrogen may also be used to treat osteoporosis.
• PTH and prostaglandins are known to be potent stimulators of bone resorption and formation.
• the acceleration in turnover seen with these known bone anabolic agents may be detrimental to an already osteoporotic skeleton since the increased resorption may cause perforation and loss of trabeculae, or may weaken the existing trabecular structure.
• increased resorption may occur in cortical bone.
• PGF 2 ⁇ has also been shown to be a stimulator of bone resorption, but it is not as potent as PGE 2 . It has been suggested that some of the effects of PGF 2Ct on bone resorption, formation, and cell replication may be mediated by an increase in endogenous PGE 2 production.
• Prostaglandins in addition, have several drawbacks which limit their desirability for systemic administration.
• prostaglandins are characterized by their activity at a particular prostaglandin receptor, they often bind to and stimulate other prostaglandin receptors.
• systemic administration of prostaglandins is known to cause side effects such as inflammation, as well as smooth muscle contraction, bronchoconstriction, and vasoconstriction.
• Systemic administration of non-selective prostaglandin analogs can likewise cause side effects.
• the present invention provides novel methods of increasing bone volume, methods of increasing trabecular number, and methods of treating or preventing bone disorders comprising the administration of a non-naturally-occurring FP selective agonist and an antiresorptive compound to a subject in need of such treatment.
• the invention provides methods of increasing bone volume, methods of increasing trabecular number, and methods of treating or preventing bone disorders by administering to a subject a safe and effective amount of an antiresorptive compound and a safe and effective amount of a non-naturally-occurring FP selective agonist.
• Bone disorder means the need for bone repair or replacement.
• Conditions in which the need for bone repair or replacement may arise include: osteoporosis (including post menopausal osteoporosis, male and female senile osteoporosis and corticosteroid induced osteoporosis), rheumatoid arthritis, osteomalacia, multiple myeloma and other forms of cancer, prolonged bed rest, chronic disuse of a limb, anorexia, microgravity, exogenous and endogenous gonadal insufficiency, bone fracture, non-union, defect, prosthesis implantation and the like.
• Bone turnover rate is the amount of bone resorption and formation per unit time measured or estimated using incorporation of fluorescent labels into bone, fluorescent and bright field microscopy, and histomorphometric techniques or by measurement of bone metabolism markers. For example, a subject may resorb and replace (turn over) approximately 3% of its skeleton over a 3 month period. A further description of histomorphometric techniques can be found in Bone Histomorphometry, 1994, by
• Measurement or estimation of the mineralized matrix volume can be accomplished using histomorphometry, computed tomography, or magnetic resonance imaging. Two dimensional measurements may be used to estimate the three dimensional volume. A further description of histomorphometric techniques can be found in Bone Histomorphometry, 1994, by Eriksen et al., Raven Press.
• Excitatory prostaglandin receptor means prostanoid receptors which cause contraction of smooth muscle or release of internal calcium stores. Such receptors include but are not limited to FP, EP * ,, EP 3 , TP, and TP 2 .
• FP is an abbreviation for F prostanoid.
• FP agonist is a compound with affinity for the FP receptor that results in measurable biological activity (including but not limited to an elevation in intracellular calcium or the contraction of smooth muscle) in cells, tissues, or organisms which contain the FP receptor.
• Whole cell, tissue, and organism assays which demonstrate FP activity of compounds are well known in the art.
• One particularly useful assay is the R- SATTM Assay described by Brann, et al. in J. Biomole. Screen. Vol.
• FP receptor refers to known human FP receptors, their splice variants, and undescribed receptors that preferentially bind PGF 2 ⁇ .
• a human FP receptor is disclosed in PCT Publication WO 95/00551.
• “Measurable” means the biologic effect is both reproducible and significantly different from the baseline variability of the assay.
• Non-naturally-occurring means an agent that is not biologically derived in mammals.
• Prostaglandin analog is a non-naturally-occurring compound which is structurally similar to a prostaglandin.
• Prostaglandin receptor or “prostanoid receptor” is a naturally-occurring protein that binds prostaglandins, which when bound alters the function of a cell. Prostaglandin receptors may be characterized as either excitatory or relaxant. Such receptors include but are not limited to FP, EP 1 t EP 2 , EP 3 , EP 4 , DP, IP, TP., and TP 2 . These receptors are further discussed by Coleman et al., in Pharmacological Reviews, 1994, Volume 6, No. 2, pages 205 - 229.
• Selective means having an activation preference for a specific receptor over other receptors which can be quantified based upon whole cell, tissue, or organism assays which demonstrate receptor activity, such as the R-SATTM Assay disclosed above.
• a compound's selectivity is determined from a comparison of its EC 50 (or ED 50 if using an organism assay) at the relevant receptors. For example, a compound having an EC 50 of 8nM at the FP receptor and an EC 50 of 80 nM at the EP, receptor has a selectivity ratio for the FP receptor over the EP., receptor of 1 :10.
• Subject is a living vertebrate animal such as a mammal (especially human) in need of treatment.
• Trabecular number is the number of individual trabeculae of bone per unit volume of cancellous bone measured or estimated from a two dimensional representation or a three dimensional specimen using histomorphometry, computed tomography, or magnetic resonance imaging.
• Antiresorptive Compounds involve administering one or more antiresorptive compounds.
• an "antiresorptive compound” is a compound that, when administered to a human or other animal subject, prevents bone loss by direct or indirect effect on the number of osteoclasts and/or their metabolism.
• Preferred antiresorptive compounds include those selected from the group consisting of bisphosphonates, estrogen compounds, SERMs, calcitonin compounds, antagonists of the SRC pathway, osteoprotegerin compounds, cathepsin K inhibitors, and mixtures thereof.
• Particularly preferred antiresorptive compounds include bisphosphonates, estrogen compounds, and SERMs.
• bisphosphonates As used herein, "bisphosphonate” means an analog of pyrophosphate that contains a carbon atom connecting the two phosphorus atoms instead of an oxygen atom. Thus, bisphosphonates have the following general structure:
• Patent 4,963,681 Ebetino et al., issued October 16, 1990; U.S. Patent 4,990,503, Isomura et al., issued February 5, 1991 ; U.S. Patent 5,071 ,840 Ebetino et al., issued December 10, 1991 ; U.S. Patent 5,128,244 Tru et al., issued July 7, 1992; U.S. Patent 5,137,880 Ebetino et al., issued August 11 , 1992; U.S. Patent 5,334,586 Ebetino et al., issued August 2, 1994; U.S. Patent 5,391 ,743 Ebetino et al., issued February 21 , 1995; U.S.
• Preferred bisphosphonates useful in the methods of this invention include: N-(2'- (3'-methyl)-pyridinyl)aminomethane phosphonomethylphosphinic acid; N-(2'-(5'-methyl)- pyridinyl)amino methane phosphonomethylphosphinic acid; N-(2'-(3'-methyl)-piper- idinylidene)aminomethane phosphonomethylphosphinic acid; N-(2'-(5'-methyl)- piperidinylidene)aminomethane phosphonomethylphosphinic acid; 2-(2'-pyridinyl)ethane- 1 -phosphono-1 -methylphosphinic acid; 2-(2'-piperidinyl)ethane-1 -phosphono-1 - methylphosphinic acid; 2-(p-aminophenyl)-1 -hydroxy-ethane-1 -phosphono-1 -
• Particularly preferred bisphosphonates useful in the methods of this invention include: 1-hydroxyethylidene-1 ,1 -bisphosphonic acid (etidronate); dichloromethylene bisphosphonic acid (clodronate); 3-amino-1-hydroxypropylidene-1 ,1 -bisphosphonic acid (pamidronate); 6-amino-1-hydroxyhexyIidene-1 ,1 -bisphosphonic acid (neridronate); 4- amino-1-hydroxybutylidene-1 ,1 -bisphosphonic acid (alendronate); 2-(3-pyridinyl)-1- hydroxyethylidene-1 ,1 -bisphosphonic acid (risedronate); 2-(N-imidazoyl)-1- hydroxyethylidene-1 ,1 -bisphosphonic acid (zoledronate); 3-(N-pentyl-N-methylamino)-1- hydroxypropylidene-1 ,1 -bisphosphonic acid (ibandronate); 3-(N
• Estrogen Compounds Preferred antiresorptive compounds useful in the methods of this invention include estrogen compounds.
• an "estrogen compound” refers to naturally occurring hormones, synthetic steroidal compounds, and non-steroidal compounds, and conjugates, metabolites, phytoestrogens and derivatives thereof, that have estrogenic activity.
• Naturally-occurring estrogens are steroids which contain a cyclopentanoperhydrophenathrene ring system. Such naturally-occurring estrogens are obtained from pregnant mares' urine or prepared synthetically, using methods well- known in the art.
• Estrogen compounds useful in the methods of this invention include, for example, estradiol, estrone, estriol, equilin, equilenin, estradiol cypionate, estradiol valerate, ethinyl estradiol, polyestradiol phosphate, estropipate, diethylstilbestrol, dienestrol, chlorotrianisene, and mixtures thereof.
• a preferred estrogen hormone useful herein is "conjugated estrogen", which is a mixture of sodium salts of the water-soluble sulfate esters of estrone and equilin.
• conjugated estrogens may also contain other estrogenic substances found in pregnant mares' urine, such as 17-a-dihydroequiline, 17- a-estradiol, equilenin, and 17-a-dihydroequilenin.
• SERM is a compound which has the estrogen agonist activity of inhibition of bone resorption, but which has estrogen antagonist activity on other tissues, notably breast and uterine tissue.
• SERMs may be steroids or non-steroids.
• Steroidal SERMs are exemplified by tamoxifen and related compounds.
• Non-steroidal SERMs include, for example, raloxifene, and related compounds disclosed in U.S. Patent 4,418,068, issued November 29, 1983 (incorporated by reference herein).
• Other SERMs are described in Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 3 rd Edition (M.J. Favus, Editor, 1996) and "Basic Guide To The Mechanisms Of Antiestrogen Action", J.I. MacGregor et al., Pharmacological Review. 1998, both of which are incorporated herein by reference.
• calcitonin compounds are calcium regulating hormones whose essential biological activity is to oppose the bone and renal effects of parathyroid hormone, i.e., to inhibit bone resorption and reduce urinary calcium excretion.
• Natural calcitonin is a 32 amino acid polypeptide hormone secreted from the parafollicular cells of the thyroid gland in mammals and by the ultimobranchial gland of birds and fish. The linear amino acid sequence varies between species as does the potency but when the various calcitonins are administered at similar International Unit equivalents, all such calcitonins will provide equivalent efficacy as an antiresorptive compound.
• Natural calcitonin can be isolated from mammalian glands, i.e., from pig, cow, human, etc., or from salmon, eel and other sources by a procedure similar to that described in Behrens, Grinnans Ann Rev Biochem 38, 83, 1969.
• any of the calcitonin sequences may be manufactured by synthetic processes such as by solid phase synthesis ( J Hirt, et al., Rec Trav Chim 98, 143, 1979), or produced by recombinant methods ( J W Jacobs et al., J Biol Chem 254, 10600, 1979).
• Calcitonin compounds also include synthetic-natural hybrids, and analogues, mixtures, peptidomimetics and other variants of the natural calcitonin molecule (See, Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 3 rd Edition (M.J. Favus, Editor, 1996), incorporated herein by reference.
• the methods of the present invention involve administering a non-naturally- occurring selective FP agonist.
• Particularly preferred non-naturally-occurring FP agonists are selective for the FP receptor over other excitatory prostaglandin receptors in a ratio of at least about 1 :10, more preferably at least about 1 :20, and most preferably at least about 1 :50.
• Still more preferred non-naturally-occurring FP agonists are selective for FP receptors over all other prostanoid receptors in a ratio of at least about 1 :10, more preferably at least about 1 :20, and most preferably at least about 1 :50.
• Particularly useful non-naturally-occurring selective FP agonists are prostaglandin analogs. Examples of such compounds are prostaglandin analogs having the following general structure:
• R- is CO 2 H, C(O)NHOH, CO 2 R 2 , CH 2 OH, S(O) 2 R 2 , C(O)NHR 2 , C(O)NHS(O) 2 R 2 , or tetrazole; characterized in that R 2 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 moiety, either substituted or unsubstituted.
• Prostaglandin analogs of the above structure include: cloprostenol (Estrumate ® ), fluprostenol (Equimate ® ), tiaprost, alfaprostol, delprostenate, froxiprost, latanoprost, 13,14-dihydro-16-((3-trifluoromethyl)phenoxy)-16-tetranor prostaglandin F ⁇
• 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 prostaglandin analogs are also disclosed in CRC Handbook of Eicosanoids: Prostaglandins and Related Lipids. Volume I, Chemical and Biochemical Aspects, Part B. Ed. by Anthony L. Willis, CRC Press (Boca Raton, 1987) Table Four pp. 80-97 (incorporated herein by reference), and references therein.
• the non-naturally-occurring FP selective agonists described above are useful in increasing bone volume, increasing trabecular number through formation of new trabeculae, increasing bone mass without increasing the bone turnover rate, and increasing formation at the endosteal surface without removing bone from the existing cortex. Additionally, the quality of bone formed by the administration of these compounds is superior to that formed by the administration of other bone anabolic 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 architecture which impart overall strength and fracture resistance to bone.
• the present invention provides novel methods of increasing bone volume, methods of increasing trabecular number, and methods of treating or preventing bone disorders comprising the administration of a non-naturally-occurring FP selective agonist and an antiresorptive compound to a subject in need of such treatment.
• the non-naturally-occurring FP selective agonist and the antiresorptive compound can be administered concurrently or sequentially.
• the methods provided by the invention prevent further bone loss through slowing of resorption and stimulate formation of new bone. Additionally, methods provided by the invention may stimulate formation of new bone and maintain gains in bone volume and/or trabecular number. Because it is believed that administration of a non-naturally- occurring FP selective agonist does not result in upregulation of resorption, it is expected that the dosages of both the antiresorptive compound and the non-naturally-occurring FP selective compound will not require adjustment to compensate for the increase in resorption that results from the administration of other bone anabolic agents such as PTH.
• the non-naturally-occurring FP selective agonist is first administered to the subject for the period of time required to restore the subject's bone volume to the desired level. This period can last from about 1 month to about 36 months, preferably from about 6 months to about 36 months, and more preferably from about 6 months to about 24 months.
• the antiresorptive compound is then administered to the subject to maintain the bone volume at the desired level. This may be indefinitely.
• the antiresorptive compound is administered to the subject for some period of time and then discontinued.
• the non- naturally-occurring FP selective agonist is then administered to the subject for the period of time required to restore the subject's bone volume to the desired level. This period can last from about 1 month to about 36 months, preferably from about 6 months to about 36 months, and more preferably from about 6 months to about 24 months.
• an antiresorptive compound (the antiresorptive compound previously administered or a different antiresorptive compound) is then administered to the subject to maintain the bone volume at the desired level. This may be indefinitely.
• the antiresorptive compound and the non-naturally-occurring FP selective agonist are administered to the subject at the same time for the period of time required to restore the subject's bone volume to the desired level.
• This period can last from about 1 month to about 36 months, preferably from about 6 months to about 36 months, and more preferably from about 6 months to about 24 months.
• both the antiresorptive compound and the non-naturally-occurring FP selective agonist may be discontinued and a new antiresorptive compound administered to the subject, or (3) both the antiresorptive compound and the non- naturally-occurring FP selective agonist may be discontinued.
• the antiresorptive compound and the non-naturally-occurring FP selective agonist compound are both administered in a "safe and effective amount.”
• safe and effective amount means an amount of a compound or composition high enough to significantly positively modify the symptoms and/or condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment.
• the safe and effective amount of an agent for use in the methods of the invention herein 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 concurrent therapy, the particular agent being employed, the particular pharmaceutically-acceptable excipients utilized, and like factors within the knowledge and expertise of the attending physician.
• the specific amount and dosage regimen of a particular compound administered pursuant to the methods of this invention is a function of the potency of the compound, 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, as well as other factors.
• the compound is administered in amounts and in regimens recognized in the art as useful for treating bone disorders in accordance with sound medical practice.
• the appropriate amount of the antiresorptive compound selected can be determined from the references previously cited and incorporated herein by reference. For clinically approved antiresorptive compounds, the appropriate dose can be found in the product's labeling.
• the appropriate amount of the non-naturally-occurring FP selective agonist compound to be used may be determined by routine experimentation with animal models. Such a model includes, but is not limited to, the intact and ovariectomized rat models of osteoporosis, the ferret, canine, and non human primate models of osteoporosis, as well as disuse models of osteoporosis.
• the dosage range for systemic administration of the non-naturally-occurring FP agonists of the present invention is from about 0.01 to about 1000 ⁇ g/kg body weight per day, preferably from about 0.05 to about 100 ⁇ g/kg per body weight per day, most preferably from about 0.1 to about 50 ⁇ g/kg body weight per day.
• Plasma levels are expected to be in the range of about 0.01 to about 500 ng/ml, more preferably from about 0.05 to 100 ng/ml, and most preferably from about 0.1 to 50 ng/ml.
• the non-naturally-occurring FP agonists of the present invention may be administered, based on a weekly dosage, more frequently than once daily.
• the non-naturally- occurring FP agonists of the present invention may also be administered, based on a weekly dosage, less frequently than once daily.
• the weekly dosage may be divided into 3, 4, 5, 6, or 7 daily dosages, preferably 5, 6, or 7 daily dosages.
• Prolonged delivery also referred to as “prolonged administration” of the non- naturally-occurring FP selective agonist results in improved dose separation between side effects and the desired bone effect.
• prolonged delivery or “prolonged administration” means that the total daily dosage is delivered into the subject's circulation over a period of at least about 6 hours and up to 24 hours. Preferred prolonged delivery periods are for at least about 12 hours and up to 24 hours. Examples of prolonged delivery include administration of the non-naturally-occurring FP agonist via a transdermal patch or a subcutaneous pump that delivers the total daily dosage over a twenty-four hour period.
• the antiresorptive compound and the non-naturally-occurring FP selective agonist compound may each be administered in any of a variety of pharmaceutically- acceptable compositions.
• pharmaceutically- acceptable compositions contain a pharmaceutically-acceptable carrier.
• pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a subject.
• compatible means that the components of the composition are capable of being commingled with the compound, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations.
• Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the subject being treated.
• substances which can serve as pharmaceutically-acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate; powdered tragacanth; malt; gelatin; talc; 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 oil of theobroma; polyois such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the Tweens®; wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents, excipients; tableting agents; stabilizers; antioxidants; preservatives;
• a pharmaceutically-acceptable carrier to be used in conjunction with a compound is basically determined by the way the compound is to be administered.
• the compounds of the present invention may be administered systemically, including transdermally, orally and/or parenterally, including subcutaneous or intravenous injection, and/or intranasally.
• a preferred method of administering bisphosphonates is orally, in a unit-dosage form (i.e., a dosage form containing an amount of active suitable for administration in one single dose, according to sound medical practice) and by intravenously.
• a unit-dosage form i.e., a dosage form containing an amount of active suitable for administration in one single dose, according to sound medical practice
• Preferred unit dosage forms for bisphosphonate include tablets, capsules, suspensions, and solutions, comprising a safe and effective amount of active.
• Preferred methods of administering estrogen compounds are orally and transdermally, in a unit-dosage form (i.e., a dosage form containing an amount of active suitable for administration in one single dose, according to sound medical practice).
• a unit-dosage form i.e., a dosage form containing an amount of active suitable for administration in one single dose, according to sound medical practice.
• Preferred unit dosage forms for estrogen compounds include tablets, capsules, suspensions, solutions, and transdermal patches comprising a safe and effective amount of active.
• a preferred methods of administering SERMs are orally and transdermally, in a unit-dosage form (i.e., a dosage form containing an amount of active suitable for administration in one single dose, according to sound medical practice).
• a unit-dosage form i.e., a dosage form containing an amount of active suitable for administration in one single dose, according to sound medical practice.
• Preferred unit dosage forms for SERMs include tablets, capsules, suspensions, solutions, and transdermal patches comprising a safe and effective amount of active.
• a preferred method of administering calcitonin compounds is via subcutaneous injection in a unit dosage form.
• Preferred unit dosage forms for injection include sterile solutions of water, physiological saline, or mixtures thereof. The pH of said solutions should be adjusted to about 7.4.
• Other preferred dose forms for calcitonin compounds include nasal, trandsermal, rectal, sublingual, and oral.
• Preferred oral forms include, for example, liposomes, lipid emulsions, and proteinaceous cages.
• a preferred method of administering non-naturally-occurring FP selective agonists is via transdermal delivery.
• Preferred transdermal dosage forms include transdermal patches, creams, ointments, gels and the like.
• Another preferred method of administering non-naturally-occurring FP selective agonists is via subcutaneous injection in a unit dosage form.
• Preferred unit dosage forms for injection include sterile solutions of water, physiological saline, or mixtures thereof. The pH of said solutions should be adjusted to about 7.4.
• another preferred method of administering non-naturally- occurring FP selective agonists is via subcutaneous implant or other subcutaneous slow release dosage forms.
• non-naturally-occurring FP selective agonists include nasal, rectal, sublingual, and oral.
• Suitable carriers for injection or surgical implants include hydrogels, controlled- or sustained-release devises, polylactic acid, and collagen matrices.
• Implant devices may be coated with the non-naturally-occurring FP agonist.
• the non-naturally-occurring prostaglandin FP agonist may be dissolved in a buffer and may be mixed with a collagen gel which is then coated onto the porous end of the implant device.
• Example I The FP agonist, fluprostenol, and the bisphosphonate, risedronate (ActonelTM), are administered to a 65 year old woman who has decreased bone mass and has been diagnosed with osteoporosis by her physician. She is treated daily with a transdermal patch that delivers 10 ⁇ g/kg fluprostenol over a 24 hour period and a 5 mg risedronate tablet. This treatment is continued for 24 months, at which time, vertebral bone mass is substantially increased compared to her vertebral bone mass at the onset of therapy as measured by dual energy X-ray absorptiometry (DXA).
• DXA dual energy X-ray absorptiometry
• the FP agonist, fluprostenol, and the bisphosphonate, risedronate are administered to a 65 year old woman who has decreased bone mass and has been diagnosed with osteoporosis by her physician. She is treated daily with a transdermal patch that delivers 10 ⁇ g/kg fluprostenol over a 24 hour period and a 5 mg risedronate tablet. This treatment is continued for 24 months, at which time, vertebral bone mass is substantially increased compared to her vertebral bone mass at the onset of therapy as measured by dual energy X-ray absorptiometry (DXA). At this time, she is administered a 5 mg risedronate tablet by mouth once a day to maintain the bone gains produced by fluprostenol for 2 years or as required as determined by yearly DXA measurements.
• the FP agonist, fluprostenol is administered to a 65 year old woman who has decreased bone mass and has been diagnosed with osteoporosis by her physician. She is treated daily with a transdermal patch that delivers 10 ⁇ g/kg fluprostenol over a 24 hour period. This treatment is continued for 24 months, at which time, vertebral bone mass is substantially increased compared to her vertebral bone mass at the onset of therapy as measured by dual energy X-ray absorptiometry (DXA). At this time, she is administered a 5 mg risedronate (ActonelTM) tablet by mouth once a day to maintain the bone gains produced by fluprostenol for 2 years or as required as determined by yearly DXA measurements.
• ActonelTM risedronate
• the bisphosphonate, risedronate (ActonelTM) is administered to a 65 year old woman who has decreased bone mass and has been diagnosed with osteoporosis by her physician. She is treated daily with a 5 mg tablet. This treatment is continued for 24 months. At this time, as measured by dual energy X-ray absorptiometry (DXA), no further vertebral bone loss is occurring, but the spine is still considered osteoporotic. She is then treated daily with a transdermal patch that delivers 10 ⁇ g/kg fluprostenol over a 24 hour period. This treatment is continued for 24 months, at which time, vertebral bone mass is substantially increased compared to her vertebral bone mass at the onset of therapy as measured by dual energy X-ray absorptiometry (DXA).
• DXA dual energy X-ray absorptiometry
• the estrogen supplement Premarin is administered to a 65 year old woman who has decreased bone mass and has been diagnosed with osteoporosis by her physician. She is treated daily with a 0.625 mg tablet. This treatment is continued for 24 months. At this time, as measured by dual energy X-ray absorptiometry (DXA), the spine is still considered osteoporotic. She is then treated daily with both estrogen as a 0.625 mg tablet and a transdermal patch that delivers 10 ⁇ g/kg fluprostenol over a 24 hour period. This combined treatment is continued for 24 months, at which time, vertebral bone mass is substantially increased compared to her vertebral bone mass at the onset of therapy as measured by dual energy X-ray absorptiometry (DXA).
• DXA dual energy X-ray absorptiometry
• the estrogen supplement Premarin is administered to a 65 year old woman who has decreased bone mass and has been diagnosed with osteoporosis by her physician. She is treated daily with a 0.625 mg tablet. This treatment is continued for 24 months. At this time, as measured by dual energy X-ray absorptiometry (DXA), the spine is still considered osteoporotic. She is then treated daily with a transdermal patch that delivers 10 ⁇ g/kg fluprostenol over a 24 hour period. This treatment is continued for 24 months, at which time, vertebral bone mass is substantially increased compared to her vertebral bone mass at the onset of therapy as measured by dual energy X-ray absorptiometry (DXA). At this time, she is administered a 5 mg risedronate (ActonelTM) tablet by mouth once a day to maintain the bone gains produced by fluprostenol for 2 years or as required as determined by yearly DXA measurements.
• ActonelTM risedronate
• Example VII The FP agonist, fluprostenol, is administered to a 63 year old woman who has decreased bone mass and has been diagnosed with osteoporosis by her physician. She is treated with an implantable subcutaneous pump that delivers 10 ⁇ g/kg fluprostenol over a 24 hour period. This treatment is continued for 6 months, at which time, vertebral bone mass is increased compared to her vertebral bone mass at the onset of therapy as measured by dual energy X-ray absorptiometry (DXA). At this time, she is administered a 5 mg risedronate (ActonelTM) tablet by mouth once a day to maintain the bone gains produced by fluprostenol for 6 months.
• DXA dual energy X-ray absorptiometry
• DXA dual energy X-ray absorptiometry
• she is again treated with an implantable subcutaneous pump that delivers 10 ⁇ g/kg fluprostenol over a 24 hour period. This treatment is continued for 6 months, at which time, vertebral bone mass is substantially increased compared to her vertebral bone mass at the onset of therapy as measured by dual energy X-ray absorptiometry (DXA).
• DXA dual energy X-ray absorptiometry
• ActonelTM risedronate

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