MXPA97001606A - Combination therapy to avoid the loss osea-progesterone and estrog agonists - Google Patents
Combination therapy to avoid the loss osea-progesterone and estrog agonistsInfo
- Publication number
- MXPA97001606A MXPA97001606A MXPA/A/1997/001606A MX9701606A MXPA97001606A MX PA97001606 A MXPA97001606 A MX PA97001606A MX 9701606 A MX9701606 A MX 9701606A MX PA97001606 A MXPA97001606 A MX PA97001606A
- Authority
- MX
- Mexico
- Prior art keywords
- formula
- compound
- bone
- progesterone
- loss
- Prior art date
Links
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- 239000000556 agonist Substances 0.000 title description 3
- 238000002648 combination therapy Methods 0.000 title 1
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- PDAVOLCVHOKLEO-UHFFFAOYSA-N acetyl benzenecarboperoxoate Chemical compound CC(=O)OOC(=O)C1=CC=CC=C1 PDAVOLCVHOKLEO-UHFFFAOYSA-N 0.000 description 1
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- 239000003463 adsorbent Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229960000971 altrenogest Drugs 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229950002552 anagestone acetate Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 230000003042 antagnostic Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
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- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
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- 235000013539 calcium stearate Nutrition 0.000 description 1
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- NSQGNZDVOPOVGX-UHFFFAOYSA-N chloro(difluoro)methanol Chemical compound OC(F)(F)Cl NSQGNZDVOPOVGX-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- 125000001145 hydrido group Chemical group *[H] 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 229960004400 levonorgestrel Drugs 0.000 description 1
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- 239000000314 lubricant Substances 0.000 description 1
- 229960001910 lynestrenol Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960000606 medrogestone Drugs 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 1
- 210000004914 menses Anatomy 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
- 239000010445 mica Substances 0.000 description 1
- 229910052618 mica group Inorganic materials 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000000474 nursing Effects 0.000 description 1
- 238000009806 oophorectomy Methods 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-L oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N p-acetaminophenol Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N palmityl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-M phenylacetate Chemical compound [O-]C(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-M 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- 229960004723 phenylbutyrate Drugs 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L propanedioate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000000069 prophylaxis Effects 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
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- 239000000377 silicon dioxide Substances 0.000 description 1
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Abstract
The present invention provides novel methods for inhibiting bone loss, comprising administering to a mammal in need of such treatment, an effective amount of a compound of formula I (See Formula) wherein R 1 and R 2 may be the same or different, provided that, when R1 and R2 are the same, each is a methyl or ethyl group, and, when R1 and R2 are different, one of them is a methyl or ethyl group and the other is hydrogen or a benzyl group; its pharmaceutically acceptable salts, together with a progester
Description
TERnPInG OF COMBINING PfRl TO AVOID LOST QSEfl - PROGESTERONfl AND ESTROGEN AGONISTS
NUMBER OF THE INVENTION 5 The os + oporosis describes a group of diseases < They are derived from various etiologies, but are characterized by a loss of bone mass per unit volume. One consequence of a loss of bone mass is the inability to
the skeletal structure to provide adequate structural support for the body, resulting in a bone fracture. One of the most common types of osteoporosis occurs in women shortly after menopause. Most women lose between 20-60% of the bone mass of the
trabecular compression of the bone in 3-6 years after stopping treatment. This rapid loss of bone mass is generally associated with an increase in both resorption and bone formation. However, the resorption cycle is more dominant; and the result is a net loss of bone handle. 20 In this way, osteoporosis is a common and serious disease among postmenopausal women. It is estimated that only in the United States, about 25 million women suffer from this disease. The results of this disease are harmful both economically and financially. The big losses
Economic reasons are due to their chronic nature and to the need for extensive and long-term support (hospitalization and nursing home care) of the after-effects of the disease. The losses are especially large in elderly patients. In addition, although osteoporosis is not generally considered a life-threatening disorder, there is a mortality rate of 20-30% related to hip fractures in elderly women. A large percentage of this mortality rate can be directly associated with postmenopausal o-t-eoporosis. The bone tissue most vulnerable to the effects of postmenopausal osteoporosis is trabecular bone. This tissue is often called spongy or cancellous bone and is concentrated in a particular way near the ends of the bones, near the joints and in the vertebrae of the spine. The trabecular tissue is characterized by small osteoid structures that interconnect with each other and with the most solid and dense cortical tissue constituting the external surface and the central area of the bone. This interlaced network of trabeculae provides lateral support to the external cortical structure and is critical to the biomechanical strength of the structure as a whole. Mainly, the net resorption and loss of the trabeculae is what leads to the failure and bone fracture in postmenopausal osleoporosis. In view of the loss of trabeculae in women-it is postmenopausal, it is not surprising that common fractures are those associated with bones that are highly dependent on trabecular support, eg, vertebrae, the neck of bones that support weight (femur) and the forearm. Indeed, hip fracture, Gol les fractures, and vertebral crush fractures are hallmarks of post-mortem osteoporosis. A very important concept in the treatment and study of postmenopausal osteoporosis is the concept of fracture threshold., The fracture threshold is the point at which bone density (hence, bone strength) decreases to a value in which there is a high probability of bone fracture. This point is not a value-defined for all women, but rather a relative-value for an individual and depends on a number of factors such as weight, lifestyle or other risks that may contribute to the possibility of fracture that is. In general, most pre-nonopausal women have bone densities above the fracture threshold and there is a small chance that a fracture will occur. The bone density before a woman's menopause and the rate of bone loss after menopause will be determined when, or if, she exceeds the threshold and there is a risk of fracture. For women who have fractures due to osteoporosis, Ldeal therapy would increase bone density (resistance) to a value above the fracture threshold. As an alternative, for women whose bone density is still above the threshold, it would be advantageous to keep them above the threshold.
Currently, the only effective treatment available for postrnenopausal osteoporosis is hormone replacement therapy, specifically the replenishment of estrogen, because post-traumatic women have a deficiency of estrogens. The mechanism of action of estrogens in the treatment of osteoporosis is not well understood; however, it is generally thought to inhibit bone resorption. The net effect of estrogen replacement therapy (ERT) is to maintain the bone density of the woman at the level at which the therapy was started, that is, to maintain bone density. If a woman is above the fracture threshold when the ERT starts and if the ERT is maintained, she will remain at the threshold and have a low risk of fracture. This fact could justify the introduction of women into an ERT at, or shortly after, cessation of menstruation. However, for women whose bone density has already fallen below the fracture threshold, ERT will only maintain the density at the level it was at when therapy began. In this way, these women will remain below the threshold and will have an additional risk of fracture. TRE is still advisable for these women since it will prevent a bad situation from getting worse. However, it would obviously be advantageous to have a therapy that restores density ós < at above the frac threshold to the most normal levels and then keep them. Currently, there are no approved effective therapies that demonstrate a capacity to increase bone density up to that level. As indicated, ERT is currently the only approved effective treatment for post-neoplastic osteoporosis. In those women who do not have a uterus, estrogens can be administered as they are (usually administered in the form of conjugated estrone). However, in most posttrnenopausal women who have a uterus, estrogen alone increases the risk of endocrine-related cancer. In this way, a progesterone is often administered, either as a combination or cyclical therapy, in order to reduce this risk. "Anties rogeno" is a term that "has been applied quite broadly to several different types of compounds that inhibit or modify the action of estrogens." The progestones and androgens have been described as antaesthogens ... "(Goodman and Gilrnan, The Pharrnacologí cal asis of Therapeutics, 6th Ed., p.131). In addition, certain synthetic compounds, such as tamoxifen, clomiphene, droloxifene and nafoxidine are called antioestrogens and have been shown, both experimentally and clinically, to block one of the effects of estrogens. The synthetic "antiestrogens" were developed primarily for the treatment of estrogen-dependent breast carcinoma. These compounds are classical mixed agonists / antagonists that demonstrate some activity is rogenica. For example, tarnoxyphene, the most widely used pesticide, has been shown to have estrogenic effects in humans. It has been found that the combination of certain 3-benzoyl-1-benzotensins and one pr-oesterone is effective in preventing bone loss. EP 665,015 A2"
HRFVI7 DESCRIPTION OF THE INVENTION
The present invention relates to methods of inhibiting bone loss, comprising administering to a mammal in need of such treatment, an effective amount of a compound of formula 1.
wherein Rl and R2 may be the same or different, provided that, when R and R2 < On the same, each is a methyl or ethyl group R1 and R2 are different, one of them is a motile group
'. ***; or ethyl and the other is hydrogen or a benzyl group; or one of its pharmaceutically acceptable salts; along with an effective amount of a progesterone. The preferred progesterones are rnedrox i progesterone, norethindrone or norethrine ,. A preferred compound of formula I is that in which R and R2 are methyl. A preferred salt is the citrate salt.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to methods for inhibiting bone loss. The term "inhibit" is defined to include its generally accepted meaning, which includes the prophylactic treatment of a subject to prevent the onset of one or more of these disorders or disease states, to keep the symptoms of said disorder under control or state of illness and / or treat such symptoms. Thus, the present methods include medical therapeutic treatment and / or prophylactic treatment, as appropriate. The methods of this invention are carried out by administering to an individual in need of treatment an effective amount of a compound of formula
(I)
wherein Ri and R2 may be the same or different, provided that, when R and R2 are equal, each is a methyl or ethyl group, and, when R1 and R2 are different, one of them is a methyl group or ethyl and the other is hydrogen or a benzyl group; or one of its pharmaceutically acceptable salts; together with an effective amount of a progesterone selected from rnedroxiprogester ona, noretj ndrona or noret inodrel.,
The progesterones are available from your commercial agents and include: Algestone, Acetophenide, Altrenogest, Amad Ione Acetate, Anagestone Acetate,
Clor adinone Acetate, Cingestol, Clogestone Acetate,
C 1 orne ge s tona Acetate, From rnadi nona Acetate, Desogestrel, Dirnet i sterona, Didrogesterone, Etinerone, Etmodiol Diacefato, Etonogestrel, Fluorogestone Aceta + o, Gestaclone, Gestodeno, Gestonorona Caproate, Gestpnona, Haloprogesterone,
Hydro iprogesterone Caproate, Levonorgest reí, Linestrenol, Medrogestone, Medroxy progesterone Acetate, Melengestrol
Acetate, Petmodiol Diacetate, Norethindrone, Noret Indrona Acetate, Noretmodrel, Norgestirnato, Norgesto et, Norgestrel, Oxogestone Fenpropionate, Progesterone -. , Quingestanol Acetate,
Oumgestrona and Tigestol.
The preferred progesterones are rnedroxyprogesterone, noret mdrona and norethinodrel.
The dosage of progesterone ranges from 0.1 to 10 mg per day; the preferred dose being approximately 0.25 to mg per day in combination with a compound of formula I.
The compounds of formula I are known in the art and are essentially prepared by methods described in U.S. Patent No. 5 047 321, which is hereby incorporated by reference.
A preferred compound of formula I is one in which R1 and R2 are both methyl. This preferred compound is known as droloxifene (E) -1-T4 '- (2-d? Metlarnmoethoxy) -phenyl J-1 - (3-h? Drox? Phen? L) -2-femlbut-i-ene, which has been previously described as an anti-estrogen agent and is useful for the treatment of hormone-dependent breast tumors (U.S. Patent No. 5,047,431) and for alleviating bone diseases caused by estrogen deficiency or similar (U.S. Patent No. 5,254,594). In addition, droloxy is known to have lower uterotropic effect than other antiestrogenic compounds such as t ino if not.
Although the free base form of compounds of formula I can be used in the methods of the present invention, it is preferred to prepare and use a pharmaceutically acceptable salt form. Therefore, the compounds used in the processes of this invention form pharmaceutically acceptable acid and base addition salts with a wide variety of inorganic and, preferably, organic acids and include the physiologically acceptable salts that are often used in chemistry. pharmaceutical Said salts are also part of this invention. Typical inorganic acids used to form said salts include hydrochloric acid, brornhidpco, yodhídpco, nitric, sulfuric, ic, forbidden hiccups and the like. It is also possible to use salts derived from organic acids, such as aliphatic acids mono- and dicarboxyi, alkanoic acids, phenyls, and the like., hydroxyalkanoic and hydroxyalkanedioic acids, aromatic acids and sulphonic aliphatic and aromatic acids. Said pharmaceutically acceptable salts include, therefore, acetate, phenylacetate, tnf luoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, di ni t robenzoat or, hi d rox i benzoate, methoxy benzoate, ethyl benzoate, or acetoxy benzoate, na tal ene - 2-benzoate, bromide, isob? Thiolate, phenylbutyrate, (1-hydroxybutyrate, but-1, 4-d? Oato, hexame- 1, 4-d? Oato, caprate, apnlate, chloride, inamate, treatment, for urate, fumarate, glycolate, heptanoate, hippurate, lactate, rnalate, rnaleate, hydroxyalnone, malonate, mandelate, mesylate, nicotmate, isonicotmate, nitrate, oxalate, phthalate, terephthalate, phosphate, rnonohydrngenophosphate, dihydrogen phosphate, metaphosphate, pyrophosphate , propiolate, propionate, ferulpr-opionate, salicylate, sebacate, sucemate, suberate, sulfate, bisulfate, rosulfate, sulphite, bisulfite, sulfonate, benzenesulfonate, p-br-ornofemlsulfonate, chlorobenzenes? lfonat or, ethanolols fonate, 2-h Drox? et anosulfonate, rnetanolsul fonate, naft aleño-1-sul f onate, na phthalene-2-sulphonate, p-to-L-like-fonate, xylene sulfonate, tartrate and the like. A preferred salt is the second one.
The pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula T with an equimolar or excess amount of an acid. The reactants are generally combined in a mutual solvent, such as diethyl ether or benzene. The salt normally precipitates in the solution in a time of approximately one hour to ten days and can be isolated by filtration or the solvent can be separated by conventional means.
In general, the pharmaceutically acceptable salts of compounds of formula I have improved solubility characteristics, compared to the compound from which they are derived, and are therefore often more manageable for their formulation as liquids or emulsions.
Once prepared, the free base or salt form of the compounds of formula I can be administered by the methods described herein to an individual in need of treatment. The following non-limiting examples of tests illustrate the methods of the present invention.
In the processes of the present invention, the compounds of formula I are administered continuously or 1 to 4 times a day.
As used herein, the term "effective amount" means an amount of a composition used in the methods of the present invention that is capable of inhibiting the symptoms of the pathological conditions described herein. The specific dose of the compounds administered according to this invention will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compounds administered, the route of administration, the condition of the patient and severity of the pathological tr-asthenic to be treated. A typical daily dose will contain a non-toxic level of dose of about 0.25 mg to about 10 mg / day of a composition of the present invention. Preferred target doses will vary from about 1 ng to about 20 ing / day. Formulation compound I will be co-administered with about 0.1, ng to 10 rng of? Na pr-ogest and i? Na.
The compounds of this invention can be administered by a series of routes, including 1 < s oral, rectal, ransdé mica, subcutaneous, intravenous, int amuscular and mtranasal routes. Preferably, these compounds are stored before their admission, the selection of which will be decided by the attending physician. Typically, a compound of formula E or an acceptable pharmaceuticarboxylic salt thereof is combined with a pharmaceutically acceptable carrier, diluent or excipient, to form a protein formulation.
The total active ingredients in these formulations constitute from 0.1% to 99.9% in that of the formulation. "Pharmaceutically acceptable" means that the vehicle, diluent, excipients and / or salt must be compatible with the rest of the ingredients of the formulation and not harmful to the recipient thereof.
Pharmaceutical formulations containing a compound of formula T can be prepared by procedures known in the art, using well-known and readily available ingredients. For example, the compounds of formula I can be formulated with common excipients, diluents or vehicles and formulated into tablets, capsules, suspensions, powders and similar formulations. Examples of excipients, diluents and vehicles that are suitable for such formulations include the following fillers and extensor-es such as starch, sugars and nanitol; binding agents such as silicic derivatives, carboxymethylcellulose and other cellulose derivatives, mattes, gelatin and polyvinylpyrrole idone; wetting agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; dissolving retarding agents such as for fine; resorption accelerators such as quaternary ammonium compounds; tea agents such as cetyl alcohol and glycerol monostearate; adsorbent vehicles such as kaolin and benfomta; and lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycols.
The compounds can also be formulated as elixirs or solutions for convenient oral administration, or as solutions suitable for parenteral administration, for example, by * /? To instmuscular, subcutaneous or intravenous.
Additionally, the compounds are well suited to be formulated as sustained release dosage forms and the like. The formulations may be constituted so that they release the active ingredient alone or preferably in a particular physiological location, possibly over a period of time. The coatings, envelopes and protective matrices can be made, for example, of polymeric substances or waxes.
The compounds of formula I will generally be admixed in a convenient formulation. The following examples of formulations are illustrative only and are not intended to limit the scope of the present invention.
In the following formulations, "active ingredient" means a compound of formula I or a salt thereof; and one royes < erona
Formulation 1; Gelatin capsules Gelatin hard capsules are prepared using the following ingredients: Ingredient Amount (m? / Eaps? La)
Active ingredient 0.25-100
Starch (NF) 0-650
0-50 starch fluid powder
Fluid silicone, 350 centi stol - is 0-15
A tablet formulation is prepared using the following information:
Formulation 2: Tablets Ingredient Quantity (rng / coinppmi do)
Active ingredient 0.25-100
Microcrystalline cellulose 200-650
Pyrolysis silicon dioxide 10-650 Stearic acid 5-15
The compounds are mixed and compressed to form tablets. Alternatively, they are prepared as follows tablets each containing 0.25-100 mg of active ingredient.
Formulation 3: Tablets Ingredient Amount (g / cornpiido)
Active ingredient 0.25-100 Starch 4 ^
Microcpstal cellulose i 35
Pol i inilpirrol idona (10% aqueous solution) 4 Carboxi etiicel ulosa sodium 4.5
Magritic stearate 0.5 Talcum 1
The active ingredient, starch and cellulose are mixed thoroughly and passed through a No. 45 mesh U.S. The solution of poly-inylpyrrolidone is mixed with the resulting powder, which is then passed through a U.S. The granules thus produced are dried at 50-60 ° C and passed through an 18 mesh U.S. sieve. Then the sodium carboxymethyl cellulose, stearate and talc, previously passed through a No. 60 sieve of rnal U.S., are added to the granules which, after mixing, compress e > a compressing machine to produce tablets.
Suspensions are prepared each containing 0.25-100 mg of drug per 5 l dose, as follows:
Formulation 4: Suspensions Ingredient Quantity / 5 rnl
Active ingredient 0.25-100 rng C imbo Icelulose sodium 50 mg
Syrup 1.25 rng
Solution «Benzoic acid 0.1 ml
Aroma c.s.
Color-ante c.s. Purified water c.s.p 5 rnl
The drug is passed through a No. 45 mesh U.S. and it is mixed with sodium carboxymethylene cellulose and with the syrup to form a uniform paste. The benzoic acid solution, the aroma and the dye are diluted with some water and added with agitation. Then enough gaseous is added to produce the required volume. A solution of an aerosol containing the following ingredients is prepared:
Formulation 5: Aei-ooo1 Ingredient Quantity (% by weight)
Active ingredient 0.25 Ethanol 25.75 Propellant 22 (chlorodi fluoromethanol) 70.00 The active ingredient is mixed with ethanol and the mixture is added to a portion of propellant 22, cooled to 30 ° C and transferred to a filling device. The required amount is then added to a stainless steel vessel and diluted with the remaining propellant. The valve units are then coupled to the container. Suppositories are prepared as follows:
Formulation 6: Suppositories Ingredient Amount (g / suposi tone)
Active ingredient 250
Glucose two of saturated fatty acids 2,000
The active ingredient is passed through a No. 60 mesh U.S. and is suspended in the glycends of saturated fatty acids, previously melted using the minimum necessary heat. The mixture is then poured into a suppository mold of 2 g nominal capacity and allowed to cool. An intravenous formulation is prepared co or follows:
Formulation 7: Intravenous solution Ingredient e Cant idad
Active ingredient 20 rng
Isotonic saline solution 1,000 rnl The solution of the above ingredients is administered intravenously to a patient, at a rate of approximately 1 rnl per minute.
Example 1 In these examples, a model of post-neoplastic osteoporosis is used in which the effects of various treatments on the density of the femur are determined. Sixty-five-day-old female Sprague Dawley rats (weight ranges from 225 to 275 g) are obtained from the Charles River
Laboratopes (Port ge, MI). They are housed in groups of 3 and have ad libitum access to food (calcium content of approximately 1%) and water. The ambient temperature is maintained at 22.2 ° C ± 1.7 ° C with a minimum relative humidity of 40%. The lighting period in the room is 12 hours of light and 12 hours of darkness. One week after arrival, the rats were subjected to ovarian bilateral lectomy with anesthesia (44 mg / kg Ketamine and 5 mg / kg Xiiazine (Butier, Indianapolis, TN), administered intramuscularly). Treatment with vehicle or a compound of formula I and a progesterone is started on the day of operation, after recovery from anesthesia, or 35 days after the operation. Oral dosing is carried out by gav e in 0.5 ml of carboxymethylcellulose (CMC) at 1%. Body weight is determined at the time of the operation and analyzed during the study, and the dose is adjusted to changes in body weight. Ovapectorized rats (ovex) treated with vehicle and rats not ectorn ized (intact) are evaluated in parallel with each experimental group to serve as negative and positive controls. The rats are treated daily for 35 days (6 rats per treatment group) and sacrificed by decapitation on the thirty-sixth day. The 35-day period is sufficient to allow a maximum reduction in bone density, measured as described below. At the time of sacrifice, the uteri are removed, they are free from foreign tissue and the liquid content is expelled before determining the wet weight in order to confirm the estrogen deficiency associated with complete ovariectomy. The weight of the uterus is routinely reduced by approximately 75% as a response to ovapectornia. The uteri are placed in 10% neutral buffered form to allow subsequent histological analysis. The right femurs are cut and explored in the dietal metaphors, 1 mm from the patellar sulcus by photon absorption spectrometry. The results of the measurements of the denser tornetro represent a calculation of the bone density based on the mineral content of the bone and the thickness of the bone.
Claims (2)
- NOVELTY OF THE INVENTION CLAIMS i. i 1 use of a formula I compound wherein R1 and R2 may be the same or different, provided that, when R1 and R2 are equal, each is a methyl or ethyl group and, when R1 and R are different, one of them is a methyl group or ethyl and the other is hydrogen or a benzyl group; or one of its pharmaceutically acceptable salts; together with a proyestone, in the preparation of compositions for inhibiting bone loss in a mammal in need of such treatment. 2. The use of a compound of formula I according to claim 1, further characterized in that the compound of formula I that is used is a compound in which R1 and R2 are each methyl, or one of their far-maceut salts They are acceptable. I I use a compound of formula I, I followed »! < t "> ')
- Claim 2, further characterized in that the compound of formula T which said salt is used is the salt treatment. k. The use of a compound of the formula I, according to claim 1, characterized further so that < The progesterone is selected from the group consisting of medroxyprogesterone, noret mdrona and noret i nodrel.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US012400 | 1987-02-09 | ||
US1240096P | 1996-02-28 | 1996-02-28 |
Publications (2)
Publication Number | Publication Date |
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MXPA97001606A true MXPA97001606A (en) | 1998-04-01 |
MX9701606A MX9701606A (en) | 1998-04-30 |
Family
ID=21754794
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
MX9701606A MX9701606A (en) | 1996-02-28 | 1997-02-27 | Combination therapy to prevent bone loss- progesterone and strogen. |
Country Status (9)
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US (1) | US6057309A (en) |
EP (1) | EP0791356A1 (en) |
JP (1) | JPH09315977A (en) |
KR (1) | KR970061245A (en) |
AU (1) | AU712656B2 (en) |
CA (1) | CA2198574A1 (en) |
IL (1) | IL120263A0 (en) |
MX (1) | MX9701606A (en) |
ZA (1) | ZA971718B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6653297B1 (en) * | 1997-07-03 | 2003-11-25 | Medical College Of Hampton Roads | Control of selective estrogen receptor modulators |
US6326392B1 (en) | 1997-11-06 | 2001-12-04 | American Home Products Corporation | Anti-estrogen plus progestin containing oral contraceptives |
ID24568A (en) * | 1997-11-06 | 2000-07-27 | American Home Prod | ORAL CONTRACEPTION THAT CONTAINS ANTI-ESTROGEN PLUS PROGESTIN |
EP1523328A4 (en) * | 2002-05-24 | 2007-10-31 | Univ Pennsylvania | Methods and compositions for inhibiting hiv replication |
WO2017205451A1 (en) * | 2016-05-24 | 2017-11-30 | Temple University-Of The Commonwealth System Of Higher Education | Novel functionalized n,n-dialkylamino phenyl ethers and their method of use |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3046719C2 (en) * | 1980-12-11 | 1983-02-17 | Klinge Pharma GmbH, 8000 München | 1,1,2-Triphenyl-but-1-ene derivatives, processes for their preparation and pharmaceuticals |
JPH04312526A (en) * | 1991-04-09 | 1992-11-04 | Fujisawa Pharmaceut Co Ltd | Remedy for osteopathy |
TW366342B (en) * | 1992-07-28 | 1999-08-11 | Lilly Co Eli | The use of 2-phenyl-3-aroylbenzothiophenes in inhibiting bone loss |
JPH06312930A (en) * | 1993-04-30 | 1994-11-08 | Kuraray Co Ltd | Agent for treatment of osteoporosis |
US5591753A (en) * | 1994-01-28 | 1997-01-07 | Eli Lilly And Company | Combination treatment for osteoporosis |
US5455275A (en) * | 1994-05-11 | 1995-10-03 | Eli Lilly And Company | Methods for inhibiting endometriosis and uterine fibroid disease with 1,1,2-triphenylbut-1-ene derivatives |
US5384332A (en) * | 1994-05-11 | 1995-01-24 | Eli Lilly And Company | Methods for inhibiting aortal smooth muscle cell proliferation and restenosis with 1,1,2-triphenylbut-1-ene derivatives |
US5441986A (en) * | 1994-07-19 | 1995-08-15 | Pfizer Inc. | Estrogen agonists as remedies for prostate and cardiovascular diseases |
ID24568A (en) * | 1997-11-06 | 2000-07-27 | American Home Prod | ORAL CONTRACEPTION THAT CONTAINS ANTI-ESTROGEN PLUS PROGESTIN |
-
1997
- 1997-02-20 IL IL12026397A patent/IL120263A0/en unknown
- 1997-02-21 EP EP97301173A patent/EP0791356A1/en not_active Withdrawn
- 1997-02-24 JP JP9039073A patent/JPH09315977A/en active Pending
- 1997-02-26 CA CA002198574A patent/CA2198574A1/en not_active Abandoned
- 1997-02-27 MX MX9701606A patent/MX9701606A/en unknown
- 1997-02-27 KR KR1019970006287A patent/KR970061245A/en not_active Application Discontinuation
- 1997-02-27 ZA ZA971718A patent/ZA971718B/en unknown
- 1997-02-27 AU AU14967/97A patent/AU712656B2/en not_active Ceased
-
1998
- 1998-11-16 US US09/193,265 patent/US6057309A/en not_active Expired - Fee Related
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