MXPA96005327A - Use of certain derivatives of acidometanisphisphonic to prevent the loosening of protesis and the emigration of proteins - Google Patents

Abstract

The present invention relates to the use of a methanobisphosphonic acid derivative selected from: 3-amino-1-hydroxypropan-1,1-diphosphonic acid, 3- (N, N-dimethylamino-1-hydroxypropan-1,1- Diphosphonic acid, 4-amino-1-hydroxybutan-1,1-diphosphonic acid, 6-amino-1-hydroxyhexan-1,1-diphosphonic acid, 3- (N-methyl-Nn-pentylamino) -1-hydroxypropane 1,1-di phosphonic acid, 1-hydroxy-2- (imidazol) -1-yl) ethane-1,1-diphosphonic acid, 1-hydroxy-2- (3-pyridyl) ethane-1,1-diphosphonic acid, and N-methyl pyridinium salts thereof: 1- (4-chlorothiophenyl) methan-1,1-diphosphonic acid, 3- [N- (2-phenylthioethyl) -N-methylamino-1-hydroxypropane-1, 1 -diphosphonic acid, 1-hydroxy-3- (pyrrolidin-1-yl) propan-1,1-diphosphonic acid, 1- (N-phenylaminothiocarbonyl) methan-1,1-diphosphonic acid, 5-benzoyl-3-tetraethyl ester , 4-dihydro-2H-pyrazole-3,3-diphosphonic acid, 1-hydroxy-2- (imidazo [1,2-a] pyridin-3-yl) ethan-1,1-d ifosphonic acid, and acid 1.1 -dichloromethane-1,1-diphosphonic acid, or a pharmaceutical salt you acceptable of them, or any hydrate of the same

Description

USE OF CERTAIN METABANPHISPHONIC ACID DERIVATIVES TO PREVENT LOOSENING OF THE PROSTHESIS AND EMIGRATION OF THE PROSTHESIS Arthroplasty, especially of the hip joint, is now a common procedure for the treatment of patients with osteoarthritis, rheumatoid arthritis, and osteoporotic fracture. Approximately 800,000 hip replacements are performed globally each year. This number is rising steadily, and younger patients are being treated, and patients are living much longer and everyone hopes to lead an independent and mobile life. Despite the indisputable success of this technique, complications frequently occur, and occasionally they may require expensive surgical revision. (not being rare three or four revisions for a single patient). The most common complications are loosening of the aseptic prosthesis [see, for example, H. Marchau et al., Acta Orthop. Scand. 64 (1993) 497-506; R.D. Mulroy Jr, and W.H. Harris, J. Bone Joipt Surg. (Br) 72-B (1990) 757-760; M. Winter et al., Clin. Orthop. I laughed Research 282 (1992) 73-80], and the migration of the prosthesis through the bone without obvious loosening [see, for example, B.B. Wroblewski and P.D. Siney, Clin. Orthop. I laughed Research 285 (1992) 45-47; M. Winter et al., Loe. cit.]. These complications result in considerable morbidity, such as pain and mobility reduced. They occur with both cemented and uncemented prostheses, regardless of design, material, or coating. Different approaches to prevent these complications have focused on the alterations to the design of the prosthesis and the selection of different materials for its construction [see, for example, H. Marchau et al., Loe. cit .; R.D. Mulroy Jr. and W. H. Harris, loe. cit .; M. Winter et al., Loe. cit .; B.B. Wroblewski and P.D. Siney, loe. cit .; J. Wilson-MacDonald et al., J. Bone Joint Surg. (Br) 72-B (1990) 423-430]. Apart from some preliminary research with nonsteroidal apti-inflammatory drugs [A. Ohlin and U.H. Lerner, Bone and Mineral 20 (1993) 67-78; J.H. Herman et al., J. Rheumatol. 21 (1994) 338-343], a pharmacological approach to prevent or treat complications of arthroplasty, especially hip arthroplasty, has not been successful. Metanbisphosphonic acid derivatives, in particular bisphosphonate compounds (= bisphosphopates), are used clinically to inhibit excessive bone resorption in a variety of diseases, such as tumor-induced osteolysis, Paget's disease, and osteoporosis [H. Fleisch, Handbook of Expl. Pharmacol. 83 (1988) 441-465]. Radiolabelled bisphosphonates are also used in diagnosis to identify sites of high bone turnover [B.D. Collier et al., J. Nucí. Med. 34 (1993) 2241-2246; I. Fogelman and collaborators, J. Nucí. Med. 34 (1993) 2247-2252]. In the orthopedic field in general, there is a strong prejudice against the use of bisphosphonates. First, attempts to use commercially available bisphosphonate etidronate in the prevention of heterotopic ossification - which is another complication after arthroplasty, but very different from loosening of the prosthesis and migration of the prosthesis - were ineffective, or even harmful, due to a rebound effect [see, for example, DE Garland, Clin. Orthop. I laughed Research 263 (1991) 13-29; B.J. Thomas and H.C. Amstutz, The Hip 1987, 59-69; B.J. Thomas, Orthop. Clin. North America 23 (1992) 347-358]. In addition, there is growing evidence that some bisphosphonates can inhibit bone formation and mineralization. Kanis, for example, describes in Lancet 1984, 27-33, that bisphosphonates, as inhibitors of bone resorption, can delay the repair of icro fractures, reducing the speed of remodeling. As another example, Reid et al., In Lancet 1988, 143-146, discovered that the bisphosphonate treatment, in this particular case, made with disodic pamidronate, caused a reduction in bone formation, and a very low rate of bone turnover. raised the possibility of damaging microfracture repair. Ada and collaborators [Lancet 342 (1993) 1459-1460] report that pamidronate can inhibit bone mineralization in the disease of Paget. Surprisingly, it has now been discovered that certain metapbisphosphonic acid derivatives are useful for the prevention or treatment of these replacement complications of the joint, at an effective cost, especially hip replacement, in mammals, including man. This can be demonstrated by appropriate tests in vitro and in vivo. In particular, the experiments in vivo show that the bisphosphonates according to the invention are effective to prevent loosening of prosthesis in treated animals, for example, sheep. This is demonstrated, for example, by the following test methods: 12 adult female sheep, approximately 50 kilograms of body weight, are randomly divided into two groups of 6 animals, and all suffer a total unilateral hip replacement operation with implantation of a titanium prosthesis. Immediately after surgery, one group of animals receives an intravenous infusion of bisphosphonate, and the other group receives serum. This treatment can be repeated subsequently, for example, at 4 and at 8 weeks. At regular monthly intervals, the hip and femoral region of each animal is subjected to digital radiography, both standard and quantitative, to assess changes in bone density around the prosthesis, as an early indicator of loosening of the prosthesis. In addition, the animals are made to walk on a force plate of "Kistler" to measure the strength of reaction to the vertical floor of both limbs prevented, to determine the functionality of the limb, and indirectly, the pain. At 12 months after the operation, and 2 weeks before slaughter, the animals receive a double injection, 10 days apart, of the osseous fluorescent label oxytetracycline, to facilitate the histomorphometric analysis. At the end of the labeling period, the "** 'animals are sacrificed and the femurs are removed with the implants for post-mortem analysis. accurately polished the femurs, undergo icrorradiography to determine bone loss around the implant. Similar sections are also analyzed by histomorphometry to evaluate bone resorption and formation at the tissue level. Finally, sections of the bone that the implant contains undergo a mechanical "push out" mechanical test on a material testing machine to measure the strength of the bond between the metal implant and the surrounding bone. A comparison of test animals treated with A bisphosphonate according to the invention, with the controls, clearly shows that the bisphosphonate treatment is beneficial to prevent and treat the loosening of the prosthesis. Accordingly, the invention relates to the use of a methanobisphosphonic acid derivative selected from: 3-amino-l-hydroxypropan-1, 1-diphosphonic acid (acid pamidronic), for example, pamidronate; 3- (N, N-dimethylamino) 1-hydroxypropan-1, 1-diphosphonic acid, for example, di-ethyl-APD; 4-amino-l-hydroxybutap-1, 1-diphosphonic acid (alendronic acid), for example, alepdronate; 6-amino-l-hydroxyhexan-1,1-diphosphonic acid, for example, to ino-hexyl-BP; acid 3- (N-methyl-N-n-pentylamino) -l-hydroxypropan-1, 1-diphosphonic, for example, ethyl-pentyl-APD (= BM 21.0955); l-hydroxy-2- (i idazol-1-yl) ethan-1, 1-diphosphonic acid; l-hydroxy-2- (3-pyridyl) ethan-1, 1-diphosphonic acid (risedronic acid), for example, risedronate, including N-methyl pyridinium salts thereof, for example, N-methyl pyridinium iodides such as NE-10244 or NE-10446; l- (4-chlorothiophenyl) methan-1, 1-diphosphonic acid (tiludronic acid), for example, tiludronate; 3- [N- (2-phenylthioethyl) -N-methyl amino] -1-hydroxy ipropan-1, 1-diphosphonic acid; l-hydroxy-3- (pyrrolidip-l-yl) propan-l, 1-diphosphonic acid, for example, EB 1053 (Leo); 1- (N-phenylamothiocarbonyl) methan-1,1-diphosphonic acid, for example, FR 78844 (Fujisawa); 5-benzoyl-3,4-dihydro-2H-pyrazole-3,3-diphosphonic acid tetraethyl ester, for example, U-81581 (Upjohn); l-hydroxy-2- (imidazofl, 2-a] pyridin-3-yl) ethan-1, 1-diphosphonic acid, for example, YM 529; 1, 1-dichloromethane-1, 1-diphosphonic acid (clodronic acid), for example, clodronate; or a pharmaceutically acceptable salt thereof, or any hydrate thereof, (for the manufacture of a pharmaceutical composition) for the prevention and treatment of prosthetic loosening and emigration of prostheses in mammals, including man. As previously mentioned, prosthetic loosening and prosthesis migration frequently appears as a complication after arthroplasty. The arthroplasty 5 means a partial, for example, partial or total arthroplasty of any joint, especially of the hip and knee, and in particular of the hip. , * "The pharmaceutically acceptable salts are preferably salts with bases, conveniently metal salts derived from the groups Ia, Ib, Ha, and Ib from the Periodic Table of the Elements, including alkali metal salts, for example. salts of potassium and especially of sodium, or alkaline earth metal salts, preferably calcium or magnesium salts, and also ammonium salts with ammonia or organic amines r The pharmaceutically acceptable salts are especially preferred where one, two , three, or four, in particular one or two of the acid hydrogens of bisphosphonic acid, are replaced by a pharmaceutically cation acceptable, in particular sodium, potassium, or ammonium, in the first instance sodium. A most preferred group of pharmaceutically acceptable salts is characterized by having an acid hydrogen and a pharmaceutically acceptable cation, especially sodium, in each one of the phosphonic acid groups.

All the metapbisphosphonic acid derivatives mentioned above are well known from the literature. This includes its manufacture (see, for example, U.S. Patent Number EP-A-513,760, pages 13-48). For example, 3-amylo-l-hydroxypropan-1, 1-diphosphoic acid is prepared as described, for example, in U.S. Patent No. 3,962,432, as well as in U.S. Pat. Numbers 4,639,338 and 4,711,880, and l-hydroxy-2- (imidazol-1-yl) ethan-1, 1-diphosphonic acid is prepared as described, for example, in U.S. Patent No. 4,939,130. A particular embodiment of the invention is represented by the use of an ethanobisphosphonic acid derivative, which is selected from 3-amino-l-hydroxypropan-1,1-diphosphonic acid, 3- (N, N-dimethylamino- 1-hydroxypropan-1, 1-diphosphonic acid, 4-amino-1-hydroxybutan-1, 1-diphosphonic acid, 6-amino-1-hydroxyhexan-1, 1-diphosphonic acid, 3- (N-methyl 1-Nn) acid -pentylamino) -1-hydroxy-propan-1,1-diphosphonic acid, l-hydroxy-2- (imidazol-1-yl) ethane-1,1-diphosphonic acid, l-hydroxy-2- (3-pyridyl) ethan-1, 1-diphosphonic, and N-methyl pyridinium salts thereof; l- (4-chlorothiophenyl) methan-1, 1-diphosphonic acid, 3- [N- (2-phenylthioethyl) -N-methylamino] ] -l-hydroxypropan-1, 1-diphosphonic acid, l-hydroxy-3- pyrrolidin-1-yl) propan-1,1-diphosphonic acid, 1- (N-phenylaminothiocarbonyl) ethane-1,1-diphosphonic acid, 5-benzoyl-3,4-dihydro-2H-pyrazole-3-tetraethyl ester, 3-diphosphonic acid, l-hydroxy-2- (imidazo [1,2- a] pyridin-3-yl) ethane-1,1-diphosphonic acid, a pharmaceutically acceptable salt thereof, and any hydrate thereof. A preferred embodiment of the invention is represented by the use of an acid derivative - methanbisphosphonic acid, which is selected from 3-amino-1-hydroxypropan-1, 1-diphosphonic acid, 3- (N, N-dimethylamino-1-hydroxypropan-1, 1-diphosphonic acid, 4-amino acid) l-hydroxybutan-1,1-diphosphonic acid, 6-amino-l-hydroxyhexan-1, 1-diphosphnanoic acid, 3- (N-methyl-Nn-pentylamino) -1-hydroxypropan-1, 1- diphosphonic acid, -hydroxy-2- (imidazol-1-yl) ethan-1, 1- diphosphonic acid l-hydroxy-2- (3-pyridyl) ethane-1,1-diphosphonic acid, 3- [N- (2-phenylthioethyl) ) -N-methylamino] -1-hydroxypropan-1, 1-r-diphosphonic acid l-hydroxy-3- (pyrrolidin-1-yl) propan-l, 1- diphosphonic acid, l-hydroxy-2- ( imidazo [1,2- a] pyridin-3-yl) ethan-1,1-diphosphonic acid, a pharmaceutically acceptable salt thereof, and any hydrate thereof.

A most preferred embodiment of the invention is represented by the use of a methanobisphosphonic acid derivative, which is selected from pamidridnic acid, alendronic acid, 3- (N-methyl-N-n- pentylamino) -l-hydroxypropan-1, 1-diphosphonic acid, l-hydroxy-2- (imidazol-1-yl) ethan-1, diphosphonic acid, risedronic acid, and tiludronic acid, a pharmaceutically acceptable salt thereof, and any hydrate thereof. An especially preferred embodiment of the invention is represented by the use of a metapbisphosphonic acid derivative, which is selected from 1-hydroxy-2- (imidazol-1-yl) ethan-1, 1-diphosphonic acid, and acid 3-amino-1-hydroxypropan-1, 1-diphosphonic acid, a pharmaceutically acceptable salt thereof, and any hydrate thereof. In addition, the invention relates to the use of 1-hydroxy-2- (imidazol-1-yl) ethan-1, 1-diphosphonic acid or a pharmaceutically salt thereof or any hydrate thereof. In addition, the invention relates to the use of 3-amino-1-hydroxypropan-1,1-diphosphoic acid or a pharmaceutically acceptable salt thereof or any hydrate thereof. The pharmaceutically useful methanobisphosphonic acid derivatives can be used in the form of a possible isomer or a mixture of isomers, typically as optical isomers, such as enantiomers or diastereoisomers or geometric isomers, typically cis-trans isomers. The optical isomers are obtained in the form of pure antipodes and / or as racemates. The pharmaceutically useful methansulfonic acid derivatives can also be used in the form and &e its hydrates, or may include other solvents used for its crystallization. The methanobisphosphonic acid derivative is preferably used in the form of a pharmaceutical preparation containing a therapeutically effective amount of the active ingredient, optionally together with, or in admixture with, inorganic or organic, solid or liquid, pharmaceutically acceptable carriers, which are suitable for the administration. The pharmaceutical compositions can be, for example, compositions for enteral administration, such as oral, rectal, aerosol inhalation, or nasal, compositions for parenteral administration, such as intravenous or subcutaneous administration, or compositions for transdermal administration (e.g., passive or iontophoretic). In addition, direct local administration is considered at the time of the operation. What the last type of administration means is the coating of the exposed bone surface to which the implant is attached, with a bisphosphonate according to the invention, for example, by washing the surface of the bone with a bisphosphonate solution. What does not mean this type of administration, is the coating of the prosthesis with bisphosphonates. Preferably, the pharmaceutical compositions are adapted for oral or parenteral administration (especially intravenous or transdermal) before, during or after implanting the prosthesis, or for local administration during implantation of the prosthesis. Intravenous and oral administration, first of all intravenously, is considered of particular importance. The particular mode of administration and administration will be selected by the attending physician, taking into account the particulars of the patient, especially age, weight, lifestyle, level of activity, hormonal status (for example, after the menopause), bone mineral density, and the type of prosthesis that will be implanted. The dosage of the active ingredient may depend on different factors, such as the effectiveness and duration of action of the active ingredient, the mode of administration, the warm blood species, and / or sex, age, weight, and condition. individual of the warm-blooded animal. Typically, the dosage is such that a single dose of 0.002 to 3.40 milligrams / kilogram, especially 0.01 to 2.40 milligrams / kilogram, is administered to a warm-blooded animal weighing approximately 75 kilograms. If desired, this dose can also be taken in several partial, optionally equal doses. "milligrams / kilogram" means milligrams of the drug per kilogram of body weight of the mammal - including the man - to be treated. The dose mentioned above - either administered as a single dose (which is preferred) or in several doses partial - can be repeated, for example, once a day, once a week, once a month, once every three months, once every six months, or once a year. In other words, the pharmaceutical compositions can be administered in regimens from a continuous daily therapy, to an intermittent cyclic therapy. Preferably, methanobisphosphonic acid derivatives are administered in doses of the same order of magnitude as those used in the treatment of diseases conventionally treated with methanobisphosphonic acid derivatives, such as Paget's disease, tumor-induced hypercalcemia, or osteoporosis. . In other words, preferably the methanobisphosphonic acid derivatives are administered in doses that would be therapeutically effective in the treatment of diseases of Paget, tumor-induced hypercalcemia, or osteoporosis, that is, they are preferably administered in doses that would effectively inhibit bone resorption. Formulations in a single unit dosage form preferably contain from about 1 percent to about 90 percent, and formulations that are not in a unit dosage form contain about 0.1 percent a approximately 20 percent of the active ingredient. Unitary forms of a single dose, such as capsules, Tablets, or dragees, contain, for example, from about 1 milligram to about 500 milligrams of the active ingredient. The invention further relates to the use of a composition for the manufacture of a medicament, for example, in a unitary single-dose form, for the prevention and treatment of prosthetic loosening and migration of prostheses in mammals, including man, in wherein the composition contains from 0.002 to 3.40 milligrams / kilogram, especially from 0.01 to 2.40 milligrams / kilogram, of a methanbisphosphonic acid derivative as defined above, by dosage form. Moreover, the invention relates to the use of a methanobisphosphonic acid derivative as defined above, in a dose of 0.002 to 3.40 milligrams / kilogram, especially 0.01 to 2.40 milligrams / kilogram, per dosage form, for the manufacture of a medicine for the prevention and treatment of prosthesis loosening and emigration of prostheses in mammals, including man. Pharmaceutical preparations for enteral and parenteral administration are, for example, those which are in unit dosage forms, such as dragees, tablets, or capsules, and also ampoules. They are prepared in a manner known per se, for example, by means of conventional mixing, granulating, confectioning, dissolving, or lyophilization. For example, pharmaceutical preparations for oral administration can be obtained by combining the active ingredient with solid carriers, where it is appropriate to granulate a resulting mixture, and process the mixture or granulate, if desired or necessary, after the addition. of the appropriate auxiliaries, in tablets or dragee cores. Suitable carriers are especially fillers, such as sugars, for example, lactose, sucrose, mannitol, or sorbitol, cellulose preparations and / or calcium phosphates, for example, calcium triphosphate or calcium acid phosphate, and also binders, such as as starch pastes, using, for example, corn starch, wheat starch, rice starch, or potato starch, gelatin, tragacanth, methyl cellulose, and / or polyvinyl pyrrolidone, and if desired, disintegrators, such as the aforementioned starches , and also carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof, such as sodium algipate. Auxiliaries are especially flow regulators and lubricants, for example, silicic acid, talc, stearic acid, or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable coatings that can be resistant to gastric juices, using, among others, concentrated sugar solutions that optionally contain gum arabic, talc, polyvinyl polyglycol pyrrolidone, and / or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures, or, to produce coatings that are resistant to gastric juices, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate, or hydroxypropylmethyl cellulose phthalate . Colorants or pigments can be added to tablets or dragee coatings, for example, for identification purposes, or to indicate different doses of the active ingredient. Other pharmaceutical preparations that can be administered orally are dry-filled capsules made of gelatin, and also sealed soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The dry-filled capsules can contain the active ingredient in the form of a granulate, for example, mixed with fillers, such as lactose, binders, such as starches, and / or brighteners, such as talc or magnesium stearate, and wherein be appropriate, stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil, or liquid polyethylene glycols, it also being possible for stabilizers to be added. Parenteral formulations are especially injectable fluids that are effective in different ways, such as intravenously, intramuscular ep, intraperitopeally, intranasally, ipradermally, or subcutaneously. These fluids are preferably aqueous, isotonic solutions or suspensions, which can be prepared before use, for example, from freeze-dried preparations containing the active ingredient alone or together with a pharmaceutically acceptable carrier. The pharmaceutical preparations can be sterilized and / or can contain and adjuvants, for example, preservatives, stabilizers, wetting agents, and / or emulsifiers, solubilizers, salts for regulate the osmotic pressure, and / or pH regulators. Formulations suitable for transdermal application include an effective amount of the active ingredient with a carrier. Convenient vehicles include pharmacologically acceptable solvents that can be absorbed, to assist in passing through the skin of the host. In a characteristic manner, the transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with vehicles, optionally a speed control barrier for applying the Active ingredient to the skin of the host at a controlled rate and previously determined for a prolonged period of time, and elements to secure the device to the skin. The following examples illustrate the invention described hereinabove. The term "active ingredient" should be understood as any of the acid derivatives methanobisphosphonic substances mentioned above as useful according to the present invention.

Example 1: Capsules containing granules coated with, for example, disodium pamidronate pentahydrate, as the active ingredient: Core granule: active ingredient (ground) 197.3 milligrams microcrystalline cellulose (Avicel PH 105) 52.7 milligrams 250. 0 milligrams + Internal coating: HP-M 603 cellulose 10.0 milligrams Polyethylene glycol 2.0 milligrams Talco 8.0 milligrams 270. 0 milligrams + External coating resistant to gastric juice: Eudragit »L30 D (solid) 90.0 milligrams Triethyl citrate 21.0 milligrams Antiespumapte AF 2.0 milligrams Water Talca 7.0 milligrams 390. 0 milligrams A mixture of disodium pamidronate with Avicel PH 105, moistened with water and kneaded, extruded, and formed into spheres. The dried granules are then successively coated in the fluidized bed with an internal coating, consisting of cellulose HP-M 603, polyethylene glycol (PEG) 8000, and talc, and the coating resistant to aqueous gastric juice, consisting of Eudragit L 30 D, triethyl citrate, and Aptiespumante AF. The coated granules are pulverized with talc and filled into capsules (capsule size 0) by means of a commercial capsule or filling machine, for example, "Hofliger and Karg".

Element 2: Monolithic adhesive transdermal system containing, as an active ingredient, for example, 1-hydroxy-2- (imidazol-1-yl) -ethan-1, 1-diphosphonic acid: 5 Composition: Polyisobutylene (PIB) 300 5.0 grams (Oppanol Bl, BASF) 0 PIB 35000 3.0 grams (Oppapol B10, BASF) PIB 1200000 9.0 grams (Oppanol B100, BASF) Hydrogenated hydrocarbon resin 43.0 grams 5 (Escorez 5320, Exxon) l-dodecylazacycloheptan-2-one 20.0 grams (Azone, Nelson Res., Irvine / CA) active ingredient 20.0 grams Total 100.0 grams Preparation: The above components are dissolved together in 150 grams of a petroleum fraction of a special boiling point 100-125, rolling on a bed of roller gears. The solution is applied to a polyester film (Hostaphan, Kalle) by means of a spreader device using a 300 micron blade, giving a coating of approximately 75 grams / square meter. After drying (15 minutes at 60 ° C), a silicone-treated polyester film (thickness of 75 microns, Laufenberg) is applied as the separation film. The finished systems are drilled in sizes and in the desired shape from 5 to 30 square centimeters, using a drilling tool. The complete systems are individually sealed in aluminized paper bags.

Example 3: Bottle containing 1.0 milligrams of dry 1-hydroxy-2- (imidazol-1-yl) -etap-1, 1-diphosphoic acid (mixed sodium salts thereof). After dilution with 1 milliliter of water, a solution (concentration of 1 milligram / milliliter) is obtained for intravenous infusion.

Composition: Active ingredient (free diphosphonic acid) 1.0 milligrams Mannitol 46.0 milligrams Trisodium citrate x 2 H ^ 3 approximately 3.0 milligrams Water 1 milliliter Water for injection 1 milliliter In 1 milliliter of water, the active ingredient is titrated with trisodic citrate x 2 HrO until a pH of 6.0. Then mannitol is added and the solution is lyophilized, and the lyophilizate is filled in a flask.

Example 4: Ampoule containing disodium pamidronate pentahydrate dissolved in water. The solution (concentration of 3 milligrams / milliliter) is for intravenous infusion after dilution. Composition: Active ingredient 19.73 milligrams (= 15.0 milligrams of active ingredient anhydrous) Mannitol 250 milligrams Water for injection 5 milliliters Example 5: Tablets each containing 50 milligrams of 3- [N- (2-phenylthioethyl) -N-methylamino] -l-hydroxypropane-1,1-diphosphonic acid, can be prepared as follows: Composition (10,000 tablets) Active ingredient 500.0 grams Lactose 500.00 grams Potato starch 325.0 grams Gelatine 8.0 grams Talcum 60.0 grams Magnesium stearate 10.0 grams Silicon dioxide 20.0 grams (finely divided) Ethanol q.s.

The active ingredient is mixed with lactose and 292 grams of potato starch, and the mixture is moistened with an ethanolic solution of the gelatin, and is granulated through a sieve. After the granules have dried, the rest of the potato starch, magnesium stearate, and silicon dioxide are mixed, and the mixture is compressed to give tablets each weighing 145.0 milligrams, and containing 50.0 milligrams of active ingredient, which, if desired, can be provided with slots to break, to enable the dosage to be adjusted more finely.

Claims (18)

1. The use of a methanbisphosphonic acid derivative selected from: 3-amino-1-hydroxy-1-diphosphonic acid, 3- (N, N-dimethylamino-1-hydroxypropan-1, 1-diphosphonic acid , 4-amino-l-hydroxybutan-1, 1-diphosphonic acid, 6-amylo-l-hydroxyhexap-1, 1-diphosphonic acid, 3- (N-methyl-Nn-pentylamino) -l-hydroxypropan-10 acid , 1-diphosphonic, l-hydroxy-2- (imidazol-1-yl) ethan-1, 1-diphosphonic acid, 1-hydroxy-2- (3-pyridyl) ethan-1, 1-diphosphonic acid, and salts of N-methyl pyridinium thereof, l- (4-chlorothiophenyl) methan-l, 1-diphosphonic acid, 3- [N- (2-phenylthioethyl) -N-methylamino] -l-hydroxypropan-1, 1-diphosphonic acid l-hydroxy-3- (pyrrolidin-1-yl) propane-1,1-diphosphonic acid, 1- (N- < "• phenylaminothiocarbonyl) methan-l, 1-diphosphonic acid, tetraethylester -benzoyl-3,4-dihydro-2H-pyrazole-3,3-diphosphonic acid, 1-hydroxy-2- (imidazo [1, 2-a] pyridip-3-yl) ethan-1, 1-diphosphonic acid, and 1, 1-dichloromethane-1, acid -difosphonic, or a salt

Pharmaceutically acceptable thereof, or any hydrate thereof, for the manufacture of a pharmaceutical composition for the prevention and treatment of prosthetic loosening and migration of prostheses in mammals, including man. 2. The use according to claim 1, of a

Metanbisphosphonic acid derivative, which is selected from 3-amino-1-hydroxypropan-1, 1-diphosphonic acid, 3- (N, N-dimethylamino-1-hydroxypropan-1, 1-diphosphonic acid, 4-amino acid -1-hydroxybutan-1, 1-diphosphnalene, 6-amino-1-hydroxyhexan-1, 1-diphosphonic acid, 3- (N-methyl-Nn-pentylamino) -1-hydroxypropan-1, 1-diphosphonic acid, -hydroxy-2- (imidazol-1-yl) ethan-1, 1-diphosphonic acid, 1-hydroxy-2- (3-pyridyl) ethan-1, 1-diphosphonic acid, and N-methyl pyridinium salts thereof l- (4-chlorothiophenyl) methan-1,1-diphosphonic acid, 3- [N- (2-phenylthioethyl) -N-methylamino] -1-hydroxypropan-1, 1-diphosphonic acid, acid-hydroxy-3- ( pyrrolidin-1-yl) propan-l, 1-diphosphonic, 1- (N-phenylaminothiocarbonyl) methan-1, diphosphonic acid, 5-benzoyl-3,4-dihydro-2H-pyrazole-3-tetraethyl ester, 3-diphosphonic acid, l-hydroxy-2- (imidazo [1,2-a] pyridin-3-yl) ethan-1, 1-diphosphonic acid, a pharmaceutically acceptable salt thereof, and any hydrate of the same 3. The use according to claim 1, of a methanbisphosphonic acid derivative, which is selected from 3-amino-l-hydroxypropan-1,1-diphosphonic acid, 3- (N, N-) acid. dimethylamino-1-hydroxypropane-1, diphosphonic acid, 4-amino-1-hydroxybutan-1, 1-diphosphonic acid, 6-amino-1-hydroxyhexan-1, 1-diphosphonic acid, 3- (N-methyl-N- pentylamino) -1-hydroxypropan-1,1-diphosphonic acid, l-hydroxy-2- (imidazol-1-yl) ethan-1, 1-diphosphonic acid; l-hydroxy-2- (3-pyridyl) ethan-1, diphosphonic acid, 3- [N- (2-phenylthioethyl) -N-methylamino] -l-hydroxypropan-1,1- acid , - diphosphonic; l-hydroxy-3- (pyrrolidin-l-yl) propan-l, 1- diphosphonic acid, 1-hydroxy-2- (imidazo [1,2-a] pyridin-3-yl) ethan-1, 1- acid diphosphonic, a pharmaceutically acceptable salt thereof, and any hydrate thereof.

4. The use according to claim 1, of a methanbisphosphonic acid derivative which is selected from paronic acid, alendronic acid, 3- (N-methyl-Nn-pentylamino) -1-hydroxypropan-1, acid. diphosphonic acid, 1- hydroxy-2- (imidazol-1-yl) ethan-1, 1-diphosphonic acid, acidic acid, and tiludronic acid, a pharmaceutically acceptable salt thereof, and any hydrate thereof.

5. The use according to claim 1, of a methanbisphosphonic acid derivative, which is selected from l-hydroxy-2- (imidazol-1-yl) ethane-1,1-diphosphonic acid, and -amino-1-hydroxypropan-1, 1-diphosphonic acid, a pharmaceutically acceptable salt thereof, and any hydrate thereof

6. The use according to claim 1, of l-hydroxy-2- (imidazole) -l-yl) ethan-1, diphosphonic acid or a pharmaceutically salt thereof or any hydrate thereof

7. The use according to claim 1, of 3-amino-l-hydroxypropan-1, 1-diphosphonic acid or a pharmaceutically acceptable salt thereof or any hydrate thereof.

8. The use according to claim 1, of pamidronate disodium, or any hydrate thereof.

9. The use according to any of claims 1 to 8, wherein the prosthesis is a prosthesis of 5 hip.

10. The use according to any of claims 1 to 9, wherein the pharmaceutical composition is "- adapted for intravenous administration

11. The use according to any of claims 1 to 9, wherein the pharmaceutical composition is adapted for transdermal administration

12. The use according to any of claims 1 to 9, in wherein the pharmaceutical composition is adapted for oral administration

13. The use of a methanobisphosphonic acid derivative selected from: 3-amino-1-hydroxypropan-1, 1-diphosphonic acid, 3- (N, N-dimethylamino) -l-hydroxypropan-1, 1-diphosphonic acid, 4-amino-l-hydroxybutan-1,1-diphosphonic acid, 6-amylo-l-hydroxyhexan-1, 1-diphosphoic acid, 3- (N-methyl) acid Nn-pentylamino) -l-hydroxypropan-1,1-diphosphonic acid, l-hydroxy-2- (imidazol-1-yl) ethan-1, 1-diphosphonic acid, l-hydroxy-2- (3-? Iridyl) ethan-1, 1-diphosphonic, and N-methyl pyridinium salts thereof; l- (4-chlorothiophenyl) methan-1, 1-diphosphonic acid, 3- [N- (2-phenylthioethyl) -25 N- methylamino] -1-hydroxy propan-l, 1-diphosptopic, l-hydroxy-3- acid (pyrrole idin-1-yl) propan-1, 1-diphosphopic, 1- (N-phenylaminocarbonyl) methan-1, diphosphonic acid, 5-benzoyl-3,4-dihydro-2H-pyrazole tetraethyl ester -3,3-diphosphonic acid, l-hydroxy-2- (imidazo [1,2-a] pyridin-3-yl) ethan-1, 1-diphosphonic acid, and 1,1-dichloromethane-1,1-diphosphonic acid co; or a pharmaceutically acceptable salt thereof, or any hydrate thereof, for the prevention and treatment of prosthetic loosening and migration of prostheses in mammals, including man.

14. The use according to claim 13, of a methanbisphosphonic acid derivative, which is selected from 3-amino-l-hydroxypropan-1, 1-diphosphonic acid, 3- (N, N-dimethylamino) acid. l-hydroxypropan-1, 1-diphosphonic, 4-amino-1-hydroxybutan-1, 1-diphosphonic acid, 6-amino-1-hydroxyhexan-1, 1-diphosphonic acid, 3- (N-methyl-Nn- pentylamino) -l-hydroxypropan-1,1-diphosphonic acid, l-hydroxy-2- (imidazol-1-yl) ethan-1, diphosphonic acid, l-hydroxy-2- (3-pyridyl) ethan-l , 1-diphosphonic, and N-methyl pyridinium salts thereof; l- (4-chlorosiphenyl) methan-1, 1-diphosphonic acid, 3- [N- (2-phenylthioethyl) -N-methylamino] -1 acid -hydroxypropan-1, diphosphoic acid, l-hydroxy-3- (pyrrolidin-1-yl) propan-1,1-diphosphonic acid, 1- (N-phenylaminothiocarbonyl) methan-1, 1-diphosphonic acid, tetraethyl ester of 5-benzoyl-3,4-dihydro-2H-pyrazole-3,3-diphosphonic acid, l-hydroxy-2- (imidazo [l, 2-a] pyridin-3-yl) etap-1, 1 acid -difosphonic, a The pharmaceutically acceptable salt thereof, and any hydrate thereof.

15. A method for preventing or treating prosthetic loosening and migration of prostheses in mammals, which comprises administering to a mammal in need thereof, a therapeutically effective amount of a methanobisphosphonic acid derivative selected from: 3-amino acid -l-hydroxypropan-1, 1-diphosphonic, 3- (N, N-dimethylamino-1-hydroxypropan-1, 1-diphosphonic acid, 4-amino-1-hydroxybutan-1, 1-diphosphonic acid, 6-amino acid -l-hydroxyhexan-l, 1- diphosphonic, 3- (N-methyl-Nn-pentylamino) -l-hydroxypropan-1,1-diphosphonic acid, l-hydroxy-2- (imidazol-1-yl) ethan- l, diphosphonic acid, l-hydroxy-2- (3-pyridyl) ethan-1, 1-diphosphonic acid, and N-methyl pyridinium salts thereof; l- (4-chlorothiophenyl) methan-1 -diphosphonic acid, 3- [N- (2-phenylthioethyl) -N-methylamino] -1-hydroxypropan-1, 1-diphosphonic acid-acid-hydroxy-3- (pyrrolidin-1-yl) propan-1, 1-diphosphdane, 1- (N-phenylaminothiocarbonyl) methan-1,1-diphosphonic acid, tetraethyl ester co-acid 5-benzoyl-3,4-dihydro-2H-pyrazole-3, 3-diphosphonic acid, l-hydroxy-2- (imidazo [1,2- a] pyridin-3-yl) ethan-1, 1 -diphosphonic, and 1,1-dichloromethane-1, 1-diphosphonic acid; or a pharmaceutically acceptable salt thereof, or any hydrate thereof.

16. A method according to claim 15, wherein the methanobisphosphonic acid derivative administered is selects from 3-amino-1-hydroxypropan-1, 1-diphosphonic acid, 3- (N, N-dimethylamino-1-hydroxypropan-1, 1-diphosphonic acid, 4-amino-1-hydroxybutan-1, 1-diphosphonic, acid 6-amino-l-hydroxyhexan-l, 1-diphosphonic, 3- (N-methyl-Nn-pentylamino) -1-hydroxypropan-1, 1-diphosphonic acid, l-hydroxy-2- (imidazol-l-yl) ) ethan-1, diphosphnadic; l-hydroxy-2- (3-pyridyl) ethan-1, 1-diphosphonic acid, and N-methyl pyridinium salts thereof; l- (4-chlorothiophenyl) methan-1, 1-diphosphonic acid, 3- [N- (2-phenylthioethyl) -N-methylamino] -1-hydroxypropan-1, 1-diphosphonic acid; l-hydroxy-3- (pyrrolidin-l-yl) propan-l, l-diphosphonic acid, l- (N-phenylaminothiocarbonyl) methan-l, 1- diphosphonic acid, 5-benzoyl-3,4- tetraethyl ester dihydro-2H-pyrazole-3,3-diphosphonic acid, l-hydroxy-2- (imidazo [1,2- a] pyridin-3-yl) ethan-1, 1-diphosphonic acid, a pharmaceutically acceptable salt thereof, and any hydrate thereof.

17. A pharmaceutical composition for the prevention and loosening of prosthesis and migration of prostheses, which comprises a methanobisphosphonic acid derivative selected from: 3-amino-l-hydroxypropan-1, 1-diphosphnadic acid, 3- (N-acid , N-dimethylamino-l-hydroxypropan-1,1-diphosphonic acid, 4-amino-l-hydroxybutan-1,1-diphosphonic acid, 6-amino-l-hydroxyhexan-1, l-diphosphonic acid, 3- (N -methyl-N-pentylamino) -1-hydroxypropan-1,1-diphosphnadic acid, l-hydroxy-2- (imidazol-1-yl) ethan-1, 1-diphosphnadic acid, l-hydroxy-2- (3- pyridyl) ethan-1, diphosphonic, and N-methyl pyridinium salts thereof; l- (4-dorothiophenyl) methan-1,1-diphosphnanoic acid, 3- (N- (2-phenylthioethyl) -N-methylamino] -1-hydroxypropan-1, 1-diphosphonic acid; Acidol-hydroxy-3- (pyrrolidin-1-yl) propan-1, 1-diphosphadic acid, 1- (N-phenylaminothiocarbonyl) methan-1, 1-diphosphonic acid, 5-benzoyl-3,4-dihydro tetraethyl ester -2H-pyrazole-3, 3-diphosphonic acid, l-hydroxy-2- (imidazo [1, 2-a] pyridin-3-yl) ethan-1, 1-diphosphnadic acid, and 1,1-dichloromethane-1 acid , 1-diphosphonic; or a pharmaceutically acceptable salt thereof, or any hydrate thereof; together with a pharmaceutically acceptable vehicle.

18. A pharmaceutical composition according to claim 17, which comprises a methanobisphosphonic acid derivative selected from 3-amino-1-hydroxypropan-1,1-diphosphnanoic acid, 3- (N, N-dimethylamino-1) acid. - hydroxypropan-1,1-diphosphonic acid, 4-amino-l-hydroxybutan-1,1-diphosphonic acid, 6-amino-l-hydroxyhexan-1, 1-diphosphonic acid, acid, * "- * - (N-methyl) -N-pentylamino) -? - hydroxypropan-1,1-diphosphnadic acid, l-hydroxy-2- (imidazol-1-yl) ethan-1, 1-diphosphnadic acid 1-hydroxy-2- (3-pyridyl) ethan-1, 1-diphosphdane, and N-methyl pyridinium salts thereof; l- (4-chlorothiophenyl) methan-1, 1-diphosphonium, 3- [N- (2-phenylthioethyl) -N-methylamino] ] -1- hydroxypropan-1,1-diphosphnadic acid l-hydroxy-3- (pyrrolidin-1-yl) propan-l, 1-diphosphnadic acid, l- (N-phenylaminothiocarbonyl) methan-1, 1-diphosphnadic acid, tetraethyl ester of 5-benzoyl-3,4-dihydro-2H-pyrazol-3, 3-diphosphnadic acid, l-hydroxy-2- acid ; imidazo [1,2-a] pyridin-3-yl) ethan-1, 1-diphosphonic acid, a pharmaceutically acceptable salt thereof, and any hydrate thereof, together with a pharmaceutically acceptable carrier. SUMMARY The invention relates to the use of certain metanbisphospic acid derivatives (for the manufacture of a pharmaceutical composition), for the prevention and treatment of prosthesis loosening and migration of prostheses in mammals, including man. * * * * * Me, ANA ELENA FERRER RAMÍREZ, translator member of the Mexican Organization of Translators, A.C., with address at Av. Clavería ** > '- 224-205, Col. Clavería, México, D.F. 02080, Tels. 3962669 and 396 5201, I certify that the preceding document is, to the best of my knowledge, a faithful and accurate translation of the original document in English that I had in view. Mexico, D.F., August 14, 1996. Ana E ena Ferrer Ram rez