MXPA01010085A - A pharmaceutical formulation comprising an bisphosphonate and an additive agent providing an enhanced absorption of the bisphosphonate - Google Patents

Abstract

The present invention provides pharmaceutical formulations comprising at least one bisphosphonate and an additive consisting of one or more absorption enhancing agents. The said pharmaceutical formulations are useful for the inhibition of bone resorption and for the treatment and prevention of osteoporosis.

Description

A PHARMACEUTICAL FORMULATION COMPRISING A BISPHOSPHONATE AND AN ADDITIVE AGENT THAT SUPPLIES A GROWING ABSORPTION OF THE BISPHOSPHONATE. Field of Invention The present invention relates to pharmaceutical formulations comprising bisphosphonates. The invention also relates to a process for the preparation of such pharmaceutical formulations, to the use of such pharmaceutical formulations for the inhibition of bone resorption and for the treatment and prevention of osteoporosis. Description of Previous Art. Bisphosphonates Bisphosphonates are substituted pyrophosphate analogs in coal, which include potent inhibitors of bone resorption, such as alendronate (4-amino-1-hydroxybutylidene-1, biphosphonic acid) (Sato et al., (Sato et al. 1991) J. Clin. Invest. 88, 2095-2105). alendronate Ref: 133224 The oral bioavailability of bisphosphonates (etidronate, clodronate, pamidronate, alendronate) in humans is between 1% and 10% according to Lin (Bone 18, 75-85, 1996) and absorption decreases when it occurs with food, especially in the presence of calcium. Therefore, bisphosphonates should never be given at the time of food and never together with milk or milk products according to Fleisch (Bisphosphonates in bone diseases, Stampli &Co. Bern 1993. P.50, and references cited therein) . In Dowty M.E. and collaborators, Pharm. Sci. Suppl., Vol. 1, No. 1: 448 (1998) describes the low permeability of risedronate. The oral bioavailability of alendronate has been studied by Gertz et al. (Clinical Pharmacology &Therapeutics, vol.58, pp. 288-298, 1995). It was found that taking alendronate 60 or 30 minutes before breakfast, reduced the bioavailability by 40% compared to a wait of 2 hours before a meal. When taking alendronate either concurrently with, or 2 hours after breakfast, drastically deteriorated availability (> 85%). A practical dosing recommendation, derived from these findings, was that patients should take the medication with water after fasting at night and at least 30 minutes before any food or drink.

In addition, the labeling information in an existing commercial formulation of alendronate (FOSAMAX®) contains a warning that the formulation, like other bisphosphonates, can cause local irritation of the upper gastrointestinal mucosa. This clearly shows that a solution to the problems associated with the poor and variable absorption of the orally administered bisphosphonates, which have been known for a long time, has not yet been found. Consequently, there is a need for pharmaceutical formulations comprising bisphosphonates, such as alendronate, which reduces the aforementioned drawbacks and allows the patient to take the drug more conveniently, for example along with the food intake. Enrichment of absorption Pharmaceutical excipients can be classified as functional or non-functional (M E Aulton: Pharmaceutics - The science of dosage form design, Chuchill Livingstone 1988, Hong Kong). Non-functional excipients are, for example, binders, fillers, dryers, etc., and are used to comply with aspects of pharmaceutical formulating technology, such as size, hardness, appearance (eg color) etc. Functional excipients, on the other hand, are used, for example, to achieve certain types of release profiles such as immediate release, prolonged release, controlled release, etc., by the use of polymeric materials that hydrate, swell, and erode rapidly or slowly. , etc.; to achieve rapid dissolution of the drug by incorporating surface active substances; on reaching the control of the pH in the formulation or in the immediate environment of the medicine, by means of the use of buffer solutions in the formulation, etc. Another important aspect of the excipients, is the influence from functional excipients in the biological environment that is obtained with certain substances, often called enriching in the literature, for example, changing the permeability of the biological membrane, to inhibit the formation of complexes with biological substances present (for example proteins, lipids, bile salts, ions), and so on. The rationale for the use of such excipients is then to achieve, for example, higher availability, a smaller variation in absorption due, for example, by avoiding instability through interactions with food (Charman N et al., J Pharm Res 86 ( 3): 269-282 (1997)) in the Gl medium, to decrease the influence of the drug on the integrity of the membrane, etc. Detailed reviews have been presented on the effect of enriching agents and their use in pharmaceutical formulations by E J van Hoogdalem et al (Pharm Theor vol 44, 407-443 (1989)); by S Muranishi et al (Crit Rev Ther Drug Carrier Syst vol 7.1-33 (1990)); by E S Swenson and W J Curatolo (Adv Drug Deliv Rev vol 8, 39-92 (1998)); in Drug Absorption Enhancement (Ed: A B G of Boer, Harwood Academic Publishers 1994); in Baughman RA et al Circulation 98 (16): 1610-1615 (1998); in Bai JP et al, Crit Rev Therap Drug Carrier Syst 12 (4): 339-371 (1995); in Bowe CL et al, Proc Nat Acad Sci 94 (22): 12218-23 (1997); in Chao AC et al, J Pharm Sci 87 (11): 1395-1399 (1998); in Chao AC et al, J Drug Targeting 6 (1): 37-43 (1998); and in Fix JA. J Pharm Sci 85 (12) 1282-1285 (1996). In many circumstances, enrichments combine various varied effects. However, the degree of influence on the biological environment is rarely known a priori, and the mechanisms behind the effects are obscure and difficult to ensure in vivo. Different types of such functional excipients include for example, lipids, chelators, and polymers that can act, for example, by preventing or enriching complex formation with species from the biological environment (eg, proteins, bile salts, lipids, ions such as Ca2 + etc. ), by influencing the permeability of the membrane in a reversible or irreversible way, by presenting the drug in a small form in particles, and thus avoiding high local concentrations that can irritate near the membranes of the drug, etc. Description of the invention. It has surprisingly been found that the absorption of the bisphosphonates can be substantially improved by incorporating one or more additives into pharmaceutical formulations containing bisphosphonates. The use of the additives as enriching agents will result in advantageous positive effects, such as an enriched and / or less variable absorption when the bisphosphonates, for example alendronate, is given by different routes of administration, such as oral, rectal, buccal, nasal. and pulmonary route. The patient will be allowed to take the medication more conveniently, for example, along with the food intake. Lateral effects such as local irritation of, for example, the upper gastrointestinal mucosa will also be reduced. Therefore, the present invention provides a pharmaceutical formulation comprising at least one bisphosphonate and one or more additives selected from the group consisting of: A surfactant, such as a non-ionic surfactant, eg, a sorbitan ester (Span series) ), a polysorbate (Tween series), a polyoxyethylated glycol monoether (such as the Brij series, a polyoxylated alkyl ester (Myrj series), a polyoxyethylated alkyl phenol (such as the Triton series), an alkyl glucoside, such as the glycosides of sugar for example dodecylmaltoside, fatty acid esters of sugar, for example sucrose laurate, sucrose monostearate and saponins, an ampholytic surfactant, for example a betaine, an anionic surfactant, for example a sulfated fatty alcohol, an alcohol sulfated polyoxyethylated, others such as dioctyl sulfosuccinate; - A cationic surfactant, for example an ammonium compound; - A bile salt, such as a bile salt; dihydroxy such as sodium deoxycholate, a trihydroxy biliary salt such as sodium glycolate and fusidates, for example sodium dihydrofusidate; - A soap and a fatty acid and a salt thereof, for example octanoic acid, decanoic acid and sodium decanoate; - A lipid (with the exception of those described in PCT Application No. SE98 / 01790), such as a phospholipid, for example DPPC and DMPC; - An oil, for example soybean oil and sunflower oil; An enamine such as DL-phenylalanine and ethylacetoacetate enamine; - A chelating agent, for example, EDTA, EGTA, and citric acid; - A phenothiazine, such as chlorpromazine; - A fatty acid derivative of carnitine and peptides, for example, palmitoyl-DL-carnitine; - A substance selected from the group consisting of azone, concanavilin A, a phosphate and a phosphonate derivative such as DL-α-glycerol phosphate and 3-amino-1-hydroxypropylidene-1,1-diphosphonate, diethyl maleate and malonate of diethylethoxymethylene; - A product of the Maillard reactions, that is, a product obtained by reacting the sugars with amino acids, for example a compound of the glucoselysin reaction; A polymer, such as polyacrylic acid, for example Carbopol®, polycarbophil; - A chitosan and a derivative of chitosan; and - A block copolymer, for example, a poloxamer, poloxamine and meroxapol. A biodegradable polymer, for example, polylactic acid, polyglycolic acid and copolymers thereof. The intended appropriate combinations of the enriching agents are but are not limited to: Lipids (also those described in the application PCT No. SE 98/01790) and surfactants, for example monoolein and sodium taurocholate, monoolein and Tween 80 (polyoxyethylene (20) sorbitan mono-oleate, also called polysorbate 80); Lipids of non-phospholipid character (also those described in SE 98/01790) and phospholipids, for example, medium chain glycerides and lecithins; Lipids (also those described in SE 98/01790) and block copolymers, for example monoolein and Pluronic F 127 (which is the polyoxyethylene / polyoxypropylene / polyoxyethylene triblock copolymer of poloxamer 407); Surfactants and oils, for example, sucrose esters of fatty acids and soybean oil; and Polymers and lipids, for example polycarbophils and monoolein. The combinations may be in the form of emulsions and microemulsions comprising, for example, monoolein / triglyceride / water or isopropyl myristate / lecithin / water. Preferred additives of the invention are - Nonionic surfactants such as sugar glycosides and sugar esters of fatty acids; - Lipids such as a phospholipid, for example DPPC and DMPC; - An oil, such as soybean oil and sunflower oil; A chelating agent for example EDTA, EGTA, citric acid; A fatty acid derivative of carnitine or a peptide; for example palmitoyl-DL-carnitine; - Polymer such as polyacrylic acid, for example Carbopol, polycarbophil - A block copolymer, for example, a poloxamer, poloxamine and meroxapol; - A saponin; - The combinations mentioned above. The lipids referred to above as described in the PCT application no. SE 98/01790, are a medium chain glyceride or a mixture of medium chain glycerides, particularly those having the formula wherein R 1, R 2 and R 3 are the same or different and each represents a hydrogen atom or an alkanoyl chain having from 6 to 18 carbon atoms, preferably from 6 to 12 carbon atoms, with the proviso that at least one of R1, R2 and R3 is an alkanoyl group. The dosage form used can be a semi-solid or liquid solid preparation prepared by the techniques known per se. Usually, the active substance will constitute between 0.001% and 99% by weight of the preparation, preferably 0.003 to 1.3% by weight, more preferably 0.1 to 1%. Preferably, the bisphosphonate has the general formula II II wherein R4 is H, OH or Cl; and R5 is (a) alkyl having 1 to 6 carbon atoms, optionally substituted with amino, alkylamino, dialkylamino or heterocyclyl; (b) halogen; (c) arylthio, preferably substituted with chlorine; (d) cycloalkylamino with 5 to 7 carbons; or (e) saturated 5- or 6-membered nitrogen containing heterocyclyl with 1 or 2 heteroatoms. The alkyl groups in the alkylamino and dialkylamino can have from 1 to 5 carbon atoms and can be combined independently in the dialkylamino group. The term "heterocyclyl" means an unsaturated 5- to 7-membered heterocyclic group with one or two rings and 1 to 3 heteroatoms, independently chosen from N, O and S. Unless otherwise stated or indicated, the term "aryl" "denotes a substituted or unsubstituted phenyl, furyl, thienyl or pyridyl group, or a fused ring system of any of these groups such as naphthyl. The term "substituted aryl" denotes an aryl group as defined above which is substituted with one or more alkyl, alkoxy, halogen, amino, thiol, nitro, hydroxy, acyl, aryl or cyano groups. Compounds of formula II include: 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid (alendronate), N, N-dimethyl-3-amino-1-hydroxypropylidene-1, 1-bisphosphonic acid (mildronate, olpadronate ), l-hydroxy-3- (N-methyl-N-pentylamino) propylidene-1,1-bisphosphonic acid (ibandronate), l-hydroxy-2- (3-pyridyl) ethylidene-1,1-bisphosphonic acid (risedronate ), 1-hydroxyethylidene-1, 1-bisphosphonic acid (etidronate), l-hydroxy-3- (1-pyrrolidinyl) propylidene-1,1-bisphosphonic acid, l-hydroxy-2- (1-imidazolyl) ethylidene-1,1-bisphosphonic acid (zoledronate), l-acid hydroxy-2- (imidazo [1, 2-a] pyridin-3-yl) ethylidene-1,1-bisphosphonic acid (minodronate), 1- (4-chlorophenylthio) methylidene-l, 1-bisphosphonic acid (tiludronate), acid 1- (cycloheptylamino) methylenedi-1,1-bisphosphonic acid (cimadronate, incadronate), 6-amino-1-hydroxyhexylidene-1, 1-bisphosphonic acid (neridronate) and pharmaceutically acceptable salts thereof. The most preferred compounds of formula II are 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid (alendronate) and its pharmaceutically acceptable salts. In a preferred form, the pharmaceutical formulation according to the invention is adapted for oral administration and can be given under fed or fasting conditions. In the preparation of the pharmaceutical formulations according to the invention, in the form of unit doses for oral administration, the bisphosphonate and the absorption-enhancing agent can be filled into soft or hard gelatin or cellulose capsules; mixed with solid ingredients in powder, such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin or other appropriate ingredient; with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then processed into particulate forms, granules or pressed into tablets.

In one embodiment of the invention, the bisphosphonate and the additive are mixed in an appropriate manner considering that the particulate form (solid, semi-solid or liquid) can preferably be chosen to avoid the presentation of the drug in high local concentrations which can be irritating to the membranes of the mucosa. Such particulate forms can be obtained by well-known methods such as the dispersion of the bisphosphonate as a micronized powder (<10 μm) in an appropriate medium such as sesame oil, soybean oil, etc., or by forming a carrier system. medication in a particle form. Micronized bisphosphonates or carrier / drug systems can be prepared by techniques such as, but not limited to, dry and wet milling, freeze milling, air jet micronization, spray drying, spray ice cream, spray drying, electroatomization, supercritical crystallization (RESS or GAS methods), evaporation of solvents by emulsion, extraction of solvents by emulsion and diffusion of solvents by emulsion. This suspension of the bisphosphonate in oil or the carrier / bisphosphonate system is then orally administered as a suspension or in capsules. The appropriate daily doses of bisphosphonates in the therapeutic treatment of humans are about 0.001 to 100 mg / kg of body weight in the peroral administration, preferably 0.001 to 10 mg / kg, more preferably 0.005 to 0.3 mg / kg. The enriching agent, or the combination of enriching agents, and an appropriate carrier or non-functional excipients when required, will constitute between the 0. 1 to 99.9% by weight of the preparation, preferably between 80% to 99.9% by weight. The pharmaceutical formulations according to the invention are useful for inhibiting bone resorption and thus for the treatment or prevention of bone loss related to osteoporosis, age, steroid therapy, rheumatism, Paget's disease or cancer. The pharmaceutical formulation according to the invention is also useful for the prevention and / or treatment of secondary osteoporosis, except osteoporosis induced by steroids, periodontitis, osteoarthritis. The pharmaceutical formulations according to the invention are also useful for the treatment of hypercalcemia. Consequently, the use of said pharmaceutical formulations for the treatment of these conditions are additional aspects of the invention. In another aspect, the invention provides a process for the preparation of a pharmaceutical formulation according to the invention, said process comprises the formation of a mixture of (i) bisphosphonate, (ii) an additive and (iii) a pharmaceutically acceptable carrier.

In a further aspect, the invention provides the use of bisphosphonate in conjunction with an absorption-enhancing agent for the manufacture of a medicament for the inhibition of bone resorption, or so, for the treatment or prevention of bone loss related to osteoporosis, age, steroid therapy, rheumatism, Paget's disease or cancer. The pharmaceutical formulation according to the invention is also useful in the prevention and / or treatment of secondary osteoporosis, except osteoporosis induced by steroids, periodontitis, osteoarthritis. Preferably, the aforementioned medicament is adapted for oral administration. In still a further aspect of the invention, there is provided a method for the inhibition of bone resorption, or so for the treatment or prevention of bone loss related to osteoporosis, age, steroid therapy, rheumatism, Paget's disease or cancer. . The pharmaceutical formulation according to the invention is also useful in the prevention and / or treatment of secondary osteoporosis, except osteoporosis induced by steroids, periodontitis, osteoarthritis, which method comprises administration to a mammal, including man, which needs of said treatment, an effective amount of a pharmaceutical formulation according to the invention. Preferably, said pharmaceutical formulation is administered orally. Biological Evaluation The effectiveness of the formulations according to the present invention to prevent bone loss has been analyzed in studies using an intact model of growing young rats, developed and well established to predict the effectiveness of bisphosphonates in subsequent clinical practice . Results The ED50 values obtained in an intact rat model show that orally administered formulations according to the invention, which have been tested, are more potent than equimolar bisphosphonate alone. In a 14-day study of intact young growing rats, a clear response effect was found at the enrichment dose. No effects were found for the bisphosphonate in saline solution and given by os. The bone density effects obtained with the enrichment / bisphosphonate were similar to those obtained with given bisphosphonate subcutaneously, while no effects were found for the bisphosphonate in saline given by os. All the rats seemed normal and gained normal weight. Conclusions Rat studies strongly support the concept that enrichments as suggested in the present disclosure may increase the oral bioavailability of a bisphosphonate as described in the current specification even in the presence of food. EXAMPLES Examples of the pharmaceutical formulations according to the invention: Formulation 1 Alendronate 2.3 mg Caprylic acid, sodium salt 11.5 mg 50 mM Tris with 100 mM NaCl (buffer) 1.0 g Approximately 2.3 mg of alendronate and 11.5 mg of caprylic acid were dissolved in buffer solution and the pH was adjusted to 7.5 using sodium hydroxide. Formulation 2 Alendronate 2.3 mg Monolein 11.5 mg Tween 80 11.5 mg 50 mM Tris with 100 mM NaCl (buffer) 1.0 g Approximately 2.3 mg of alendronate and 11.5 mg of monolein were dissolved in buffer containing Tween 80 and the pH was adjusted to 7.5 using sodium hydroxide. Formulation 3 Alendronate 2.3 mg Quil A 11.5 mg 50 mM Tris with 100 mM NaCl (buffer) 1.0 g Approximately 2.3 mg of alendronate and 50 mg of Quil A were dissolved in buffer solution, and the pH was adjusted to 7.5 using sodium hydroxide. Formulation 4 Alendronate 2.3 mg Carbopol 934P 5.0 mg 50 mM Tris with 100 mM NaCl (buffer) 1.0 g Approximately 2.3 mg of alendronate and 5.0 mg of Carbopol were mixed with buffer solution to form a dispersion and the pH was adjusted to 7.5 using hydroxide of sodium. Formulation 5 Alendronate 2.3 mg Carbapol 934P 15.0 mg 50 mM Tris with 100 mM NaCl (buffer) 1.0 g Approximately 2.3 mg of alendronate and 15.0 mg of Carbopol were mixed with buffer solution, to form a dispersion and the pH was adjusted to 7.5 using sodium hydroxide. Formulation 6 Alendronate 2.3 mg Isopropylimistrate 630 mg Lecithin (Epicuron 200) 270 mg 50 mM Tris with 100 mM NaCl (buffer) 100 mg About 23 mg of alendronate were dissolved in buffer and the pH was adjusted to a pH of 7.5 using sodium hydroxide. sodium and was added to a mixture of isopropyl myristate and lecithin (70/30 w / w) while swirling. Formulation 7 Alendronate 2.3 mg Isopropilmiristato 450 mg Tween 21 450 mg 50 mM Tris with 100 mM NaCl (buffer) 100 mg Approximately 23 mg of alendronate was dissolved in buffer and the pH was adjusted to a pH of 7.5 using sodium hydroxide and added to a mixture of isopropylmyristate and Tween 21 (50/50 p / p) while swirling.

Formulation 8 Alendronate 2.3 mg Monoolein 630 mg Soy triglycerides 270 mg 50 mM Tris with 100 mM NaCl (buffer) 100 mg Approximately 23 mg of alendronate was dissolved in buffer and the pH was adjusted to a pH of 7.5 using sodium hydroxide and was added to a mixture of monoolein and soy triglycerides (70/30 p / p) while swirling. Formulation 9 Alendronate 2.3 mg Soy triglycerides 0.1 g 2.3 mg of alendronate were added to triglycerides of solia and micronized using ultrasonication while cooling with ice. It is noted that in relation to this date the best known method for carrying out the invention is that which is clear from the present description of the invention.

Claims (46)

1. Claims Having described the invention as above, the content of the following claims is claimed as property. A pharmaceutical formulation characterized in that it comprises at least one bisphosphonate and one or more of an additive agent, the additive agent is present in an amount sufficient to provide an enriched absorption of the bisphosphonate, and the additive is a substance selected from the group consisting of : -a surfactant; -an ampholytic surfactant; -an anionic surfactant; - a cationic surfactant; -a biliary salt; -a fatty acid and soap, and a salt thereof; - a lipid, with the exception of a medium chain glyceride or a mixture of medium chain glycerides that have the formula H2C- • O- & wherein R1, R2 and R3 are the same or different and each represents a hydrogen atom or an alkanoyl chain having from 6 to 18 carbon atoms, preferably from 6 to 12 carbon atoms, with the proviso that at least one or R1, R2 and R3 is an alkanoyl group. -an oil; an enamine; -a chelating agent; -a phenothiazine; - a fatty acid derivative of carnitine or a peptide; - a substance selected from the group consisting of azone, concanavalin A, a phosphate, a phosphonate derivative, such as DL-a-glycerophosphate, and 3-amino-1-hydroxypropylidene-1,1-diphosphonate, diethyl maleate and diethylethoxymethylene malonate; -a product of Maillard's reactions; - a polymer such as a block copolymer and a biodegradable polymer; -a chitosan and a derivative of chitosan; 2. The pharmaceutical formulation according to claim 1, characterized in that the additive is a nonionic surfactant. 3. The pharmaceutical formulation according to claim 2, characterized in that the nonionic surfactant is a sugar glycoside or a fatty acid sugar ester. 4. The pharmaceutical formulation according to claim 1, characterized in that the additive is a lipid. 5. The pharmaceutical formulation according to claim 4, characterized in that the lipid is a phospholipid. 6. The pharmaceutical formulation according to claim 1, characterized in that the additive is an oil. 7. The pharmaceutical formulation according to claim 6, characterized in that the oil is soybean oil or sunflower oil. 8. The pharmaceutical formulation according to claim 1, characterized in that the additive is a chelating agent. 9. The pharmaceutical formulation according to claim 8, characterized in that the chelating agent is EDTA, EGTA or citric acid. 10. The pharmaceutical formulation according to claim 1, characterized in that the additive is a fatty acid derivative of carnitine or a peptide. 11. The pharmaceutical formulation according to claim 10, characterized in that the additive of the carnitine fatty acid derivative or a peptide is palmitoyl-DL-carnitine. 12. The pharmaceutical formulation according to claim 1, characterized in that the additive is a polymer. 13. The pharmaceutical formulation according to claim 12, characterized in that the polymer is a polyacrylic acid. 14. The pharmaceutical formulation according to claim 1, characterized in that the additive is a block copolymer. 15. The pharmaceutical formulation according to claim 14, characterized in that the block copolymer is a poloxamer, a poloxamine or meroxapol. 16. The pharmaceutical formulation according to claim 1, characterized in that the additive is a saponin. 17. The pharmaceutical formulation according to claim 1, characterized in that the additive is a biodegradable polymer. 18. The pharmaceutical formulation according to claim 17, characterized in that the biodegradable polymer is a polylactide acid or polyglycolic acid. 19. The pharmaceutical formulation according to claim 1, characterized in that the additive is a combination of a lipid and a surfactant. 20. The pharmaceutical formulation according to claim 19, characterized in that the combination of the lipid and the surfactant is monoolein and sodium taurocholate, or monoolein and Tween 80. 21. The pharmaceutical formulation according to claim 1, characterized in that the Additive is a combination of a lipid of a non-phospholipid character and a phospholipid. 22. The pharmaceutical formulation according to claim 21, characterized in that the combination of non-phospholipid lipid and the phospholipid is a medium chain glyceride and a lecithin. 23. The pharmaceutical formulation according to claim 1, characterized in that the additive is a combination of a lipid and a block copolymer. The pharmaceutical formulation according to claim 23, characterized in that the combination of lipid and the block copolymer is monoolein and Pluronic F 127. The pharmaceutical formulation according to claim 1, characterized in that the additive is a combination of a surfactant and an oil. 26. The pharmaceutical formulation according to claim 25, characterized in that the combination of the surfactant and the oil is a sucrose ester of fatty acid and soybean oil. 27. The pharmaceutical formulation according to claim 1, characterized in that the additive is a combination of a polymer and a lipid. 28. The pharmaceutical formulation according to claim 27, characterized in that the combination of the polymer and the lipid is polycarbophil and monolein. 29. The pharmaceutical formulation according to claim 1, characterized in that the additive combination is chosen to form an emulsion or a microemulsion. 30. The pharmaceutical formulation according to any of claims 1 to 29, characterized in that the bisphosphonate has the formula II wherein R 4 is H, OH or Cl RD is (a) alkyl having 1 to 6 carbon atoms, optionally substituted with amino, alkylamino, dialkylamino or heterocyclyl; (b) halogen; (c) chlorosubstituted arylthio or arylthio; (d) cycloalkylamino with 5 to 7 carbon atoms or (e) saturated 5 or 6 membered nitrogen containing heterocyclyl with 1 or 2 heteroatoms. 31. The pharmaceutical formulation according to claim 30, characterized in that the bisphosphonate has the formula II, wherein R4 is H or OH and R5 is (a) alkyl having 1 to 6 carbon atoms optionally substituted with amino, alkylamino, dialkylamino or heterocyclyl; (d) cycloalkylamino with 5 to 7 carbon atoms; or (e) saturated 5- or 6-membered nitrogen containing heterocyclyl with 1 or 2 heteroatoms. 32. The pharmaceutical formulation according to claim 30, characterized in that the bisphosphonate has the formula II wherein R4 is OH and R5 is (a) alkyl having 1 to 6 carbon atoms optionally substituted with amino, alkylamino, dialkylamino or heterocyclyl; Jd) cycloalkylamino with 5 to 7 carbon atoms; or (e) saturated 5- or 6-membered nitrogen containing heterocyclyl with 1 or 2 heteroatoms. 33. The pharmaceutical formulation according to claim 30, characterized in that the bisphosphonate is: 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid (alendronate), N, N-dimethyl-3-amino-1-acid hydroxypropylidene-1, bisphosphonic acid (mildronate, olpadronate), l-hydroxy-3- (N-methyl-N-pentylamino) propylidene-1,1-bisphosphonic acid (ibandronate), l-hydroxy-2- (3- pyridyl) ethylidene-1,1-bisphosphonic acid (risedronate), 1-hydroxyethylidene-1, biphosphonic acid (etidronate), l-hydroxy-3- (l-pyrrolidinyl) propylidene-1, biphosphonic acid, l-acid hydroxy-2- (1-imidazolyl) ethylidene-1,1-bisphosphonic acid (zoledronate), l-hydroxy-2- (imidazo [1,2- a] pyridin-3-yl) ethylidene-1,1-bisphosphonic acid ( minodronate), 1- (4-chlorophenylthio) methylidene-1, 1-bisphosphonic acid (tiludronate), 1 (cycloheptylamino) methylidene-1, 1-bisphosphonic acid (cimadronate, incadronate), 6-amino-1-hydroxyhexylidene-1 acid , 1-bisphosphonic (neridronate) and pharmaceutical salts Only acceptable of them. 34. A pharmaceutical formulation according to claim 33, characterized in that the bisphosphonate is alendronate (4-amino-1-hydroxybutylidene-1,1-biphosphonic acid) or pharmaceutically acceptable salts thereof. 35. A pharmaceutical formulation according to any of claims 1 to 34, which is adapted for oral administration. 36. A pharmaceutical formulation according to any of claims 1-35, which is adapted for a non-colonic delivery. 37. A pharmaceutical formulation according to any of claims 1-36, characterized by inhibiting bone resorption. 38. The pharmaceutical formulation according to any of claims 1-36, characterized in that it is used in the treatment and prevention of osteoporosis and bone loss related to age, steroid therapy, rheumatism, Paget's disease, cancer, secondary osteoporosis. except osteoporosis induced by steroids, periodontitis or osteoarthritis. 39. The pharmaceutical formulation according to any of the preceding claims, characterized in that the formulation is in the form of particles. 40. The pharmaceutical formulation according to claim 39, characterized in that the particulate form is solid or semi-solid. 41. The pharmaceutical formulation according to any of claims 39 and 40, characterized in that the bisphosphone is in the form of a micronized powder. 42. A process for the preparation of a pharmaceutical formulation according to any of claims 1 to 40, characterized in that a mixture of (i) is formed at least one bisphosphonate, (ii) an additive and (iii) a pharmaceutically carrier acceptable. 43. The use of a pharmaceutical formulation according to any of claims 1 to 41, for the manufacture of a medicament for the inhibition of bone resorption. 44. The use of a pharmaceutical formulation according to any of claims 1 to 41, for the manufacture of a medicament for the treatment and prevention of osteoporosis and age-related bone loss, steroid therapy, rheumatism, Paget or cancer, secondary osteoporosis except osteoporosis induced by steroids, periodontitis or osteoarthritis. 45. A method for the inhibition of bone resorption, characterized in that it comprises administration to a mammal, including man, in need of such treatment, an effective amount of a pharmaceutical formulation according to any of claims 1 to 41. 46. A method for the treatment and prevention of osteoporosis and age-related bone loss, steroid therapy, rheumatism, Paget's disease, cancer, secondary osteoporosis except steroid-induced osteoporosis, periodontitis or osteoarthritis, characterized in that it comprises administration to a mammal including man, which needs such treatment of an effective amount of a pharmaceutical formulation according to any of claims 1 to 41.