KR20010104389A - A Pharmaceutical Formulation Comprising an Bisphosphonate and an Additive Agent Providing an Enhanced Absorption of the Bisphosphonate - Google Patents

Abstract

The present invention provides a pharmaceutical formulation comprising an additive consisting of at least one bisphosphonate and at least one absorption enhancer. The pharmaceutical formulations are useful for inhibiting bone resorption and for treating and preventing osteoporosis.

Description

A Pharmaceutical Formulation Comprising an Bisphosphonate and an Additive Agent Providing an Enhanced Absorption of the Bisphosphonate}

Bisphosphonates

Bisphosphonates are carbon-substituted pyrophosphate analogs that include potent bone resorption inhibitors such as alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid) [Sato et al. (1991) J. Clin. Invest. 88, 2095-2105.

Alendronate

According to Lin, the oral bioavailability of bisphosphonates (ethedronate; cladronate; pamideronate; alendronate) in humans is 1% to 10% [Bone 18, 75-85, 1996], Together, their absorption is reduced, especially when taken in the presence of calcium. Thus, according to Fleisch, bisphosphonates should never be taken at mealtimes and should not be taken with milk or dairy products [Bisphosphonates in bone disease. Stampli & Co., Bern 1993, p. 50 and references cited therein. Dowty M.E. Et al., Pharm. Sci. Suppl., Vol 1, No 1: 448 (1998), describes the low permeability of risedronate.

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 taking 2 hours before meals. The use of alendronate concurrently with breakfast or 2 hours after a meal drastically reduced the utilization (greater than 85%). As a result of this, in actual dosing recommendations, patients should take the drug with water at least thirty minutes before eating any other food or drink after starving overnight.

In addition, the labeling information of currently available Alendronate formulations (FOSAMAX®) contains a warning that, like other bisphosphonates, this formulation can cause local irritation to the upper gastrointestinal mucosa. This clearly shows that no solution to the problem associated with poor and variable absorption of orally administered long known bisphosphonates has yet been found.

Thus, there is a need for pharmaceutical formulations comprising bisphosphonates such as alendronate, which alleviate the above problems and allow patients to take medications more conveniently, for example with food intake.

Absorption enhancer

Pharmaceutical excipients may be classified as functional or nonfunctional excipients [M E Aulton: Pharmaceutics-The science of dosage form design, Churchill Livingstone 1988, Hong Kong]. Nonfunctional excipients include, for example, binders, fillers, desiccants, and the like, and are used to meet pharmaceutical technical aspects of the formulation, such as size, hardness, appearance (eg, color), and the like. Functional excipients, on the other hand, obtain certain types of release profiles, such as immediate release, extended release, controlled release, etc., for example, by quickly or slowly hydrating, swelling, and eroding the polymeric material; Quickly dissolving the drug by incorporating a surface active substance; The use of a buffer in the formulation is used to adjust the pH of the immediate environment of the formulation or drug.

Another important aspect of excipients is the presence of biological materials (eg, proteins) that have been influenced by functional excipients in the biological environment, for example by changing the permeability of the biofilm, which can be obtained by certain substances commonly referred to in the literature as enhancers. , Lipids, bile salts, and ions). The primary reason for using such excipients is to increase their utilization rate, for example, to reduce the absorption change due to interaction with food [Charman WN et al., J Pharm Res 86 (3): 269-282 (1997)], GI- To avoid instability in the environment and to reduce drug effects on membrane integrity. A comprehensive review of the action of enhancers and their use in pharmaceutical formulations is described in E J van Hoogdalem et al. (Pharm Theor vol 44, 407-443 (1989)); S Muranishi et al. (Crit Rev Ther Drug Carrier Syst vol 7, 1-33 (1990)); E S Swenson and W J Curatolo (Adv Drug Deliv Rev vol 8, 39-92 (1998)); drug Absorption Enhancement (Ed: A B G de Boer, Harwood Academic Publishers 1994); Baughman RA et al. Circulation 98 (16): 1610-1615 (1998); Bai JP et al., Crit Rev Therap Drug Carrier Syst 12 (4): 339-371 (1995); Bowe CL et al., Proc Nat Acad Sci 94 (22): 12218-23 (1997); Chao AC et al., J Pharm Sci 87 (11): 1395-1399 (1998); Chao AC et al., J Drug Targeting 6 (1): 37-43 (1998); And Fix JA. J Pharm Sci 85 (12) 1282-1285 (1996).

In many situations, enhancers have several different functions. However, the degree of influence on the biological environment is not known at all, and the mechanism of action is not clear and it is difficult to confirm in vivo. Other types of such functional excipients include, for example, preventing or increasing complex formation with species in the biological environment (eg, ions such as proteins, bile salts, lipids, Ca ^2+, etc.), reversible or irreversible Lipids, chelators, and polymers that affect membrane permeability and can act by blocking the high local concentrations of drugs that can form drugs into granules and irritate near the membrane.

The present invention relates to pharmaceutical formulations comprising bisphosphonates. The present invention also relates to methods of making such pharmaceutical formulations, inhibition of bone resorption and the use of such pharmaceutical formulations for the treatment and prevention of osteoporosis.

Surprisingly, it has been found that incorporation of one or more additives into pharmaceutical formulations containing bisphosphonates can substantially improve bisphosphonate absorption. The use of additives as enhancers will have beneficial effects such as improved absorption and / or reduced change when bisphosphonates such as alendronate are administered by other routes of administration such as oral, rectal, buccal, intranasal and intrapulmonary routes. This will allow the patient to take the medication more conveniently, for example with food intake. It will also reduce side effects such as, for example, local irritation of the upper gastrointestinal mucosa.

Accordingly, the present invention provides a pharmaceutical formulation comprising at least one bisphosphonate and at least one additive selected from the group consisting of:

Surfactants such as nonionic surfactants such as sorbitan esters (Span series), polysorbates (Tween series), polyoxyethylated glycol monoethers (Brij series) Alkyl glucosides such as polyoxylated alkyl esters (Myrj series), polyoxyethylated alkyl phenols (Triton series), sugar glucosides, for example dodecyl maltoside, sugar fatty acid esters Such as sucrose laurate, sucrose monostearate and saponin;

Amphoteric surfactants such as betaine;

Anionic surfactants such as sulfated fatty alcohols, sulfated polyoxyethylated alcohols, other species such as dioctyl sulfosuccinate;

Cationic surfactants, for example ammonium compounds;

Bile salts, for example dihydroxy bile salts such as sodium deoxycholate, trihydroxy bile salts such as sodium glycocholate and pushed salts such as sodium dihydrofulate;

Alkali metal salts and fatty acids and salts thereof, such as octanoic acid, decanoic acid and sodium decanoate;

Lipids, such as phospholipids (except as described in PCT Application SE 98/01790), for example DPPC and DMPC;

Oils such as soybean oil and sunflower oil;

Enamines such as DL-phenylanaline and ethylacetoacetate enamine;

Chelating agents, for example EDTA, EGTA and citric acid;

Phenothiazines, for example chlorpromazine;

Fatty acid derivatives of carnitine and peptides, for example palmitoyl-DL-carnitine;

Substances selected from the group consisting of azone, concanavalin A, phosphate and phosphonate derivatives, for example DL-a-glycerophosphate and 3-amino-1-hydroxypropylidene-1,1-diphospho Nates, diethyl maleate and diethylethoxymethylene malonate;

Products of the Maillard reaction, ie products obtained by the reaction of sugars with amino acids, for example compounds of the glycoslysin reaction;

Polymers such as polyacrylic acid, for example Carbopol®, polycarbophil;

Chitosan and chitosan derivatives, and

Block copolymers, for example poloxamer, poloxamine and meroxapol;

Biodegradable polymers such as polyactic acid, polyglycolic acid and copolymers thereof.

Desired suitable combinations of enhancers are as follows, but are not limited to these.

Lipids (also described in PCT Application No. SE 98/01790) and surfactants such as monoolein and sodium taurocholate, monoolein and tween 80 (polyoxyethylene (20) sorbitan mono-oleate , Also called polysorbate 80);

Lipids of nonphospholipid properties (also described in SE 98/01790) and phospholipids such as medium chain glycerides and lecithin;

Block copolymers with lipids (also described in SE 98/01790), for example monoolefins and Pluronic F 127 (triblock copolymers of polyoxyethylene / polyoxypropylene / polyoxyethylene poloxamer 407 );

Surfactants and oils such as sucrose fatty acid esters and soybean oil; And

Polymers and lipids such as polycarbophil and monoolein.

These combinations may be in the form of emulsions and microemulsions, for example comprising monoolein / triglycerides / water or isopropyl myristate / lecithin / water.

Preferred additives of the present invention

Nonionic surfactants such as sugar glycosides and sugar fatty acid esters;

Lipids such as phospholipids, for example DPPC and DMPC;

Oils such as soybean oil and sunflower oil;

Chelating agents, for example EDTA, EGTA, citric acid;

Fatty acid derivatives of carnitine or peptides, for example palmitoyl-DL-carnitine;

Polymers such as polyacrylic acid, for example carbopol, polycarbophil;

Block copolymers, for example poloxamer, poloxamine and meroxapol;

Saponins;

Combinations of the above.

Said lipids as described in PCT Application No. SE 98/01790 are medium chain glycerides or mixtures of medium chain glycerides, in particular compounds of 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 6 to 18 carbon atoms, preferably 6 to 12 carbon atoms, but R ¹ , R ² and R ³ At least one is an alkanoyl group.

Dosage forms used may be solid, semisolid or liquid formulations prepared by known techniques. Usually the active material constitutes 0.001% to 99% by weight, preferably 0.003 to 1.3% by weight, most preferably 0.1 to 1% by weight of the formulation.

Preferably, the bisphosphonates have the formula II.

In the formula,

R ⁴ is H, OH or Cl;

R ⁵ is

(a) alkyl of 1 to 6 carbon atoms which may be substituted by amino, alkylamino, dialkylamino or heterocyclyl;

(b) halogen;

(c) arylthio, preferably chlorosubstituted arylthio;

(d) cycloalkylamino having 5 to 7 carbon atoms;

(e) saturated 5 or 6 membered nitrogen containing heterocyclyl having 1 or 2 heteroatoms.

In alkylamino and dialkylamino the carbon number of the alkyl group may be 1 to 5 and may be independently bonded to the dialkylamino group.

The term "heterocyclyl" means a saturated or unsaturated 5-7 membered heterocyclic group having 1 or 2 rings and 1 -3 heteroatoms independently selected from N, O and S.

Unless otherwise stated or mentioned, the term “aryl” means 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" means an aryl group as defined above 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),

1-hydroxy-3- (N-methyl-N-pentylamino) propylidene-1,1-bisphosphonic acid (ibandronate),

1-hydroxy-2- (3-pyridyl) ethylidene-1,1-bisphosphonic acid (lizedronate),

1-hydroxyethylidene-1,1-bisphosphonic acid (ethedronate),

1-hydroxy-3- (1-pyrrolidinyl) propylidene-1,1-bisphosphonic acid,

1-hydroxy-2- (1-imidazolyl) ethylidene-1,1-bisphosphonic acid (zoledronate),

1-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 (shimadronate, incadronate),

6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (neridronate) and pharmaceutically acceptable salts thereof.

Most preferred compounds of formula (II) are 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (alendronate) and pharmaceutically acceptable salts thereof.

In a preferred form, the pharmaceutical preparations according to the invention are suitable for oral administration and may be administered on an empty stomach or in a meal.

In the preparation of a pharmaceutical preparation according to the invention in dosage unit form for oral administration, bisphosphonates and absorption enhancers are filled into soft or hard gelatin or cellulose capsules: solid powder components, for example lactose, saccharose, sorbitol, mannitol, starch. , Amylopectin, cellulose derivatives, gelatin or other suitable ingredients; It can be mixed with disintegrants and lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol wax. This mixture is then treated with granular powder or compressed into tablets.

In one embodiment of the present invention, bisphosphonates and additives are considered in that the granule (solid, semi-solid or liquid) form may be preferably selected to avoid the presence of the drug at high local concentrations that may irritate the mucosal layer membranes. Mix in a suitable form. Such granular forms can be obtained by well-known methods, for example, by dispersing bisphosphonates in fine media (10 μm) in a suitable medium such as sesame oil, soybean oil or the like, or by forming a carrier / drug system in granular form. Finely divided bisphosphonates or carrier / drug systems can be dried or wet pulverized, freeze pulverized, air jet ultra fine pulverized, spray dried, spray cooled, spray lyophilized, electrospray, supercritical crystallization (RESS or GAS method), emulsion solvent evaporation, emulsion It may be prepared by techniques such as but not limited to solvent extraction and emulsion solvent diffusion.

The suspension of bisphosphonates in the oil or carrier / bisphosphonate system is then administered orally in suspension or capsule.

The daily dosage of bisphosphonates suitable for the treatment of humans is from 0.001 to 100 mg, preferably from 0.001 to 10 mg, most preferably from 0.005 to 0.3 mg per kg of body weight upon oral administration.

Enhancers or combinations of enhancers, and, if necessary, suitable carriers or nonfunctional excipients comprise from 0.1 to 99.9% by weight, preferably from 80 to 99.9% by weight of the formulation.

The pharmaceutical preparations according to the invention are useful for inhibiting bone resorption to treat or prevent bone loss associated with osteoporosis, aging, steroid treatment, rheumatism, Paget's disease or cancer. The pharmaceutical preparations according to the invention are also useful for the prophylaxis and / or treatment of secondary osteoporosis except steroid induced osteoporosis, periodontitis, osteoarthritis. Pharmaceutical formulations according to the invention are also useful for the treatment of hypercalcemia. Thus, the use of the pharmaceutical formulation to treat these diseases is another aspect of the present invention.

In another aspect of the present invention there is provided a process for the preparation of a pharmaceutical formulation according to the invention comprising forming a mixture of (i) bisphosphonates, (ii) additives and (iii) pharmaceutically acceptable carriers.

Another aspect of the invention provides the use of bisphosphonates in combination with absorption enhancers for the manufacture of a medicament for inhibiting bone resorption to treat or prevent bone loss associated with osteoporosis, aging, steroid treatment, rheumatoid, Paget's disease or cancer do. The pharmaceutical preparations according to the invention are also useful for the prophylaxis and / or treatment of secondary osteoporosis except steroid induced osteoporosis, periodontitis, osteoarthritis. Preferably, the medicament is suitable for oral administration.

Another aspect of the present invention provides a method of inhibiting bone resorption to treat or prevent osteoporosis, aging, steroid treatment, rheumatism, Paget's disease or bone loss associated with cancer. The pharmaceutical preparations according to the invention are also useful for the prophylaxis and / or treatment of secondary osteoporosis, except for steroid-induced osteoporosis, periodontitis, osteoarthritis, which method is effective for humans in need of such treatment. Administration to a mammal, including. Preferably, the pharmaceutical formulation is administered orally.

Biological assessment

The effect of the formulations according to the invention to prevent bone loss has been analyzed, developed and established in studies using an intact growing young rat model to predict the effect of bisphosphonates in actual clinical practice.

result

ED ₅₀ values obtained in an intact rat model indicate that the oral dosage formulations according to the invention tested are more potent than when administered in equimolar amounts of bisphosphonates alone.

Intact growing young rats were studied for 14 days to determine the apparent dose-response effect of the enhancer. Oral administration of bisphosphonates in saline had no effect.

The effect on bone density obtained by enhancer / bisphosphonate was similar to that obtained by subcutaneously administered bisphosphonate, but had no effect on bisphosphonates in saline administered orally.

All rats were normal and showed normal weight.

conclusion

Rat studies strongly support the idea that enhancers as proposed herein can increase oral bioavailability of bisphosphonates such as those described herein, even in the presence of food.

Examples of pharmaceutical formulations according to the invention:

Formulation 1

Alendronate 2.3 mg

Caprylic Acid, Sodium Salt 11.5 mg

1.0 g of 50 mM Tris (buffer) with 100 mM NaCl

About 2.3 mg of alendronate and 11.5 mg of caprylic acid were dissolved in buffer and the pH was adjusted to 7.5 with sodium hydroxide.

Formulation 2

Alendronate 2.3 mg

Monoolein 11.5 mg

Tween 80 11.5 mg

1.0 g of 50 mM Tris (buffer) with 100 mM NaCl

About 2.3 mg of alendronate and 11.5 mg of monoolein were dissolved in a 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

1.0 g of 50 mM Tris (buffer) with 100 mM NaCl

About 2.3 mg of Alendronate and 50 mg of Quill A were dissolved in buffer and the pH was adjusted to 7.5 with sodium hydroxide.

Formulation 4

Alendronate 2.3 mg

Carbopol 934P 5.0 mg

1.0 g of 50 mM Tris (buffer) with 100 mM NaCl

About 2.3 mg of Alendronate and 5.0 mg of Carbopol were mixed with the buffer to form a dispersion and the pH was adjusted to 7.5 with sodium hydroxide.

Formulation 5

Alendronate 2.3 mg

Carbopol 934P 15.0 mg

1.0 g of 50 mM Tris (buffer) with 100 mM NaCl

About 2.3 mg of Alendronate and 15.0 mg of Carbopol were mixed with the buffer to form a dispersion and the pH was adjusted to 7.5 with sodium hydroxide.

Formulation 6

Alendronate 2.3 mg

Isopropyl myristate 630 mg

Lecithin (Epicuron 200) 270 mg

100 mg 50 mM Tris (buffer) with 100 mM NaCl

About 23 mg of Alendronate was dissolved in buffer and added to isopropyl myristate and lecithin mixture (70/30 w / w) with pH adjusted to 7.5 using sodium hydroxide.

Formulation 7

Alendronate 2.3 mg

Isopropyl myristate 450 mg

Twin 21 450 mg

100 mg 50 mM Tris (buffer) with 100 mM NaCl

About 23 mg of Alendronate was dissolved in buffer and adjusted to pH 7.5 with sodium hydroxide and added to the isopropyl myristate and Tween 21 mixture (50/50 w / w) with stirring.

Formulation 8

Alendronate 2.3 mg

Monoolein 630 mg

Soybean Triglycerides 270 mg

100 mg 50 mM Tris (buffer) with 100 mM NaCl

About 23 mg of Alendronate was dissolved in buffer and added to the monoolein and soy triglyceride mixture (70/30 w / w) with pH adjusted to 7.5 with sodium hydroxide and stirring.

Formulation 9

Alendronate 2.3 mg

1.0 g of soy triglycerides

2.3 mg of alendronate was added to soy triglycerides and sonicated while cooling on ice and ground.

Claims (46)

At least one bisphosphonate, and - Surfactants; Amphoteric surfactants; Anionic surfactants; Cationic surfactants; Bile salts; Alkali metal salts and fatty acids, and salts thereof; Lipids, excluding medium chain glycerides or mixtures of medium chain glycerides 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 6 to 18 carbon atoms, preferably 6 to 12 carbon atoms, but R ¹ , R ² and R At least one of ³ is an alkanoyl group) - oil; Enamines; Chelating agents; Phenothiazines; Fatty acid derivatives of carnitine or peptides; Phosphate and phosphonate derivatives such as azone, concanavalin A, DL-a-glycerophosphate and 3-amino-1-hydroxypropylidene-1,1-diphosphonate, diethyl maleate and diethyl Materials selected from the group consisting of ethoxymethylene malonate; The product of the mailard reaction; Polymers such as block copolymers and biodegradable polymers; Chitosan and Chitosan Derivatives A pharmaceutical formulation comprising at least one additive in an amount sufficient to enhance absorption of bisphosphonates, selected from the group consisting of: The pharmaceutical formulation of claim 1, wherein the additive is a nonionic surfactant. The pharmaceutical formulation of claim 2, wherein the nonionic surfactant is sugar glycoside or sugar fatty acid ester. The pharmaceutical formulation of claim 1, wherein the additive is a lipid. The pharmaceutical formulation of claim 4, wherein the lipid is phospholipid. The pharmaceutical formulation of claim 1, wherein the additive is an oil. The pharmaceutical formulation of claim 6, wherein the oil is soybean oil or sunflower oil. The pharmaceutical formulation of claim 1, wherein the additive is a chelating agent. The pharmaceutical formulation of claim 8, wherein the chelating agent is EDTA, EGTA or citric acid. The pharmaceutical formulation of claim 1, wherein the additive is a fatty acid derivative of carnitine or a peptide. The pharmaceutical formulation according to claim 10, wherein the additive which is a fatty acid derivative of carnitine or peptide is palmitoyl-DL-carnitine. The pharmaceutical formulation of claim 1, wherein the additive is a polymer. 13. The pharmaceutical formulation of claim 12, wherein said polymer is polyacrylic acid. The pharmaceutical formulation of claim 1, wherein the additive is a block copolymer. The pharmaceutical formulation of claim 14, wherein said block copolymer is poloxamer, poloxamine or meroxapol. The pharmaceutical formulation of claim 1, wherein said additive is saponin. The pharmaceutical formulation of claim 1, wherein the additive is a biodegradable polymer. The pharmaceutical formulation of claim 17, wherein the biodegradable polymer is polyactic acid or polyglycolic acid. The pharmaceutical formulation of claim 1, wherein the additive is a combination of a lipid and a surfactant. The pharmaceutical formulation of claim 19, wherein the combination of lipid and surfactant is a combination of monoolein and sodium taurocholate, or a combination of monoolein and tween 80. The pharmaceutical formulation of claim 1, wherein the additive is a combination of lipid and phospholipids of non-phospholipid properties. The pharmaceutical formulation of claim 21, wherein the combination of lipid and phospholipids of non-phospholipid properties is medium chain glycerides and lecithin. The pharmaceutical formulation of claim 1, wherein the additive is a combination of a lipid and a block copolymer. The pharmaceutical formulation of claim 23, wherein the combination of lipid and block copolymer is monoolein and Pluronic F 127. The pharmaceutical formulation of claim 1, wherein the additive is a combination of a surfactant and an oil. The pharmaceutical formulation of claim 25, wherein the combination of surfactant and oil is sucrose fatty acid ester and soybean oil. The pharmaceutical formulation of claim 1, wherein the additive is a combination of polymer and lipid. The pharmaceutical formulation of claim 27, wherein the combination of polymer and lipid is polycarbophil and monoolein. The pharmaceutical formulation of claim 1, wherein the combination of additives is selected to form an emulsion or microemulsion. The pharmaceutical formulation according to any one of claims 1 to 29, wherein the bisphosphonate has the structure of formula II. <Formula II> In the formula, R ⁴ is H, OH or Cl; R ⁵ is (a) alkyl of 1 to 6 carbon atoms which may be substituted by amino, alkylamino, dialkylamino or heterocyclyl; (b) halogen; (c) arylthio or chlorosubstituted arylthio; (d) cycloalkylamino having 5 to 7 carbon atoms; (e) saturated 5 or 6 membered nitrogen containing heterocyclyl having 1 or 2 heteroatoms. The method of claim 30, wherein the bisphosphonate is R ⁴ is H or OH; R ⁵ is (a) alkyl of 1 to 6 carbon atoms which may be substituted by amino, alkylamino, dialkylamino or heterocyclyl; (d) cycloalkylamino having 5 to 7 carbon atoms; (e) A pharmaceutical formulation having the structure of Formula II which is a saturated five or six membered nitrogen containing heterocyclic having one or two heteroatoms. The method of claim 30, wherein the bisphosphonate is R ⁴ is OH; R ⁵ is (a) alkyl of 1 to 6 carbon atoms which may be substituted by amino, alkylamino, dialkylamino or heterocyclyl; (d) cycloalkylamino having 5 to 7 carbon atoms; (e) A pharmaceutical formulation having the structure of Formula II which is a saturated five or six membered nitrogen containing heterocyclyl having one or two heteroatoms. The method of claim 30, wherein the bisphosphonate is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (alendronate), N, N-dimethyl-3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (mildronate, olpadronate), 1-hydroxy-3- (N-methyl-N-pentylamino) propylidene-1,1-bisphosphonic acid (ibandronate), 1-hydroxy-2- (3-pyridyl) ethylidene-1,1-bisphosphonic acid (lizedronate), 1-hydroxyethylidene-1,1-bisphosphonic acid (ethedronate), 1-hydroxy-3- (1-pyrrolidinyl) propylidene-1,1-bisphosphonic acid, 1-hydroxy-2- (1-imidazolyl) ethylidene-1,1-bisphosphonic acid (zoledronate), 1-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 (shimadronate, incadronate), Pharmaceutical formulations which are 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (neridronate) and pharmaceutically acceptable salts thereof. 34. The pharmaceutical formulation of claim 33, wherein the bisphosphonate is alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid) or a pharmaceutically acceptable salt thereof. 35. The pharmaceutical formulation of any one of claims 1 to 34, which is suitable for oral administration. 36. A pharmaceutical formulation according to any one of claims 1 to 35 suitable for non-collective delivery. 37. A pharmaceutical formulation according to any one of claims 1 to 36 for inhibiting bone resorption. 37. The method according to any one of claims 1 to 36 for treating and preventing osteoporosis and secondary osteoporosis except aging, steroid treatment, bone loss associated with rheumatoid, Paget's disease or cancer, and steroid induced osteoporosis, periodontitis or osteoarthritis. Pharmaceutical formulations for The pharmaceutical formulation according to any one of claims 1 to 38, wherein said formulation is granular. 40. The pharmaceutical formulation according to claim 39, wherein said granular form is solid or semi-solid. 41. The pharmaceutical formulation according to claim 39 or 40, wherein the bisphosphonate is finely divided. 41. A method of making a pharmaceutical formulation according to any one of claims 1 to 40, comprising forming (i) at least one bisphosphonate and (ii) an additive and (iii) a pharmaceutically acceptable carrier. Use of the pharmaceutical formulation according to any one of claims 1 to 41 for the manufacture of a medicament for inhibiting bone resorption. Claims 1 to 41 for the preparation of a medicament for the treatment and prevention of osteoporosis and secondary osteoporosis except aging, steroid treatment, bone loss associated with rheumatism, Paget's disease or cancer, and steroid-induced osteoporosis, periodontitis, osteoarthritis. Use of a pharmaceutical formulation according to any one of the preceding. 42. A method of inhibiting bone resorption comprising administering an effective amount of a pharmaceutical formulation according to any one of claims 1 to 41 to a mammal, including a human, in need thereof. 42. Osteoporosis and aging, steroid treatment, rheumatoid, Paget's disease or cancer, comprising administering an effective amount of a pharmaceutical formulation according to any one of claims 1 to 41 to a mammal, including a human, in need thereof. And methods for treating and preventing secondary osteoporosis except bone loss associated with, and steroid-induced osteoporosis, periodontitis, osteoarthritis.