Use of bisphosphoric acid derivatives for the manufacture of a medicament to improvement bone repair.

Description: TECHNICAL FIELD [Detailed description of the invention]

【0001】

The present invention relates to the use of bisphosphonic acid derivatives for the preparation of pharmaceutical compositions intended to promote bone repair in human or veterinary medicine.

【0002】

The present invention also relates to a pharmaceutical composition containing the derivative for promoting bone repair.

【0003】

The physiological process of bone repair is defined as the continuous appearance of different scar tissue. These tissues are as follows and are listed in order of appearance. : Cartilage, primary bone (unorganized) and lamellar bone (organized). Each of these tissues is formed only after the previous tissue has been destroyed. Therefore, such changes are due to absorption. This absorption is assured by macrophage cells, i.e. cartilage resorbent cells for cartilage resorption and osteoclasts for bone resorption. This is Le Tissu Osseux (Bone Tissue) (Collection: Biologi e de l'appareil locomoteur (Biology of the locomotor apparatus), Diffusion) edited under the guidance of L. Teot, J. VIdal and J. Dossa. Vigot, 1989) and HMFrost's The biology of fracture healing. A summary for clinicians can be found in I and II, Clin. Orthop., 1989, 248, 283, etc.

【0004】

In the present specification and claims below, a bisphosphonic acid derivative is understood to mean a compound represented by the following general formula and a salt thereof with a pharmaceutically acceptable mineral acid or organic acid.

【0005】

[Chemical 3]

(In the formula, -R₁Are hydrogen atom, halogen atom, hydroxyl, amino, mono-C₁-C₄-Alkylamino or di-C₁-C₄-Alkylation amino, -R₂Is an unsubstituted linear alkyl, chlorine atom, hydroxyl, amino, mono-C having a halogen atom or 1 to 5 carbon atoms.₁-C₄-Alkylamino, di-C₁-C₄-Alkylamino and C₃-C₇-A linear alkyl having 1-5 carbon atoms substituted with a group selected from cycloalkylaminos, or R₂Are phenoxy, phenyl, thiol, phenylthio, chlorophenylthio, pyridyl, pyridylmethyl, 1-pyridyl-1-hydroxymethyl, imidazolylmethyl or thiomorpholine-4-yl. ) These compounds are known and specifically disclosed in the following patents as pharmaceutical compositions in the treatment of bone disorders: BE 902308, BE 865434, DE 2130794, US 4134969, EP 162510, FR 2525223, EP 39033. , US 4578376, EP 203549, BE 822930, US 4621077, JP55-98193, EP 186405, EP 100718, WO 86/00902, WO 87/03598, US4922007, EP 304961, JP 63-150291, EP 325482.

【0006】

Among these bisphosphonic acid derivatives, the following compounds will be particularly described: 1-hydroxyethylidene bisphosphonic acid (international non-owned name (common name) etidronic acid) and its sodium salt, 2-pyridine-2-ylethylidenebisphosphonic acid ( Common name pyridroic acid) and its sodium salt, dichloromethylene bisphosphonic acid (common name clodronic acid) and its sodium salt, 3-amino-1-hydroxypropyridenebisphosphonic acid (common name pamidronic acid) and its sodium salt, 4-amino -1-Hydroxybutylidenebisphosphonic acid (commonly known as alendronic acid) and its sodium salt, 6-amino-1-hydroxyhexylidenebisphosphonic acid and its salt phenoxymethylenebisphosphonic acid and its salts, thiomorpholinomethylenebisphosphonic acid and its salts Salts, 4-chlorophenylthiomethylenebisphosphonic acid (conventional name tildronic acid) and its pharmaceutically acceptable salts (particularly disodium salts), 1-hydroxy-2- (pyridine-3-yl) etylidenebisphosphonic acid (conventional) Name lysedronic acid) and its sodium salt, 1-hydroxy-2- (imidazol-3-yl) ethyl-1,1-bisphosphonic acid and its salt, (cycloheptylamino) methylenebisphosphonic acid and its salt, 2-hydroxyethi Lysine-2- (pyridine-3-yl) -1,1-bisphosphonic acid and its sodium salt.

【0007】

The salts of the bisphosphonic acid derivatives described above are commonly referred to as bisphonates.

【0008】

According to the present invention, it is particularly preferred to use tildronic acid and a pharmaceutically acceptable salt thereof, in particular a disodium salt.

【0009】

The pharmacological effect of bisphosphonic acid derivatives is to inhibit bone resorption by reducing the activity of osteoclasts, as shown in the following literature: H. Fleisch, RGG Russel and. MDFrancis: Diphosphonates inhibithydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo; Science, 1969,165,1262-1264; PM Boonekamp, LJA Van der Wee-Pals, MML Van Wijk-Lennep, CWThesing and OLM Bijvoet: Two modes of action of bisphosphonates on osteoclastic resorption of mineralized matrix; Bone Miner., 1986,1,27-39; AM Flanaghan and TJ Chambers: Dichloromethylene bisphoshonate (Cl₂, MBP) inhibits bone resorption through injury to osteoclasts that resorb ClMBP coated bone; Bone Miner., 1989, 6, 33.

【0010】

Several bisphosphonic acid derivatives have traditionally been developed for humans and are marketed for use in the treatment of bone diseases such as Paget's disease and osteoporosis. These diseases are characterized by osteoclast-stimulating effects (more prominent in Paget's disease than in osteoclasts). This is being investigated.

【0011】

A paper by HCTennenbaum et al., Published in Bone, 1992, 13, 249-255, relates to an increase in enzymatic markers of bone formation in vitro after administration of small doses of bisphosphonate.

【0012】

The literature by Feretti et al., Published in Bone Miner., 1990, 11, 111-122, shows the improvement in the biomechanical properties of bone without increased bone mass observed ex vivo after administration of bisphosphonate. Regarding.

【0013】

In addition, administration of bisphosphonate has a beneficial effect on bone repair because bisphosphonate inhibits bone resorption and the resorption stage is essential for the process of bone repair that follows fracture or bone surgery. I can't expect it. On the contrary, bisphosphonate can be expected to show symptoms of bone repair. In this regard, F. Bonnel and B. Tachot (Biologie de la cicatrisation osseuse des fracture (Biology of bone healing in fractures) in Le Tissu Osseux (op. cit .: edited under the guidance of L.Teot, J.Vidal and Dossa, collection: Biologie de l'appareil locomoteur, Diffusion Vigot, 1989). The document states, "Diphosphonate. It has the effect of stimulating the resorption of osteoclasts while suppressing bone remodeling. In fractures, medication should be discontinued until hardening occurs." It is described as.

【0014】

Nevertheless, quite unexpectedly, bisphosphonic acid derivatives were found to be useful in bone repair, especially in promoting bone repair.

【0015】

That is, the present invention relates to the use of bisphosphonic acid derivatives for the preparation of pharmaceutical compositions intended to promote bone repair, especially after fracture or bone surgery.

【0016】

The present invention also relates to a pharmaceutical composition containing the derivative to promote bone repair.

【0017】

This pharmaceutical composition can be used in human medicine and veterinary medicine.

【0018】

The pharmaceutical composition can be administered in different dosage forms such as, for example, oral administration, parenteral administration, transdermal administration or transplantation.

【0019】

When oral preparations are prepared, suitable excipients, especially excipients that enhance the absorption of pharmaceutical compositions such as sodium laurel sulphate, can be used.

【0020】

The dosage of the pharmaceutical composition of the present invention depends on the bisphosphonic acid derivative used, the dosage form and the magnitude of the desired effect on bone repair.

【0021】

The pharmaceutical composition of the present invention can be administered in single-dose units or repeated-dose units. When administered in repeated dose units, continuous daily administration of 1 to 3 times per day during fracture repair (several months), or, for example, 1 to 1 week for 1 to several months You can choose intermittent administration to be administered daily.

【0022】

The administration unit contains 0.001 mg to 400 mg, particularly 0.01 mg to 400 mg, of at least one of the bisphosphonic acid derivatives of the general formula (I).

【0023】

That is, the dose of the pharmaceutical composition prepared according to the present invention can be changed within the range of 0.001 mg to 1.2 mg, particularly 0.01 mg to 400 mg per day.

【0024】

The unit of administration preferably contains 0.1 to 250 mg of at least one of the bisphosphonic acid derivatives of the general formula (I).

【0025】

For oral administration, the pharmaceutical compositions of the present invention can be in tablets, gelatin capsules, powders, granules, drops, or other dosage forms suitable for oral administration.

【0026】

The pharmaceutical composition of the present invention may also contain ingredients commonly used in dispensing for the preparation of oral dosage forms. That is, the pharmaceutical composition of the present invention can contain a disintegrant, a flow activator, a lubricant and a suitable bulk excipient.

【0027】

Available bulk excipients are lactose, cellulose or starch. Possible lubricants are, for example, stearic acid, magnesium stearate, L-leucine, or glycerol tribehate. Usable disintegrants are, for example, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, or cross-linked polyvinylpyrrolidone. The fluid activators that can be used are pure silica or colloidal silicone dioxide.

【0028】

Furthermore, the present invention relates to an instantly soluble oral dosage form and an effervescent oral dosage form obtained by adding a combination of effervescent components to the pharmaceutical composition of the present invention. Examples of available effervescent component combinations are tartaric acid and sodium bicarbonate, or citric acid and sodium bicarbonate.

【0029】

Tablets are the preferred dosage form of the present invention. The present invention further relates to instantly soluble tablets, effervescent tablets and coated tablets. Compositions containing sodium laurel sulphate from European patent EP 336851 are particularly suitable.

【0030】

For oral administration of chilledronate, the unit dose is changed within the range of 0.05 mg to 1000 mg, preferably 0.05 mg to 400 mg, especially 0.1 mg to 250 mg.

【0031】

For oral administration of pamidronate, the unit dose is changed within the range of 0.05 mg to 1 g, preferably 0.05 mg to 400 mg.

【0032】

For oral administration of one of alendronate, risedronic acid or (cycloheptylamino) methylenebisphosphonic acid or salts thereof, the daily dose administered is in the range of 0.001 mg to 100 mg, preferably 0.01 mg to 100 mg. Change with.

【0033】

Parenteral administration uses, for example, an aqueous suspension, an isotonic saline solution or a sterile injectable solution, which may contain a compatible pharmacological dispersant and / or wetting agent such as propylene glycol or butylene glycol. Can be done.

【0034】

For transdermal administration, the pharmaceutical composition of the present invention can be in the form of a cream, ointment or composition for transdermal administration.

【0035】

[Example]

Example 1 An experimental study of bone repair was performed on dogs using a hemi-cutting model.

【0036】

The essence of hemiosteotomy is to create an incomplete fracture line belonging to the double radius along the diaphysis of the long bone (ulna). That is, this semi-fracture is fixed by the unfractured portion of the same bone and the second bone without any fixation device.

【0037】

Three groups of four male beagle dogs were used. Each of these groups was treated with gastrointestinal nutrition once daily for 6 weeks (D0-D45) after hemi-cutting. The product was administered in the form of gelatin capsules.

【0038】

[table 1]

Two doses of tetracycline were given in several days at two different times, days D26 and D27 and then D41 and D42, to label the mineralization line.

【0039】

The animal was sacrificed at D45 after the hemiosteotomy. Semi-cut bone was removed and fixed for the next histomorphological measurement experiment: -mm²Measurement of the number of osteoclasts per -Measurement of active area of absorption (%): This is the area occupied by osteoclasts relative to the total area. This measurement makes it possible to assess bone resorption. ; -Measurement of double labeled area (%) relative to total bone area: This measurement allows quantification of lamellar bone. ;and -Measurement of trabecular volume (TV); this is expressed as a percentage of total bone volume (BV). This volume represents the amount of bone formed at the site of fracture formed by hemi-cutting, including bone-like edges and mineralized tissue.

【0040】

A biomechanical test was also performed by analyzing the resonance frequency on the day after the hemibone cutting D45. : The resonance frequency was measured on the vertical plane of the ulna, the vibration was recorded with a microphone placed 1 cm above the bone, and stimulation was performed by hitting the middle along the length of the ulna with a hammer. This signal was transmitted to a spectral analyzer to obtain the frequency of the spectrum and the resonance frequency was determined.

【0041】

The average of the four measurements was calculated from the recorded signal. Two parameters were evaluated this way: 1) Bone strength: Evaluation of resistance to vibration in the vertical plane.

【0042】

Calculated robustness is F²M (Hz²× g).

【0043】

F: Resonance frequency (Hertz) M: quantity (grams) 2) Bending strength: Calculation of the force against vibration in the vertical plane.

【0044】

Bending strength is F²ML (Hz)²× g × mm).

【0045】

L: Length (mm) The results (mean and root-mean-square error: rms error) are shown in the table below.

[Table 2]

This result indicates that the final lamellar bone mass was increased for the two bisphosphonic acids, but no modification of the bone resorption parameters occurred at the same time.

【0046】

[Table 3]

These results show after treatment with bisphosphonic acid: -The trabecular volume did not decrease significantly.

【0047】

-Improved biomechanical properties. In fact, bone toughness and bending strength were increased, especially in the case of chilledronate.

【0048】

Example 2: Tablets for Improving Bone Repair Separable tablets: Equivalent to 200 mg of acid Disodium tildronic acid 240 mg Sodium Laurel Sulfate 4.5mg Crosslinked carboxymethyl cellulose Sodium 24 mg Microcrystalline lactose 177 mg Magnesium stearate 4.5mg 450 mg Example 3: Tablets for Improving Bone Repair Separable tablets: Equivalent to 50 mg of acid Disodium tildronate 60 mg Sodium Laurel Sulfate 3 mg Crosslinked carboxymethyl cellulose Sodium 6 mg Anhydrous lactose 44.25 mg Magnesium stearate 1.25 mg 114.5 mg Example 4: Tablets for Improving Bone Repair Equivalent to 25 mg of acid Disodium tildronate 30 mg Crosslinked carboxymethyl cellulose sodium 3 mg Magnesium stearate 0.75mg Microcrystalline lactose 22.25 mg 56 mg Example 5: Injection for improving bone repair Disodium phosphate salt 300mg Water for injectable preparation 6ml Example 6: Reflux formulation for improving bone repair Sodium Pamidronate Dry Frozen 15 mg Water for injectable preparation 6 ml Example 7: Reflux formulation for improving bone repair Disodium clodronate 300 mg Sodium hydroxide qsp pH5 Water for injectable preparation 5ml