MXPA97009838A - Stable pharmaceutical compositions containing tiludronate hydrates and process to produce pharmaceutical compositions - Google Patents

Abstract

Sodudronate disodium tetrahydrate is provided for use in pharmaceutical compositions for oral administration in the form of a tablet, effervescent composition, capsule and the like

Description

STABLE PHARMACEUTICAL COMPOSITIONS CONTAINING TILUDRONATE HYDRATES AND PROCESS TO PRODUCE COMPOSITIONS PHARMACEUTICALS DESCRIPTION OF THE INVENTION The present invention relates to pharmaceutical compositions containing tiludronate hydrates for oral administration and a process for their preparation. The pharmaceutical compositions are stable and possess therapeutic properties that allow their use in the treatment of osteoporosis, rheumatoid polyarthritis and Pager's disease. The bisphosphonic acid derivatives having the formula n i i 'F "' - - '- C - -" r1 wherein R. represents a hydrogen atom, a halogen atom, a hydroxyl, an amino or dialkyl (C, -C-) amino, and R represents a halogen atom, a linear alkyl containing from 1 to 5 carbon atoms which is substituted or unsubstituted by a chlorine atom, a hydroxyl, an amino or dialkyl (C -) amino, or R- represents a phenoxy, a phenyl, a thiol, a phenylthio, a chlorophenylthio, a pyridyl or a thiomorpholin-4-yl, and its salts with pharmaceutically acceptable organic or mineral acids, are known compounds that have been described in the following patents: BE NO. 902308 FR NO. 251088 BE NO.865434 JP NO. 55-98193 BE NO 822930 PAT. FROM E.U.A. DO NOT. 4,134,969 DE NO. 2130794 PAT. FROM E.U.A. DO NOT. 4,578,376 EP NO. 203649 PAT. FROM E.U.A. DO NOT. 4,980,171 EP NO. 162510 PAT. FROM E.U.A. DO NOT. 5,405,994 EP NO. 39033 WO NO. 86/00902 EP NO.100718 WO NO. 87/03598 FR NO.2525223 The compounds have been described as being useful in the oral treatment of bone diseases and / or joint complaints of the arthritis type. Among the compounds is tiludronic acid, that is, 4-chlorophenylthiomethylenebisphosphonic acid, and its disodium salt that has the structure which has been extensively researched for the development of a drug useful in the treatment of rheumatoid arthritis, Paget's disease and osteoporosis.

U.S. Patent No. 5,405,994 describes two forms of disodium tiludronate: disodium tiludronate hemihydrate and disodium tiludronate monohydrate. Sodudronate disodium hemihydrate is prepared in situ from an aqueous solution of tiludronic acid by the addition of a sufficient amount of sodium hydroxide to have the pH between 4.6 to 4.8. Sodudronate disodium hemihydrate is prepared by heating the disodium tyludronate hemidrate in aqueous solution at a temperature of between 60 ° C to 90 ° C for approximately 2 to 4 hours, cooling the solution to a temperature between room temperature and 5 ° C, separating by filtering the precipitate formed and then drying the precipitate. The preparation of 4-chlorophenylthiomethylene bisphosphonate, 4-chlorophenylthiomethylenebisphosphonate disodium hemidrated and 4-chlorophenylthiomethylenebisphosphonate disodium monohydrate and 4-chlorophenylthiomethylenebisphosphonate disodium monohydrate is described as follows. A) Preparation of 4-chlorophenylthiomethylenebisphosphonic acid The tetraisopropyl 4-chlorophenylthiomethylenebisphosphonate is prepared by applying the method described in European Patent 100 718. This compound is treated with water and hydrochloric acid and heated at 90 ° C for several hours. After cooling, extraction is carried out with dichloroethane. The aqueous phase is concentrated under vacuum to remove the hydrochloric acid and water. The toluene is added and the residual water is removed by distillation. The 4-chloro-femthiomethylenebisphosphonic acid precipitates on cooling. This precipitate is collected by filtration, washed with toluene and dried at a temperature of less than or equal to 70 ° C.

B) Preparation of 4-chlorophenylthiomethylenebisphosphonate disodium hemidrate The sodium hydroxide is added, either in flakes or as an aqueous solution, to an aqueous suspension of the acid obtained above until the pH is approximately 4.7. Activated charcoal is added and the mixture is clarified by filtration. The filtrate is mixed with acetone and the expected salt precipitates at room temperature.

The precipitate is collected by filtration, washed with acetone and dried at a temperature less than or equal to 70 ° C.

C) Preparation of 4-chlorophenylthiomethylenebisphosphonate disodium monohydrate An aqueous solution of disodium tiludronate is prepared by mixing 100 g of the salt with 1 liter of water and this solution is clarified by filtration. 2.3 liters of acetone are brought to reflux and the above aqueous solution is emptied at reflux, which is maintained for 3 hours. The medium is left to bring to room temperature and is then cooled for 1 hour at 10 ° C. The formed precipitate is filtered off and then dried overnight at 60 ° C in a vented oven to give 95 g of the expected product in the form of crystals.

It was found that pharmaceutical tablets using 4-chlorophenylmethylenebisphosphonate disodium monohydrate stored for 15 months at room temperature are stable.

It has been surprisingly found that 4-chlorophenylthiomethylenebisphosphonate disodium monohydrate also exists as a tetrahydrate. It has also been found that the tetrahydrated form of the 4-chlorophenylthiomethylenebisphosphonate disodium is more stable at high relative humidity than the monohydrated or hemihydrated forms and is not converted to either the monohydrated or hemihydrated form thereof at ambient temperature and humidity. This surprising discovery carries by itself both advantages of the process and product therefore not realized by the prior art. In the process for preparing disodium 4-chlorophenylthiomethylenebisphosphonate (hereinafter sometimes referred to as tiludronate) Disodium 4-chlorophenylthiomethylenebisphosphonate is initially obtained as in the tetrahydrate form of disodium tiludronate which has not been recognized by the European Patent No 100718 or US Pat. No. 5405994. The disodium tyludronate tetrahydrate is then dried to obtain the disodium tyludronate hemihydrate. To obtain the final product, ie, disodium monohydrate, used in the dosage form, the disodium tiludronate hemihydrate is subjected to wet granulation, during which it is converted from the disodium hemihydrate to its tetrahydrated form, and the granulate is dried to give the disodium monohydrate. The present invention recognizes that the tetrahydrate form of disodium tiludronate is stable through this conversion process and produces several advantages including: the drying step required to convert the initially obtained tetrahydrate to hemihydrate can be eliminated; the need to ensure the total conversion of the hemihydrate to the tetrahydrate during wet granulation can be avoided to avoid any product variability that can be caused by the presence in the granulate of a mixture of tetrahydrate and unconverted hemihydrate; it may be obvious to dry the product at about 60 ° to convert the hemihydrate to the monohydrated form of tiludronate; and the tetrahydrated form in a drug product can be used to ensure physical stability at high relative humidity. According to the invention, the disodium tyludronate tetrahydrate is provided for use in pharmaceutical compositions for oral administration in the form of a tablet, effervescent composition, capsule and the like. Sodudronate disodium tetrahydrate is provided by the process of: (a) Reacting the tiludronic acid with sodium hydroxide in an aqueous solution and then adding a non-solvent such as acetone to cause the precipitation of the tetrahydrate; or (b) Submit the disodium tyludronate hemihydrate to an excess of water; or (c) Submit the sodium disodium monohydrate to an excess of water BRIEF DESCRIPTION OF THE DRAWINGS Figures la, Ib, 2a, 2b, 3, 4a, 4b, 4c, 4d and 5 through 9 show the physical characteristics of disodic tiludronate in the hemihydrate, monohydrate and tetrahydrate form which will help to describe the present invention. The effects of moisture on disodium tiludronate for drug substance are investigated by the Gravimetric Termination Analysis (TGA), Fourier Transform Infrared Spectroscopy (FTIR), and X-ray powder diffraction (XRPD). The structure of the disodium tiludronate hemihydrate changes to the tetrahydrated form at high humidity (95% RH) and to a mixture of forms at 75-85% RH. The mixture is composed of tetrahydrate and monohydrate or possibly all forms. It is observed that the tetrahydrated form contains 16.4% water, in excellent compliance with the theoretical value (16.6%) for a tetrahydrate. The FTIR and XRPD spectrum data are significantly different for the tetrahydrate with respect to the substances for non-compressed drug, thus confirming a crystalline change at lower relative humidity (12-58% RH), the disodium tiludronate hemihydrate shows no changes TGA and FTIR.

The following describes the studies and results obtained by it.

Study / Design Methods A) Hygroscopicity The samples of disodic tiludronate are compressed at moisture levels of 12-95% RH using different saturated solutions to obtain a range of relative humidity.

The salt solutions used and the corresponding relative humidity are tabulated below: Saline solution% RH (20 ° C) Lithium Chloride 12 Potassium Acetate 13 Calcium Chloride 31 Potassium Carbonate 43 Sodium Bromide 58 Sodium Chloride 75 Potassium Bromide 84 Sodium Phosphate 95 The samples are kept for two weeks at each humidity at 20 ° and analyzed by TGA for moisture content. The samples are also analyzed by FTIR to determine if spectroscopic changes are observed. The samples which increase their moisture content after two weeks are then moved to a lower relative humidity to determine if the water uptake is reversible. A sample of the monohydrated form is also compressed with respect to moisture. Compress the samples at 58-95% RH at 20 ° for two weeks. B) Thermal gravimetric analysis (TGA) The thermal gravimetric analysis is performed on the Perkin Elmer TGA-7 system. The samples are weighed on a platinum weight and swept at a rate of 5 ° C / min. under gas with nitrogen purge. C) Fourier Transform Infrared Spectroscopy (FTIR) The FTIR spectrum is obtained in the Nicolet 730 equipment equipped with an MCT detector. The samples are run, as KBr dispersions at approximately a 1% concentration.

D) X-ray Diffraction of Powder (XRPD) XRPD data is provided by Kodak Technology Division (Rochester, NY) using a Rigaku RU 300 system at 2 ° C (2-theta) / min. E) Solubility The solubility of the non-compressed hemihydrated form, the monohydrated form and a sample which has been equilibrated at 95% RH, ie tetrahydrate in acetate buffer, is compared. A pH value of 4.8 is chosen. Approximately 250 mg of the drug is added to one ml of solvent and agitated with a laboratory rotator at 20 ° C. Filter the sample (0.45 microns) and dilute (20 ul to 25 ml). The solution is then diluted by a factor of 5 before the UV analysis. The samples are analyzed at the time points of 0.5, 3.0, and 24 hours with the Hewlett Packard 8451A diode array spectrophotometer. The absorbance at 264 nm is measured against a standard prepared in acetate buffer. Solubility (based on an anhydrous drug) is determined for two different samples (of each form) at each time point. F) Relationship of intrinsic dissolution. The intrinsic dissolution ratios of the hemihydrate, the monohydrated form and the tetrahydrated form in acetate buffer (pH = 4.8) at 20 ° C are determined. A disc (0.5 cm2) is compressed under the following conditions: 225-250 mg of drug, 4000 pounds of pressure, and 30 seconds of compaction time. The disk is dissolved in a Vander Kamp VK 6000 solution bath in 250 ml of solvent at 100 RPM. Samples are extracted in minutes 2, 4, 6, 8, 10 and 15 by a factor of 2 for UV analysis. The samples are analyzed at 264 nm with the Hewlett Packard 8451A diode array spectrophotometer. Traces of intrinsic solution are generated by plotting the concentration / area against time and the slope is determined by linear regression. Each dissolution experiment is run in triplicate.

G) Compression of 200 mg tablets.

The samples of the dosage form are compressed with respect to moisture. The samples of tablets (200 mg) are compressed at 12-95% RH for two weeks. Results of the study.

A) Hygroscopicity The hygroscopicity data in the figure is shown for hemihydrated samples compressed in a range of relative humidity values. At moisture levels of 12-58% mg the water content (TGA Analysis) remains at approximately 5%, similar to the substance for non-compressed drug. This humidity level is approximately equal to the theoretical moisture content for a monohydrated form (4.7%). Nevertheless, at higher humidity levels (75-95% RH) significant water uptake is observed. At a RH of 95% a moisture level of 16.4% is determined. This value corresponds closely to the theoretical value for a tetrahydratad form of tiludronate (16.6%). The sample compressed at 95% HR shows a significant change in the FTIR spectrum and the X-ray pattern indicative of the crystalline rearrangement. The data of TGA, FTIR, and X-ray Diffraction of Dust confirm the isolation of the tetrahydrated form.

Hysteresis data (samples stored at high humidity move from high humidity to low humidity) for samples compressed at 75-95% RH are shown in Figure Ib. When samples compressed at 75.95% RH move in a form of caps to chambers of lower relative humidity, the level of humidity does not decrease. This behavior is indicative of crystalline changes and shows that moisture uptake is not a hygroscopic behavior. If the humidification is hygroscopic in nature it could be expected that the level of humidification would decrease as soon as the humidity level decreases. The hysteresis data indicate the stability of the tetrahydrated form at moisture levels as low as 31% RH.

Typically a substance is hygroscopic it will increase its water content as soon as the humidity increases. Tiludronate does not increase its water content as the relative humidity increases until a relative humidity is reached where crystalline changes do not occur.

The TGA sweep for the hemihydrate is shown in Figure 2a.

The TGA sweep is shown for the drug substance which is compressed at 95% RH in Figure 2b. The total weight loss (16.4%) is similar to the theoretical value for a tetrahydrate of tiludronate (16.6%). If the water is hygroscopic water, then the changes in the XRPD pattern in reference to section D may not be significant. Figure 3 shows the TGA data for the monohydrated form run at 5 ° C minute.

B) FTIR The FTIR spectrum of hemihydrated samples maintained at high humidity shows evidence of crystal changes. The samples do not exhibit changes in the spectrum after two weeks of storage at humidity of 58% and less; these spectra equal the spectrum of the starting material. The spectrum of the hemihydrated samples stored at 75% RH and 84% RH indicates a partial change for monohydrate and tetrahydrate (Figure 4a-c). A peak at 2919 cm -1 that is observed in samples compressed at 75% RH is indicative of the presence of the crystal form monohydrate. The 84% RH sample also appears to contain a fraction of the monohydrated form, meshed with an increased fraction of the tetrahydrate. Since the water content of these samples is 8.4% and 13.7% at 75% and 84% RH respectively, it appears that the samples may be a mixture of the tetrahydrated form and the monohydrate or possibly all three forms.

At 95% RH, the FTIR spectrum of the tetrahydrate shows little evidence of the monohydrate form. The peak locations of the uncompressed hemihydrate, compressed at 75% RH, and compressed at 95% RH are tabulated below. For reference, peak locations for the monohydrated form are included.

Sample Peak Location (cm-1) Hemihydrate 3623 3638 1621 75% HR 3613 3396 2919 1626 1599 Tetrahydrate at 95% HR 3578 3543 3394 1696 1635 1597 Monohydrate 3613 3399 2919 1597 The FTIR spectra of the initial hemihydrate forms, the monohydrate and the tetrahydrate are shown in Figure 4d. The spectra are unique and indicative of different crystalline structures.

D) XRPD The powder X-ray diffraction patterns for the drug hemihydrated substance and the monohydrated forms are compared with a sample of the hemihydrate which is compressed at 95% RH in Figure 5. The patterns for the initial hemihydrate and the Substance for compressed drug (tetrahydrate) are clearly unique and indicate a rearrangement in the internal structure of the drug substance to high huedad rather than hygroscopic behavior. The X-ray data confirm the conversion of the hemihydrated form to the tetrahydrate.

E) Solubility The concentration of tiludronate in acetate buffer solution (pH = 4.8) versus time in figure 6 is shown. The initial solubility of the hemihydrate substance for drug and the monohydrated form is greater than for the tetrahydrated form (hemihydrate compressed at 95% RH). A concentration of 147 mg / ml was observed at 0.5 hours for the non-compressed sample, while a concentration of 175 mg / ml was observed for the monohydrated form. In contrast, a concentration of 140 mg / ml is observed. for the tetrahydrate at 0.5 hours. The concentration of the non-compressed hemihydrated sample and the monohydrate decreases with time and at 24 hours is equivalent to the tetrahydrate. The analysis of the FTIR of the residual solid in the hemihydrated and monohydrated samples indicates the conversion to the tetrahydrate. This explains the decrease in solubility over time.

F) Relationship of intrinsic dissolution.

The intrinsic dissolution experiments are run on the drug hemihydrated substance, the monohydrate form, and the tetrahydrated form (hemihydrate compressed at 95% RH). The data shown in figures 7-9 are for each form in triplicate. Average grades are similar for the tetrahydrated form (0.0359 mg / (ml * cm2 * min.) Against the monohydrated form of the drug substance (0.0351 mg / (ml * cm2 * min.), While the substance hemihydrate for drug is slightly lower (0.0332 mg / (ml * cm2 * min.). FTIR analysis of the disc for the substance hemihydrate for drug in the end of the experiment indicates that the conversion to the tetrahydrated form is occurring, in this way it is difficult to make the data interpretation.The monohydrate disk shows no transformation to the tetrahydrate at the end of the experiment but it is possible that the thickness of the transformation layer is small and therefore it is difficult to remove and analyze.

G) Compression of Tablets.

The FTIR spectrum of the non-compressed tablet is similar to the spectrum of the non-compressed substance for drogra due to the high drug content of the tablet. The FTIR spectrum of samples maintained at high humidity shows evidence of crystal changes. The spectrum of the sample compressed at 95% RH for one week indicates the transformation to the monohydrated and tetrahydrated forms. The presence of the peaks at 3613 cm-1 and 2920 seems to be related to the presence of the monohydrated form, mixed with a fraction of the tetrahydrate. The tablet stored at 95% RH appears to predominantly contain the tetrahydrated form, although the FTIR spectrum shows some fraction of the monohydrated form.

In summary, the changes that occur in the spectrum FTIR and the powder X-ray diffraction pattern of the disodium hemohydrate tiludronate which is compressed at 95% RH clearly indicate that the crystal changes accompany the increase in water content. This indicates that the increased water is not hygroscopic water. The water level observed after two weeks at 95% RH (16.4%) corresponds closely to the theoretical value for a tetrahydrated form of disodium tiludronate (16.6%). The TGA, FTIR, and X-ray data confirm the existence of a tetrahydrated form. The water content increased to 75% and 85% seems to indicate partial transformation to the tetrahydrated form. The FTIR spectrum of these samples (compressed at 75% and 84% RH) indicates the presence of the monohydrated form. The water increased to 75-95% RH is not reversible; These samples retain water when they move at a lower relative humidity. Water collected at 95% RH is retained and does not revert at 31% RH.

Disodium tyludronate tetrahydrate is incorporated into a pharmaceutical composition which comprises from about 1 to about 99% w / w of disodium tiludronate tetrahydrate and from about 99 to about 1% w / w of a pharmaceutically acceptable carrier. The pharmaceutical composition can be in the form of tablets, capsules, powders, granules, drops and the like which can be administered orally. The shape of the tablet is preferred. The pharmaceutical composition may contain ingredients used commercially in the pharmacy for the preparation of the oral forms.

In this way, the composition according to the invention can contain a disintegrating agent, a flow agent, a lubricant and any excipient of adequate volume. The composition may also contain adjuvants, for example absorption enhancers such as sodium lauryl sulfate.

They can be used as the volume excipient lactose, cellulose or starches. It can be used as the lubricant stearic acid, magnesium stearate, L-leucine or, for example, glycerol tribehenate. Can be used as the disintegrating agent carboxymethyl starch of sodium and crosslinked polyvinylpyrrolidone. They can be used as the silicepura flow agent or colloidal silicon dioxide. The present invention also relates to oral forms that dissolve instantly and to effervescent oral forms obtained by adding a pair of effervescent compounds to the composition according to the invention. Examples of pairs of effervescent compounds which may be used are tartaric acid and sodium bicarbonate or citric acid and sodium bicarbonate. The form of the tablet is a preferred form according to the invention. The invention also relates to tablets that dissolve instantly, effervescent tablets and coated tablets.

The pharmaceutical compositions are described as examples and in no way limit the scope of the invention.

Example 1 Wet granulation.

Sodudronate tetrahydrate, sodium lauryl sulfate, polyvinylpyrrolidone and lactose are combined as dry ingredients and passed through a 30 mesh screen to obtain a uniform mixture.

The hydroxypropylmethylcellulose is dissolved in purified water which is preheated to about 65 ° C. To mix the dry ingredients, the hydroxypropylmethylcellulose is slowly added while mixing to obtain a wet granulate which is then passed through a 10 mesh screen. The wet sieved granulate is dried at a temperature of about 25-35 ° C to remove the excess of water. The granulate thus obtained is tabletted with standard equipment and procedure according to accepted pharmaceutical practices.

Tablets Tiludronate Tetrahydrate 267mg Sodium Lauryl Sulfate (LSS) 4.5mg Hydroxypropylmethylcellulose 5.25mg Polyvinylpyrrolidone (PVP) 15.0mg Lactose 4.5mg For a finished tablet of 300mg water * (approximately 1 mg / 2.5 mg of drug) * removed during the process Example 2 Example of Preparation of Tetrahydrate.

Dissolve 60 grams of disodium tiludronate hemihydrate in 600ml of water at 20 ° C-25 ° C. Slowly add about 600ml of acetone to precipitate. The precipitate is stirred at 20 ° C-25 ° C for several hours and then filtered and air dried at 25 ° C-30 ° C the water content of the product is approximately 16.69 per TGA.

Example 3 Tablets Disodium thiludronate 267mg tetrahydrate Sodium Lauryl Sulfate 4.5mg Sodium Carboxymethylcellulose 24mg Crosslinked Microcrystalline cellulose 150mg Magnesium stearate 4.5mg 450mg Example 4 Tablets Tiludronate disodium 267 mg tetrahydrate Sodium lauryl sulfate 8 mg Sodium carboxymethyl cellulose 24 mg crosslinked Lactose 1 6.5 mg Magnesium stearate 4.5 mg 450 mg Example 5 A tablet having the following composition is prepared by dry granulation: Disodium thiludronate 267mg tetrahydrate Sodium lauryl sulfate 4.5mg Anhydrous colloidal silica 1.3mg Crystalline cellulose 21.6mg Crosslinked polyvinylpyrrolidone 8. Omg Magnesium stearate 5.6mg Anhydrous lactose for a 320mg tablet terminated from: Example 6 A tablet having the following composition is prepared by wet granulation: Disodium thiludronate 267mg tetrahydrate Sodium lauryl sulfate 4..5cmg Hydroxypropylmethylcellulose,. ", - Crosslinked polyvinylpyrrolidone 115c. O_mg Magnesium stearate Q 60 Purified water Lactose for a 30Omg tablet finished from: Having described the invention with reference to its preferred embodiments, it is understood that modifications within the scope of the invention will be apparent to those skilled in the art.

Claims (12)

1. CLAIMS 1. Tiludronate disodium tetrahydrate
2. 2. A pharmaceutical composition characterized in that it comprises an effective amount of the disodium tyludronate tetrahydrate and a pharmaceutically acceptable carrier comprising sodium lauryl sulfate.
3. 3. The pharmaceutical composition according to claim 2 characterized in that it is in a form suitable for oral administration.
4. 4. The pharmaceutical composition according to claim 2 characterized in that it is in the tablet form.
5. 5. The pharmaceutical composition according to claim 2, characterized in that it is in the effervescent oral form.
6. 6. The pharmaceutical composition according to claim 2, characterized in that it is in the form of a capsule.
7. 7. A process for preparing disodium tetraudronate tetrahydrate characterized in that it comprises: reacting the acid tiludronic acid with sodium hydroxide in an aqueous solution.
8. 8. A process for preparing disodium thiludronate tetrahydrate characterized in that it comprises: subjecting the disodium tiludronate hemihydrate to an excess of water.
9. 9. A process for preparing disodium tetraudronate tetrahydrate characterized in that it comprises: subjecting the disodium monohydrate to an excess of water.
10. 10. A process for preparing a pharmaceutical composition characterized in that it comprises the steps of: preparing the disodium tyludronate tetrahydrate by reacting tiludronic acid with sodium hydroxide in an aqueous solution; and forming in composition the disodium tyludronate tetrahydrate therefore obtained with a pharmaceutically acceptable carrier.
11. 11. A process for preparing a pharmaceutical composition characterized in that it comprises the steps of: subjecting the disodium tyludronate hemihydrate to an excess of water to obtain disodium tiludronate tetrahydrate and forming the disodium trifudronate tetrahydrate in composition with a pharmaceutically acceptable carrier.
12. 12. A process for preparing a pharmaceutical composition characterized in that it comprises the steps of: subjecting the disodium tyludronate monohydrate to an excess of water to obtain disodium tiludronate tetrahydrate; and forming the disodium tetraudronate tetrahydrate in composition with a pharmaceutically acceptable carrier.