DK200200115U1 - Novel salts of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, their preparation and use - Google Patents

Description

1DK 2002 00115 U3

AREA OF PRODUCTION

The present invention relates to novel salts of the compound, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, more particularly the monocalcium salt and hydrates thereof, especially the monohydrate and dihydrate, pharmaceutical compositions containing such salts as active ingredient and their pharmaceutical use.

The generic name for 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid is alendronic acid.

BACKGROUND OF THE MAKING

US 4,621,077 discloses a method for treating urolithiasis and inhibiting bone absorption by administering alendronic acid, in the patent called 4-amino-1-hydroxybutane-1,1-biphosphonic acid. Salts with alkali metals, organic bases and basic amino acids are generally mentioned and the sodium, aniline and lysine salts are specifically mentioned.

In the literature several forms of alendronic acid sodium salts have been described.

Thus, the monosodium salt trihydrate is described in EP 0 4 02 152 B1 and the monosodium salt tanhydrate in WO

96/39149.

WO 96/39410 relates to a pharmaceutical composition comprising the disodium salt or hydrates thereof with the hemihydrate (CAS NO 185960-02-5), the monohydrate (CAS NO 185959-98-2), the dihydrate, the trihydrate (CAS NO 185960-00-3), the tetrahydrate , the pentahydrate (CAS NO 185959-99-3) and the hemipentahydrate (CAS NO 185960-01-4) cited as examples of hydrates. The anhydrate (CAS NO 134605-40-9) is also mentioned.

Furthermore, the sesquinodium anhydrate and the tetraodium anhydrate have been assigned CAS numbers (CAS NO 186090-70-0 and 114075-88-6, respectively). Even an alendronic acid sodium salt with an undefined number of sodium atoms (CAS NO 160982-64-9) has been reported.

Several other salts of alendronic acid are referenced in the literature, both salts with inorganic and salts with organic cations, e.g. the monotrish hydroxymethylammonium salt (CAS NO 219937-54-9) and salts with zinc, calcium, barium, magnesium and cadmium. The water-insoluble alendronic acid calcium salts, monoalendronic acid mono-calcium salt and its monohydrate, dialendronic acid monocalcium salt and trialendronic acid tetracalcium salt and their pharmaceutical use are described in EP 0 449 405 B1. Further, the anhydrous dicalcium alendronic acid salt and the hydrates thereof, especially the pentahydrate and their pharmaceutical use, are described in WO 99/20635.

NO 178 228 B is directed to a process for the preparation of 4-amino-1-hydroxybutylidene-1,1-bis-phosphonic acid salt trihydrates of the formula

K3N-Oh'2-OH2-CH2-ζ'-OK · 3Η2O o = p-o: -: 1 wherein M is NH4 +, Na +, K +, Ca2 * or Mg2t.

The only exemplary embodiment of the specification illustrates the preparation of the monosodium salt trihydrate. The present generators have attempted to prepare the corresponding potassium compound by proceeding in an analogous manner, but without obtaining the monocalcium trihydrate as claimed. Instead, a monocalcium dihydrate was obtained. Accordingly, NO 178 228 B does not disclose either the mono-potassium trihydrate or any other alendronic acid mono-potassium salt.

The alendronic acid salts mentioned above have various deficiencies. Some of them are hygroscopic or unstable, others are of undefined composition and especially for the sodium salts there is a risk of rearrangement from one hydrate form to another during granulation and tableting. In addition, in many patients, monosodium salt trihydrate has been reported to result in oesophagitis as a serious side effect.

For commercial use, it is important to have a stable physiologically acceptable salt which is not hygroscopic, has good bioavailability, good handling properties and exhibits a stable crystalline morphological form.

DESCRIPTION OF THE MOVEMENT

The present invention provides novel alendronic acid salts which meet the above requirements.

In a first aspect, the preparation relates to the monocalcium salt of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and hydrates thereof.

Both the anhydrous 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monocalcium salt and the monohydrate and dihydrate have been isolated in crystalline form. Furthermore, both the monohydrate and dihydrate have been shown to be stable at 20 ° C and relative humidity between 0 and 80%. It follows that they neither absorb water nor lose their crystal water under normal room conditions. Furthermore, the melting points have well above 100 ° C. The mono potassium salt, and especially the monohydrate and its dihydrate, exhibit particular advantages from a formulation technical and stability point of view. Furthermore, there is a possibility that the new salts, according to the invention, will be able to reduce the occurrence of oesophagitis.

4 4GB 2002 00115U3

The temperature at which the monohydrate releases its crystal water is 20 to 30 ° C higher than that of the dihydrate and from this point of view the monohydrate is particularly preferred.

In a further aspect, the preparation provides a pharmaceutical composition comprising the monocalcium salt of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or a hydrate thereof as active ingredient.

The pharmaceutical composition may be of any conventional form such as a tablet, a pellet, a film, sugar or enteric coated tablet or pellet, a capsule, a suspension, a solution, an emulsion, etc.

In formulating a pharmaceutical composition, the active ingredient can be combined with all conventional formulation aids such as one or more formulation aids selected from suitable carriers, fillers, diluents, disintegrants, binders, dyes, surfactants, lubricants, preservatives etc.

The salts and pharmaceutical compositions of the invention are valuable for the treatment or prophylaxis of various diseases related to calcium metabolism. In particular, they can be used to treat urolithiasis or to treat or prophylaxis of bone resorption-related diseases, especially osteoporosis, hypercalcaemia and Paget's disease.

In the present context, the term "salt of the preparation" is to be understood as including both the 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monochrome salt and all hydrates thereof.

A salt of the preparation can be prepared by a process which comprises reacting approximately equimolar amounts of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and potassium hydroxide in a common solvent and isolating the resulting 4 -amino-1-hydroxybutylidene-1,1-bisphosphonic acid monocalcium salt, optionally as a hydrate thereof. The crystallization of the salt according to the preparation from the solution can be assisted by the addition of another solvent which is capable of reducing the solubility of the salt in the combined solvent.

Among non-limiting examples of solvents which may be useful in the process are 10 water and organic solvents such as alcohols, ketones and tetrahydrofuran and mixtures thereof, including mixtures of water and organic solvents. Examples of alcohols are lower aliphatic alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-15 butanol, 2-butanol and 1-pentanol. Acetone and 2-butanone are examples of ketones. The choice of a suitable solvent or combination of solvents will be within the ordinary skill of one skilled in the art.

Typically, the two components will be dissolved in water at 20-60 ° C, crystallization initiated, the mixture cooled to ca. 5 ° C, and the crystals formed are collected by filtration.

Eg. For example, an aqueous solution of alendronic acid can be neutralized with potassium hydroxide to pH 4.3-4.5, and crystallization is initiated by the addition of a lower alkanol such as methanol and the crystals obtained are collected by filtration.

The dosage regimen will be prescribed by the 30 treating physician, depending, among other things, on the patient's condition, age, weight, etc. In general, daily doses corresponding to from ca. 0.001 mg / kg to 10 m9 / kg, preferably from ca. 0.01 mg / kg to approx. 1.0 mg / kg body weight of alendronic acid are prescribed. The preparation 35 may be administered continuously e.g. daily, or 6 6GB 2002 00115U3 sequentially.

BRIEF DESCRIPTION OF THE DRAWING

FIG. Figure 1 shows an FT-IR spectrum of mono potassium alumonate monohydrate, and

FIG. 2 shows an X-ray diffractogram of the same. FIG. Fig. 3 shows an FT-IR spectrum of monocal potassium alendronate anhydrate, and

FIG. 4 shows an X-ray diffractogram of the same. FIG. 5 shows an FT-IR spectrum of monocal potassium aldeonate dihydrate, and

FIG. 6 shows an X-ray diffractogram of the same. FIG. Figure 7 shows a TGA diagram of mono potassium alendroate monohydrate, and

FIG. Figure 8 shows a TGA diagram of mono potassium alendronate dihydrate.

DETAILED DESCRIPTION OF THE MOVEMENT

A composition for oral administration containing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid calcium salt monohydrate as an active ingredient may e.g. prepared as follows:

Formuleringseksemoel.

A tablet comprising the following ingredients is prepared by conventional tabletting techniques such as direct compression of a dry blend formulation.

7 DK 2002 00115U3 mg pr. tablet 12.25 123.25 27.2 18.2 17.1 2.0 200

ingredients

Active ingredient *)

lactose

Microcrystalline cellulose

Calcium hydrogen phosphate

talc

Magnesium Stearate Total *) 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid monochalium monohydrate corresponding to 10 mg of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid.

The present invention will now be further illustrated by the following examples which represent presently preferred embodiments. The features described in the foregoing description and in the following Examples can be both separate and in any combination thereof material for carrying out the production in various forms.

Example 1.

4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid monocellium monohydrate.

Alendronic acid anhydrate (2.491 g) was dissolved in 1.0 M potassium hydroxide solution (10 ml) at 25 ° C. The solution was added to methanol (50 ml). The mixture was stirred for 12 hours and the crystalline product was filtered off and dried in a vacuum dryer at 50 ° C for 5 hours. Yield 3.06 g (100%). Mp. 167 ° C (decomp.). Elemental:

Calculated: C: 15.74 H: 4.62 N: 4.59

Found: C: 15.66 H: 4.41 N: 4.30 FT-IR spectrum as shown in FIG. 1. (Sample mixed with KBr and pressed to tablet).

8 8GB 2002 00115 U3 X-ray diffractogram as shown in Figs. 2nd

A thermogravimetric analysis (TGA) was performed using a METTLER TOLEDO STAR System, whereby the weight loss on heating as a function of the heating time and temperature was recorded. The resulting diagram is shown in FIG. 7th

Example 2.

4-Amino-l-hvdroxvbutvliden-l, 1-bisphosphonsvremonoka-1iumanhvdrat.

4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid mono-potassium monohydrate (10.0 g) prepared as described in Example 1 was suspended in toluene and refluxed for 24 hours in a flask equipped with a Dean-Stark trap. The suspension was cooled and the product was filtered off and dried in a vacuum oven at 120 ° C for 16 hours at 50 mm Hg.

Yield 9.5 g (99%). Mp. 264 ° C (decomp.). Elemental:

Calculated: C: 16.73 H: 4.21 N: 4.88

Found: C: 16.62 H: 4.42 N: 4.80 FT-IR spectrum as shown in Figs. 3. (Sample mixed with KBr and pressed to tablet).

X-ray diffractogram as shown in FIG. 4th

Example 3

4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid mono-potassium dihydrate 4 - Amino-1 - hydroxybutylidene-1,1-bi-phosphorous acid-potassium anhydrate (15.0 g) was dissolved in water (20 ml ) at reflux temperature. The solution was cooled to room temperature overnight and the crystals formed were filtered off and dried at room temperature in vacuo to constant weight.

Yield 2.7 g (16%). Mp. 130 ° C (decomp.) And 250-260 ° C

DK 2002 00115 U3 9 (decomp.).

Identity confirmed by elemental analysis: Calculated: C: 14.86 H: 4.99 N: 4.33

Found: C: 14.84 H: 5.06 N: 4.32 FT-IR spectrum as shown in FIG. 5. (Sample mixed with KBr and pressed to tablet).

X-ray diffractogram as shown in FIG. 6th

A thermogravimetric analysis (TGA) was performed in the same manner as explained in Example 1. The resulting diagram is shown as Figs. 8th

10 10DK 2002 00115 U3

UTILITY MODEL REQUIREMENTS

1. Monocalium salt of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and hydrates thereof.

2. 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid mono potassium salt monohydrate.

3. 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid remonocal potassium salt dihydrate.

4. Anhydrous 4-amino-1-hydroxybutylidene-1,1-bisp-hosphonic acid monocalcium salt.

The salt of any one of claims 1 to 4 in crystalline form.

The salt according to any one of claims 1 to 5 having substantially an FT-IR spectrum as shown in FIG. 1, 3 or 5 or an X-ray diffractogram as shown in FIG. 2, 4 or 6.

The salt of any one of claims 1 to 6 for use as a medicament.

Use of a salt according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment or prophylaxis of diseases related to calcium metabolism, in particular for the treatment of urolithiasis or for the treatment or prophylaxis of bone resorption-related diseases, in particular osteoporosis. , hypercalcaemia and Paget's disease.

A pharmaceutical composition comprising a salt according to any one of claims 1 to 6 as an active ingredient.

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