PHARMACEUTICAL COMPOSITION FOR PROPHILAXYS AND TREATMENT OF CALCIUM METABOLISM DISORDERS The object of the present invention is to provide a pharmaceutical composition containing disodium clodronate, tetrahydrate, for oral use, filled in hard gelatin capsules, using an excipient from the group of triglycerides, for example atomized glyceryl palmitostearate, with double role, of lubricant and binder. The preparation is used for the treatment and prophylaxis of calcium metabolism disorders, as bone resorbtion, hypercalcemia and osteoporosis and contains as active ingredient a bisphosphonic acid derivative, for example disodium clodronate. The active ingredient disodium clodronate tetrahydrate, granulated by fluid bed wet granulation method, is released from the preparation in a proportion of at least 75% during the first 5 minutes and at least 95% in 30 minutes.

Clodronate (disodium salt of dichlormethylen bisphosphonic acid, tetrahydrate) is administered by the oral route, as tablets or hard gelatin capsules, being used for the treatment and prophylaxis of calcium metabolism disorders, like bone resorbtion, hypercalcemia and osteoporosis.

The active ingredient is a powder with a big bulk volume and inadequate flowing.

For processing the active ingredient classical methods were used: wet granulation and dry granulation. Wet granulation consists in agglomeration of particles using a solvent or a binder solution, in order to obtain a high-density powder mixture. Dry granulation is performed by compaction of the powder under high pressure.

EP 275 468 describes a preparation which contains 80 to 90% clodronate, 2 to 10% diluents and 1 to 10% lubricants and a method to obtain the preparation by mixing the components and wet granulation using an aqueous binder solution. The granulate is then dried, lubricants are added 1 to 5% and mixed and the mixture is compressed into tablets or it is used for filling hard gelatin capsules. Over 90% of the active ingredient are released from the preparation after 30 minutes.

WO 95/13054 describes a method of crystallization of disodium clodronate tetrahydrate and dry granulation by compaction under controlled conditions, which do not affect the tetrahydrate structure. This processing method allows to obtain granulate with adequate flowing (rheological) properties and which needs small amounts of lubricants.

WO 99/15155 discloses that by using an excipient named silicated microcrystalline cellulose in preparations containing clodronate, obtained by wet or dry granulation, powders with adequate characteristics are obtained, in terms of flowing and compressibility, and tablets have a good mechanical resistance and, especially, a low friability.

Various excipients are used for preparations with clodronate intended for oral use, having the following functions : diluents (weight compensators) such as lactose or starch derivatives, lubricants such as stearic acid and its salts of calcium or magnesium, talc, starch, sodium lauryl sulphate or combinations of two or more lubricants. These excipients are well known and their use is described in patents: US 3683080, US 4234654, EP 336851, EP 275 468, WO 95/13054, WO 99/15155.

In order to improve active ingredient release and, consequently, its bioavailability, enteric-coated pharmaceutical preparations may be manufactured (allowing the release of the active ingredient at enteric level), method described in WO 93/21907 or several excipients, like sodium lauryl sulphate or microcrystalline cellulose may be used.

According to EP 336851, the use of sodium lauryl sulphate in a proportion of 1.5 to 6% relative to the amount of bisphosphonic acid derivative leads to increased bioavailability of the active ingredient. According to WO 94/26310 the use of microcrystalline cellulose as excipient leads to clodronate tablets with better absorption.

Other excipients can be used as lubricants for hard gelatin capsule filling, such as fatty acids triglycerides. EP 336851 describes the use of glyceryl tribehenate as lubricant (it is obtained from the esterification of glycerol with behenic acid, fatty acid with 22 carbon atoms).

According to the present invention it is possible to obtain clodronate hard gelatin capsules using an excipient from the group of triglycerides, namely glyceryl palmitostearate, which has a double role, of lubricant and binder and which replaces usual excipients like talc or magnesium stearate, because they can have a negative effect on the release of the active ingredient from the preparation. The preparation contains disodium clodronate tetrahydrate as active ingredient, which is granulated using the method of wet granulation in fluid air bed and which is released in a proportion of at least 75% during first 5 minutes and at least 95% in 30 minutes (Fig. l).

The atomized glyceryl palmitostearate is compatible with hard gelatin capsules and it is composed from uniform spherical particles, therefore having very good lubricant properties as compared to classical lubricants, no matter the type of blender, the mixing time or the nature of other excipients. The atomized glyceryl palmitostearate has also binding properties, allowing a better compressibility of the powder mix in the dosing disk of the capsule filling machine, having effects on the number of excipients used in the formulation and, consequently, on the weight of the dosage unit.

In the present invention, the atomized glyceryl palmitostearate is used for preparing hard gelatin capsules containing disodium clodronate because it allows the reduction of the quantity of excipients required for a powder mix with good flowing properties. Using the atomized glyceryl palmitostearate we obtain a better uniformity of the capsule filling content, the uniformity of the dosage of active ingredient per unit being very important because of the low digestive absorption of the clodronate, which is also negatively affected by food. The atomized glyceryl palmitostearate does not delay the release of the active ingredient from the preparation, because it has no hydrophobic properties like classical lubricants (ex: talc, magnesium stearate) The atomized glyceryl palmitostearate (for example PRECIROLO ATO 5, registered trade name of GATTEFOSSE-FRANCE product) is used in hard gelatin capsules formulations in a percentage of 1-3 %. It is a mixture composed of mono-, di- and tri-glycerides, the diester fraction being the most important. It is obtained by esterification of glycerol and palmitostearic acid (C16-C18 fatty acid). The product is then spray atomized. Raw materials are strictly of vegetal origin and the process for obtaining the product does not use any catalysts.

To obtain the present formulation a capsule filling machine was used, which works on the principle of powder compression into a dosing disk. The dosing disk contains five stations for compression of the powder mix with the help of a set of punches. The obtained powder plug is then transferred into the body of the capsule. For high speed filling machines the presence of lubricants is absolutely necessary. With usual excipients inadequate powder mixtures are obtained, which can stick on the dosing punches and on the plug ejection system, leading to an insufficient dosage. For capsule filling machine which work on the principle of compression, the powder material should have binding properties, so as to form the plug of material into the dosing disk which is then transferred into the body of the capsule without losses of material.

In the present invention the disodium clodronate, tetrahydrate, is processed by wet granulation, which is widely used in pharmaceutical industry because of its technological advantages as compared to dry granulation. By wet granulation materials with good wetting properties are obtained, having an adequate size and shape for a good flowing. The shape of the particles obtained by dry granulation is irregular or plane and a bigger quantity of lubricants is necessary for a good flowing.

Fluidized bed wet granulation of disodium clodronate, tetrahydrate, is performed without binding agents, using as wetting liquid a mix of water and alcohol 1: 1 in volumes.

The mixture of solvents used for agglomeration of the particles partially dissolves the active ingredient. During the drying stage this active ingredient crystallizes, acting like a binder. The size of the obtained particles depends on the drying speed: the lower the speed, the larger the size of the particles. Care must be taken not to obtain too big particles by re-crystallizing, because they can reduce the dissolution rate. The fluidized bed wet granulation has the advantage of a short drying time, in comparison with the classical wet granulation methods. Also, by adding the wetting liquid by spray the risk of over-wetting is avoided.

The disodium clodronate tetrahydrate granulated by fluidized bed method is a mix of isolated and structured aggregates, with a water content of 18-20%, corresponding to the tetrahydate and the remaining water traces from the granulation process. The granulate has good flowing properties, so that only a small quantity of lubricants is necessary.

Monohydrate lactose is used to compensate the capsule filling weight.

Monohydrate lactose is a diluting agent widely used in oral preparation because it is water soluble and not hygroscopic. The type 200 mesh was chosen due to its good flowing properties, so the granulometric distribution of the powder is in a narrow range, thus avoiding the segregation during the filling process. Colloidal silicon dioxide is used as gliding agent.

In the present invention the pharmaceutical preparation contains 92,6% disodium clodronate tetrahydrate, 3,9-6, 3 % monohydrate lactose, 0,1-0, 5 % silicon dioxide and 1-3 % atomized glyceryl palmitostearate, relative to the total weight. A fully automatic and reproducible process is used to obtain the preparation and the powder mix is obtained with a fine and uniform granulometric distribution and adequate flowing properties for capsule filling. Using a capsule filling machine with a dosing disk, the powder is not sticking to the punches and uniform filled capsules are obtained, with a RSD of the filling mass less then 1% (table 1). The following example illustrates the present invention, without limiting it: Example 1 Name of the component Quantity Percentage (mg/capsule) Disodium clodronate tetrahydrate, 500,00 92,6% corresponding to 400 mg disodium clodronate anhydrous Lactose monohydrate (200 mesh) 28, 20 5, 22% Colloidal silicon dioxide (Aerosil 200) 1, 00 0, 18% Atomized glyceryl palmitostearate 10,80 2,00% (PRECIROL ATO 5) Total weight 540, 00 100% The method of obtaining the powder mix for capsule filling is the following : Disodium clodronate tetrahydrate is wet granulated by fluid bed method, using a mix of water and alcohol as wetting liquid. The granulate is dried at 35-40°C until a water content of 18-20% is reached. The dried and homogeneous granulate is blended with other excipients: lactose, silicon dioxide and atomized glyceryl palmitostearate and the powder mix is used for hard gelatin capsule filling.

Capsules prepared according to the composition and method of preparation described above have been tested for their physical-chemical parameters: filling mass per capsule, dosage of the active ingredient in the capsule and dissolution of the active ingredient. The results are presented in Table 1.

Table 1 Test Average RSD Disodium Disodium clodronate Production no. filling mass (%) clodronate dosage dissolution in 30 yield (%) (mg/cps) (mg/cps) minutes (%) 1 539 0. 9 400 99, 0 97, 0 2 540 0. 7 401 99, 5 96, 5 The use of atomized glyceryl palmitostearate allows obtaining very good production yields are obtained, because of the binding properties of the material which helps the formation of the powder plug and its transfer into the body of the capsule without losing material.

An important aspect of the quality in pharmaceuticals for oral use, especially for those with low bioavailability, because of the low solubility in water and/or in simulated acidic media, is the dissolution rate. The active ingredient of the present invention is water soluble at room temperature (2,5 g/10 ml). In oral administration, because of the acidic gastric environment, the active ingredient passes into the acid form, with lower absorption and reduced bioavailability. Because of the ionic structure, the disodium clodronate, respectively clodronic acid, cannot pass through the lipidic barriers, which leeds to an extremely low bioavailability. The physico-chemical parameters recorded during a comparative bioequivalence study using single dose administration on 24 volunteers show that the intervariability (41%) is bigger than the intravariability and the maximum plasmatic concentration (Cmax = 336,50 134,07 mg/mL) is obtained in a maximum time (Tmax) of 1, 44 + 1 (ore).

In the case of hard gelatin capsules, the characteristics of the powder and the nature of excipients have the main influence on the dissolution of the active ingredient and its bioavailability. The characteristics of the powder can by influenced by the granulation method and by the nature of binding agents. Among the excipients, the diluting agents (ex: lactose) have hydrophilic properties, so they will not reduce the dissolution. Classical lubricants (like talc and magnesium stearate) can have a negative influence, because they can be absorbed on the surface of the particles and make them hydrophobic, delaying the dissolution.

The dissolution test parameters were selected according to the official monograph of Etidronate Dissodium Tablets (USP XXIII, pg. 647), as the disodium clodronate doesn't exist in any official pharmacopeia. For this reason the dissolution test parameters are: Apparatus 1-basket : 100 rpm ; Medium: distilled water, 1000 mL; Time: 30 minutes.

The results show that the pharmaceutical prepared according to the present invention has a good dissolution. For the composition in example 1 the active ingredient is released in a proportion of at least 75% in first 5 minutes and at least 95% in 30 minutes (Fig. 1).

According to the present invention, for preparing hard gelatin capsules used for treatment and prophylaxis of calcium metabolism disorders, such as bone resorbtion, hypercalcemia and osteoporosis, an excipient with double role can be used, as lubricant and binder, which allows the release of the active ingredient from the preparation at least 75% in first 5 minutes and at least 95% in 30 minutes. The active ingredient is a derivate of bisphosphonic acid, and in this formulation it is proved to be physico-chemically stable also in accelerated conditions (40° t 2°C/75% RH 5%, 6 months) and on long term (25° 2°C/60% RH 5%), at least one year (the study is in progress).