Porous hydroxyapatite particles as carriers for drugs

 

(57) Abstract:

The invention relates to medicine, namely to the development of new dosage forms for oral administration. A composition comprising (1) at least one fatty, oily or sticky substance and at least one pharmaceutically active substance, or (2) at least one pharmaceutically active substance, which in itself is a greasy, oily or sticky, is in the form of a variety of porous inorganic particles consisting of ceramic hydroxyapatite, which has a diameter of 20-150 μm nominal pore diameter of 5-100 μm and a porosity of 50-70 vol.%, which contain these substances, and the content of component (1) or (2) is 15-40 wt.%, and molecular weight of the pharmaceutically active substance is less than 1000 daltons. The method of preparation of such compositions is mixed 15-40 wt.% component (1) or (2) and specified many porous inorganic particles consisting of ceramic hydroxyapatite. The composition is dry, easy to handle and has the properties of fast release. 2 s and 5 C.p. f-crystals.

The scope of the invention

The present invention relates to a new perorally amounts of fat, oily or sticky (greasy/oily/sticky) substance, characterized in that it is dry and easy to handle, and also has the properties of fast release.

Background of the invention

In many therapeutic areas, there is a need to incorporate amplifiers absorption (for example, esters of glycerol to increase the absorption of heparin or fragments of heparin or its derivatives as described in WO 95/00152, pharmacy), solubilizing agents (such as polyethoxysiloxane hydrogenated castor oil for felodipina, as described in EP 0249587, AB Hassle), suspendida agents (e.g., soybean oil or fractionated coconut oil for 1,2,4-benzotriazines, as described in U.S. patent 5597582, Sanofi) or similar means in the dosage form for drug delivery.

Has long been recognized that the inclusion in the pharmaceutical dosage form of large quantities of greasy, oily or sticky substances causes technical problems. One of such problems was to obtain pharmaceutically acceptable dry materials that are easy in handling and use as such or for use in subsequent stages pererube/sticky substances such as soft gelatin capsules, as described, for example, in U.S. patent 5589455 (Han Mi Pharm), which revealed concentrate for filling soft gelatin capsules containing cyclosporine and oil component (improving bioavailability).

Many researchers over the years have described the advantages of use as a medicinal form of many small granules (unit) in relation to their behavior in vivo, namely in respect of their properties to promote gastric emptying, see, for example, Bogentoft et al., J. Clin. Pharmacol. 1978, 14, 351-5.

Another way of overcoming this problem, in accordance with the above data, is the use of microencapsulation. However, this method is expensive, since it involves many stages, and is often associated with difficulties in large-scale production. The method is described, for example, Luzzi in J. Pharm.Sci, 1970, 59, (10), 1367-76.

Art

Described (WO 94/23703 (Kabi Pharmacia AB) production of porous cellulose matrices and the product in the form of an integral unit that includes a bioactive substance containing particles of porous cellulose matrices. However, this reference does not deal with the problem of manipulation of fatty, oily or clagny silica, possessing certain characteristics, containing up to 50% by weight of SIO, SIS2included material, such as, for example, therapeutic agents. However, this reference does not deal with the problem of manipulating fatty/oily or sticky substances and does not demonstrate any achievements properties quick release.

Description of the invention

It is established that the delivery system of drugs for oral administration in solid dry form of greasy, oily or sticky substance (s) and pharmaceutically active substance (s) or pharmaceutically active substance (s), which is itself (which themselves are greasy, oily or sticky(and), characterized in that it contains a porous inorganic particles of small size, United with significant quantities of oily, greasy, or sticky substances, and has the properties of fast release, able to address the shortcomings typical of previous methods. Thus, the present invention proposes the principle of a new dosage form for inclusion greasy, oily or sticky materials into particles of small size, thus making the possibility of use are highly porous inorganic particles.

One of the distinctive features of the present invention is the small size of the porous particles. This size is in the range from 5 to 150 μm, preferably from 20 to 100 μm.

Another distinguishing feature of the present invention is a significant amount of greasy, oily or sticky substance. Under significant number in this description is meant from 15 to 40 wt.%, preferably from 20 to 40 wt.%, most preferably 30 to 40 wt. %.

Include greasy, oily or sticky substances can be, but are not limited to, pharmaceutically active substances, such as elocuent or vitamin a; pharmaceutically active substances, such as felodipine, melagatran or inogatran, which themselves are not greasy, oily or sticky, but together with greasy, oily or sticky substance is particularly suitable for inclusion in the drug; amplifiers absorption, which are greasy, oily or sticky and is selected from among mono-, di - or triglycerides or mixtures thereof, such as AkolineMCM, Imvitor 308, Imvitor 742, Imvitor 928, Imvitor 988, glycerol de caprylate; soljubilizatory, such as semi-solid or liquid non-ionic esters, selected from polyethoxylated fatty acids, hydroxylated fatty acids and fatty alcohols, and especially from the group polyethoxyethanol castor oil, polycistronically hydrogenated castor oils (Cremophors), polyethoxyethanol fatty acid from castor oil or polyethoxyethanol fatty acid from hydrogenated castor oil, and are known by such trade names as Cremophor, Myrj, Polyoxol 40 stearate, Emerest 2675, Lipal 395 and VAT 50.

The system of delivery of the drug according to the invention is characterised by the properties of fast release, when in the test for dissolution in vitro release within 30 minutes or shorter period is not less than 60% (preferably 70 wt.%) pharmaceutically active substances and fatty/oily/sticky substances or drugs, when this medicine is a greasy, oily or sticky substance.

For these greasy, oily or sticky substances, the rate of dissolution is determined using an apparatus of the United States Pharmacopeia 2 (paddle) operating at 100 rpm Medium for dissolution has a temperature of 37o. In addition, there is the requirement together with a dose of smooth homogeneous distribution of the released fatty/oily/sticky substance within this environment.

For specific fatty, oily or sticky substances presented in the examples, suitable environment is described in each example.

For drugs, the dissolution rate is determined using an apparatus of the United States Pharmacopeia 2 (paddle) operating at 100 rpm Medium for dissolution has a temperature of 37oC. in Addition, there is a requirement regarding the number and status of the environment for dissolution, which is that it should provide for all the tested doses smooth homogeneous distribution of the released drugs within this environment (subsidence).

For specific drugs, are presented in the examples, suitable environment is described in each example.

It should be noted that if the drug is greasy, oily or sticky substance and pharmaceutically active substance, depending on which of them will be tested, for the same drug can be selected in different environments for dissolution depending on the properties of the tested substance.

The material of the porous inorganic particles used in this invention is a ceramic watch is STIC between 5-150 microns, preferably between 20-80 microns, nominal pore diameter of between 5-100 μm, preferably 50-100 μm, and the surface area is between 40-50 m2/, Ceramic hydroxyapatite is issued by the industry, for example BIO-RAD Laboratories under the trade name Macro-Prep.

Download porous particles

The inclusion of greasy, oily or sticky materials in the particles can be carried out using conventional known methods. One of them consists in dissolving the oil in a suitable solvent and then mixed with the material in the form of porous particles and drying. Otherwise, the oil can be directly mixed with the materials in the form of porous particles. Another way is to use the phase separated from the solution containing the particles, by adding herstories.

The porosity of these particles is 50 to 70 (vol.%), preferably 62 (vol. %).

When used in the delivery system drug loaded porous particles can be used as such, or they may be filled in capsules, they can pressoffice in pill or covered well known in this area ways. Filling in capsules, pressed into pellets or coated daggets quick release in the small intestine, loaded porous particles can be coated intersolubility shell.

Working examples

Example 1. Particles of hydroxyapatite containing felodipine and 19.5% CremophorRH 40.

Fatty/oily substance CremophorRH 40 (312 mg) was melted at a temperature of about 30oWith and used to dissolve it felodipina (88 mg). The solution was poured into 1200 mg of hydroxyapatite particles having an average diameter of 80 microns (Macro PrepCeramic Hydroxyapatite; BIO-RAD Laboratories), with moderate manual stirring and the stirring was continued until homogeneity.

The obtained particles were analyzed in relation to the dissolution felodipina using the apparatus for dissolving Farmacopea USA 2 (paddle) operating at 100 rpm Used medium for the dissolution temperature of the 37oWith, was phosphate buffer pH 6.5, containing 0.4% bromide, cetyltrimethylammonium. The number of released felodipina were determined using UV spectrometry.

After 30 minutes, the amount of dissolved felodipina was 84% (average, n=2) from the specified content.

Example 2. Particles of hydroxyapatite containing melagatran and 37% AkolineoWith and used for the dissolution of melagatran (21 mg).

This solution was poured into particles of hydroxyapatite (1200 mg) having the average particle diameter of 80 microns (Macro PrepCeramic Hydroxyapatite; BIO-RAD Laboratories), with moderate stirring and the stirring was continued until homogeneity.

The obtained particles were analyzed in relation to the dissolution of AkolineMSM and melagatran using the apparatus for dissolving 2 the U.S. Pharmacopoeia (paddle) operating at 100 rpm Used medium for the dissolution temperature of the 37oWith was a phosphate buffer with a pH of 6.8 with the addition of 2 mm lecithin and 5 mm taurocholate in order to make the absorption of homogeneous samples. Components of the sample separated by liquid chromatography. The number of released Akoline was determined using light scattering detector, and the number of the released melagatran were determined using UV spectrometry.

After 20 minutes, the amount of dissolved AkolineMSM accounted for 71% (average, n= 2) from the installed content. The number of melagatran dissolved after 20 minutes, was 94% (average, n=2) from the specified content.

Example 3. Particles matney temperature) was poured into particles of hydroxyapatite (1200 mg), having an average diameter of 80 microns (Macro PrepCeramic Hydroxyapatite; BIO-RAD Labaratories), with moderate manual stirring and the stirring was continued until homogeneity.

The obtained particles were analyzed in relation to the dissolution of alokananda using the apparatus for dissolving United States Pharmacopeia 2 (paddle) operating at 100 rpm Used medium for the dissolution temperature of the 37oWith, was phosphate buffer with pH 6.8. The number of released alokananda were determined using UV spectrometry.

After 30 minutes, the amount of dissolved alokananda was 100% (mean, n=2) from the specified content.

Example 4. Particles of hydroxyapatite containing 17.4 per cent of allacapan.

Oily/sticky substance elocuent (0.35 g at room temperature) was poured into particles of hydroxyapatite (1.7 g) having an average diameter of 80 microns (Macro PrepCeramic Hydroxyapatite; BIO-RAD Laboratories), with moderate manual stirring and the stirring was continued until homogeneity.

The obtained particles were analyzed in relation to the dissolution of alokananda using the apparatus for dissolving United States Pharmacopeia 2 (paddle) operating at 100 rpm Isvisiblechanged of alokananda were determined using UV spectrometry.

After 30 minutes, the amount of dissolved alokananda was 80% (average, n=2) from the specified content.

Example 5.

The particles obtained in example 1 was filled in hard gelatin capsules of size 3. Each capsule was filled with 190 mg of particles felodipine/hydroxyapatite.

1. Solid composition for delivery of drugs having the properties of fast release, which contains (1) at least one fatty, oily or sticky substance and at least one pharmaceutically active substance, or (2) at least one fatty, oily or sticky pharmaceutically active substance, wherein the composition is in the form of a variety of porous inorganic particles consisting of ceramic hydroxyapatite having a diameter of from 20 to 150 μm nominal pore diameter of from 5 to 100 μm and a porosity of from 50 to 70 vol.%., which contain these substances, and the specified composition comprises from 15 to 40 wt.% component (1) or (2), where the pharmaceutically active compound has a molecular weight less than 1000 daltons.

2. Composition for drug delivery under item 1, where the ceramic hydroxyapatite has a particle size of 20-80 microns.

3. It is a great remedy, inhibiting thrombin.

4. Composition for delivery of the drug according to any one of paragraphs.1-3, where the pharmaceutically active substance is melagatran.

5. A composition for delivery of a drug on PP.1-3, where the pharmaceutically active substance is felodipine.

6. A composition for delivery of a drug on PP.1-3, where the pharmaceutically active substance is alotalot.

7. Method of preparation of solid compositions for delivery of a drug with properties quick release, which contains (1) at least one fatty, oily or sticky substance and at least one pharmaceutically active substance, or (2) at least one fatty, oily or sticky pharmaceutically active substance, wherein the composition is in the form of a variety of porous inorganic particles consisting of ceramic hydroxyapatite having a diameter of from 20 to 150 μm nominal pore diameter of from 5 to 100 μm and a porosity of from 50 to 70 vol.%, which contain these substances, and the specified composition comprises from 15 to 40 wt.% component (1) or (2), where the pharmaceutically active compound has a molecular weight less than 1000 daltons, this mix is as hydroxyapatite.

 

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