MXPA00005116A - Porous hydroxyapatite particles as carriers for drug substances - Google Patents

Abstract

A drug delivery system for oral administration in solid dry form of a greasy/oily/sticky substance and a pharmaceutically active substance of a pharmaceutically active substance which itself is greasy/oily/sticky characterized by having a plurality of porous inorganic particles of small size incorporated with considerable mounts of greasy/oily/sticky substances and having fast release characteristics and a process for the preparation of such porous inorganic particles containing greasy/oily/sticky substances.

Description

POROUS PARTICLES OE HIDROXIAPATITA AS CARRIERS FOR MEDICAL SUBSTANCES FIELD OF THE INVENTION The present invention relates to novel oral pharmaceutical dosage forms comprising porous inorganic particles incorporated with considerable amounts of fatty, oily, or viscous substances (oily / oily / viscous) where the new dosage forms are characterized by They are dry and easy to handle and have quick release properties.

BACKGROUND OF THE INVENTION In many therapeutic areas the need to incorporate absorption elevators (eg, glycerol esters to increase heparin uptake or heparin fragments or their derivatives as described in WO 95/00152 by Pharmacia), solubilizing agents (such as polyethoxylated castor oils hydrogenated by felodipine as described in EP 0249587 by AB Hassle) suspending agents (e.g., soybean oil or coconut oil fractionated by 1, 2, -benzotriazine oxide as described in the patent. US 5,597,582 by Sanofi), or REF .: 120060 similar in the dosage forms for administration of drugs that have arisen.

The incorporation of large quantities of fatty, oily or viscous substances in the form of pharmaceutical dosages which has since been known as a cause of technical problems. One of the problems has been to obtain dry, pharmaceutically acceptable materials that are easy to handle and use as such or use them in later steps of a process.

The first ways of solving the problem included filling the greasy / oily / viscous substances as such into soft gelatine capsules as per instance described in US 5589455 (Han Mi Pharm) where a concentrate was described for filling soft gelatin capsules comprising a cyclosporin and an oily component (which improved bioavailability).

Many researchers over the years have described the advantages of using very small pellets (multiple units) as a dosage form, with respect to their behavior in vivo, that is, especially with respect to their gastric emptying properties, see for instance Bogentoft et al. al, J. Clin. Pharmacol. 1978, 14, 351-5.

Another way to solve the problem in line with the procedures above is the use of microencapsulation. This method is, however, expensive since it includes many steps and has been associated with large scaling problems. The method has been described, for example, by Luzzi in J. Pharm. Sci, 1970, 59, (10), 1367-76.

Prior art WO 94-23703 (Kabi phar acia AB) describes the manufacture of porous cellulose matrices and a multi-unit preparation containing a bioactive substance comprising particles of a porous cellulose matrix. However, this reference pertains to the problem of handling greasy, oily or viscous substances and does not belong to inorganic matrices.

EP 294 206 (Unilever NB) describes porous silica spheroids having certain characteristics that have up to 50% by weight of SiO of included material such as for example therapeutic agents, however this reference does not pertain to the problem of handling oily, oily or viscose nor show any achievement of fast release properties.

DESCRIPTION OF THE INVENTION It has been found that a drug distribution system for oral administration in a dry solid form of oily, viscous or greasy substance (s) and pharmaceutically active substances (s) which are / are themselves / are greasy, oily or viscous characterized in that they have incorporated particles of small size with considerable amounts of fatty, oily or viscous substances and that have fast release characteristics that can overcome the disadvantages associated with the previous techniques.

In this way, the present invention provides a new prile of a dosage form for the incorporation of fatty, oily or viscous materials into small sized particles, thereby enabling a possibility to make systems of multiple units thereof. To achieve this it has been found that the highly porous inorganic particles are of beneficial use.

A feature of the present invention is the small size of the porous particles. The size is between 5 to 150 μm, preferably 20 to 100 μm.

Another feature of the present invention is the considerable amount of the fatty, oily or viscous substance. Considerable amount in this specification means 15% w / w at 40% w / w, preferably 20% w / w at 40% w / w, more preferably 30% w / w at 40% w / w.

The fatty, oily or viscous incorporated substances may be, but are not restricted to, pharmaceutically active substances, such as almokalant or vitamin A; pharmaceutically active substances which are not themselves fatty, oily or viscous, but which together with a fatty, oily or viscous substance are especially suitable for incorporation into the formulation and which are such as felodipine, melagatran, or indogatran; absorption elevators that are fatty, oily or viscous and selected from mono-, di-, or triglycerides, such as Alkolin® MSM imvitor 308, imvitor 742, imvitor 928, imvitor 988, glycerol caprylate; solubilizers, such as semi-solid or liquid non-ionic surface active agents, for example, those containing polyethylene glycols as esters or ethers and which are chosen from polyethoxylated fatty acids, hydroxylated fatty acids and fatty alcohols and especially those chosen from the group of polyethoxylated castor oils, polyoxyethylenated and hydrogenated castor oils (Cre ophors.1, polyexotilados fatty acids of castor oil hydrogen and are known under the trade names such as CremophorT, Myrj Estereato polioxoi 40, Emerest 2675, Lipa! 95 and HCO 50.

The drug distribution system according to the invention is also characterized as having rapid release characteristics when they released with an in vitro dissolution test not less than 60% and preferably 70% w / w) to a pharmaceutically active substance and fatty / oily / viscous substances, drugs cuanac the drug is the oily, oily or viscous substance in 30 minutes or less.

For fatty, oily or viscous substances the dissolution rate was determined using a USP No. 2 (paddle) apparatus operated at 100 rpm. The dissolution medium had a temperature of 37 ° C plus there is an aemana on the amount and technique of a dissolution medium that allows the whole dose to be tested with a homogeneous non-delayed distribution of the oily, viscous or greasy substance released in the medium.

For the greasy, oily or viscous substances shown in the examples, the medium described in each example is appropriate.

For pharmaceutical substances the dissolution rate was determined using a USP No. 2 (paddle) apparatus, operated at 100 rpm. The dissolution medium had a temperature of 37 ° C which allowed the complete dose to be tested with a homogeneous non-delayed distribution of the oily or viscous fatty substance released in the medium (precipitation conditions).

For the specific drugs shown in the examples, the medium described in each example is appropriate.

It should be noted that for the same formulation different means of dissolution could be chosen depending on the properties of the substances to be tested, whether there is a fatty, oily or viscous substance, and a pharmaceutically active substance, depending on which of these is tested.

The material of the porous inorganic particles used in the invention is hydroxyapatite ceramics.

The hydroxyapatite ceramic is characterized in that it has a range of diameter sizes between 5-150 μm, preferably between 20-80 μm, a nominal pore diameter between 5-100 μm, preferably 50-100 μm and a surface area between 40-50 m2 / gr. Hydroxyapatite ceramics are commercially available from, for example, BIO-RAD Laboratories under the trade name Macro-PrepT.

Loaded with porous particles The incorporation of fatty, oily or viscous materials into the particles can be achieved by known conventional methods. One is to dissolve the oil in a suitable solvent and then mix it with the material of the porous particle and then dry it. Alternatively the oil can be mixed with the porous particle materials. Another way is to use phase separation from a solution containing the particles by the addition of a non-solvent.

The porosity of the particles is 50-70% (v / v), preferably 62% (v / v).

When used in a drug delivery system the charged porous particles can be used as such or filled into capsules, compressed into tablets or coated by methods well known in the art. Capsule filling, tablet compression or coating should be carried out so that the rapid release characteristics are not substantially changed. If rapid release into the small intestine is desired, they could be enterically coated.

Work examples Example 1- Hydroxyapatite particles containing fenodipine and 19.5% of Cremophor® and RH 40.

The oily / fatty substance Cremophor® RH 40 (312 mg) was melted at about 30 ° C and was used to dissolve felodipine (88 mg). The solution was poured over 1200 mg of hydroxyapatite particles having an average diameter of 80 μm (Macro prep® Hydroxyapatite Ceramics, BIO-RAD Laboratories) under gentle manual mixing and continuously mixing until homogeneous.

The particles obtained were analyzed with respect to the felodipine solution using a USP No. 2 dissolution apparatus (paddle) operated at 100 rpm. The dissolution medium used, which had a temperature of 37 C, was phosphate buffer pH 6.5 containing 0. 4 percent cetyltrimethylammonium bromide. The amount of felodipine released was determined by UV-spectrometry.

After 30 minutes the amount of dissolved felodipine was 84% (on average, n = 2) of the content found.

Example 2-Hydroxyapatite particles containing melagatran and 37% AJcolina® The fatty, oily substance Akolina® (779 mg) was melted at approximately 30 ° C and used to dissolve melagatran (21 mg). The solution was poured onto hydroxyapatite particles (1200 mg) having an average particle diameter of 80 μm (Macro Prep® Crámica de Hidroxiapatita; BIO-RAD Laboratories), under gentle mixing and mixing was continued until homogeneous.

The obtained particles were analyzed with respect to the Akolina® MCM and melagatran using a dissolution USP apparatus No. 2 (of paddles), operated at 100 rpm. The dissolution medium used, which had a temperature of 37 ° C, was pH 6.8 phosphate buffer with additions of 2 mM lecithin and 5mM taurocholate to make the sample homogeneous. The components of the sample were separated by liquid chromatography. The amount of Akoline released was determined using a light scattering detector and the amount of melagatran released was determined by UV-spectrometry.

After 20 minutes the amount of Akolina® MCM dissolved was 71% (on average, n = 2) of the content found. The amount of melagatran dissolved after 20 minutes was 94% (on average, n = 2) of the content found.

Example 3-Hydroxyapatite particles containing 33.33% almolant The oily / viscous substance almokalant (0.6g temp obtained) was poured onto hydroxyapatite (1200 mg) the particles had an average diameter of 80 μm (Macro Prep® Hydroxyapatite Ceramics, BIO-RAD Laboratories) under gentle manual mixing and mixing is continued until homogeneous.

The particles were analyzed with respect to the aimokaiant solution using a USP No. 2 dissolution apparatus (paddle) operated at 100 rpm. The used dissolution medium having a temperature of 37 C, was phosphate buffer pH 6.8. The amount of almokalant released was determined by UV-spectrometry.

After 30 rr.inu the amount of dissolved almokalant was 1001 (on average, n = 2) of the content found.

Example 4-Hydroxyapatite particles containing 17.4% almokalant The fatty / viscous substance almokalant (0.35 g at room temperature) was poured onto hydroxyapatite particles (1.7 g) having an average diameter of SO μm (Macro Prep® Hydroxyapatite Ceramics; BIO-RAD Laoratories), mixed soft and the mixing is continued until homogeneity.

The particles obtained were analyzed with respect to the dissolution of the almokalant using a USP No. 2 dissolving apparatus (of paddles), operated at 100 rpm. The used dissolution medium having a temperature of 37 ° C, was phosphate buffer pH 6.8. The amount of heated catalyst was aerated using UV-spectrometry.

After 30 minutes the amount of dissolved almokalant was 80% (on average, n-2), of the contained content.

Example 5 The particles obtained in Example 1 were filled into size 3 hard gelatin capsules. Caaa capsule was filled with 190 mg of felodipine / niaroxyapatite particles. It was established that in relation to this date, the best method known to the applicant to carry out the invention, is the conventional method for the manufacture of the same strands.

The invention being described as anteceae, property is claimed as contained in the following.

Claims (9)

1. A solid, dry drug distribution composition characterized by comprising: i; at least one fatty, oily or viscous active substance and at least one pharmaceutically active substance, or ii; at least one fatty, oily or viscous pharmaceutically active substance, characterized in that the composition is in the form of a plurality of porous organic particles composed of hiarox apatite ceramic having a diameter of 5 to 150 μm, said composition having release characteristics rappiaa and that incorporates from 15% P to 40% P of component (i) or (ii).

2. A system for distributing a drug according to claim 2, characterized in that the hydroxyapatite ceramic has a diameter of 20 to 80 μ.

3. A distribution system of a drug according to the claims claims characterized in that the pharmaceutically active substance has a molecular weight less than 1000 dalton.

4. A drug delivery system according to the preceding claims characterized in that the pharmaceutically active substance is a thrombin inhibiting peptide drug.

5. A drug delivery system according to the preceding claims characterized in that the pharmaceutically active substance is melagatran.

6. A drug delivery system according to claims 1-3, characterized in that the pharmaceutically active substance is felodipine.

7. A drug delivery system according to claims 1-3, characterized in that the pharmaceutically active substance is almokalant.

8. A process for the preparation of a dry, solid drug distribution composition, characterized in that it comprises: i) at least one fatty, oily or viscous substance and at least one pharmaceutically active substance, or ii) at least one pharmaceutically active greasy substance , oily or viscous, characterized by mixing from 15% P to 40 P of component (i) or (ii) and a plurality of porous inorganic particles composed of hiaroxyapatite ceramic having a diameter of 5 to 150 μ.

9. The use of a plurality of porous inorganic particles composed of hydroxyapatite having a diameter from 5 to 150 μm, incorporated with from 15% P to 40% P of a component i) at least one pharmaceutically active, oily or viscous pharmaceutically active substance, or ii) at least one pharmaceutically active, oily or viscous fatty substance in the preparation of a dry solid drug distribution composition and having lyoeracyroid characteristics. * ** MEDICAL SUBSTANCES Summary A drug delivery system for oral administration of a dry solid of a greasy / oily / viscous substance and a pharmaceutically active substance which is fatty / oily / viscous, characterized by having a plurality of small inorganic porous particles incorporated with considerable amounts of fatty / oily / viscous substances and having fat release characteristics and a process for the preparation of such porous inorganic particles containing fatty / oily / viscous substances.