MXPA00005112A - Polyethylene glycol matrix pellets for greasy, oily or sticky drug substances - Google Patents

Abstract

A drug delivery system for oral administration in solid dry form of greasy/oily/sticky substance(s) and pharmaceutically active substance(s) or pharmaceutically active substance(s) which itself/themselves is/are greasy/oily/sticky characterized by having a plurality of solid, polymeric matrix beads comprising considerable amounts of greasy/oily/sticky substances and having fast release characteristics and a process for the preparation of such solid, polymeric matrix beads comprising greasy/oily/sticky substances.

Description

POLYETHYLENE GLYCOL MATRIX PILLARS FOR OILY, STICKY OR OILY MEDIUM SUBSTANCES Field of the Invention This invention relates to a pharmaceutical dosage form comprising polymeric matrix beads, solid, for oral administration, comprising considerable amounts of fatty, oily or sticky substances (greasy / oily / sticky) and alternatively to a pharmaceutically active substance which quantifies considerable quantities of pharmaceutically active substances, greasy, oily or sticky and wherein the new dosage form is further characterized by having fast release characteristics.

Background of the Invention In many therapeutic areas the need has arisen to incorporate absorption enhancers (ie glycerol esters for the increased absorption of heparin or fragments or derivatives of heparin as described in WO 95/00152 of Pharmacia), Ref.120061 solubilization agents (similar to polyethoxylated hydrogenated castor oils for felodipine as described in EP 0249587 of AB Hássle), suspending agents (for example soybean oil or fractionated coconut oil for 1, 2, 4- oxide) benzotriazine as described in US Patent No. 5,597,582 to Sanofi), or the like in dosage forms for drug delivery. In many cases the above substances are greasy, sticky or oily products. The incorporation of large quantities of such substances into the pharmaceutical dosage forms has long been known to cause technical problems. One of the problems has been to provide pharmaceutically acceptable dry materials that are easy to handle and use as such or in the final process steps. Older forms of avoiding the problem include filling fatty, oily or sticky substances as such in hard gelatin capsules, as described for example in US 5 598 455 (Han Mi Pharm.) Where a concentrate for the filling of the Soft gelatin capsule comprises a cyclosporin and an oily component to improve bioavailability are described.

Many researchers have described over the years the advantage of using many small pills (multiple units) as a dosage form, with respect to their in vivo behavior, ie especially with respect to their gastric emptying properties, see for example Bogentoft et al, J. Clin. Pharmacol. 1978, 14, 351-5. Also for example, Edgar et al. Describes the advantages obtained with the use of a large number of pills compared to a single unit, see Biopharmaceutics & Drug Disposition 1984, 5, 251-60. The risk of local irritation and the accumulation of several losses due to constriction in the feeding channel is also considered to be reduced, see McMahon F.G. et al. in The Lancet, 1982, November 13, 1982, 1059-61. Using complex coacervation microencapsulation is a way to avoid the problem online or related to previous discoveries. This method has been described by Jizomoto et al in Pharmaceutical Research vol. 10, No. 8, 1115-22. The method comprising the formation of a surrounding coating layer consists of two oppositely charged polymers that form an uncharged complex, frequently associated with technical problems, for example with respect to scaling, sustained oral delivery system removal, which it releases small portions of the drug and the improver at the same time over a prolonged period of time.

Description of the invention It has now been found that a drug delivery system for oral administration in a solid dry form of the oily (s), oily (s) or sticky (s) substance (s) (hereinafter g / o / s) and the pharmaceutically active substance (s) or a pharmaceutically active substance (s) which by themselves are / are the g / o / s characterized because they have a plurality of polymer matrix beads, solid, comprising substantial amounts of g / o / s substances and because they have fast release characteristics, can overcome the disadvantages associated with previous systems and (when applicable) facilitate simultaneous administration of the two components. Accordingly, the present invention provides a new dosage form principle for the incorporation of g / o / s materials and / or including pharmaceutically active substances, into particles of small to moderate size which are easy to handle. The invention also makes it possible to manufacture multi-unit dosing systems therefrom. The present invention is directed to the rapid release approach, which will ensure that the drug and solubility enhancer / absorption enhancer is delivered to the desired site simultaneously and at as high a concentration as possible, and effect a better concentration gradient which provides a high impulse force and which reinforces the possibilities of absorption of the drug. This is effected using readily soluble, solid, polyethylene glycol polymers, which will dissolve rapidly in the gastrointestinal system at the desired site. It is also a feature of the invention to have a considerable content of fatty, oily or sticky materials in the particles produced, to ensure high concentrations locally in vivo. By transforming the polymer used from the solid state to a liquid one, it is possible to emulsify or suspend the drug and the improvers therein. After this procedure a suitable aliquot of the emulsion / suspension is separated and transferred back to the solid state. This is done with all the aliquots assuring the transfer of all the material to the solid state. If necessary, the emulsions can be stabilized by the addition of surfactants. When rapid release is required, any chemical treatment with hardening agents is outside the scope of this invention. It has now been found that the disadvantages usually associated with the particles having g / o / s materials incorporated in them have been overcome. The incorporated oily substances may be but are not restricted to pharmaceutically active agents, absorption enhancers or solubilizers.

Detailed description of the invention Polymeric solid matrix, pharmaceutical pearls for oral administration comprising considerable quantities of pharmaceutically active substance (s) g / or substance (s) are pharmaceutically active [g / o / no] plus such substances of g / o / s, with the characteristics of rapid release according to the invention, are in this patent application considered to have fast release characteristics when they have an in vitro dissolution test release of not less than 60% p / p (preferably 70% w / w) of the pharmaceutically active substance and the substance of g / o / s, or the pharmaceutically active substance when the pharmaceutically active substance is the substance of g / o / s, within the course of 30 minutes or shorter. The calculation is based on water-free pearls. For substances of g / o / s the rate of dissolution is determined using USP No. 2 apparatus (paddle or propeller), operated at 100 rpm. The dissolution medium has a temperature of 37 + 0.5 ° C. In addition there is a request on the amount and art of the dissolution medium, which makes it possible for the total dose to be tested in a homogeneous non-delayed distribution of the g / o / s substance released into the medium. For the specific g / o / s substances shown in the examples, the medium described in each example is an appropriate one. For pharmaceutically active substances, the rate of dissolution is determined using the apparatus (USP) No. 2 (paddle or propellers), operated at 100 rpm. The dissolution medium has a temperature of 37 + 0.5 ° C. In addition there is a demand on the amount and art of the dissolution medium, which makes possible for the full dose to be tested, a homogeneous non-delayed distribution of the drug released into the medium (sinking conditions). For the pharmaceutically specific active substances, shown in the examples, the medium described in each example is an appropriate one. It should be noted that the first and the same means of dissolution different from the formulation could be chosen depending on the properties of the substances to be tested, ie if there is a substance of g / o / s and an active substance pharmaceutically present in the the formulation, depending on which of these are going to be tested. To have the desired handling characteristics, the solid polymeric beads, ie the particles of the invention, are small to moderate in size, that is they have an average particle size from 0.1 mm to 10 mm, preferably from 0.25 to 3 mm. The shape of the pearls is not restricted to a spherical shape, the pearls can also be irregular in shape. As a considerable amount of the fatty, oily and / or sticky substance of the invention is considered from 15% w / w up to 70% w / w, preferably % w / w up to 70% w / w, even more preferably 40% w / w up to 70% w / w.

The remainder of the drug delivery system comprises the active drug (when the oily / fatty substance is not itself in the drug), the polymer matrix former, and if necessary, surfactants, water, and pharmaceutically acceptable excipients like example to pH buffers, antioxidants, pigments or the like. Drugs with a molecular weight below 1000 daltons and which can withstand a shorter heating period up to a maximum of 60-70 ° C are considered to be usable in the invention and can be exemplified, but not restricted to drugs of peptides that inhibit thrombin and dihydropyridine compounds. Particular examples of drugs are melagatran, inogatran, alendronate, felidipine, nifedipine and almokalant. The polymeric materials which function in the invention are water-soluble polyethylene glycols, solids, with an average molecular weight from 4000 (PEG 4000) to 100000 (polyox N-10), preferably from 6000 to 20000. Polymeric materials that function as unique matrix formers with polyethylene glycol polymers designed to have a molecular weight ranging from 4000 to 20,000, including start and end values. Non-exclusive examples of this group are PEG 4000, PEG 6000 and Carbowax 20M. If considerations are taken to maintain the desired rapid release characteristics, it is also possible to use mixtures of polyethylene glycol polymers with different molecular weights such as matrix formers. In this case the invention can be practiced with polymers designed to have a molecular weight ranging from 4000 to 100000, including the start and end values. To modify the mechanical properties and / or to modify the release characteristics of the matrix formulation, it might be appropriate to include some liquid polyethylene glycols in a mixture with some solids, provided that they are in proportions such that the matrix beads resulting become solid. In such cases, the invention can be practiced with the designed polymers having a molecular weight ranging from 400 to 10,000, including the start and end values. Non-exclusive examples of this group are PEG 400 and polyox WSR N-10. Examples of the surfactants are, but are not restricted to; polyoxyethylenated sorbitan ester (for example Tweens), sorbitan esters (for example Spans), polyoxyethylene esters (Myrjs, some Arlatones), polyoxyethylenated hydrogenated castor oils (Cremophors), sodium lauryl sulfate.

Preparation of matrix beads First, a transformation of the polymer from the solid state to a liquid is carried out, which can be carried out by a heat treatment alone (for example polyethylene glycol) or by the addition of compounds that lower the melting point and after that heat treatment. Sometimes the addition of surfactants is beneficial, and they can be chosen from any pharmaceutically acceptable surfactants since the choice of the amount and the compound does not affect the required properties of the solution. The oily compound is added and emulsified. The drug (if not the oily component) can be added to either the oily phase or the molten polymer phase or a combination thereof and can be dissolved or dispersed. After stirring, suitable aliquots of the suspensions / emulsions can be produced by various techniques such as dripping, spraying, using centrifugal force techniques with spouts or rotating blades (Goodwin JT, Sommerville GR, Chem. Technol. 74; vol. 4 (10); page 623-626). By the selection of the operative equipment and the process variables used, the size of the drop obtained (size of the aliquot), and therefore the size of the coagulated particles obtained at the end (and dried when desired and applicable), will be controlled. ). The transformation of the drops / aliquots of the polymer suspensions / emulsions from the liquid to the solid state is usually effected by coagulation, and can be achieved in a non-solvent fluidizing medium, that is, in non-solvent gases or liquids. The coagulation can also be carried out on a bed of powder. After coagulation, drying can be carried out if desired and applicable. The gases usable as the fluidizing medium include: air, nitrogen, helium or other inert gases. If a rapid coagulation effect is desired, the gases used can be used cold as liquids, for example liquid nitrogen. Usable liquids depend on their solubility properties, the general demand is that you should not dissolve the polymer or some considerable amounts of it in the compounds included in the modality. As an example of non-general work can give liquid paraffin oil. This is because the liquids that are to be used have to be carefully selected for each new embodiment of the invention. With regard to the dust for the dripping of the powder bed, those which do not dissolve in the emulsion / suspension dripped on it or in which the emulsion / suspension is not absorbed and do not affect the characteristics of the release rate can be used. of the formed particles. The example given is corn starch, potato starch, sodium aluminum silicate, talc, crosslinked polyvinylpyrrolidone, calcium phosphate, starch glycolate and sodium.

Work examples Example 1 Polyethylene glycol 6000 beads contain felodipine and Cremophor® RH 40. The content of Cremophor® RH 40 was 51% w / w in dry base.

Felodipine 0.32 g Cremophor® RH 40 4.43 g polyethylene glycol 6000 approx. 4.0 g The polyethylene glycol was melted in a laboratory beaker at a temperature between 50-60 ° C. In a separate laboratory beaker the sticky, creamy substance Cremophor® RH 40 was heated to effect liquefaction. A magnetic Teflon-coated stirrer was added to the laboratory beaker. This was placed on a plate with control of agitation and heating. Felodipine was dissolved in the liquefied Cremophor® during gentle agitation. The molten polyethylene glycol was poured into the laboratory beaker containing Cremophor® RH 40 and felodipine. After stirring the molten mixture formed is immersed in a bed of corn starch powder, and allowed to coagulate until it hardens. The powder bed with the coagulated beads was transferred to a 0.7 mm sieve and the corn starch was separated from the beads. The collected beads were analyzed with respect to the dissolution of felodipine using the USP No. 2 dissolution apparatus (paddle or propeller), operated at 100 rpm. The dissolution medium used, which has a temperature of 37 ° C, was the phosphate buffing solution of pH 6.5 which contains 0.4 percent of the cetyltrimethylammonium bromide. The amount of felodipine released was determined by UV spectrometry. After 30 minutes the amount of dissolved felodipine was 95% (on average, n = 3) of the content found. The particles were visually observed during the dissolution and after 20 minutes the particles were completely dissolved (showing that Cremophor® RH 40 was completely dissolved).

Example 2 The beads of polyethylene glycol 6000 and polyethylene glycol 400 contain felodipine and Cremophor® RH 40. The content of Cremophor® RH 40 was 41% w / w in dry base.

Felodipine 0.32 g Cremophor® RH 40 4.43 g polyethylene glycol 6000 5.8 g polyethylene glycol 400 0.2 g Polyox® N-10 0.1 g Polyethylene glycol 6000 was melted in a laboratory beaker at a temperature between 50-60 ° C and polyethylene glycol 400 is added. In a separate laboratory beaker the sticky, creamy substance Cremophor® RH 40 was heated to effect liquefaction. A stirrer coated with Teflon, magnetic, is added in the laboratory beaker. This was placed on a plate with control of the stirring and heating. Felodipine was dissolved in the liquefied Cremophor® during gentle agitation. The molten mixture of the polyethylene glycols was poured into the laboratory beaker containing Cremophor® RH 40 and felodipine. After stirring the molten mixture formed is immersed in a bed of corn starch powder, and allowed to coagulate until it hardens. The powder bed with the coagulated beads was transferred to a 0.7 mm sieve and the corn starch was separated from the beads.

Example 3 The polyethylene glycol 6000 beads contain melagatran and Akoline® MCM. The content of Akoline® MCM was 43% w / w in dry basis.

Melagatran 0.26 g polyethylene glycol 6000 5.0 g Tween® 20 0.6 g Akoline® MCM 4. 4 g The components were fused together during the stirring with a magnetic Teflon-coated stirrer on a plate with the control of heating and stirring. After melting, the dough was dripped onto a bed of corn starch powder, and allowed to coagulate. After about 30 minutes the powder bed with coagulated beads was transferred to a 0.5 mm screen and the corn starch was separated from the beads. The collected beads were analyzed for the dissolution of Akoline® MCM and melagatran using a USP No. 2 dissolution apparatus (paddle or propeller), operated at 100 rpm. The dissolution medium used, which has a temperature of 37 ° C, was a phosphate buffer solution of pH 6.8 with additions of 2 mM lecithin and 5 mM taurocholate to make the absorption of 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 30 minutes the amount of Akoline® dissolved was 71% (on average, n = 2) of the content found. The amount of melagatran dissolved after minutes was 97% (on average, n = 2) of the content found.

Example 4 The polyethylene glycol 6000 beads contain almokalant at 48% w / w in dry base.

Almokalant 4.63 g polyethylene glycol 6000 4.91 g The polyethylene glycol was melted in a laboratory beaker at a temperature between 50-60 ° C. The molten polyethylene glycol was poured into the laboratory beaker containing almokalant. After stirring the molten mixture formed is immersed in a bed of corn starch powder, and allowed to coagulate until it hardens.

The powder bed with the coagulated beads was transferred to a 1.0 mm sieve and the corn starch was separated from the beads. The collected beads were analyzed with respect to the dissolution of almokalant using the USP No. 2 dissolution apparatus (paddle or propeller), operated at 100 rpm. The dissolution medium used, which has a temperature of 37 ° C, was a phosphate buffer of pH 6.8. The amount of almokalant released was determined by UV spectrometry. After 30 minutes the amount of dissolved almokalant was 74% (on average, n = 2) of the content found. EXAMPLE 5 The beads obtained in Example 1 were filled into size 3 hard gelatin capsules. Each capsule was filled with 0.15 g beads. This corresponds to a content of the capsule of 5 mg of felodipine. It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following

Claims (15)

1. A composition for the delivery of a solid, dry drug, comprising: (i) at least one fatty, oily or sticky substance and at least one pharmaceutically active substance, or (ii) at least one pharmaceutically active, fatty, oily or sticky substance, characterized in that the composition is in the form of a plurality of beads containing a polymeric matrix composed of a polyethylene glycol or a mixture of polyethylene glycols that is solid at room temperature, the composition has rapid release characteristics, and contains from 15% by weight up to 70% by weight of the components (i) or (ii).

2. A composition for the delivery of drugs according to claim 1, characterized in that the polymer matrix is composed of a polyethylene glycol having a molecular weight from 4000 to 20,000.

3. A composition for the delivery of drugs according to claim 1, characterized in that the polymer matrix is composed of a mixture of polyethylene glycols having molecular weights from 4000 to 100000.

4. A composition for the delivery of drugs according to claim 1, characterized in that the polymer matrix is composed of a mixture of polyethylene glycols having molecular weights from 400 to 100,000, provided that they are in proportions such that the beads of the resulting matrix become solid at room temperature.

5. A composition for the delivery of drugs according to any of the preceding claims, characterized in that the beads of the polymeric matrix have a particle size of 0.1-10 mm.

6. A composition for the delivery of drugs according to any of the preceding claims, characterized in that the beads of the polymeric matrix have a particle size of 0.25-3 mm.

7. A composition for the delivery of drugs according to any of the preceding claims, characterized in that the content of the fatty, oily and / or sticky substance is in the range from 40% w / w to 70% w / w.

8. A composition for the delivery of drugs according to any of the preceding claims, characterized in that the pharmaceutically active substance has a molecular weight of less than 1000 daltons.

9. A composition for the delivery of drugs according to any of the preceding claims, characterized in that the pharmaceutically active substance is a drug of peptides that inhibit thrombin.

10. A composition for the delivery of drugs according to any of the preceding claims, characterized in that the pharmaceutically active substance is a dihydropyridine compound.

11. A composition for the delivery of drugs according to claim 9, characterized in that the pharmaceutically active substance is melagatran.

12. A composition for the delivery of drugs according to claim 10, characterized in that the pharmaceutically active substance is felodipine.

13. A composition for the delivery of drugs according to any of claims 1-8, characterized in that the pharmaceutically active substance is alendronate.

14. A process for the preparation of a solid drug delivery composition, comprising: (i) at least one fatty, oily or sticky substance and at least one pharmaceutically active substance, or (ii) at least one pharmaceutically active, oily, greasy or sticky active substance, characterized by the transformation of the solid state to the liquid of a polyethylene glycol or a mixture of polyethylene glycols that are solid at room temperature, which will be composing the beads of the matrix, adding oily / greasy / sticky substance (s) and optionally substance (s) ) pharmaceutically active (s) and prepare an emulsion / suspension of the mixture obtained, after which the appropriate droplets / aliquots of the emulsion / polymer suspension obtained are transformed to a plurality of beads in the solid state.

15. The use of a plurality of beads containing a polymeric matrix composed of a polyethylene glycol or a mixture of polyethylene glycols which are solid at room temperature, such beads contain from 15% by weight to 70% by weight of a component (i) at least one fatty, oily or sticky substance and at least one pharmaceutically active substance, or (ii) at least one pharmaceutically active, oily, greasy or sticky active substance, in the preparation of a composition for the supply of drugs, solid, dry, which has rapid release characteristics. POLYETHYLENE GLYCOL MATRIX PILLARS FOR OILY, STICKY OR OILY MEDIUM SUBSTANCES SUMMARY OF THE INVENTION The present invention relates to a system for the delivery of drugs for the oral administration in a solid dry form of fatty substance (s) / oily (s) / sticky (s) and active substance (s) pharmaceutically or pharmaceutically active substance (s) which themselves are / are greasy / oily / sticky, characterized in that they have a plurality of polymeric matrix beads, solid, comprising considerable amounts of greasy / sticky substances and having fast release characteristics and a process for the preparation of such polymeric matrix beads, solid, comprising fatty / oily / sticky substances.