HRP921038A2 - New pharmaceutical formulations containing a macologically active ionizable substance as well as ess for the preparation thereof - Google Patents

Description

Field of invention

This invention relates to pharmaceutical formulations and their production. One or more pharmaceutical active substances are introduced into new formulations for release during the desired period of time and, at the same time, the dependence of the release rate on the part of the substance remaining in the formulation is reduced.

Background of the invention

Pharmaceutical preparations based on eroded, hydrophilic matrices, which show extended release properties, are described as pharmacologically active substances with low and high solubility in water. The release can be described using a simple exponential function:

M(t)/M(∞) = k • tn (1)

where n affects the kinetic base of the release (Ritger and Peppas, J.Contr.Rel. 5 (1987, 23 -26). The most favorable situation is when the release rate is completely independent of the part of the substance remaining in the formulation, i.e. n = 1.

Active substances exhibiting low solubility in water are successfully formulated into hydrophilic, eroding matrices. This is described in US 4,803,081, which shows favorable release kinetics. The same technique applied to substances with high water solubility, such as metoprolol succinate, does not give the same favorable release kinetics. This has limited the medical utility of this pharmaceutical principle.

Attempts have been made to improve the release kinetics of hydrophilic eroding matrices by using special geometric arrangements, or by introducing a gradient into the drug concentrate, formulation (P.I.Lee, Proc.Int.Symp.Contr.Rel.Bioact.Matr, 15 (1988) 97 -98) .It has also been proposed to limit excess water in the eroding matrix by applying coatings in selected areas, which increases the kinetics of the exponent n in Equation 1 (P. Colombo et al Int J. Pharm., 63 (1990) 43-48). It is likely that none of these concepts made it to market, as the complicated manufacturing processes would have made the products too expensive.

The technique of complexing pharmacologically active substances into ionizable, cross-linked polymer particles (ion-exchange resins) is well known (A.T. Florence and D. Attwood, Physiochemical Principles of Pharmacy, Macnullan Press, London, 1982, 297 -300, GB Pat 907,021 (1962) .The release of the active substance can be controlled by varying the density by cross-linking and sizing the resin. The rate of release, however, is dependent on the fraction of the substance that remains in the particles. The complex is also coated to further reduce the rate of release (US Patent 4,221,778 (1980). In order to achieve an improvement in the overall release kinetics, pellets with different coatings must be mixed.

It has been suggested that in order to reduce the rate of release from hydrophilic matrices, the use of an ion-exchange resin (L.C. Feeley and S.S. Davis, Int.J.Pharm.44 (1988) 131-139). Pure resins are mixed with a pharmacologically active substance in salt form and a high viscosity gel-forming polymer, hydroxypropylmethyl cellulose (HPMC). However, the complex per se is not formed and the effect of the ion-exchange resin is only in reducing the rate of release.

GB 2 218 333 describes a preparation containing one active ingredient, i.e. ranitidine, together with a synthetic cation-exchange resin. Hydroxypropyl methylcellulose can be added and in this case it is used as a granulation additive and does not control the release rate.

EP 241 178 describes a pharmaceutical preparation comprising one or more therapeutically active ingredients dispersed in a carrier. In this case no complex is formed.

EP 338 444 describes a preparation containing azelastine which can be bound to a cation exchange resin. It is not suggested, however, that a hydrophilic eroding matrix should be added.

EP 195 643 describes release by diffusion through a gel-forming layer in a transdermal preparation. Salt must also be added to the preparation to make the preparation suitable for use.

Brief description of the invention

Active substances, in the form of dissociating ions, are complexed to insoluble, oppositely charged polymers, such as ion-exchange resins. The formed particles, the complex, are formed into layers in a hydrophilic eroding matrix. Surprisingly, the release rates achieved were better, showing a higher value of the exponent n (Equation 1) than that of the common salt, alkali or acid.

Description of the invention

The new preparations defined above provide equal release of the active substance with high solubility in water. The various ingredients in the preparation are defined in more detail in the following:

Active substances are defined as compounds that produce a pharmacological effect when administered to humans or animals. To be used in this invention, the substance must be in the form of dissociating ions. Therefore, substances such as glucose cannot be used. Alkalis, acids or amphoteric substances can be used instead.

It is preferable to use an active substance that has a solubility greater than 10 mg/ml in water.

The ion-exchange resin must be compatible with the active substance and its physicochemical properties. Weak bases are best complexed with strongly acidic ion exchangers such as sulfonic acids. These are usually based on polystyrene cross-linked with divinylbenzene and are marketed under the trade names Resonium, Amberlite and Dowex.

Active substances can be used in the process as salts or as free alkali. The resin can be used in acid form or as a salt of a suitable cation, such as sodium.

Stronger alkalis can be complexed into ion-exchange resins of lower acidity, such as cross-linked poly(acrylic acids) or styrene-divuylbenzene modified to contain carboxyl groups. It is also possible to use the mentioned sulfonic acid ion exchangers.

Acids can be complexed with cross-linked polystyrenes with quaternary amines, or other basic anion exchangers. The acids can be used as free acids or suitable salts. Anion exchangers can be used as a base, with a hydroxyl ion on each amine, or as a salt of a suitable anion, such as chloride.

Hydrophilic eroding matrices may consist of polysaccharides. Particularly useful are cellulose derivatives such as methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), both marketed under the trade names Metolose and Methocel, and ethylhydroxy ethylcellulose (EHEC). We found that HMPC, Metolose 60SH50 (viscosity of a 2% solution in water at 20°C of about 50 mPas, 27.0 - 30.0% w/m methoxy groups and 7.0 - 12.0% w/m hydroxyl group) is particularly suitable. A mixture of low and high molecular weight HPMC can also be used. The use of different mixtures of HPMC gives, according to known techniques, different rates of release of the active ingredient. CfJ. Contr. Rel. 5 (1987) p. 159-172. The eroding matrix may also consist of synthetic hydrophilic polymers, such as polyvinyl alcohol or polyvinylpyrrolidone.

Other useful materials are bioerodible polymers such as polyorthoesters and polyanhydrides, as described by Nguyen et al (J. Contr. Rel. 4 (1986), 9-16) and polyanhydrides (R. Langer et al, Proc. Int. Symp. Control. Re. Bioact. Mater, 16 (1989) 119 -120, 161 - 162, 338 - 339).

Procedure

Tablets are preferably prepared by forming layers of the complex in a hydrophilic erodible matrix by compression in a conventional tablet press. Processes include solvent evaporation, precipitation, or polymerization may also be used.

Examples

Example 1

1 kg Dowex 50W-X4, 200 - 400 mesh, was washed with 2 L 1 M NaOH, 8 L deionized water, 2 L 0.1 M NaOH, 8 L deionized water, 0.8 L methanol, 4 L water, 1 .6 L of 10% HCl and 12 L of deionized water. The resin was dried overnight at 80°C, yielding 352 g of resin with 8.5% moisture and 4.86 meq/g of dry resin. 30.15 g of resin was dissolved in deionized water and a solution containing 44.06 g of metoprolol succinate was added. After 10 minutes of mixing, the resin was filtered through sintered glass cloth. Another 8.01 g of metoprolol succinate in water was added to the resin, and filtered. The resin was washed with 2 L of deionized water and dried overnight at 80°C to give 64.44 g of the complex with a metoprolol content, determined spectrophotometrically at 274 mn, of 1.98 mmol/g. 1 g of the complex was carefully mixed with 3 g of Metolose 60SH50 (viscosity 49 mPas in 2% aqueous solution, 28.2% methoxy groups and 8.2% hydroxypropoxy groups) in a pestle and mortar. 400 mg of the mixture was manually filled into 20 mm holes and compressed into tablets. The release of metoprolol was measured in USP apparatus no. 2 (blade) at 50 rpm, with tablets placed in a stationary basket, in 1 L of phosphate buffer at pH 7.5 and 37°C. The amount of released drug was measured spectrophotometrically, for metoprolol at 274 nm.

Reference Example 1. 1 g of metoprolol succinate was mixed with 3 g of Metolose 60SH50 (as above) in a pestle and mortar. 400 mg of the mixture was manually filled into 20 mm flat holes and compressed into tablets.

Part of the released drug was applied versus time to S11. The exponent describing the release kinetics, defined by Equation 1, was determined using non-linear least-squares in the RS/1 package (RTM). The exponent was found to be 0.92 for the tablet containing the drug in the complex and 0.61 for the low molecular weight salt, succinate.

Example 2

0.9 kg of Dowex 50W-X8 200-400 mesh was treated similarly to Example 1. The resin contained 5.10 meq/g dry resin and 7.3% moisture. 30.02 g of resin was treated with 44.06 g and 8.00 g of metoprolol succinate in a similar manner as in Example 1. 57.76 g of the complex with 1.80 mmol/g was thus obtained. Tablets were produced and analyzed similarly to Example 1 and the same references can be used. The release of the tablet is shown in FIG. 2. The exponent describing the release of Equation 1 is 0.97 for the tablets prepared according to the invention, compared to 0.61 for the reference tablets.

Example 3

1 g of the complex from Example 1 was mixed with 3 g of Metolose 65SH50 (viscosity of 2% aqueous solution 47 mPas, 27.3% methoxy groups and 4.2% hydroxypropoxy groups), compressed into tablets and analyzed in a similar way.

Reference Example 3: 1 g of metoprolol succinate was mixed with 3 g of Metolose 65SH50 (same sample as above), compressed into tablets and analyzed by a similar procedure as described in Example 1.

The kinetic exponent, defined by Equation 1, increases from 0.44 for the succinate salt to 0.68 for the complex.

Example 4

1 g of the complex from Example 1 was mixed with 3 g of Methocel E4MCR (viscosity 2% aqueous solution 4077, 30.0% methoxy groups and 8.6% hydroxypropoxy groups), compressed into tablets and analyzed in a similar manner.

Reference Example 4: 1 g of metoprolol succinate was mixed with 3 g of Methocel E4MCR (same as above), compressed into tablets and analyzed by the procedure described in Example 1.

The exponent describing the release kinetics increases from 0.46 (low molecular weight salt) to 0.66 ion-exchange resin complex).

Example 5

14.67 g of Dowex 50W-X4 (from Example 1) was dissolved in water. An aqueous solution of 20.25 g lidocaine HC1-H20 deionized water was added. After drying, the complex (824.84 g) contained 1.86 mmol/g, determined spectrophotometrically at 262 nm. Tablets were prepared according to Example 1 with the same polymer and were analyzed.

Reference Example 5: Tablets are also prepared from lidocaine HCl-H2O and Metolose 60SH50.

The kinetic exponent of Equation 1 was 0.95 for tablets containing the complex and only 0.58 for the low molecular weight salt.

Example 6

14.67 g of Dowex 50W-X4 (from Example 1) was dissolved in water. An aqueous solution of 19.20 g of terbutaline sulfate was added. After 10 minutes of mixing, the complex was filtered and washed with 4 L of deionized water. After drying, the complex (25.57 g) contained 1.91 mmol/g, determined spectrophotometrically at 278 nm. The tablets were prepared according to Example 1 i

analyzed.

Reference Example 6: Tablets are also prepared from terbutaline sulfate.

The release profile in Fig. 4 shows that the kinetic exponent is improved to 1.00 from 0.60 for the corresponding sulfate salt.

Example 7

13.70 g of Dowex 50W-X4 (from Example 1) was dissolved in water and filtered through a synthetic glass cloth. The resin was washed with 1 L of water with 5% NaCl content. The resin was further washed with 2 L of deionized water. The resin was dissolved in 100 mL of water containing 20.05 g of alprenolol HCL. After 10 minutes of mixing, the complex was filtered and washed with 4 L of deionized water. After drying, the complex (27.15 g) contained 1.97 mmol/g, determined spectrophotometrically at 270 nm. Tablets were made according to example 1 and analyzed.

Reference Example 7: Tablets are also made from alprenolol HCl. The hydrochloride salt had an exponent of 0.63, significantly lower than the complex, 1.16.

Example 8

100 g Dowex 1X-2 was washed with 0.5 L 0.1 M HCl, 1 L water, 200 mL methanol, 0.5 L water, 0.5 L 0.5 M NaOH, 200 mL methanol, 0, 5 L of water, 1 L of 5% NaCl, and then 2 L of deionized water. The resin was dried at 80°C overnight to give about 60 g of resin containing 11.5% water and 4.49 meq/g of dry resin. 6.68 g of resin was treated with 100 mL of 1 M NaOH, filtered and washed with 2 L of water and 2 times with 200 mL of 95% ethanol and suspended in 200 mL of ethanol. 3.46 g of salicylic acid was added and the suspension was stirred for 9 hours. The complex was filtered and washed twice with 200 mL of ethanol and 2 L of water. 6.25 g of the complex contained 19.5% salicylic acid, measured spectrophotometrically at 296 nm, obtained after overnight drying. 1 g of the complex was mixed with 3 g of Metolose 60SH50 and the tablets were prepared according to Pr. 1.

Reference Example 8: 1 g of salicylic acid was mixed with 3 g of Metolose 60SH50 and compressed into tablets by the procedure described in Ex. 1.

The release curves fit Equation 1, giving an exponent of 0.56 for the acid and 0.96 for the complex.

Claims (12)

1. Preparation of a pharmacologically active ionizing substance with extended release of the active substance, indicated by the fact that the active substance is ionically complexed with an ion-exchange resin and the formed complex builds layers in a hydrophilic eroding matrix. 2. The preparation according to claim 1, characterized in that it is intended for oral use. 3. The preparation according to claim 2, characterized in that the ion-exchange resin is a cross-linked polymer oppositely charged to the active substance. 4. The preparation according to claim 2, characterized in that the hydrophilic matrix consists of more than 10% polysaccharide or its derivative. 5. The preparation according to claim 4, characterized in that the hydrophilic matrix is hydroxypropyl methylcellulose. 6. The preparation according to claim 5, characterized in that hydroxypropyl methylcellulose contains hydroxypropyl methylcellulose of both low and high molecular weight. 7. The preparation according to claim 3, indicated by the fact that the active substance is an alkali, and the resin is a cation-exchange resin. 8. The preparation according to claim 3, indicated by the fact that the active substance is an acid, and the resin is anion-exchange resin. 9. The preparation according to claim 7, characterized in that the active substance is metoprolol, and the resin is polystyrene sulfonate. 10. The preparation according to claim 7, characterized in that the active substance is terbutaline, and the resin is polystyrene sulfonate. 11. The preparation according to claim 2, characterized in that the active ionizing substance has a solubility greater than 10 mg/ml. 12. Process for the production of preparations according to claim 1, characterized in that: a) the active substance is ionically complexed with the oppositely charged ion-exchanger, whereby a complex is formed, b) this complex was introduced in layers into the hydrophilic eroding matrix i c) the resulting mixture is formed into tablets according to any suitable known method.