JPH08283146A - Preparation of molded and compressed prescribing shape of slow release unit and compressed prescribing shape of unit thus obtained - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a linear sustained-release preparation by forming a therapeutically active substance showing self-delaying properties by change of compression strength, uniformly releasing an active substance, having reproducibility. SOLUTION: At a first stage, a material packed with an active substance (e.g. bezafibrate) and an additive for suppressing or compensating the self delay of the release of the active substance is processed into particles. The material packed with the additive contains 0.1-10 wt.% based on the active substance of a medical tablet disintegrator and 0.1-10 wt.% of a wetting agent (e.g. sodium dodecylsulfate) and 0.1-10 wt.% of a medical binder. At a second stage, these particles are compressed together with a release delaying agent. The release relaying agent is a hydrogel-forming substance (e.g. sodium carboxymethyl cellulose) and 5-40 wt.% of the substance is based on the active substance. A compressed sustained-release preparation comprising a preliminarily material which is composed of the particles and shows rapid release and containing a release delaying agent in an outer phase is obtained without using another additive.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a process for the preparation of shaped, compressed, sustained release unit dosage forms from therapeutically active substances which exhibit a self-retarding property which varies with compression force. It relates to the resulting unit dosage form.

[0002]

"Molded and compressed unit dosage form".
It is known to be used in many different variants for medicinal and veterinary purposes. Although the term is used primarily to describe conventional tablets, film-coated tablets and sugar-coated tablets, the present invention may also be utilized to make a special type of therapeutic unit dosage form. However, tablets are here understood as an example for simplification and do not impair the general applicability of the invention.

Sustained-release tablets are often devised to ensure slow and constant release of the therapeutically active ingredient over an extended period of time. This can often increase the duration of action of the drug, or it can at least simplify its intake pattern for the patient. It is particularly easy to slow the release of substances whose activity depends on the pressure used for compression. An example of such an active substance is bezafibrate, a lipid-lowering drug that has become very important in the treatment of elevated blood lipid levels. This material forms acicular crystals which can be compressed into sustained release tablets and other solid unit dosage forms without the use of special release delaying agents, the delay of release here being controlled by the compression force applied. To be done. The stronger the tablet formation, the slower the release of the active ingredient. This change in the rate of release due to compressive forces is significant even at relatively low values of about 10 kN / cm ² .

Further details regarding the active substance and suitable methods for its preparation can be found in US Pat. No. 3,781,328 and German Patent Application No. 2,149,070.
Other active substances of this type are 4- [2- (chlorobenzenesulfonylamino) -ethyl] -phenylacetic acid and 4- [2-
(Benzenesulfonylamino) -ethyl] -phenoxyacetic acid. This is because the rate of in vitro release of both compounds depends to a large extent on the tableting pressure used, with the result that their release is delayed by this pressure. These active substances have two European patent applications No. 3
1,954 and 4,011 and two U.S. Pat.
43,477 and 4,258,058.

The particular advantage of these active substances with self-delayed release is that they require very small amounts of additives,
The result is that a relatively large amount of the active substance itself can be packed into a relatively small unit dosage form.

[0006]

Despite their advantageous properties, however, known sustained-release preparations of this type are not satisfactory in all respects. In particular, their delayed release shows rather large fluctuations. This means that the manufacturing parameters need to be controlled very accurately, and there is a great risk that some of the output must be rejected because it does not have the required pharmaceutical properties. is there. However, it is desirable from a medical point of view to ensure that the release of the active ingredient is as uniform, reproducible and linear as possible.

The object of the present invention is therefore to improve these properties of the sustained release formulations described in the introduction. At the same time, the total amount of admixed additives should be as low as possible to allow the production of compact unit dosage forms with high active substance content.

[0008]

In order to achieve this object in a way of the type described in the introduction, additive loadings and active substances which suppress or compensate for the self-delaying of the release of the active substance are incorporated into A (preliminary) compressed body (slug) prepared from this granulate without the use of an additive has a rapid release (slow release required and slow release over the range of compression force values intended for the production of unit dosage forms). (Comparatively) is converted to particles in the first stage of manufacture in a manner such as shown below, after which the particles and the release-retarding additive are compressed into the final unit dosage form required in the second stage of manufacture.

The unit dosage form of the invention, which comprises compressed particles containing a therapeutically active substance whose release delay depends on the compression force used, and an external phase containing certain tablet-forming additives. , Particles are (preliminary) compressed bodies (these are made from these particles without the use of further additives) a rapid release over the entire range of intended values of compression force (slow required) (Compared with release) in a manner such that the self-retardation of the active substance is suppressed or compensated, and the external phase of the tablet comprises the release-retarding substance.

The granules prepared in the first stage of production are preferably granules, especially granules obtained by wet granulation. However, it can also be made by other conventional methods, notably dry granulation or conventional method pelletization. Pellets which are particularly suitable for the production of tablets are described in European patent application EP 218,928.

The size of the particles prepared in the first stage of manufacture can vary within wide limits. The most frequently occurring particle size d'in the RRSB mesh system is preferably about 0.2-0.5 mm, and the particle size can range from about 0.01 mm-2.0 mm.
This description refers to the "release requirement", ie the release of the active substance from a precompressed body made of particles without the use of further additives and the required delay of release of the active substance from the unit dosage form. It enables the person skilled in the art to select suitable additives which satisfy the above relationship between In particular, the active substance may be treated with high amounts of hydrophilic additives such as sugars, sugar alcohols or polyethylene glycols. Also, the first stage of manufacture may involve the use of certain additives having a large specific surface area, these additives acting as some core in the tablet and water in the tablet structure. Or it promotes the penetration of gastric juice.

However, the following operation is particularly preferable. This is because they are particularly suitable for the subject of the invention and allow the use of very small amounts of additives. The first stage of manufacture is suitable for use with drugs and is commonly used in the pharmaceutical industry for tablet disintegration additives (Tablettenzerfallhil
fsmittel), eg PHList and UAMuazzam: “Quel
lung-die treibende Kr-aft beim Tablettenzerfall "(
Swelling-propulsion force after tablet disintegration), Pharm. Ind., 41, No. 5 (1
979) 459ff preferably with the use of disintegrating additives. These materials accelerate the disintegration of aggregates into discrete discrete particles (primary particles), three examples of which are modified starch, modified cellulose and crosslinked polyvinylpyrrolidone. For the sake of brevity, these substances are referred to herein by their common, but less precise, name “disintegrants”.
(Sprengmittel) ".

In another preferred embodiment, the first stage of manufacture involves the use of a wetting agent, preferably with a water soluble binder. This is precisely a combination which is not only particularly uniform, but which also ensures a reproducible release of the active substance in different production batches of tablets. Suitable additives, notably tablet disintegrants, wetting agents and water-soluble binders, are
Regular medical literature research, especially Georg T-hieme Ve in 1978
H. Sucker, P. Fuchs issued by rlag, Stuttgart
And P. Speiser (edit): “Pharmazeutische Technologi
e "(medical technology).

[0014]

The present invention is further illustrated by the experimental data shown in the drawings and tables. FIG. 1 shows a diagram for in vitro release from prior art unit dosage forms. Figure 2 shows a diagram for in vitro release from a unit dosage form of the invention. FIG. 1 shows in vitro dissolution rates (expressed as% over time) for six formulations of the prior art sustained release bezafibrate formulation, all of which had a diameter of 11
It is in the form of tablets of mm. The compressive force changed as follows.

P1 = 10kN (for curves 1a and 1b), P2 = 20k
N (for curves 2a and 2b) and P3 = 28kN (for curves 3a and
3b) Bezaf used for curve a for each pair a and b
And the bezafibrate used for curve b are
The bulk volume (Schutt-volumen) was different. Field of curve a
, The bulk volume is the lower limit of the sustained release formulation (about 0.4 m²/ g
Corresponding to the specific surface area) and in the case of curve b
The bulk volume of the ²Specific surface of / g
Was equivalent to the product).

FIG. 1 clearly shows that the rate of in vitro dissolution of such sustained release tablets known from the prior art is significantly changed by the compression force, and the bulk volume of bezafibrate has a very small effect on it. To do. In contrast, FIG.
Shows the corresponding diagram for a formulation of the invention prepared as described in Example 7a. The tablets had the same size as in Figure 1 and were compressed at the same pressure (10, 20 and 28 kN for curves 4, 5 and 6, respectively). Here it can be seen that the rate of dissolution in vitro is actually independent of the compression force and is indeed linear. It was also found that this pattern had excellent reproducibility over various manufacturing batches.

Examples 1-4 and the corresponding Table 1 serve to illustrate the "release requirements". This requirement is that the particles prepared in the first stage of manufacture should include an additive charge that suppresses or compensates for the self-delay of the release of the active substance, so that the particles can be used without further additives. To stipulate that the precompressed body obtained from exhibits a rapid release (compared to the slow release required) over a range of compression force values intended for the manufacture of unit dosage forms Will.

In each of Examples 1-4, the specified ingredients of the granulate formulation suitable for tablet formation ("granule formulation") were dry mixed and then operated at normal speed. Compressed into unit dosage forms with a diameter of 11 mm with the help of. Conventional tableting additives (3 mg of highly dispersed silica and 10 mg of magnesium stearate) were added to the granules in the dry state in order to improve the processing properties of the substance, namely its flowability and release from the die, , Which did not actually affect the dissolution rate in vitro.

The rate of in vitro release was measured under the following conditions, which gives an indication of the release of the active substance. Solvent: Kuster Thiel Phosphate buffer 1000 ml pH: 6.8 Paddle stirrer speed: 90 rpm Temperature: 37 ° C In vitro methods release a given formulation using a method that correlates well with in vivo release It is generally convenient to see if the requirements are met. Of course, the same in vitro model was used here to measure the release from the precompressed body with respect to measuring the release from the final unit dosage form with sustained release.

[0020]

Example 1 Bezafibrate 400 mg Monosaccharides or oligosaccharides (here lactose D80) 51 mg Polyvinylpyrrolidone 25,000 15 mg This formulation is normally used as a diluent in the formation of granules as usual, but also granules into tablets. Containing oligosaccharides that promote compression of the. Polyvinylpyrrolidone is a water-soluble polymer commonly used as a binder in such granular formulations.

The formulation therefore does not contain additives with a specific purpose for suppressing or offsetting the self-delay of the release of the active substance. The data in Table 1 show that the rate of in vitro dissolution is indeed very slow and varies to a great extent with compressive forces. 33% dissolution after 5 hours
And 23%, well below the values required for sustained release formulations (see example corresponding to Figure 2).

Example 2 Bezafibrate 400 mg Monosaccharide or oligosaccharide (here lactose D80) 51 mg Sodium dodecyl sulphate (wetting agent) 10 mg Wetting agent (sodium dodecyl sulphate) increases the rate of dissolution in vitro when low compressive force is used. Although significantly increased, this speed is still significantly changed by compressive forces, and the mechanical properties of the compressed body are not entirely satisfactory.

Examples 3A and 3B 3A 3B Bezafibrate 400 mg 400 mg Monosaccharides or oligosaccharides (here mannitol) 53 mg 53 mg Polyvinylpyrrolidone 25,000 15 mg 15 mg Sodium carboxymethyl starch 4 mg 8 mg These formulations consist of disintegrant sodium carboxymethyl starch in two concentrations. Including. As the data in Table 1 show, this results in in vitro dissolution of the compressed product, which is both rapid and independent of the amount of compression force. The release requirements specified in the present invention are fully met in the case of the products obtained in these examples. It can also be seen that even very small amounts of disintegrant (1% based on active substance) are sufficient for this purpose and thus the tablet size is not actually changed. Example 4 Bezafibrate 400mg 400mg Monosaccharides or oligosaccharides (here lactose D80) 51mg 51mg Polyvinylpyrrolidone 25,000 15mg 15mg Sodium dodecyl sulphate 10mg Macrogol stearate 2500 10mg These formulations are water soluble polymeric binders (polyvinylpyrrolidone) and wet. Agent, while the formulation of Example 4A contains the anionic wetting agent sodium dodecyl sulfate,
The formulation of Example 4B contains the nonionic wetting agent Macrogol stearate 2500. The data in Table 1 show that the release requirements are satisfied by formulation 4A for all values used for compressive force. However, the formulation
In the case of 4B, barely sufficient dissolution of the compressed body is obtained only at the relatively low values used for the compressive force.

The following general conclusions are drawn from Examples 1-4. A pre-compressed body showing rapid release of the unit dosage form (compared to the sustained release required) at normal tableting pressures, with the aid of relatively small amounts of additives that suppress or compensate for self-delay. It can be manufactured from bezafibrate. -This can be achieved particularly effectively by the use of disintegrants. Very good results can also be obtained with a combination of water-soluble binders and preferably anionic surfactants.

Examples 5-8 can be used in combination with methyl hydroxypropyl cellulose (MHPC) as a retarder to demonstrate the effectiveness of the present invention. In Examples 5-7A, 400 mg of bezafibrate are wet granulated in each case with a water-soluble binder and the disintegrant or surfactant of Examples 3B, 4A and 4B above. The granules are compressed with the ingredients indicated as the external phase to form tablets with a diameter of 11 mm. The release rate in vitro is observed as above.

Examples 5, 6 and 7A Granules: 5 6 7A Bezafibrate 400 mg 400 mg 400 mg Lactose D80 53 mg 51 mg Mannitol 53 mg Polyvinylpyrrolidone 25,000 15 mg 15 mg 15 mg Sodium carboxymethyl starch 8 mg Sodium dodecyl sulfate 10 mg Macrogol stearate 2500 10 mg Outer phase: MHPC K 100LV 51 mg 49 mg 51 mg highly dispersed silica 3 mg 3 mg 3 mg magnesium stearate 10 mg 10 mg 10 mg The results obtained with these formulations are shown in Table 2. They are,
It shows that the release of the active substance is generally independent of the compression force in all three cases. The release is similar in Examples 5 and 6, but Formulation 5 has high crush strength and low abrasion value.

Surprisingly, the granule preparations which were found to be suitable but less preferred in Examples 1 to 4, especially when they contain both anionic surfactants and water-soluble polymeric binders, Emissions are shown here that are uniform, linear, and independent of compression. Furthermore, sufficiently satisfactory mechanical properties are obtained in this case. The fact that the rate of release shows a slightly small change is particularly advantageous. This is reflected in the coefficient of variation ("CV") shown in brackets after in vitro dissolution in the table. The dissolution behavior of formulation 7a is shown in FIG.

Also, this example should not be understood in the sense that the release requirement should be that the immediate dissolution rate of the precompressed body should be higher than the final tablet rate over the entire duration of the delayed dissolution. Demonstrate. Thus, in this case, the immediate dissolution rate was both high at the first time at relatively high compressive forces, as can be seen by comparing the data for Example 4A in Table 1 with the data for Example 7A in Table 2. Is really the same as in.

However, their dissolution needs to be quite different with respect to the time intervals typical of sustained release formulations. In quantitative terms, the dissolution of the precompressed body should be at least 1.5 times greater than the dissolution of the final tablet after 3 hours. Example 7B
-7E demonstrates a delayed action in formulations of various concentrations of methyl hydroxypropyl cellulose (MHPC) (otherwise corresponding to those used in preferred Example 7A).

7B 7C 7D 7E 31mg 41mg 71mg 101mg The values shown in Table 2 show that the release delay varies with compressive force when MHPC is used in very small amounts (less than about 10% of active substance). Indicates. However, the data do not show the expected reduction in the rate of in vitro dissolution due to increased compressive forces, despite what might be expected based on the behavior of the pure active ingredient itself. Conversely, tablets prepared with high compression force will dissolve quickly.

At MHPC concentrations above the stated minimum,
The release delay can be set arbitrarily within a wide range. To separate the effect of the surfactant, a formulation similar to 7A, but containing no water-active polymer but only water-soluble polymer, was tested in the following examples. Example 8 Granules: Bezafibrate 400 mg Monosaccharides or oligosaccharides (here lactose D80) 51 mg Polyvinylpyrrolidone 15 mg Outer phase: MHPC K 100LV 51 mg Highly dispersed silica 3 mg Magnesium stearate 10 mg The data in Table 2 shows that the release delay is here. It shows that the compression force does not change that much, but this change is still problematic and, worst of all, the coefficient of variation has a very high value and thus the formulation properties do not show good reproducibility.

In general, particularly favorable effects include in the first stage of preparation (particulates): a water-soluble binder (especially polyvinylpyrrolidone) and an anionic surfactant (especially sodium dodecyl sulphate), and In the second step (formation of the external phase) -as observed with formulations containing substances (especially MHPC) that form a gel matrix as release-retarding agents (“retarders”). The amount of delayed release is better than would be expected based on the solubility of the preliminary tablets, so that synergism can be assumed here, probably due to the interaction between the anionic wetting agent and MHPC.

However, the invention can also be used advantageously in its general form with other combinations of additives, notably with other customary release-retarding agents (retarders). Thus, sodium alginate has proven suitable in a series of experiments, and among the cellulose derivatives sodium carboxymethyl cellulose may be used.

The water-soluble binder polyvinylpyrrolidone can be replaced not only by cellulose derivatives such as low-viscosity methylhydroxypropylcellulose and low-substituted hydroxypropylcellulose, but also by sugar esters and solid polyethylene glycol. .
However, the possibilities are limited with regard to surfactants. Of the ionic systems, only sodium dodecyl sulfate is allowed to be used as a pharmaceutical additive. On the other hand, nonionic surfactants also include, for example, macrogol stearate (eg, macrogol 50 stearate),
It may be a polysorbate (eg polysorbate 80) or a polyoxyethylene-polyoxypropylene copolymer (eg Pluronic F68).

Thus many pharmaceutical additives are commercially available and used in the first stage of manufacture (ie with the particles) or in the second stage of manufacture (ie with the external phase).
No rules can be given for the immediate selection of the release-retarding agent used. However, on the basis of the information contained in this description, the person skilled in the art can find the correct additives from the range available and test them for their suitability by simple experiments.

However, among the various types of methylhydroxypropyl cellulose available on the market, the products having the following values have been found to be particularly suitable. -Amount of hydroxypropyl: <9% -Average molecular weight: about 26,000 Average viscosity of a 2% solution at -20 ° C: 0.1 Pa.sec.

[Brief description of drawings]

FIG. 1 shows a diagram for extracorporeal release from prior art unit dosage forms.

FIG. 2 shows a diagram for extracorporeal release from the unit dosage form of the present invention.

[Table 1]

[Table 2]

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Alexander Var Germany D-6711 Heischel Heim Krupfalzstraße 14 (72) Inventor Fritz Demmer Germany D-6945 Hirschberg-Reuterschaosen, Castanineweck 21

Claims (14)

[Claims] 1. A method for producing a shaped and compressed sustained release unit dosage form from a therapeutically active substance which exhibits a self-retarding release which varies depending on the compression force used. , The additive charge, which suppresses or compensates for its self-delay, is converted into particles in the first production step, so that compressed objects made from these particles without the use of another additive are Over the range of compression forces intended for the manufacture of the dosage form, it exhibits a rapid release compared to the slow release required, and in a second manufacturing step, these particles are compressed with a release-retarding agent to give a unit dose. A method of obtaining a morphology. 2. The active substance is bezafibrat.
The method according to claim 1, wherein the method is e). 3. The additive charge used in the first manufacturing stage comprises a pharmaceutical tablet disintegrant.
The method described in. 4. A tablet disintegrant according to claim 2, characterized in that it is incorporated in a concentration of 0.1 to 10% by weight, preferably 0.25 to 5% by weight, calculated on the amount of active substance. Method. 5. A method according to claim 1, characterized in that the additive charge used in the first production stage comprises a wetting agent. 6. A method according to claim 4, characterized in that the wetting agent is an anionic surfactant, in particular sodium dodecyl sulfate. 7. A humectant is used in an amount of 0.1 to 10% by weight, preferably 0.5 to 5% by weight, calculated on the amount of active substance. the method of. 8. The method according to claim 4, wherein the additive charge used in the first production step comprises a medicinal binder. 9. A water-soluble binder is added in an amount of 0.1 to 10% by weight, preferably 0.25 to 6% by weight, calculated on the amount of active substance. the method of. 10. A release-retarding agent is a hydrogel-forming substance, and, calculated on the amount of active substance, 5-40.
Method according to claim 1, characterized in that it is used in an amount of% by weight. 11. A material capable of forming a hydrogel is a cellulose derivative, in particular methylhydroxypropylcellulose having a molecular weight of less than 50,000 and a hydroxypropyl content of less than 9%, or it is sodium carboxymethylcellulose. Item 8. The method according to Item 8. 12. The method according to claim 1, wherein the release-retarding agent is an alginate, especially sodium alginate. 13. A shaped and compressed sustained release unit dosage form comprising compressed particles containing a therapeutically active substance that exhibits a delayed release that varies depending on the compression force used, and an external phase containing tableting additives. Wherein the particles contain an additive charge that suppresses or compensates for the self-delaying of the release of the active substance, so that a compressed body made from the particles without the use of another additive is a unit dose. Sustained-release unit dosage form characterized by a rapid release compared to the slow release required over the range of compression forces intended for the manufacture of the form, and in addition the external phase contains a release-retarding agent. Form. 14. A sustained release unit dosage form according to claim 13, characterized in that the active substance is bezafibrate.