FI102455B - A process for preparing an oral pharmaceutical multi-unit formulation - Google Patents

Description

102455

The present invention relates to a process for the preparation of an oral pharmaceutical multi-unit formulation comprising separate cores containing a pharmacologically active substance provided with a coating consisting essentially of a polymer which is dissolved in water and digestive fluids. and non-swellable, wherein the polymer contains 80 to 95% by weight of vinyl chloride, 1 to 19% by weight of vinyl acetate and 0 to 10% by weight of vinyl alcohol, and a water-soluble pore-forming agent randomly distributed in said polymer, wherein the coated cores form units that provide a substantially zero order diffusion controlled rate of release of the active agent. Thus, according to the invention, there is provided an oral, controlled release, multi-unit pharmaceutical dosage form in which the individual units containing the active agent are surrounded by a coating which releases the active agent by diffusion.

The term "controlled release multi-unit formulation" (Bechgaard & Hegermann Nielsen 1978) means a pharmaceutical formulation containing a plurality (typically at least 100) of separate coated (i.e., "microencapsulated") units in a formulation such that separate units are released from the for-30 mutation for use when the formulation degrades into formu-. in the stomach of swallowed animals, including humans. The multi-unit formulation may typically be a gelatin capsule or tablet that disintegrates in the stomach to provide a plurality of coated units.

2 102455 Controlled release multi-unit formulations aim at controlled release of the active agent according to a predetermined pattern in order to reduce and delay the peak plasma concentration without adversely affecting the bioavailability of the drug. Due to the lower peak plasma concentration, the incidence of undesirable side effects can be reduced, and due to the longer time to peak plasma concentration and the longer duration of the therapeutically effective plasma concentration, the dosing frequency can only be reduced to once or twice daily to improve patient compliance.

An additional advantage of the controlled release multi-unit dosage form is that a high local concentration of active agent in the gastrointestinal tract is avoided due to the units being freely distributed throughout the gastrointestinal tract.

The release of the drug from the controlled release dosage form is generally controlled by a coating around the active core. The release can be achieved by a) diffusion: the coating swells in an aqueous environment so that the active substance can diffuse through the liquid phase in place in the coating polymer, or b) through osmosis: the coating is semipermeable, i.e. only water can penetrate the coating through and dissolves the active substance, resulting in an increase in pressure inside the coating; in order for the active substance to be released from the unit, a hole or channel with a well-defined surface area must be formed in the coating, which can be achieved either by laser drilling [SE Patent Publication 435,897 and U.S. Patent No. 4,256,108 (Alza)] or by including in the preparation a substance which forms channels through erosion after ingestion of the drug 3 102455 [U.S. Patent 6,687,660 and EP Application Publication No. O 171,457 (Wellcome)], and if there are weak spots or cracks in the coating, the result -increase in surface area and varying dissolution rate between different units, i.e. zero order release is not achieved for the whole dose, or c) through erosion: the coating decomposes in a process dependent on, for example, enzymes or pH and leaves the active core free to dissolve 10 rapidly. The importance of pH-independent diffusion for reproducible bioavailability and for minimizing intra- and inter-patient differences is well known (GB Patent 1,468,172 and Bechgaard & Baggesen 1980). It is also known that controlled drug release in vivo can be achieved through erosion of the enteric coating of a multi-unit dosage form (Green 1956; McDonald et al. 1977; Bogentoft et al. 1978).

This invention relates to multi-unit dosage forms in which control is by means of diffusion membranes. Unlike the previously known diffusion membranes used in multi-unit dosage forms, the membrane used according to the invention is non-swellable in water and digestive fluids. In addition, the polymer used must be insoluble in water and impermeable to water, and pores will form in the film for ingestion ”. After 25 through a pH-independent erosion process.

The pores give the coating a sponge-like appearance and are filled with a stationary liquid through which the active substance can diffuse out of the core.

Numerous coatings for use in a variety of controlled release pharmaceutical multi-unit formulations have been found to suffer from the disadvantage that their release properties change over time. This means that it is not possible to maintain a reproducible release rate of the active substance in the multi-unit formulation, as the release rate has been found to vary with such coatings. In accordance with the present invention, it has surprisingly been found that by selecting a particular type of controlled release system that has not previously been used or disclosed in connection with multi-unit formulations, many of the problems associated with multi-unit formulations can be avoided.

Controlled release systems for use on a macroscopic scale, i.e., tablets, based on coatings containing pore-forming agents are disclosed, for example, in GB Patent 1,186,990 and U.S. Patent Nos. 3,538,214 and 4,557,925. The release system of this invention is based thereon. the principle that the core containing the active substance is coated with a film consisting essentially of a polymer which is insoluble and impermeable to water and digestive liquids and in which a substance which randomly forms water-soluble pores is randomly distributed. It is also required that the polymer be non-swellable in water and digestive fluids. 20 It has surprisingly been found that important advantages have been achieved in the use of this controlled release system in multi-unit formulations.

Thus, it has been found that it is possible to coat different types of particles, including crystals, in conventional coating equipment, i.e., different types of conventional equipment commonly available in the pharmaceutical industry. It follows that the manufacturing process is relatively simple and inexpensive. In addition, it has been found that a uniform, substantially zero-order controlled release rate could be achieved, even with the use of relatively non-uniform particles as cores. This is not usually the case with conventional controlled release multi-unit formulations. For example, diffusion-controlled release from multi-unit formulations in which the polymer swells depends on the thickness of the diffusion layer, which varies as a function of time, as the polymer releases the active agent as the swelling continues. This results in different release rates at the beginning and end of the release period, resulting in a release more resembling first-order than zero-order reactions. Osmosis-controlled multi-unit preparations, in turn, depend on both the ability of the substances in the core to absorb water, which can lead to a decrease in the release rate in the release period 10-10 if the osmotically active and pharmaceutically active substance are not the same. there are weaknesses or cracks. Such errors result in different release rates for different units, i.e., zero order release is not achieved for the multiple units in the dose.

An advantage of the present invention is the ability to adjust the release rate by changing the thickness of the film. In currently commercially available multi-unit systems, this possibility appears to exist in a manner that is quite difficult to predict, and only up to a certain film thickness. In the system according to the invention, instead, there is a substantially linear correlation between the release rate and the film thickness. This means that, in the case of a certain type of film, the release rate decreases in direct proportion to the increase in film thickness according to Fick's law of diffusion.

It is also possible to change the release rate by changing the ratio of the pore-forming agent to the coating polymer 30. This offers a unique opportunity in the system according to the invention to take advantage of substances with very different solubilities, which is a great advantage over existing controlled release multi-unit systems.

6 102455

Accordingly, the present invention relates to a process for the preparation of an oral multi-unit pharmaceutical formulation comprising discrete cores containing a pharmacologically active substance provided with a coating consisting essentially of a polymer which is insoluble, impermeable and impermeable to water and digestive fluids. the polymer contains 80 to 95% by weight of vinyl chloride, 1 to 19% by weight of vinyl acetate and 0 to 10% by weight of vinyl alcohol, and a water-soluble pore-forming agent randomly distributed in said polymer, the coated cores forming units which obtain a substantially zero-order diffusion-controlled release rate of the active substance, which method is characterized in that the polymer is dissolved in a solvent, a suspension of the pore-forming agent is prepared, the pore-forming agent is mixed suspending the substance and a polymer solution to form a flowable coating agent, preparing multi-unit cores containing the active substance in the form of crystals or pellets with a diameter of about 0.1 to 1.5 mm, applying a flowable coating material to the core units and drying the units, the solvent evaporates to give polymer-coated multi-units containing - 25 water-soluble pore-forming agents randomly distributed in the coating. In addition to units of the type described above, the coating according to the invention may be combined with uncoated units containing the same or another active substance for immediate release and / or non-diffusion coated units with a coating which is a hydrophilic coating, a hydrophobic coating, a hydrophobic coating, coating or organic coating that imparts desired properties to the unit, such as acid or base resistance, storage stability, taste masking, lightfastness, color, improved processability, etc. Diffusion coated and uncoated or non-diffused or non-diffused the ratio of 5 in the composition can be adjusted, for example, according to the desired release properties of the composition, but is preferably in the range of approximately 10:90 to 90:10 (diffusion head). uncoated or non-diffusion coated units).

An oral controlled release multi-unit pharmaceutical formulation prepared in accordance with the invention is typically a gelatin capsule containing a plurality, typically more than 100, of units, a sachet containing a plurality, typically more than 500, of units, or a tablet made of a plurality of units. typically more than 100 units, in such a way that the tablet disintegrates in the stomach into a number of discrete units after ingestion. With each of the above formulations, the units are freely distributed throughout the food-20 digestive tract soon after ingestion.

Coating The coating polymer should have good film-forming and sizing properties and should be readily soluble in organic solvents such as acetone, methylene chloride, methyl ethyl ketone or mixtures of acetone and ethanol or methylene chloride. Suitable polymers include non-swellable cellulose derivatives, acrylic polymers and vinyl polymers. According to the invention, a polymer is used which contains 80 to 95% by weight of vinyl chloride, 1 to 19% by weight of vinyl acetate and 0 to 10% by weight of vinyl alcohol. The polymer preferably contains 88 to 94% by weight of vinyl chloride, 2 to 5% by weight of vinyl acetate and 3 to 5% by weight of vinyl alcohol.

The coating preferably also contains plasticizers.

The amount may range from 1 to 50, preferably from 10 to 40 8 102455% by weight of the coating polymer. Examples of suitable plasticizers are acetyl tributyl citrate, polyethylene glycol, blown castor oil and glyceryl triacetate. The coating may further contain 1 to 20, preferably 5 to 15% by weight of sodium coating carbonate as a stabilizing agent.

The pore-forming agent to be used in accordance with the present invention should be highly water-soluble, insoluble in the coating solvent, pharmacologically acceptable and substantially free of any pharmacological effect in the amounts used. Particularly preferred are sugars such as sucrose and lactose, and salts such as sodium chloride.

The particle size of the pore-forming agent may vary from 0.1 to 100, preferably from 0.5 to 50. The ratio between the amounts of pore-forming agent and the amount of coating polymer depends on the desired dissolution rate. This ratio should generally be 0.05 to 5, preferably 0.1 to 2.

The thickness of the coating also depends on the desired dissolution rate. It can be in the range of 5 to 300 pm, preferably 10 to 150 pm.

Cores The individual units of the multiunit formulations obtainable in accordance with this invention are coated cores of crystals or pellets. Crystalline single bonds are roughly monocrystalline units. Pellets consist of a combination of active ingredient and excipient. One important type of pellet consists of a filler seed particle on the surface of which the active ingredients have been applied. Typical pellets of this type are the so-called "nonpareil pellets", in which the seed particles are in the form of spherical sucrose particles. In another pellet formulation of this type, the seed particles are in the form of crystalline sucrose. An important type of pellet 35 consists of particles of approximately homogeneous cross-section, prepared, for example, by wet granulation or extrusion.

The diameter of the core is normally about 0.1 to 1.5 mm, preferably about 0.4 to 1.2 mm; the range is preferably up to about 0.4 mm in one formulation.

Active substance

The active ingredient in the formulations obtainable according to the invention may be any active ingredient which is preferably administered in controlled release multi-unit formulations. Examples of suitable active ingredients can be found in almost all therapeutic agent groups, including diuretics, antiepileptics, sedatives, antiarrhythmics, antirheumatic drugs, beta-blockers, vasodilators, analgesics, bronchodilators, bronchodilators, hormones, vitamins. inflammatory agents, antimicrobial agents, antidepressants, polypeptides, enzymes and mucopolysaccharides.

Examples of active ingredients are phenylpropanolamine, potassium chloride, quinidine salts, lithium carbonate, acetylcysteine, depyridamole, theophylline, choline theophylline, dextropropoxyphene, dextromethorphan, salbutamol, terbutaline, digbutaline, digbutaline, : .25 mine, morphine, nitroglycerin, clonidine, disopyramide, verapamil, captopril, prazosin, nifedipine, diltiazem, paracetamol, indomethacin, ticlopedine, oxybutynin and noscapine.

Some of these substances are characterized by pH-independent solubility and some by pH-dependent solubility. Active substances with a pH-dependent solubility are preferably incorporated into the cores in combination with buffering agents such as sodium bicarbonate, citric acid, succinic acid or tartaric acid to provide a solubility of the active substance which is substantially independent of pH-varying , through which the units pass.

Method

Generally speaking, in the method of the invention to prepare a coated multi-unit formulation, the polymer is dissolved in a solvent, a pore-forming agent suspension is prepared, a pore-forming agent suspension and a polymer solution are mixed to form a flowable coating agent, in the form of, applying a flowable coating material to the core units and drying the units to evaporate the solvent and obtain polymer-coated units having a water-soluble pore-forming agent randomly distributed in the coating.

The solvent for the polymer may be, for example, acetone, methylene chloride, methylene ethyl ketone or a mixture of acetone and ethanol or methylene chloride.

The pore-forming particles are comminuted by either dry or wet grinding to a specified particle size, preferably in the range of 0.5 to 50. The particles are dispersed in solvents such as those mentioned above and mixed with the terpolymer solution.

*:. The flowable coating material may, as mentioned above, contain a plasticizer and sodium bicarbonate.

A colorant can also be included in the flowable coating agent, with insoluble colorants being preferred.

The flowable coating material in the form of a suspension is then applied to the drug-containing cores. A particularly advantageous feature is that the coating method can be carried out in a conventional coating apparatus, i.e. in various types of conventional apparatus commonly available in the pharmaceutical industry.

11 102455 This is due to the good film-forming and gluing properties of the coating material and the ease of evaporation of the solvent from the system. Examples of such coating methods are pan coating in sugar coating pans or perforated film coating pans,

Wiirster coating and other fluidized bed coating methods. It follows that the manufacturing process is relatively easy and inexpensive.

The following examples further illustrate the invention, but are not to be construed as limiting the invention.

Example 1

Theophylline is a weak acid (pKa = 8.7) that is sparingly soluble in water. The cores used in this example contain 60% theophylline on nonpareils and have a particle size of 0.8 to 1.0 mm. These cores (1.0 kg) are coated with a coating suspension having the following composition:

Terpolymer containing 92% by weight of vinyl chloride, 4% by weight of vinyl acetate and 4% by weight of vinyl alcohol 390 g

Micronized sucrose (particle size 1-10 μm) 930 g

Acetyl tributyl citrate 89 g

Blown castor oil 68 g • ·. · 25 Sodium bicarbonate 34 g

The acetone is made up to 10,000 g. The coating suspension is applied to the cores in an airless spray coater in a coating pan. Samples are taken after the addition of 1,0, 2,0 and 3,0 kg of suspension.

Table 1 shows the dissolution rate of a dose corresponding to 90 mg theophylline. The dissolution test is carried out by the basket method USP XXI (speed 100 min-1). There is a linear correlation between the release rate and the thickness of the coating, and the release rate is largely independent of pH. For most of the release time, the release rate is uniform and non-zero order.

12 102455 TABLE 1

Amount of theophylline released (%)

Time 0.2 M TRIS buffer, pH 7.4 0.1 M HCl

5 (hours) ABC C

1 46 18 10 11 2 84 39 24 28 3 98 58 37 44 4 100 76 49 59 10 5 90 62 73 6 96 73 86 7 99 83 94 8 90 99 9 94 100 15 10 96 101 11 97 101 12 98 102 A : 2.5 mg of coating material / cm2 of core surface 20 B 5.9 mg of coating material / cm2 of core surface C: 9.0 mg of coating material / cm2 of core surface

Example 2

Choline theophylline is an easily water-soluble salt of theophylline. The cores used in this example contain 30% choline theophyllinate with sugar crystals and have a particle size of 0.7 to 1.0 mm. These cores (1.0 kg) are coated with a suspension having the following composition: Terpolymer containing 92% by weight of vinyl chloride, 4% by weight of vinyl acetate and 4% by weight of vinyl alcohol 295 g

Micronized sucrose (particle size 1-10 μm) 930 g

Acetyl tributyl citrate 30 g 35 Blown castor oil 23 g 13 102455

Sodium bicarbonate 34 g

Titanium oxide 59 g

The acetone is made up to 10,000 g. 5 The coating suspension is applied with a coreless airless spray coater in a coating pan. Samples are taken after the addition of 2.0, 2.5 and 3.0 kg of suspension.

Table 2 shows the dissolution rate of 10 doses corresponding to 90 mg theophylline. The dissolution rate is tested by the USP XXI body method (100 rpm). The dissolution rate is considerably higher than in Example 1, due to the fact that the solubility of the choline salt of theophylline is much higher than that of theophylline alone. Concerned about the higher dissolution rate, there is still a linear correlation between the release rate and the coating thickness.

TABLE 2 20

Amount of theophylline released (%)

Time 0.2 M TRIS buffer, pH 7.4

(hours) AB C

0.33 96 86 76. * 25 0, 67 100 99 98 1.00 100 100 A: 3.7 mg of coating material / cm2 of core surface B 4.6 mg of coating material / cm2 of core surface 30 C: 5.5 mg of coating material / cm2 core surface • «

Example 3

Diltiazem hydrochloride is an easily water-soluble ammonium salt. The cores 35 used in this example contain 44% diltiazem hydrochloride on nonpareils, 14 102455 and have a particle size of 0.7 to 1.1 mm. These cores (0.9 kg) are coated with a coating suspension having the following composition:

Terpolymer containing 92% by weight of vinyl chloride, 4% by weight of vinyl acetate and 4% by weight of vinyl alcohol 409 g

Micronized sucrose (particle size 1-10 μm) 930 g

Acetyl tributyl citrate 70 g 10 Blown castor oil 52 g

Sodium bicarbonate 34 g

The acetone is made up to 10,000 g. The coating suspension is applied to the cores by means of an airless spray coating apparatus in a coating pan. Samples are taken after the addition of 1.6, 2.3 and 3.0 kg of suspension.

Table 3 shows the dissolution rate of a dose corresponding to 120 mg diltiazem hydrochloride. The dissolution test is performed by the USP XXI method (20 rpm). The solubility of this ammonium salt is similar to that of the salt of Example 2. The dissolution rate is therefore also similar. Also in this case, a linear correlation between the release rate and the thickness of the coating is obvious.

• · 25 «·« 15 102455 TABLE 3

Amount of theophylline released (%)

Time 0.2 M TRIS buffer, pH 7.4

5 (hours) AB C

0.25 48 34 27 0.50 79 67 56 0.75 91 85 80 1.00 96 91 85 10 1.25 98 94 91 1.50 99 97 94 1.75 100 98 96 2.00 101 99 97 15 A: 6, 8 mg of coating material / cm2 of core surface B 9.8 mg of coating material / cm2 of core surface C: 12.4 mg of coating material / cm2 of core surface

Claims (3)

102455 A process for preparing an oral multi-unit pharmaceutical formulation comprising 5 separate cores containing a pharmacologically active substance provided with a coating consisting essentially of a polymer which is insoluble, impermeable and insoluble in water and gastrointestinal fluids, wherein the polymer contains 80 to 95% by weight of vinyl chloride, 1 to 19% by weight of vinyl acetate and 0 to 10% by weight of vinyl alcohol, and a water-soluble pore-forming agent randomly distributed in said polymer, the coated cores forming units which obtain providing a substantially zero-order diffusion-controlled rate of release of the active agent, characterized in that the polymer is dissolved in a solvent, a suspension of the pore-forming agent is prepared, a suspension of the pore-forming agent and a polymer solution are mixed to form purchase a flowable coating material, prepare multi-unit cores containing the active substance in the form of crystals or pellets with a diameter of about 0.1 to 1.5 mm, preferably about 0.4 to 1.2 mm, apply the flowable coating material to the core units and dry · Units in which the solvent evaporates to give polymer-coated multi-units with a water-soluble pore-forming agent randomly distributed in the coating. Process according to Claim 1, characterized in that the polymer is a terpolymer which contains 88 to 94% by weight of vinyl chloride, 2 to 5% by weight of vinyl acetate and 3 to 5% by weight of vinyl alcohol. Process according to Claim 1 or 2, characterized in that the pore-forming agent is a sugar or a salt. 102455