BG64764B1 - Multiparticulate pharmaceutical form with programmed and timed release and preparation method - Google Patents

Abstract

The invention concerns a multiparticulate pharmaceutical form with delayed and timed release for starting to make the active principle available 4 to 8 hours after said pharmaceutical form has been ingested, then for gradually releasing the totality of the active principle within the following 8 to 20 hours. The invention is characterised in that it is free of organic acid and it is in the form of medicated spheroids consisting of a neutral spherical carrier comprising a first coating based on a mixture of at least a water soluble polymer and at least a water insoluble polymer wherein are uniformly distributed particles consisting an active principle, the whole comprising a second coating based on at least two independent pH polymers, having degrees of permeability with respect to different gastric and intestinal environments, optionally at least a dependent pH polymer, at least a plasticising agent and at least an inert filler distributed in said coating.

Description

(54) MULTI-PARTICULAR PHARMACEUTICAL FORM WITH DELAYED AND PULSIONAL RELEASE AND METHOD FOR PREPARING IT

Technical field

It is an object of the invention to provide a delayed and gradual release multiparticulate oral formulation. It is also an object of the invention to provide this pharmaceutical form.

BACKGROUND OF THE INVENTION

Numerous delayed release oral dosage forms are available on the market. The release of the active ingredient should be controlled according to therapeutic needs and the pharmacological properties of the active ingredient. Therefore, it is not always recommended that the amount of active ingredient be constant. On the contrary, in order to avoid any habituation and to limit the secondary phenomena provoked by the active component, it would be perfectly appropriate for the plasma percentage to follow the metabolic rhythm and specific needs of the patient during the relevant periods of the day. For example, in order to reduce nighttime symptoms or wake-ups similar to those of cardiac ischemia, asthma and arthritis, medications should be administered in such a way that the desired plasma therapeutic level is reached at the desired moment, ie. during sleep or at waking time.

In the article "An Organic Acid-Induced Sigmoidal Release System for Oral ControlledRelease Preparations", Pharmaceutical Research Oral Preparations, Pharmaceutical Research, Vol. 11, 1,1994, discloses a pharmaceutical formulation of the sigmoidal type. However, this article states that the type of sigmoidal release of the active ingredient can only be achieved if organic acid is added to the pharmaceutical form. It should be noted that the presence of organic acid in such pharmaceutical forms can lead to an irritant effect, which is a major drawback, especially with prolonged treatment.

Up to this point, therefore, there is no multi-particle formulation with no organic acid content capable of making available strong concentrations of the active ingredient at a time when the patient is in greatest need while maintaining daily minimum plasma therapeutic concentration.

The applicant company has the merit of having discovered in an unexpected and surprising way such pharmaceutical forms which are convenient to take and have no irritating effect.

SUMMARY OF THE INVENTION

Thus, the multiparticulate pharmaceutical formulation according to the invention, which is delayed and gradual release and allows the beginning of delivery of the active ingredient 4 to 8 hours after administration of the pharmaceutical form, then the gradual release of the entire active ingredient in subsequent 8 to 20 h, characterized in that it is free of organic acid and that it is medicated granules or spheroids composed of a neutral core coated with a mixture of at least one water-soluble polymer and not one water-insoluble polymer comprising particles of the active ingredient uniformly, the whole covered by one second coating based on at least two pH-independent polymers having a degree of permeability with respect to the various gastric and intestinal media, optionally at least one pH-dependent polymer and at least one inert filler evenly spaced in said coating.

The concentration of the active ingredient is very high in the layer enclosing the inactive spherical base, which enables the production of drug spheroids of reduced size and, consequently, the production of extremely small drug formulations which are easier and more convenient to take2 not from the patient and allow higher doses for therapeutic use to be prescribed.

According to a preferred embodiment, the pharmaceutical formulation according to the invention is characterized in that the active ingredient represents from 20 to 100% by weight of the inactive spherical base coating layer, preferably 60 to 90% by weight and more successfully 80 to 90% by weight.

The water-soluble polymer present in the composition of the inactive spherical base coating layer and containing the active component is selected from the group consisting of polyvinylpyrrolidone, cellulose hydroxypropylmethyl and mixtures thereof, and the insoluble polymer is selected from the group including in particular acrylic resins and / or acrylic resins methacrylic resins, cellulosic polymers and mixtures thereof.

The mass ratio between the water-soluble polymer and the water-insoluble is from 0.3 to 0.9, preferably from 0.3 to 0.7, and more preferably from 0.45 to 0.55.

The second coating of the pharmaceutical formulation according to the invention is based on at least two pH-independent polymers having a degree of permeability with respect to different gastric and intestinal media, optionally at least one pH-dependent polymer, at least one plasticizer and at least one inactive filler. arranged evenly in said coating.

In this second coating, the ratio between the lowest permeability polymer and the highest permeability polymer is from 97/3 to 80/20.

These ratios between polymers with different permeabilities should be respected. In fact, at a low-permeability polymer ratio of over 97%, the release of the active component can be significantly delayed; conversely, at low permeability ratios of less than 80%, the release of the active component is not sufficiently delayed.

The polymers that are part of the second coating are selected from the group consisting in particular of acrylic resins and / or methacrylic, cellulose polymers and mixtures thereof.

The inactive filler distributed uniformly in the second coating is selected from the group consisting of in particular talc, dehydrated colloidal silica, magnesium stearate, glycerol monostearate and mixtures thereof.

The plasticizer entering the second coating should be pharmaceutically acceptable; it is selected from the group consisting in particular of ethyl phalate, triethyl citrate, dibutyl sebacinate, triacetin and mixtures thereof.

According to one advantageous embodiment of the invention, the active ingredient is selected from the group consisting of molecules with active action on the cardiovascular system, and in particular Diltiazem and Verapamil, anti-inflammatory, anti-allergic and antihistamines.

The pharmaceutical formulation of the invention is administered at bedtime.

Thus, the active ingredient begins to release about 4 to 8 hours after administration, i.e. on awakening of the patient, the moment at which some symptoms considered to be at risk for some cardiovascular cases are considered to be the most significant.

The release progresses evenly over the next 8 to 20 hours.

Since administration of the next pharmaceutical form takes place several hours after the end of complete release of the active ingredient, the patient is provided with the minimum plasma therapeutic concentration throughout the day.

The method of the invention for the preparation of the pharmaceutical form according to the invention is characterized by a series of steps comprising:

- introduction of inactive spherical bases into a fluid bed reaction chamber,

- atomizing particles of the active ingredient in suspension in an organic solvent and / or aqueous solution of at least one water-soluble polymer and at least one water-insoluble polymer on these inactive spherical bases,

- spraying a coating suspension containing at least one inert filler in suspension in a solution of a mixture of at least two permeable polymers with respect to the various gastric and intestinal media on the coated particles obtained in the previous step,

- possibly drying the drug spheroids thus obtained.

Examples

The following pharmaceutical excipients are used in the examples below:

- EUDRAGIT RS 100: polyacrylic-polymethacrylic low-permeability resin commercialized by ROHM,

- EUDRAGIT RL 100:

- polyacrylate-polymethacrylate permeable resin commercialized by ROHM,

- PVP K 90: BASF commercialized polyvinylpyrrolidone,

- AEROSIL: commercialized by DEGUSSA,

- Pharmaceutical alcohol,

- Pharmaceutical talc

- Ethyl phthalate commercialized by WERNER'S,

- Non-active spherical sucrose and starch bases commercialized by WERNER'S,

- INWITOR 900: glycerin monostearate, commercialized by UHLS,

- EUDRAGIT LI00: a methacrylic acid and methyl methacrylate resin commercialized by ROHM.

Example 1

Preparation of drug spheroids, an integral part of the pharmaceutical formulation according to the invention and whose active ingredient is DILTLAZEM

0.7 kg of inactive spherical bases with diameters of 300 to 400 mM are introduced into a GPCG1 liquefied air bed reactor, onto which a suspension of the following composition is sprayed:

EUDRAGIT RS 100 0.525 kg PVP K 90 0.525 kg DILTIAZEM 7,000 kg Pharmaceutical alcohol 18,760 kg

EUDRAGIT RS 100 2,000 kg EUDRAGIT RL 0.100 kg Ethyl phthalate 0.192 kg AEROSIL 0.320 kg Acetone 4,500 kg

About 400 to 500 of the drug spheroids obtained are inserted into hard gelatin capsules of classic composition.

The release of the active component is investigated in vitro as follows. One conventional pallet type solubility meter is used and purified water is used for the soluble medium; the conditions for using the solubility meter are 900 ml of purified water and 100 t / m; the amount of capsules administered corresponds to one therapeutic dose.

Measure the amount of active ingredient released (expressed as a percentage by weight) with respect to the total amount of active ingredient contained in the capsules administered, proceeding as follows:

Samples are taken from the solution from 0 to 4 hours every hour and from 4 to 16 hours every two hours. The released DILTIAZEM in the samples was dosed using a CLHP apparatus equipped with a 240 shi UV detector.

The results obtained are given in Table 1.

Table 1

HOURS DISSOLVED% 0 0 1 0.8 2 2.0 3 3.4 4 5.1 5 11.7 6 40,4 8 88,0 10 99,4 12 100,9

Then, a slurry of coating with the following composition is sprayed onto the particles thus formed:

Example 2

Preparation of drug spheroids, an integral part of the pharmaceutical formulation according to the invention and whose active ingredient is DILTIAZEM.

The drug spheroids were prepared as in Example 1 described above, the coating slurry being one suspension with the following composition:

EUDRAGIT RS 100 3,060 kg EUDRAGIT RL 100 0.340 kg Ethyl phthalate 0.340 kg Isopropanol 14.28 kg Acetone 9.52 kg

As in Example 1 described above, dissolution was measured. The results are given in Table 2 below.

TABLE 2

HOURS DISSOLVED% 0 0 1 2.8 2 6.4 3 11.6 4 18,4 6 32.3 8 49,1 10 68,7 12 85,3 16 103,6

Example 3

Preparation of drug spheroids, an integral part of the pharmaceutical formulation according to the invention and whose active ingredient is DILTIAZEM.

The drug spheroids were prepared as described above in Example 1, with the coating suspension used having the following composition:

EUDRAGIT RS 100 3,612 kg EUDRAGIT RL 100 0.638 kg Ethyl phthalate 0.425 kg Inventor 900 0.213 kg Isopropanol 17,850 kg Acetone 11,900 kg

The dissolution measurement was performed as in Example 1. The results are shown in the following Table 3.

Table 3

HOURS DISSOLVED% 0 0 1 1.1 2 7.2 3 84,3 4 90 6 92,7 8 94.8 10 94 12 95,1 14 95,1 16 96

Example 4

Preparation of drug spheroids, an integral part of the pharmaceutical formulation according to the invention and whose active ingredient is VERAPAMIL.

The drug spheroids were prepared as described in Example 1 above, replacing DILTIAZEM with VERAPAMIL as the active ingredient, and the coating suspension having the following composition:

EUDRAGIT RS 100 1,650 kg EUDRAGIT RL 100 0.087 kg EUDRAGIT L 100 0.063 kg Ethyl phthalate 0.165 kg Aerosil 0.274 kg Talc 0,343 kg Pharmaceutical alcohol 9,000 kg Acetone 3,857 kg

As in Example 1 above, the dissolution was measured, and the released VERAPAMIL was dosed using a UV spectrophotometer at 278 nm. The results are illustrated in Table 4 below.

TABLE 4

HOURS DISSOLVED% 0 0 1 1.9 2 6.1 3 12.3 4 21.2 6 49,6 8 82,1 9 0.0 10 94.7 12 97,4 14 97.8 16 98.6

Claims (9)

ΜΊΜ Claims 1. A delayed and pulsatile release multiparticulate form, allowing the active ingredient to be delivered 4 to 8 hours after ingestion of said pharmaceutical form and then gradually releasing the entire basic component over the next 8 to 20 hours, characterized in that it is a liberated organic acid and that it is a drug spheroid consisting of a neutral spherical base with a first coating based on a mixture of at least one water-soluble polymer and at least one water-insoluble a polymer in which the constituent particles of the active constituent are evenly spaced, the whole having one second coating based on at least two pH-independent polymers having different degrees of permeability with respect to the various gastric and intestinal media, optionally at least one pH-dependent polymer , at least one plasticizer and at least one inert filler evenly distributed in said coating. A pharmaceutical formulation according to claim 1, characterized in that the active component represents from 20 to 100% by weight of the coating layer n on the inactive spherical base, preferably 60 to 90% by weight and more preferably 80 to 90% by weight. Pharmaceutical form according to one of Claims 1 and 2, characterized in that the ratio of the masses between the water-soluble polymer and the water-insoluble polymer is from 0.3 to 0.9, preferably 0.3 to 0.7, and more preferably from 0.45 to 0.55. Pharmaceutical form according to any one of claims 1 to 3, characterized in that the water-soluble polymer is selected from the group consisting of polyvinylpyrrolidone, cellulose hydroxypropylmethyl and mixtures thereof and the water-insoluble polymer is selected from the group consisting of in particular acrylic resins and / or methacrylic resins, cellulosic polymers and mixtures thereof. Pharmaceutical form according to any one of claims 1 to 4, characterized in that the ratio between the lowest permeability polymer and the highest permeability polymer is from 97/3 to 80/20. 5 Pharmaceutical form according to any one of Claims 1 to 5, characterized in that the polymers included in the second coating are selected from the group consisting of in particular acrylic resins and / or methacrylic resins, cellulosic polymers and mixtures thereof. Pharmaceutical form according to any one of claims 1 to 6, characterized in that the inactive filler uniformly distributed in the second coating is selected from the group consisting in particular of talc, dehydrated colloidal silica, magnesium stearate , glycerol monostearate and mixtures thereof. A pharmaceutical formulation according to any one of claims 1 to 7, characterized in that the active ingredient is selected from the group consisting of, in particular, molecules with active action on the cardiovascular system, and especially DILTIAZEM and VERAPAMIL, anti-inflammatory, anti-allergic and antihistamines. The method of preparing the pharmaceutical form according to any one of claims 1 to 8, is characterized by a series of steps comprising: introducing inactive spherical bases into a fluid bed reaction chamber; - spraying particles of the active ingredient in suspension, in an organic and / or aqueous solvent of at least one water-soluble polymer and at least one water-insoluble polymer on these inactive spherical bases; - spraying a coating suspension containing at least one inert filler in suspension in a solution of a mixture of at least two permeable polymers with respect to the various gastric and intestinal media on the resulting coated particles in the preceding step; - possibly drying the drug spheroids thus obtained.