HK1116341B

HK1116341B - Use of polymer mixtures for the production of coated pharmaceutical formulations and pharmaceutical formulation with mixed polymeric coating

Info

Publication number: HK1116341B
Application number: HK08106684.0A
Authority: HK
Inventors: C.梅尔; K．努彭; H-U．彼德雷特
Original assignee: 赢创运营有限公司
Priority date: 2005-05-25
Filing date: 2006-03-03
Publication date: 2014-10-17

Description

Use of polymer mixtures for producing coated pharmaceutical preparations and pharmaceutical preparations having mixed polymer coatings

The invention relates to the use of polymer mixtures for producing coated pharmaceutical preparations and to pharmaceutical preparations having a mixed coating of the polymers.

Background

The use of so-called neutral methacrylate copolymers, which refer to methacrylate copolymers consisting predominantly (at least 95%) of (meth) acrylate monomers having neutral groups, such as methyl methacrylate or ethyl acrylate, as coating agents and binders for pharmaceutical preparations with delayed release of the active ingredient has been known for a long time. The use in mixtures with anionic dispersions is described, for example, in EP-A152038, EP-A208213 or EP-A617972. WO 01/68767 describes the preparation of dispersions comprising neutral methyl acrylate copolymers using from 1 to 10% by weight of a non-ionic emulsifier having an HLB of from 15.2 to 17.3. These methods allow the production of pharmaceutical formulations in which phase separation, which occurs with the formation of a crystal structure, is suppressed using an emulsifier while maintaining the stability of the dispersion and its particle size distribution.

EP 0152038 a2 describes coated pharmaceutical preparations with a mixed coating consisting of a water-soluble carboxyl-containing polymer and a water-insoluble film-forming polymer. The polymers may be present in a ratio of 60: 40 to 5: 95. For example, hybrid coatings composed of polymers are described, which on the one hand may consist of equal parts of ethyl acrylate and methacrylic acid and on the other hand may consist of ethyl acrylate and methyl methacrylate in a ratio of 2: 1.

The content of EP 0208213 a1 is essentially the same as EP 0152038 a2, but additionally the effect of high extensibility and elasticity corresponding to the hybrid coating is disclosed.

EP 0704208 a2 describes coating agents and binders for drug coatings that are soluble in intestinal fluid. This is a copolymer of 10 to 25% by weight of methacrylic acid, 40 to 70% by weight of methyl acrylate and 20 to 40% by weight of methyl methacrylate. The specification mentions multi-layer coating systems in addition to single layer coatings. They consist, for example, of a core containing a basic or water-sensitive active ingredient, with a separate layer of a further coating material, such as a cellulose ether, a cellulose ester or, for example, an EUDRAGITEUDRAGIT of RS and RLType cationic polymethacrylates, then additionally provided with the above-mentioned coating soluble in intestinal fluid.

WO 03/072087 describes a process for the preparation of pharmaceutical preparations, wherein copolymers are used which consist of:

20-34% by weight of methacrylic acid and/or acrylic acid,

20 to 69% by weight of methyl acrylate and

0-40 wt.% ethyl acrylate and/or optionally

0 to 10 wt.% of other vinyl copolymerizable monomers,

with the proviso that the glass transition temperature of the copolymers is not more than 60 ℃ in accordance with ISO 11357-2, clause 3.3.3.

For controlled release of the active ingredient, it may be advantageous here in the individual case to mix further polymers into the copolymer. The proportion of the other polymers in the mixture can vary within wide limits and is from 1 to 99% by weight, preferably from 10 to 90% by weight, particularly preferably from 25 to 85% by weight, based on the polymer mixture.

Examples of such other polymers are: polyvinylpyrrolidone, polyvinyl alcohol, anionic (meth) acrylate copolymers of methyl and/or ethyl methacrylate and methacrylic acid (EUDRAGIT)L 100、EUDRAGITS 100、EUDRAGITL100-55), anionic (meth) acrylate copolymers of methyl methacrylate, methyl acrylate and methacrylic acid of the prior art (see, for example, EP-A0704207 or EP-A0704208), salts of carboxymethylcellulose, Hydroxypropylcellulose (HPMC), neutral (meth) acrylate copolymers of methyl methacrylate and ethyl acrylate (dry matter from EUDRAGIT)NE 30D), copolymers of methyl methacrylate and butyl methacrylate (PLASTOID)B) Or (meth) acrylate copolymers having quaternary ammonium groups (EUDRAGIT)RL and EUDRAGITRS)。

WO 2004/096185 describes a process for producing a pharmaceutical preparation in the form of a coated pharmaceutical preparation or a matrix containing an active ingredient, in which a copolymer, the active pharmaceutical ingredient, optionally a core and/or pharmaceutically customary additives, is processed in a manner known per se by melting, injection molding, extrusion, wet granulation, casting, impregnation, painting, spraying or compacting to give a coated pharmaceutical preparation and/or to give a matrix containing an active ingredient, wherein a copolymer consisting of the following components is used:

20-33% by weight of methacrylic acid and/or acrylic acid,

5-30% by weight of methyl acrylate and

20-40% by weight of ethyl acrylate and

more than 10-30% by weight of butyl methacrylate and

optionally, optionally

0 to 10% by weight of other vinylic copolymerizable monomers,

wherein the proportion of monomers is added up to 100% by weight,

provided that the glass transition temperature of the copolymer is from 55 to 70 ℃.

For controlled release of the active ingredient, it may be advantageous here in the individual case to mix further polymers into the copolymer. The proportion of the other polymers in the mixture can vary within wide limits and is from 5 to 95% by weight, preferably from 10 to 90% by weight, particularly preferably from 25 to 85% by weight.

Examples of such other polymers are: polyvinylpyrrolidone, polyvinyl alcohol, methyl methacrylate and/or ethyl acrylateAnd anionic (meth) acrylate copolymer of methacrylic acid (EUDRAGIT)L 100、EUDRAGITS 100、EUDRAGITL100-55), anionic (meth) acrylate copolymers of methyl methacrylate, methyl acrylate and methacrylic acid of the prior art (see, for example, EP-A0704207 or EP-A0704208), salts of carboxymethylcellulose, Hydroxypropylcellulose (HPMC), neutral (meth) acrylate copolymers of methyl methacrylate and ethyl acrylate (dry matter from EUDRAGIT)NE 30D), copolymers of methyl methacrylate and butyl methacrylate (PLASTOID)B) Or (meth) acrylate copolymers having quaternary ammonium groups (EUDRAGIT)RL and EUDRAGITRS)。

Task and solution

EP 0152038 a2 starts from a pharmaceutical preparation with a coating of a carboxyl group containing polymer. These carboxyl-containing polymers, in particular methacrylic acid-containing (meth) acrylate copolymers, are resistant to gastric juices, but at the same time are soluble in intestinal juices. Depending on the content of carboxyl groups, they dissolve at a specific pH. Pharmaceutical formulations coated with equal parts of polymers of ethyl acrylate and methacrylic acid, for example from about pH 5.5, release the active ingredient rapidly. According to EP 0152038A 2, the effect observed in mixtures of water-insoluble, film-forming polymers was a dissolution-pH value (Ausl)se pH-Wert) drift upward, but the release profile of the active ingredient or its time course remains largely unaffected. The effect of the mixture can be described as "pH drift". If one wishes to influence the time course of the release profile of the active ingredient, it is clear that this can only be achieved by varying the monomer composition of the carboxyl-containing polymer. A problem encountered by those skilled in the art of pharmaceutical technology is that only a limited number of polymers can be utilized. Therefore, there is a need to develop new polymers containing new monomer compositions in order to obtain variants of the time course which, at the same dissolution-pH value, exhibit different release characteristics of the active ingredient,

there is therefore a need to find a solution which makes it possible in a simple manner to vary the time course of the release profile of the active ingredient of anionic or carboxyl-containing polymers without at the same time affecting their dissolution-pH value.

This task is solved as follows:

use of a mixture of 2 to 60% by weight of one or more polymers (I) and 40 to 98% by weight of one or more polymers (II) for the production of a coated pharmaceutical preparation, wherein

The polymer (I) is a (meth) acrylate copolymer comprising 90 to 100% by weight of radical polymerizable units consisting of 40 to 95% by weight of C of acrylic acid or methacrylic acid, and 0 to 10% by weight of other vinyl-polymerizable monomers₁-to C₄-alkyl esters and 5 to 60% by weight of (meth) acrylate monomer units having an anionic group, and

polymer (II) is a vinyl polymer or polysaccharide derivative, different from polymer (I), comprising 88 to 100% of neutral monomer units and up to 12% by weight of polymerized monomer units having ionic groups,

the coated pharmaceutical preparation comprises a core containing the active ingredient and a polymer coating consisting of a mixture of polymers (I), (II),

it is characterized in that the preparation method is characterized in that,

the glass transition temperature of polymer (I) does not exceed 70 ℃ and a release profile is achieved which starts to release the active ingredient at the same pH but is slower than that of a coated pharmaceutical formulation with polymer (I) alone.

(meth) acrylate copolymers described in EP 0152038A 2, e.g. EUDRAGITL or EUDRAGITL100-55, having a glass transition temperature greater than 100 ℃. Such polymers are not suitable for use as polymer (I) for the purposes of the present invention. The invention is based on the recognition that the "pH drift" effect of the polymer mixtures described in EP 0152038A 2 does not occur in the selection of anionic or carboxyl-containing polymers having a glass transition temperature of not more than 70 ℃. It was found completely surprisingly that the time course of the release profile of the active ingredient can be modified in a task-specific manner without altering the dissolution pH.

A part of the polymer mixtures concerned is known in principle from WO 03/072087 and WO 2004/096185. According to the broad teaching of EP 0152038A 2, the mixtures described therein lead to undesirable pH drift effects according to the invention. The use of the mixtures selected in WO 03/072087 and WO 2004/096185 to solve the stated task opens up new promise in pharmaceutical technology. The person skilled in the art will be able to adjust the time course of the active ingredient release profile by the mixing ratio of the polymers, starting from the enteric soluble active ingredient release profile of the anionic or carboxyl group containing polymers with the specified specific dissolution-pH value. It is thus possible to avoid expensive alternative developments, specific complex coating formulations or the development of polymers with alternative monomer compositions.

Copolymers of 10 to 30% by weight of methyl methacrylate, 50 to 70% by weight of methyl acrylate and 5 to 15% by weight of methacrylic acid are disclosed in EP 0704208A 2. No disclosure has hitherto been made of mixtures with other polymers of the type corresponding to the polymers (II) described herein. In addition, according to the broad teachings of EP 0152038 a2, it has been expected that such mixtures will lead to the known pH-drift effect. In addition, the invention is based on the recognition that the pH drift effect of the polymer mixtures described in EP 0152038A 2 is not adjusted by the choice of anionic or carboxyl-containing polymers having a glass transition temperature of not more than 70 ℃; but rather the effect according to the task of the invention of modifying the time course of the release profile of the active ingredient is achieved without changing the dissolution-pH value.

Therefore, the task is also solved in particular as follows:

pharmaceutical preparation comprising a core containing an active ingredient, said core being coated with a mixed coating of polymers, characterized in that the mixed coating is a mixture of 2 to 60% by weight of polymer (I) and 40 to 95% by weight of one or more polymers (II),

it is characterized in that the preparation method is characterized in that,

polymer (I) is a copolymer of 10 to 30% by weight of methyl methacrylate, 50 to 70% by weight of methyl acrylate and 5 to 15% by weight of methacrylic acid, and polymer (II) is a vinyl polymer different from polymer (I) which comprises 90 to 100% of neutral vinyl-polymerizable monomer units and may comprise up to 10% by weight of vinyl-polymerizable monomer units having an ionic group.

Practice of the invention

Mixing ratio of Polymer (I) to Polymer (II)

Said mixture comprises, or consists essentially of, or preferably 100%: 2 to 60% by weight, preferably 2 to 30% by weight, of one or more polymers (I) and 40 to 98% by weight, preferably 70 to 98% by weight, of one or more polymers (II). Within this range, almost all transitions between the release characteristics of polymers (I) and (II) can be adjusted in order to provide the skilled person with new alternatives for the formulation of pharmaceutical formulations.

Preferred mixtures comprise, or consist essentially of, or preferably 100% of: 2-15% by weight of one or more polymers (I) and 85-98% by weight of one or more polymers (II). Within this range, surprisingly, even a relatively small proportion of polymer (I) would shift the undesired strong delayed release properties of polymer (II) into the desired range from a therapeutic point of view for a long-lasting, almost constant release of a large amount of active ingredient in different sections of the intestine. In the USP release test (USP 28-NF23), the release of active ingredient is preferably less than 50% within 60 minutes at the pH at which the polymer (I) starts to dissolve. Of particular interest is a release of more than 10% of the active ingredient in 60 minutes at the pH-value at which the polymer (I) starts to dissolve in the USP release test.

The extent of release is also always influenced by the thickness of the coating layer. This can be increased or decreased by a preset mixing ratio to control the release in a desired range.

Active ingredient release can be determined according to USP, in particular USP 28-NF23, General Chapter <711>, Disolution, Apparatus 2, (Paddle), Method <724> "DelayedRelease (Enteric coated) arms-General Drug release, Method B (100 rpm, 37 ℃), using the following changes: the coated pellets were first tested for resistance to gastric fluid in simulated gastric fluid (USP) at pH1.2 for 120min, and then the buffer was changed to phosphate buffer at pH 7.5, which corresponds to simulated intestinal environment. Depending on the active ingredient, the concentration of the active ingredient in the test medium can be determined, for example, by photometric methods.

Polymer (I)

Glass transition temperature

The glass transition temperature of the polymer (I) is not more than 70 ℃ and preferably from 45 to 68 ℃.

The glass transition temperature is understood here to mean, in particular, the midpoint temperature T in accordance with ISO 11357-2 of 3.3.3_mg. The measurements were carried out under the following conditions: no plasticizer was added, the residual monomer content (REMO) was less than 100ppm, the heating rate was 10 ℃/min, and under a nitrogen atmosphere.

Composition of polymer (I)

The polymer (I) is a (meth) acrylate copolymer comprising or consisting of: from 90 to 100% by weight, preferably from 95 to 100% by weight, particularly preferably 100% by weight, of free-radically polymerizable units, optionally from 0 to 10% by weight of further vinyl-polymerizable monomer residues may be present in the polymer (I). The radical polymerization unit consists of 40 to 95 wt.%, preferably 66 to 95 wt.%, of C of acrylic acid or methacrylic acid₁-to C₄-alkyl esters and 5-60 wt.%, preferably 5-34 wt.% of (meth) acrylate monomer units having an anionic group.

C of acrylic acid or methacrylic acid₁-to C₄Alkyl esters are, in particular, methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate.

The (meth) acrylate monomer having an anionic group may be, for example, acrylic acid, but methacrylic acid is preferred.

Usually C of said acrylic or methacrylic acid₁-to C₄-the sum of the fractions of alkyl ester and (meth) acrylate monomer having an anionic group is 100% by weight. Most commercially available polymers (I) do not contain residues of other monomer types.

However, small amounts of other vinyl-copolymerizable monomers, e.g. hydroxyethyl methacrylate or hydroxyethyl acrylate, butyl acrylate, vinylpyrrolidone, vinyl malonate, styrene, vinyl alcohol, vinyl acetate and/or derivatives thereof, in the range from 0 to 10% by weight, e.g. from 1 to 5% by weight, may additionally be present without causing impairment or modification of the basic properties of the polymer (I). However, preferably no other vinyl copolymerizable monomers are present.

The glass transition temperature of the polymer (I) is not more than 70 ℃, preferably 40 to 70 ℃, particularly preferably 45 to 65 ℃, especially 45 to 55 ℃.

Dispersion/partial neutralization

The polymers (I) are generally emulsion polymerization products, preferably prepared and used in the form of 10 to 50% by weight, in particular 20 to 40% by weight, aqueous dispersions. A solids content of 30 wt.% is the preferred commercial form. Partial neutralization of the methacrylic acid unit can be omitted in the process; however, if it is desired to stabilize or thicken the coating agent dispersion, this is to a degree of, for example, up to 5 or 10 mol%. The weight average latex particle size (radius) is generally from 40 to 100nm, preferably from 50 to 70nm, in order to ensure a viscosity of less than 1000mpa · s, which is advantageous for the processing technology. Particle size may be determined by laser diffraction, for example using a Mastersizer 2000 (available from Malvern).

To achieve a higher degree of neutralization, for example 10 to 50 mol% or complete neutralization, the copolymer can be converted into the dissolved state.

In order to prepare the anionic copolymer solution, it is generally necessary to partially or completely neutralize the acidic groups. For example, the anionic copolymer can be gradually stirred into water to a final concentration of 1-40% by weight while being partially or completely neutralized by the addition of a basic substance such as NaOH, KOH, ammonium hydroxide, or an organic base such as triethanolamine. It is also possible to use copolymer powders, wherein for the purpose of (partial) neutralization a base, such as NaOH, has been added during their preparation, so that the powder is a polymer that has been (partially) neutralized. The pH of the solution is typically greater than 4, for example in the range of 4 to about 7. Mixtures of, for example, fully or partially neutralized dispersion batches with unneutralized dispersion phases can also be used here and processed further in the manner described, i.e. the mixtures can be used for coating or can be first freeze-dried or spray-dried to a powder.

The dispersions may also be spray-dried or freeze-dried, for example in a manner known per se, and provided in the form of redispersible powders (see, for example, EP-A0262326). An alternative method is freeze-drying or coagulation and extrusion of water in an extruder, followed by granulation (see, for example, EP-A0683028).

It has surprisingly been found that copolymer dispersions of spray-dried or freeze-dried and redispersed powders have increased shear stability. This is particularly advantageous for spray applications. This advantage is particularly pronounced when the copolymers present in the dispersion are present in partially neutralized form (based on the acid groups present in the copolymer) to 2 to 10, preferably 5 to 7, mol%. Preferably, for this purpose, partial neutralization is carried out by means of addition of NaOH. The anionic emulsifier is preferably included in an amount of 0.1-2 wt%. Sodium lauryl sulfate is a particularly preferred emulsifier.

Polymer (I) type with 5-15 wt% of methacrylic acid

Suitable polymers (I) disclosed in EP 0704208A 2 are (meth) acrylate copolymers (EUDRAGIT) composed of 10 to 30% by weight of methyl methacrylate, 50 to 70% by weight of methyl acrylate and 5 to 15% by weight of methacrylic acidFS type). The pH at which the release of the active ingredient in the intestinal fluid or simulated intestinal fluid begins in particular may be given as pH 7.0. The polymerizationThe glass transition temperature of the substance (I) is preferably 45 to 55 ℃.

EUDRAGITFS is a copolymer of 25 wt% methyl methacrylate, 65 wt% methyl acrylate and 10 wt% methacrylic acid. EUDRAGITFS 30D is a blend containing 30 wt% of EUDRAGITA dispersion of FS. Glass transition temperature T according to ISO 11357-2, clause 3.3.3_mgIs about 48 deg.c.

Polymer (I) type with 20-34 wt% methacrylic acid and good elongation at tear properties.

Other suitable polymers (I) are copolymers of the following components disclosed in WO 03/072087:

20-34% by weight of methacrylic acid and/or acrylic acid,

20 to 69% by weight of methyl acrylate and

0-40 wt.% ethyl acrylate and/or optionally

0 to 10 wt.% of other vinyl copolymerizable monomers,

with the proviso that the proportion of monomers is selected such that the glass transition temperature of the copolymers according to ISO 11357-2, version 3.3, does not exceed 60 ℃. The (meth) acrylate copolymers are particularly suitable for tableting because of their good elongation at tear properties.

The above copolymers are composed in particular of free-radically polymerized units of:

20 to 34, preferably 25 to 33, particularly preferably 28 to 32,% by weight of methacrylic acid or acrylic acid, preferably methacrylic acid,

20 to 69, preferably 35 to 65, particularly preferably 35 to 55,% by weight of methyl acrylate and optionally

0 to 40, preferably 5 to 35, particularly preferably 15 to 35,% by weight of ethyl acrylate, with the proviso that the copolymer according to ISO 11357-2 is of type 3.3.3 and has a glass transition temperature (T)_mg) (the measurement conditions were: no plasticizer is added, the residual monomer content (REMO) is less than 100ppm, the heating rate is 10 ℃/min under a nitrogen atmosphere) is not more than 60, preferably 40 to 60, particularly preferably 45 to 55 ℃.

The copolymer preferably consists essentially to exclusively of the monomers methacrylic acid, methyl acrylate and ethyl acrylate in the quantitative proportions indicated above.

However, small amounts of other vinylic copolymerizable monomers, such as methyl methacrylate, butyl acrylate or hydroxyethyl methacrylate, in the range of 0 to 10% by weight, for example 1 to 5% by weight, may additionally be present without causing impairment of the essential properties.

Mixtures of the copolymers can also be used to adjust the particular release profile or release location.

The copolymers are obtained in a manner known per se by free-radical mass, solution, bead or emulsion polymerization. They must be processed before they are to achieve the particle size range according to the invention by means of a suitable grinding, drying or spraying process. This can be done by simply crushing the extruded and cooled particle bar (granolastr)nge) or thermal cut-off (Hei β abschlag).

The use of powders may be advantageous, especially in the case of mixing with other powders or liquids. Suitable devices for producing powders are well known to the person skilled in the art, for example air-jet mills, pin-disk mills, fan mills (F)Chelmsen). Optionally, an appropriate screening step may be included. A suitable grinding mill for industrial large-scale use is, for example, a counter jet mill (Gegenstahlmluhle) (Multi No.4200), which operates at an overpressure of about 6 bar.

Polymer (I) types with 20-33% by weight of methacrylic acid with good mechanical properties, in particular for tableting

Other suitable polymers (I) are copolymers of the following components disclosed in WO 2004/096185:

20-33% by weight of methacrylic acid and/or acrylic acid,

5-30% by weight of methyl acrylate and

20-40% by weight of ethyl acrylate and

more than 10-30% by weight of butyl methacrylate and

optionally, optionally

From 0 to 10% by weight of further vinylic copolymerizable monomers, where the proportions of monomers add up to 100% by weight,

with the proviso that the monomer content is selected such that the copolymer according to ISO 11357-2, version 3.3, has a glass transition temperature of 55 to 70 ℃. These copolymers are particularly suitable for tableting because of their good mechanical properties.

20 to 33, preferably 25 to 32, particularly preferably 28 to 31,% by weight of methacrylic acid or acrylic acid, preferably methacrylic acid,

5 to 30, preferably 10 to 28, particularly preferably 15 to 25,% by weight of methyl acrylate,

from 20 to 40, preferably from 25 to 35, particularly preferably from 18 to 22,% by weight of ethyl acrylate, and

more than 10 to 30, preferably 15 to 25, particularly preferably 18 to 22,% by weight of butyl methacrylate,

wherein the monomer composition is selected such that the glass transition temperature of the copolymer is from 55 to 70 ℃, preferably from 59 to 66 ℃, particularly preferably from 60 to 65 ℃.

The copolymer preferably consists essentially to exclusively of the monomers methacrylic acid, methyl acrylate, ethyl acrylate and butyl methacrylate in the quantitative ranges mentioned above, to the extent of 90, 95 or 99 to 100% by weight.

However, small amounts of other vinyl copolymerizable monomers, such as methyl methacrylate, butyl acrylate, hydroxyethyl methacrylate, vinyl pyrrolidone, vinyl malonate, styrene, vinyl alcohol, vinyl acetate and/or derivatives thereof, in the range of 0 to 10% by weight, such as 1 to 5% by weight, may additionally be present without causing impairment of the essential properties.

Polymer (II)

Polymer (II) is a vinyl polymer or polysaccharide derivative different from polymer (I) comprising 80-100% neutral monomer units and may comprise up to 12% by weight of monomer units having ionic groups.

Vinyl polymers

The polymer (II) may be a vinyl polymer comprising 88 to 100% of neutral vinyl-polymerizable monomer units and up to 12% by weight of vinyl-polymerizable monomer units having an ionic group.

The polymer (II) may be a copolymer of methyl methacrylate and ethyl acrylate, methyl methacrylate and ethyl acrylate and methacrylic acidCopolymers of acids, copolymers of methyl methacrylate, ethyl acrylate and trimethylammonium ethyl methacrylate, polyvinylpyrrolidone (PVP), polyvinyl alcohol-polyethylene glycol graft copolymers (Kollicoat)IR), polyvinyl acetate (PVAc, Kollicoat)SR), vinyl acetate-vinylpyrrolidone copolymer (Kollidone)VA64), vinyl acetate crotonic acid 9: 1 copolymer (VAC: CRA, Kollicoat)VAC)，

Polysaccharides or derivatives

The polymer (II) may be a polysaccharide or polysaccharide derivative comprising 88-100% neutral monomer units and up to 12% by weight of polymerizable monomer units having an ionic group.

The polymer (II) may be: starch and its derivatives, hydroxyethyl cellulose (HEC, Klucel)Hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC, Pharmacoat)、Methocel、Sepifilm、Viscontran、Opadry) Hydroxymethyl ethyl cellulose (HEMC), ethyl cellulose (EC, Ethocel)、Aquacoat、Surelease) Methyl cellulose (MC, Viscontran)、Tylopur、Methocel) Cellulose esters, cellulose glycolates or mixtures of said polymers.

(meth) acrylate ester copolymer

Neutral (meth) acrylate copolymers

The polymer (II) can in particular be a (meth) acrylate copolymer which is different from the polymer (I) and comprises 88 to 100% of neutral monomer units and up to 12% by weight of polymerizable monomer units having ionic groups.

Neutral methyl acrylate copolymers prepared as dispersions according to WO 01/68767, using from 1 to 10% by weight of nonionic emulsifiers having an HLB value of from 15.2 to 17.3, are preferred. The latter has an advantage that the use of an emulsifier suppresses phase separation occurring with the formation of a crystal structure.

Polymer (II) may particularly preferably be a copolymer of 20 to 40% by weight of ethyl acrylate and 60 to 80% by weight of methyl methacrylate (EUDRAGIT)NE type).

A particularly suitable polymer (II) is a copolymer of 30% by weight of ethyl acrylate and 70% by weight of methyl methacrylate (EUDRAGIT)NE)。

(meth) acrylate copolymers having quaternary ammonium groups

The polymer (II) may also be composed of 88 to 98% by weight of a radical-polymerized C of acrylic acid or methacrylic acid₁-to C₄-an alkyl ester, and 12-2 wt% of a (meth) acrylate monomer having a quaternary ammonium group in the alkyl group.

Preferred C of acrylic acid or methacrylic acid₁-to C₄Alkyl esters are methyl acrylate, ethyl acrylate, butyl methacrylate and methyl methacrylate.

A particularly preferred (meth) acrylate monomer having a quaternary ammonium group is 2-trimethylammoniumethyl methacrylate chloride.

The polymer (II) may be a copolymer of 50 to 70% by weight of methyl methacrylate, 20 to 40% by weight of ethyl acrylate and 12 to 2% by weight of trimethylammonium ethyl methacrylate chloride (EUDRAGIT)RS/RL type).

A particularly suitable copolymer comprises 65% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 5% by weight of 2-trimethylammonioethyl methacrylate chloride (EUDRAGIT)RS)。

Particularly suitable areThe copolymer contained 60% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 10% by weight of 2-trimethylammoniumethyl methacrylate chloride (EUDRAGIT)RL)。

Pellets containing the active ingredient can be prepared, for example, by applying the active ingredient by means of a coating process. For this purpose, the active ingredients are mixed homogeneously together with further auxiliaries (mold release agents, optionally plasticizers) and dissolved or suspended in the binder. The liquid may be applied to pellets of the deactivator (Placebopellets) or other suitable carrier material by means of a fluidized bed process, where the emulsion or suspension is evaporated (document: International Journal of pharmaceuticals 143, pages 13-23). The production process may be followed by a drying step. The active ingredient may be applied in multiple layers.

Some active ingredients, such as acetylsalicylic acid, are commercially available in the form of active ingredient crystals and can be used in this form instead of pellets containing the active ingredient.

Typically, a film coating is applied to the pellets containing the active ingredient in a fluidized bed apparatus. Examples of formulations are mentioned in the present application. The film-forming agent is typically mixed with the plasticizer and mold release agent by a suitable process. The film former may here be in the form of a solution or suspension. Film-forming aids may likewise be dissolved or suspended. Organic or aqueous solvents or dispersants may be used. To stabilize the dispersion, stabilizers (examples: Tween 80 or other suitable emulsifiers and/or stabilizers) may additionally be used.

Examples of release agents are glycerol monostearate or other suitable fatty acid derivatives, silicic acid derivatives or talc. Examples of plasticizers are propylene glycol, phthalates, polyethylene glycol, sebacates or citrates, and other substances mentioned in the literature.

Between the layer containing the active ingredient and the layer of copolymer according to the invention there is a separating layer for separating the active ingredient from the coating material in order to prevent interaction. This layer may consist of an inert film former, such as HPMC, HPC or (meth) acrylic copolymers, or such as talc or other suitable pharmaceutical substances. Film formers may also be used in combination with talc or the like.

It is also possible to apply a separating layer consisting of a partially or completely neutralized copolymer dispersion.

The mixture consisting of coated granules for the preparation of tablets is prepared by mixing the pellets with a binder suitable for tableting, if necessary a disintegration-promoting substance, and if necessary a lubricant. Mixing with a suitable machine. Improper mixers, such as plowshare mixers, can cause damage to the coated particles. To achieve a suitably short disintegration time, a particular order may be required when adding the adjuvants to the coated granules. By premixing magnesium stearate as a lubricant or release agent with the coated granules, the granule surface can be hydrophobized and thus adhesion avoided.

Suitable mixtures for tableting typically comprise 3 to 15% by weight of a disintegration aid, such as Kollidon CL, and e.g. 0.1-1% by weight of a lubricant and mould release agent, such as magnesium stearate. The proportion of binder is determined by the desired proportion of coated particles.

An example of a typical binder is CellactoseMicrocrystalline cellulose, calcium phosphate, LudipressLactose or other suitable sugar, calcium sulfate or starch derivatives. Low bulk materials are preferred.

Typical disintegration aids (disintegrants) are cross-linked starch or cellulose derivatives and cross-linked polyvinylpyrrolidone. Cellulose derivatives are also suitable. By the selection of suitable binders, the use of disintegration aids may not be necessary.

Typical lubricants and mold release agents are magnesium stearate or other suitable fatty acid salts, or other materials listed in the literature for this purpose (e.g., lauric acid, calcium stearate, talc, etc.). In the case of the use of suitable machines (e.g. tablet presses with external lubrication) or suitable formulations, lubricants and mould release agents may not be necessary in the mixture.

Optionally, flow-improving aids may be added to the mixture (e.g., highly dispersed silicic acid derivatives, talc, etc.).

Compression may be carried out on a conventional tablet press, a centrifugal tablet press or a rotary tablet press with a pressure in the range of 5 to 40kN, preferably 10 to 20 kN. The tablet press may be equipped with an external lubrication system. Optionally, a special system for mold filling (Matrizenbef ü lluung) is used to avoid mold filling by means of stirring paddles.

Polymer blend

First, a mixture of one or more polymers (I) and one or more polymers (II) is prepared. For this purpose, for example, 2 organic solutions or 2 aqueous dispersions are mixed proportionally. Preferably, an aqueous dispersion mixture of one or more compounds (I) and one or more polymers (II) is prepared. In general, one polymer (I) and one polymer (II) are used in each case. The mixture comprises from 2 to 60, preferably from 10 to 55,% by weight of the polymer (I) and from 40 to 98, preferably from 45 to 90,% by weight of one or more polymers (II), the proportions making up 100% by weight. Usually, but not necessarily, pharmaceutically customary auxiliaries are additionally admixed, which are optionally dissolved or dispersed separately.

Pharmaceutical preparation

The invention also relates to pharmaceutical formulations with selected polymers (I) which are not highlighted from EP 0152038 a 2. The polymer (II) present in the pharmaceutical formulation is identical to the polymer (II) employed according to the use described herein.

The invention therefore relates to a pharmaceutical preparation comprising a core containing an active ingredient, which is coated with a mixed coating of polymers, characterized in that the mixed coating is a mixture of 2 to 60% by weight of polymer (I) and 40 to 95% by weight of one or more polymers (II),

it is characterized in that the preparation method is characterized in that,

the polymer (I) is a copolymer of 10 to 30% by weight of methyl methacrylate, 50 to 70% by weight of methyl acrylate and 5 to 15% by weight of methacrylic acid, and

polymer (II) is a vinyl polymer or polysaccharide derivative different from polymer (I) comprising 88-100% neutral monomer units and may comprise up to 12% by weight of monomer units having an ionic group.

Polymer (I) type with 5-15 wt% of methacrylic acid

Suitable polymers (I) for use in the pharmaceutical formulations of the present invention are disclosed in EP 0704208 a 2. The polymer (I) is a (meth) acrylate copolymer (EUDRAGIT) consisting of 10 to 30% by weight of methyl methacrylate, 50 to 70% by weight of methyl acrylate and 5 to 15% by weight of methacrylic acidFS type). The pH at which the release of the active ingredient in the intestinal fluid or simulated intestinal fluid begins in particular may be given as pH 7.0. The glass transition temperature of the polymer (I) is preferably from 45 to 55 ℃.

General Process for the preparation of the pharmaceutical formulations

Core

The carrier for coating is a capsule, tablet, granule, pellet, crystal of regular or irregular shape. The granules, pellets or crystals are between 0.01 and 2.5mm in size and the tablets are between 2.5 and 30.0mm in size. The capsule is made of gelatin, starch or cellulose derivatives.

Typically, they contain up to 95% biologically active substance (active ingredient), together with other pharmaceutical adjuvants, up to 99.9% by weight. The usual preparation processes are direct compression, compression of dry, moist or sintered granules, extrusion and subsequent rounding, wet or dry granulation or direct pelleting (e.g. by means of a dish), or bonding of powders to (powder layers) pellets (Nonpareilles) free of active compound or granules containing active compound.

In addition to the active ingredients, they may contain other pharmaceutical auxiliaries: binders, such as cellulose and its derivatives, polyvinylpyrrolidone (PVP), wetting agents, disintegration promoters, lubricants, disintegrants, (meth) acrylic esters, starch and its derivatives, sugar solubilizers or others.

Preparation of pharmaceutical formulations

Pellets containing the active ingredient can be prepared, for example, by applying the active ingredient by means of a coating process. For this purpose, the active ingredients are mixed homogeneously together with further auxiliaries (mold release agents, optionally plasticizers) and dissolved or suspended in the binder. The liquid may be applied to the pellets of the deactivator or other suitable carrier material by means of a fluidized bed process, where the emulsion or suspension is evaporated (document: International Journal of pharmaceuticals 143, pages 13-23). The production process may be followed by a drying step. The active ingredient may be applied in multiple layers.

First, a mixture of polymer (I) and polymer (II) is prepared. For this purpose, for example, 2 dispersions are mixed proportionally.

Polymer coatings

The polymeric coating may preferably represent, for example, 2 to 20% by weight of the core containing the active ingredient. The extent of release is also always influenced by the thickness of the coating layer. This can be increased or decreased by a preset mixing ratio to control the release in a desired range.

Outer coating

An outer coating (overcoat) of other, preferably water-soluble, polymers and auxiliaries, for example pigments and/or mold release agents, can also be applied to ensure further functions, for example coloration or blocking prevention.

Preparation of multiparticulate pharmaceutical formulations

The coated pharmaceutical formulation is preferably in the form of pellets, which are present in multiparticulate pharmaceutical formulations, especially in tablets, microtablets, capsules, sachets or reconstituted powders containing pellets.

The invention is particularly suitable for the preparation of multiparticulate pharmaceutical formulations, since the mixtures according to the invention are able to withstand high pressures during tabletting together with the filler. The coated pharmaceutical formulation is preferably in the form of pellets, which are present in multiparticulate pharmaceutical formulations, especially in tablets, microtablets, capsules, sachets or reconstituted powders containing pellets.

The preparation of multiparticulate pharmaceutical formulations by compressing pharmaceutically conventional binders with particles containing the active ingredient is described in detail, for example, in Beckert et al (1996), "Compression of organic-coated tablets to integrating tablets", International Journal of pharmaceuticals 143, S.13-23 and WO 96/01624.

Compression may be carried out on a conventional tablet press, a centrifugal tablet press or a rotary tablet press with a pressure in the range of 5 to 40kN, preferably 10 to 20 kN. The tablet press may be equipped with an external lubrication system. Optionally, a special system for mold filling is used to avoid mold filling with a stirring paddle.

Active ingredient delivery

According to the release profile of the active ingredient obtained according to the invention, the active ingredient is released starting at the same pH but more slowly than in a pharmaceutical formulation comprising only polymer (I).

According to the release profile of the active ingredient obtained according to the invention, the active ingredient is released starting at the same pH but more rapidly than in a pharmaceutical formulation comprising only polymer (II).

Preferably pharmaceutical formulations, release of the active ingredient in less than 50%, preferably less than 25%, particularly preferably 10-50% in the USP release test (USP 28-NF23) at the pH-value at which the polymer (I) starts to dissolve in 60 minutes.

Such release tests, for example, a test modified for "enteric coated product" according to USP (method B, USP 28-NF23) are known to those skilled in the art. The test conditions are in particular: paddle method, 100 rpm, 37 ℃; adjusted to pH1.2 with 0.1N HCl and brought to pH 7.5 by addition of 0.2M phosphate buffer and adjustment with 2N NaOH. See also USP 27-NF22Supplement 1, "Delayed Release", monograph <724> drug Release.

Pharmaceutical commonly used auxiliary agent

Pharmaceutically customary auxiliaries are added to the formulations of the invention, preferably during the preparation of the granules or powders. Additives may also be added to the coating agent and binder during processing. Of course, all substances employed in principle must be toxicologically safe and in particular be used in medicaments without danger to the patient.

The amounts and methods of use of the usual additives in a medicament coating or layer are well known to those skilled in the art. Examples of customary additives are mold release agents, pigments, stabilizers, antioxidants, porogens, penetration enhancers, gloss agents, aromatic substances or flavor agents. They are used as processing aids, which provide for a safe and reproducible production process and good stability over long-term storage, or they add other good properties to the pharmaceutical formulations. They are added to the polymer formulation before processing, which can affect the permeability of the coating, which optionally can be used as an additional control parameter.

Release agent：

Release agents, which are generally lipophilic in nature, are often added to spray suspensions. They are used to prevent agglomeration of the small cores during film coating. Preferably talc, magnesium or calcium stearate, ground silica, kaolin or non-ionic emulsifiers with HLB values between 3 and 8 are used. The customary amounts of release agents in the coating agents and binders according to the invention are from 0.5 to 100% by weight, based on the dry weight of the dispersion.

Pigment:

pigments incompatible with the coating agent are in particular pigments which, if added directly to the (meth) acrylate copolymer dispersion, for example by stirring, in the customary amounts, for example from 20 to 400% by weight, based on the dry weight of the (meth) acrylate copolymer, can lead to the dispersion becoming unstable, coagulated, showing signs of inhomogeneity or similar undesirable effects. Furthermore, the pigments to be used are of course non-toxic and suitable for pharmaceutical purposes. See also for example for this: deutsche Forschungsgemeinschaft, Farbstoffe fur Lebensemittel, Harald, Boldt Verlag KG, Boppard (1978); deutsche Lebensemiltellundschau 74, Nr.4, p 156 (1978); arzneimittelfarbstoffverdnung AmFarbV vom 25.08.1980.

Pigments incompatible with the coating agent may be, for example, alumina pigments. Examples of incompatible pigments are orange yellow, scarlet red lacquer (cochenilloltack), colored pigments based on alumina or azo dyes, sulfonic acid dyes, orange yellow S (E110, c.i.15985, FD & C yellow 6), indigo carmine (E132, c.i.73015, FD & C blue 2), tartrazine (E102, c.i.19140, FD & C yellow 5), scarlet 4R (E125, c.i.16255, FD & C scarlet a), quinoline yellow (E104, c.i.47005, FD & C yellow 10), erythrosine (E127, c.i.45430, FD & C red 3), azorubine (E122, c.i.14720, FD & C bisblue acid red), amaranth (E123, c.i.85, FD & C red 2), acid brilliant green (E142, c.i.44090, FD & C green S).

The E number of the pigment refers to the european number. See also "Deutsche Forschungsgemeinschaft, Farbstoffe fur Lebensemittel, Haralddoldt Verlag KG, Boppard (1978); deutsche Lebensemiltellundschau 74, Nr.4, p 156 (1978); arzneimittelfarbstoffverdnung AmFarbV vom 25.08.1980. FD & C numbers refer to numbers approved by the united states Food and Drug Administration (FDA) for use in food, drugs, and cosmetics and are described in: the U.S. Food and drug administration, center for Food Safety and Applied Nutrition (center for Food Safety and Applied Nutrition), Office of Cosmetics and tools: code of Federal Regulations-Title 21 Color additive Regulations Part 82, Listing of verified Provisional Listed Colors and specificities (CFR 21 Part 82).

Plasticizer

Other additives may also be plasticizers. The usual amount is between 0 and 50% by weight, preferably between 5 and 20% by weight.

The effect of the plasticizer on the function of the polymer layer, depending on its type (lipophilic or hydrophilic) and the amount added, respectively. The plasticizer can lower its glass transition temperature by physical interaction with the polymer, and can promote film formation depending on the amount added. Suitable materials typically have a molecular weight of between 100-.

Examples of suitable plasticizers are alkyl citrates, glycerol esters, alkyl phthalates, alkyl sebacates, sucrose esters, sorbitan esters, diethyl sebacate, dibutyl sebacate and polyethylene glycol 200-. Preferred plasticizers are triethyl citrate (TEC), acetyl triethyl citrate (ATEC) and dibutyl sebacate (DBS). Further mentioned are esters which are normally liquid at room temperature, such as citrates, phthalates, sebacates or castor oil. Preferably, citric acid esters and sebacic acid esters are used.

The addition of the plasticizer to the formulation can be carried out by well-known methods, either directly to the aqueous solution or to the thermally pretreated mixture. Mixtures of plasticizers may also be used.

Active ingredient

Drugs that can be used can be found in references such as the Roten catalog or Merck index.

Biologically active substance:

the medicaments for the purposes of the invention are for use on or in the human or animal body for the purpose of

1. Cure, alleviate, prevent or diagnose a disease, disorder, physical injury or pathological condition.

2. Identifying a physical or mental state, condition or function.

3. Instead of active substances or body fluids produced by the human or animal body.

4. Against, or eliminate, or render harmless pathogens, parasites, or foreign substances, or

5. Affecting the state, condition or function of the body or mind.

The formulations of the present invention are suitable for the administration of essentially any active pharmaceutical ingredient or biologically active substance.

Therapeutic agents

These pharmaceutically active substances may belong to one or more active ingredient classes such as ACE inhibitors, adrenergic agents, adrenocorticosteroids, acne remedies, aldose reductase inhibitors, aldosterone antagonists, alpha-glucosidase inhibitors, alpha 1 antagonists, alcoholism-treating agents, amino acids, amebiasides, anabolic hormones, revitalizing agents, anesthetic additives, anesthetics (non-inhalant), anesthetics (topical), analgesics, androgens, angina remedies, antagonists, antiallergic agents such as PDE inhibitors, antiallergic agents for asthma treatment, other antiallergic agents (e.g. leukotriene antagonists, blood tonics, antiandrogenic agents, anxiolytic agents, antiarthritic agents, antiarrhythmic agents, antiatherosclerotic agents, antibiotics, anticholinergic agents, anticonvulsants, antidepressants, drugs, pro-drugs, drugs for treating asthma, anti-drugs, anti, Antidiabetics, antidiarrheals, antidiuretic drugs, antidotensics, antiemetics, antiepileptics, antifibrinolytics, antiepileptics, anthelmintics, antihistamines, antihypertensives, anticoagulants, antimycotics, antiestrogens (non-steroidal), antiparkinson drugs, anti-inflammatory agents, antiproliferative active ingredients, antiprotozoal active ingredients, antirheumatic, antihypertensives, antispasmodics, antithrombotic agents, antitussives, appetite suppressants, arteriosclerosis inhibitors, bacteriostats, beta-blockers, bronchodilators, carbonic anhydrase inhibitors, chemotherapeutic agents, choleretic drugs, cholinergic agonists, cholinesterase inhibitors, drugs for ulcerative colitis, cyclooxygenase inhibitors, diuretic drugs, Ectoparasiticides, emetics, enzymes, enzyme inhibitors, active ingredients against emesis, fibrinolytic drugs, antifungals, gabapentin gout drugs, glaucoma therapeutics, glucocorticoids, hemostatics, cardiac glycosides, histamine H2 antagonists, hormones and their inhibitors, immunotherapeutics, cardiotonics, anticoccidial drugs, laxatives, lipid-lowering drugs, gastrointestinal therapeutics, malaria therapeutics, migraine drugs, microbicides, Crohn's disease, metastasis inhibitors, migraine drugs, mineral preparations, activity-enhancing active ingredients, muscle relaxants, neuroleptics, active ingredients for estrogen therapy, osteoporosis, otology drugs, anti-Parkinson's disease drugs, botanicals, pitavastatin, proton pump inhibitors, prostaglandins, active ingredients for benign prostatic hyperplasia therapy, Active ingredients for the treatment of pruritus, psoriasis active ingredients, psychoactive drugs, free radical scavengers, renin antagonists, thyroid therapeutic agents, active ingredients for the treatment of seborrhea, active ingredients for the treatment of seasickness, antispasmodics, alpha-and beta-sympathomimetics, tenatoprazole, platelet aggregation inhibitors, tyrosine kinase inhibitors, chlordiazepoxide, ulcer therapeutic agents, further ulcer therapeutic agents, agents for the treatment of urolithiasis, virus inhibitors, vitamins, cytokines, active ingredients for the combined treatment with cell growth inhibitors, cell growth inhibitors.

Active ingredient

Examples of suitable active ingredients are acarbose, aspirin, abacavir, aceclofenac, aclarubicin, acyclovir, actinomycin, adalimumab, adefovir dipivoxil, ademetionine, epinephrine and epinephrine derivatives, agalsidase alpha, agalsidase beta, alemtuzumab, almotriptan, alphacept, allopurinol, almotriptan, alosetron, alprostadil, amantadine, ambroxol, amisulpride, amlodipine, amoxicillin, 5-para-aminosalicylic acid, amitriptyline, amlodipine, amoxicillin, amprenavir, anagrelide, anakinra, anastrozole, androgen and androgen derivatives, apomorphine, aripiprazole, arsenic trioxide, artemether, atenolol, atorvastatin, azathioprine, azelaic acid, barbituric acid derivatives, Balsalazide, basiliximab, becloperamin, beclomethasone, bemiparin, benzodiazepines, betahistine, bexarotene, bezafibrate, bicalutamide, bimatoprost, bosentan, botulinum toxin, brimonidine, brinzolamide, budesonide, budipine, bufexamac, bumetanide, buprenorphine, bupropion, butizine, calcitonin, calcium antagonists, calcium salts, candesartan, capecitabine, captopril, carbamazepine, carifenacin, carvedilol, caspofungin, cefaclor, cefadroxil, cefalesporins, cefditoren, cefuroxime, celecoxib, cefetabine, cilastatin, cetirizine, cetrorizumab, cetuximab, cholic acid, chorionic gonadotropin, ciclovir, ciprofloxacin, cistatin, Clavulanic acid, clindamycin, chlorodinol, clonidine, clopidogrel, codeine, caffeine, cholestyramine, cromolyn, sulfamethoxazole, coumarin and coumarin derivatives, darbepoetin, cysteamine, cysteine, cytarabine, cyclophosphamide, cyproterone, cytarabine, daclizumab, dalfopristin, danaparoid, dapiprazole, darbepoetin, defepriproprone, desipramine, desloratadine, desmopressin, deoxydecetranol, desonide, dexibuprofen, dexketoprofen, disproxil, diazepam and diazepam derivatives, dehydroinosine, dihydralazine, diltiazem, dimenhydrinate, dimethysulfoxide, dimeticone, pidograden, dolasein, doxepidone, domperidone and doxepidone derivatives, diclofenac, polazimine, doxylamine, valprohexadine, doxycycline, Drospirenone, drotrecogin alpha, dutasteride, ebastine, econazole, efavirenz, eletripan, emidastine, emtricitabine, enalapril, encapur, entacapone, enfurvirtide, ephedrine, epinephrine, eplerenone, epoetin and epoetin derivatives, eprosartan, eptifibatide, ertapenem, emetanel, estrogen and estrogen derivatives, etanercept, ethenzamide, ethinyl estradiol, etofenamate, etofibrate, etohydroxytheophylline, etonogestrel, etoposide, exemestane, exetimibol, famciclovir, famotidine, faropendalonate, felodipine, fenofibrate, fentanyl, fenticonazole, fexofenadine, finasteride, fluconazole, flunarizine, flurocidine, flunarizine, fluflurocide, flufluroxypyr, fluvastatin, frovatriptan, furosemide, fusidic acid, gadobenate, galantamine, golopamide, ganciclovir, ganirelix, gatifloxacin, gefitinib, gemfibrozil, gemopatrilate, gentamicin, gepirone, progestin and progestin derivatives, ginkgo biloba, glatiramer, glibenclamide, glipizide, glucagon, sorbitol and sorbitol derivatives, glucosamine and glucosamine derivatives, glycoside antibiotics, glutathione, glycerol and glycerol derivatives, hypothalamic hormones, goserelin, gepafloxacin, gyrase inhibitors, guanethidine, gyrase inhibitors, hemin, halofantrine, haloperidol, urea derivatives as oral antidiabetics, heparin and heparin derivatives, cardiac glycosides, hyaluronic acid, hydralazine, hydrochlorothiazide and hydrochlorothiazide derivatives, carboxyomeprazole, hydroxyzine, ibritumomab, Ibuprofen, idarubicin, ifiximab, ifosfamide, iloprost, imatinib, imidapril, imiridase, imipramine, imiquimod, imidapril, indomethacin, indoramine, infliximab, insulin, long-acting insulin preparations, interferon, irbesartan, irinotecan, isoconazole, isoproterenol, itraconazole, ivabradine, iodine and iodine derivatives, hypericum, potassium salts, ketoconazole, ketoprofen, ketotifen, lacidipine, lamotrigine, lansoprazole, laronidase, latanoprost, leflunomide, leminoprazole, recombinant hirudin, lercanidipine, leprinine, letrozole, levamimethadone, levetiracetam, levocetirizine, levodopa, levopiperazine, levofloxacin, levomethadone, lipofectamine, linezolirtine, liliramine, liipir, lipoic acid derivatives and lipoic acid, Lisinopril, lisuride, lofepramine, lodoxylamine, lomefloxacin, lomustine, loperamide, lopinavir, loratadine, lornoxicam, losartan, lumefantrine, luteinizing hormone, magnesium salts, macrocyclic built-in antibiotics, mangafodipine, maprotiline, mebendazole, mebeverine, meclozine, mefenamic acid, mefloquine, meloxicam, memantine, meprolol, meprobamate, meropenem, mesalazine, mesuccinamide, analgin, metformin, methadone, methotrexate, methyl (5-amino-4-oxopentanoic acid), naloxone hydrochloride, methylnaltrexone, methylphenidate, methylprednisolone, mepiquat, metoclopramide, metoprolol, metronidazole, mianserin, miraclidine, miconazole, mifepristone, milnacipran, glitazone, glycanol, milnacipran, and glitazone, Minocycline, minoxidil, misoprostol, mitomycin, mizolastine, modafinil, moexipril, montelukast, moroxydine, levorphanol, morphine and morphine derivatives, moxifloxacin, ergot alkaloids, nalbuphine, naloxone, naproxen, naratriptan, narcotine, natamycin, nateglinide, nebivolol, nefazodone, nelfinavir, neostigmine, neramexan, nevirapine, nicergoline, nicotemamicin, nifedipine, niflumic acid, nimodipine, nimozole, nimustine, nesiritide, nisodipine, norfloxacin, analgin, narcotine, nystatin, ofloxacin, oktotride, olanzapine, olmesartan, olsalazine, oseltamivir, omeprazole, omapatrilalate, ondansetrol, ondansetron, olsalazine, oxsultap, oxsulindac, oxsulind, Oxaprozin, oxcarbazepine, oxicolone, oxiconazole, oxymetazoline, palivizumab, palanosetron, pantoprazole, acetaminophen, parecoxib, paroxetine, pemetrexed, peganine, pegenzeron, pegfield, pegfilgrastrim, penciclovir, oral penicillin, pentazocine, pentitein, pentoxifylline, peptide antibiotics, perindopril, phenazine, pethidine, plant extracts, antipyrine, pheniramine, phentolamine, phenytoin, phenothiazine, phensenrine, phenylbutazone, phenytoin, pimecrolimus, pimozolol, pindolol, pioglitazone, piperazine, piracetam, piperazepine, piribedipidil, pirlinderedil, pirlindole, piroxicam, posaconazole, pramipexole, pramlintide, pravastatin, prazosin, procaine, prochlorperazine, valosin, valprozin, propiverine, a derivative of nicotiadinine, tabersulfan, nicotinamin, nicotiniolide, nicotiniolin, peruvin, peruviol, prohydrotheophylline, quetiapine, quinapril, quinaprilate, quinupristin, ramipril, ranitidine, rabeprazole, ranoxifene, ranolazine, labyrine, reboxetine, repaglinide, reproterol, reserpine, revofloxacin, ribavirin, rifampin, riluzole, rimexolone, risedronate, risperidone, ritonavir, rivastigmine, rivastatin, risatriptan, rofecoxib, ropinirole, ropivacaine, rosiglitazone, rotigotigold, roxatidine, roxithromycin, ruscogenin, rosuvastatin, rutin and rutin derivatives, sabai, salbutamol, salicylate, salmeterol, saprola, salposazol, thyroid hormone, scopolamine, seletracenazole, sertraline, cetrimine, doxorubine, loxacin, rospinol, lox, rosolimus, rosuvastatin, lox, loxacin, rosol, rosuvastatin, troxides, troxite, rosuvastatin, troxib, loxacin, loxin, rosuvastatin, and so, Serlutamic acid, serofloxacin, spectinomycin, spiramycin, spirapril, spironolactone, stavudine, streptomycin, sucralfate, sufentanil, sulbactam, sulfonamides, sulfasalazine, sulpiride, sultamicin, sulthiazide, sumatriptan, chlorosuccinic choline, tacrine, tacrolimus, tadalafil, taliolol, tasalidine, tamoxifen, tamsulosin, tasolomine, tazarotene, tegafur, tegaserod, telmisartan, temoporfil, temozolomide, tenatoprazole, tini-a, teniposide, tenofovir, tenoxicam, teriparatide, terazosin, terbinazine, terbinafine, terbutaline, terliptide, terlipressin, tertalol, testosterone and testosterone derivatives, tetracycline, tetrahydrozolelin, tebucin, theobromine derivatives, mercaptomethazole, mercaptomethorphanol derivatives, Thiotepa, thr. auxin, tiagabine, tiapride, tibolone, ticlopidine, tilidine, timolol, tinidazole, tioconazole, thioguanine, tiotropium, ticolone, tirazetam, cinnamide, trofiban, tizanidine, tolazoline, tolbutamide, tolcapone, tolnaftate, tolperisone, tolterodine, topiramate, tolazamide, tramadol, tramazoline, trandolapril, tranylcypromine, trapidil, trastuzumab, travoprost, trazodone, trepostinil, triamcinolone and triamcinolone derivatives, triamterene pteridine, trifluperidol, trimetrexadine, trimethoprim, trimipramine, triamcinolone, trovadine, troxacin, trovafloxacin, trovazide, tranexamine, tranilide, tranexamine, tranexam, Theophylline ursodeoxycholic acid, valacyclovir, valdecoxib, valganciclovir, valproic acid, valsartan, vancomycin, vardenafil, valdecolonine, venlafaxine, verapamil, verteporfin, vidarabine, vigabatrin, vinblastine, vincamine, vincristine, vindesine, vinorelbine, vinpocetine, vequindil, vitamin D and vitamin D derivatives, voriconazole, warfarin, niceritrol, ximelagatran, xipamide, zafirlukast, zalcitabine, zaleplon, zanamivir, zidovudine, ziprasidone, zoledronic acid, zolmitriptan, zolpidem, zopiclone, zotepine, and the like.

Particularly preferred active ingredients

Preferred classes of active ingredients are analgesics, antibiotics, antidiabetics, antibodies, peptides, proteins, chemotherapeutic agents, glucocorticoids/glucocorticosteroids

Anti-inflammatory agent and enzyme preparation

Hormones and their inhibitors, parathyroid hormones

Digestion promoters, laxatives, vitamins, cytostatics and other classes of active ingredients, which for kinetic reasons are advantageously applied to the lower intestinal segment.

Examples of particularly preferred active ingredients are mesalazine, sulfasalazine, betamethasone 21-dihydrophosphate, hydrocortisone 21-acetate, cromolyn, dexamethasone, olsalazine sodium, budesonide, prednisone bismuntrate, karaya gum, methylprednisolone 21-hydrogen succinate Myhre, coffee carbon, chamomile extract, human placental preparation

Novel aptitude ingredients can be found in the literature or in related pharmaceutical databases known to those skilled in the art：

Balsalazide, adalimumab, alemtuzumab, basiliximab, daclizumab, ibritumomab tiuxetan, ifiximab, cetuximab, palivizumab, rituximab, trastuzumab, other oral peptides (e.g., RDP 58), interleukin 6, interleukin 12, iloleukin (interleukin 10), nicotine tartrate, 5-ASA conjugate (CPR 2015), anti-interleukin 12 mab, diethyldihydroxyspermine (dehao), Diethylspermine (DEHOP), cholecystokinin (cck) antagonist (CR 1795), 15 amino acid fragment of 40kd peptide derived from gastric juice (BPC 15), glucocorticoid analog (CBP 1011), natalizumab, remiliximab (remicadede) N-deacetylated lyso sheath (WILD 20), azelnine, tranilast, superoxide dismutase, phosphorothioate antisense glycyl antisense (is) isoniazid, Tazofelone ropivacaine, 5 lipoxygenase inhibitor (A69412), sucralfate.

The active ingredients can also be used, if desired, in the form of their pharmaceutically acceptable salts or derivatives, and in the case of chiral active ingredients, optically active isomers and racemic compounds or diastereomeric mixtures. The active ingredient may likewise be in the form of a physical or chemical conjugate (polymer-drug conjugate, e.g. peptide/protein-active ingredient complex). Optionally, the compositions of the present invention also comprise two or more pharmaceutically active ingredients.

Examples

Description of the experiments

Device for measuring the position of a moving object

Huttlin Mycralb fluidized bed device

A nozzle: three-substance nozzle, nozzle diameter: 0.8mm

The method comprises the following steps: bottom spray

A hose pump: ismatec MCP

Coating (Coating)

Material

Theophylline pellets (particle diameter: 0.8-1.2mm)

The content of active ingredients is as follows: about 93 percent

Batch production: 200 or 800g

Coating conditions

Inlet temperature: 33-43 deg.C

Process temperature: 25-31 deg.C

Spraying pressure: 0.6-0.75bar

Microclimate: 0.4-0.5bar

Spraying rate: 200g of batch: about 12g/min/kg

800g batch: about 5g/min/kg

Samples were taken at 6 and 10% polymer coating.

Polymer and method of making same

Polymer type (I)

EudragitFS 30 D(FS 30 D)：

Methyl acrylate methyl methacrylate methacrylic acid copolymer

Polymer type (II)

EudragitNE 30 D(NE 30 D)：

Ethyl acrylate methyl methacrylate copolymer

KollicoatSR 30 D：

Polyvinyl acetate

AquacoatECD：

Ethyl cellulose polymer

(all 30% aqueous dispersions)

Plasticizer: DBS dibutyl sebacate

Mixture of

Formulation

Examples

Spray suspension of 800g pellets and 15% polymer coating:

TS content of spray suspension: 20.0 percent

Preparation of spray suspension:

deionized water and polysorbate 80 were heated to 75 ℃ with gentle stirring. The glyceryl monostearate was heated to this temperature and homogenized by vigorous stirring for about 30 minutes. Cool to room temperature and then add the polymer dispersion and plasticizer. If desired, coagulation during mixing of the dispersion is prevented by pre-balancing the pH.

Release of active principle (tablets)

Release test according to USP

The active ingredient Release was determined according to USP 28-NF23, General Chapter <711>, resolution, Apparatus 2(Paddle), Method <724> "Delayed Release (Enteric Coated) arms-General Drug Release Standard", Method B (100 rpm, 37 ℃) using the following changes: the coated pellets were first tested for resistance to gastric fluid in simulated gastric fluid (USP) at pH1.2 for 120min, and then the buffer was changed to phosphate buffer at pH 7.5, which corresponds to simulated intestinal environment. The concentration of the active ingredient in the test medium is determined photometrically.

The release of the active ingredient should not exceed about 5% after 120 min. After 180min (corresponding to 60min at pH 7.5), the desired degree of release of the active ingredient is 5-95%, preferably 10-50%.

The results are summarized in tables 1-3. The 6%, 10% and 15% are given in each case based on the dry weight of the coating of the core.

TABLE 1

[0271] TABLE 2

TABLE 3

Claims

Use of a mixture of 1.2 to 60% by weight of one or more polymers (I) and 40 to 98% by weight of one or more polymers (II) for the production of a coated pharmaceutical preparation, wherein

The polymer (I) is a (meth) acrylate copolymer composed of 10 to 30% by weight of methyl methacrylate, 50 to 70% by weight of methyl acrylate and 5 to 15% by weight of methacrylic acid, and

the polymer (II) is a vinyl polymer or polysaccharide derivative different from the polymer (I) and comprising 88 to 100% of neutral monomer units and up to 12% by weight of polymerizable monomer units having an ionic group, the polymer (II) being a copolymer of methyl methacrylate and ethyl acrylate, a copolymer of methyl methacrylate and ethyl acrylate and methacrylic acid, a copolymer of methyl methacrylate, ethyl acrylate and trimethylammonium ethyl methacrylate, polyvinyl alcohol, a polyvinyl alcohol-polyethylene glycol graft copolymer, starch and derivatives thereof, polyvinyl acetate (PVAc), a vinyl acetate-vinylpyrrolidone copolymer, Hydroxyethylcellulose (HEC), Hydroxypropylcellulose (HPC), Hydroxypropylmethylcellulose (HPMC), Hydroxymethylethylcellulose (HEMC), Ethyl Cellulose (EC), Methyl Cellulose (MC), cellulose esters, cellulose glycolates or mixtures of said polymers,

the coated pharmaceutical preparation comprises a core containing the active ingredient and a polymer coating consisting of a mixture of polymers (I), (II),

it is characterized in that the preparation method is characterized in that,

the glass transition temperature of polymer (I) does not exceed 70 ℃ and a release profile is achieved which starts to release the active ingredient at the same pH value but is slower than that of a coated pharmaceutical preparation with polymer (I) alone.
2. Use according to claim 1, characterized in that the polymer (II) is a copolymer of 20 to 40% by weight of ethyl acrylate and 60 to 80% by weight of methyl methacrylate.
3. Use according to claim 1, characterized in that the polymer (II) is a copolymer of 50 to 70% by weight of methyl methacrylate, 20 to 40% by weight of ethyl acrylate and 12 to 2% by weight of trimethylammonium ethyl methacrylate chloride.
4. Use according to any one of claims 1 to 3, characterized in that the polymer coating represents 2 to 20% by weight of the core containing the active ingredient.
5. Use according to any one of claims 1 to 3, characterized in that the release of active ingredient in 60 minutes is less than 50% at the pH at which the polymer (I) starts to dissolve according to the USP release test.
6. Use according to any of claims 1 to 3, characterized in that the coated pharmaceutical formulation is in the form of pellets, which are present in a multiparticulate pharmaceutical formulation.
7. Use according to claim 6, characterized in that the multiparticulate pharmaceutical formulation is present in a tablet, mini-tablet, capsule, sachet or reconstituted powder containing pellets.
8. Pharmaceutical preparation comprising a core containing an active ingredient, said core being coated with a mixed coating of polymers, characterized in that the mixed coating is a mixture of 2 to 60% by weight of one or more polymers (I) and 40 to 98% by weight of one or more polymers (II),

it is characterized in that the preparation method is characterized in that,

the polymer (I) is a (meth) acrylate copolymer consisting of 10 to 30% by weight of methyl methacrylate, 50 to 70% by weight of methyl acrylate and 5 to 15% by weight of methacrylic acid, has a glass transition temperature of not more than 70 ℃ and

the polymer (II) is a vinyl polymer or polysaccharide derivative different from the polymer (I) comprising 88 to 100% of neutral monomer units and may comprise up to 12% by weight of monomer units having an ionic group, the polymer (II) being a copolymer of methyl methacrylate and ethyl acrylate, a copolymer of methyl methacrylate and ethyl acrylate and methacrylic acid, a copolymer of methyl methacrylate, ethyl acrylate and trimethylammonium ethyl methacrylate, polyvinyl alcohol, a polyvinyl alcohol-polyethylene glycol graft copolymer, starch and derivatives thereof, polyvinyl acetate (PVAc), a vinyl acetate-vinylpyrrolidone copolymer, Hydroxyethylcellulose (HEC), Hydroxypropylcellulose (HPC), Hydroxypropylmethylcellulose (HPMC), Hydroxymethylethylcellulose (HEMC), a polysaccharide or polysaccharide derivative, which comprises 88 to 100% of neutral monomer units and may comprise up to 12% by weight of monomer units having an ionic group Ethyl Cellulose (EC), Methyl Cellulose (MC), cellulose esters, cellulose glycolates or mixtures of said polymers, and achieves an initial release of the active ingredient at the same pH value, but a slower release profile of the active ingredient compared to a coated pharmaceutical formulation with polymer (I) alone.
9. Pharmaceutical formulation according to claim 8, characterized in that the polymer (II) is a copolymer of methyl methacrylate and ethyl acrylate, a copolymer of methyl methacrylate and ethyl acrylate and methacrylic acid, a copolymer of methyl methacrylate, ethyl acrylate and trimethylammonium ethyl methacrylate, polyvinyl alcohol-polyethylene glycol graft copolymer, starch and its derivatives, polyvinyl acetate (PVAc), vinyl acetate-vinylpyrrolidone copolymer, Hydroxyethylcellulose (HEC), Hydroxypropylcellulose (HPC), Hydroxypropylmethylcellulose (HPMC), Hydroxymethylethylcellulose (HEMC), Ethylcellulose (EC), Methylcellulose (MC), cellulose esters, cellulose glycolates or mixtures of said polymers.
10. Pharmaceutical formulation according to claim 9, characterized in that the polymer (II) is a copolymer of 20-40% by weight of ethyl acrylate and 60-80% by weight of methyl methacrylate.
11. Pharmaceutical formulation according to claim 9, characterized in that the polymer (II) is a copolymer of 50-70% by weight of methyl methacrylate, 20-40% by weight of ethyl acrylate and 12-2% by weight of trimethylammonium ethyl methacrylate chloride.
12. Pharmaceutical preparation according to any one of claims 8 to 11, characterized in that the polymer coating represents 2 to 20% by weight of the core containing the active ingredient.
13. Pharmaceutical formulation according to any of claims 8 to 11, characterized in that the release of active ingredient in 60 minutes at the pH value at which the polymer (I) starts to dissolve is less than 50% in the release test according to USP.
14. Pharmaceutical preparation according to any one of claims 8 to 11, characterized in that it is present in the form of a multiparticulate pharmaceutical preparation.
15. Pharmaceutical formulation according to claim 14, characterized in that it is present in the form of a tablet, a microtablet, a capsule, a sachet or a reconstituted powder containing pellets.