HK1190078A - Coating composition suitable for pharmaceutical or nutraceutical dosage forms - Google Patents

Description

Coating composition suitable for pharmaceutical or nutraceutical dosage forms

Technical Field

The present invention relates to a coating composition suitable for coating pharmaceutical or nutraceutical dosage forms comprising a core comprising one or more pharmaceutical or nutraceutical active ingredients, wherein the coating composition comprises at least 20% by weight of an enteric core/shell polymer composition obtained by an emulsion polymerization process, wherein the core of the core/shell polymer composition is formed by a water-insoluble, cross-linked polymer or copolymer and the shell of the core/shell polymer composition is formed by an anionic polymer or copolymer.

Technical Field

(meth) acrylate copolymers containing anionic groups are disclosed, for example, in EP0704208B1, EP0704207A2, WO03/072087A1, WO2004/096185A 1.

Controlled release pharmaceutical compositions with resistance against the effects of ethanol using a coating comprising a neutral vinyl polymer and excipients are known from WO2010/105672a 1.

Controlled release pharmaceutical compositions with resistance against the effects of ethanol using a coating comprising a polymer mixture and excipients are known from WO2010/105673a 1.

Pharmaceutical compositions for pH-dependent controlled release of narcotics (opioids) with reduced ethanol sensitivity on the release of the active compound are known from WO2009/036812a1 and WO2010034342a 1.

Pharmaceutical compositions for pH-dependent controlled release of non-opioid drugs with reduced ethanol sensitivity to the effect of active compound release are known from WO2009/036811a1 and WO2010034344a 1.

WO2008/049657 describes the use of a gastric acid resistant (meth) acrylate copolymer in a delayed release oral dosage form as a matrix former for the active ingredient contained therein to minimize the acceleration or deceleration effects that occur under in vitro conditions when the release of the active ingredient is affected by ethanol.

General definitions

As used in the specification or in the claims, the singular form of "a", "an", or "the" is intended to include the plural forms as defined, insofar as it is defined or limited by the definitions provided, and unless expressly stated otherwise.

For example, the term "an enteric core/shell polymer composition" will include one or more of these compositions or copolymers, such as mixtures thereof.

For example, the singular terms "a (meth) acrylate copolymer" or "the (meth) acrylate copolymer" will have the meaning of one or more (meth) acrylate copolymers within the definition or limits of the monomer composition given. Mixtures of different (meth) acrylate copolymers within the definition or definition of the monomer composition given are therefore included within the meaning of the present invention. Singular terms such as "a C of acrylic or methacrylic acid₄-to C₁₈Alkyl esters "or" another monomer of ethylene "are likewise understood to comprise one or more of these monomers.

Preferably the monomer ratios of the copolymers disclosed herein add up to 100% by weight.

Technical problem and solution

Pharmaceutical or nutritional compositions are designed to release the active ingredient in a manner that allows for a reproducible release profile. This will result in a desired and reliable blood level profile, which will provide the best therapeutic effect. If the blood level is too low, the active ingredient will not produce a sufficient therapeutic effect. This may have toxic effects if the blood level is too high. In both cases non-optimal blood level concentrations of the active ingredient may be dangerous to the patient and are therefore to be avoided. The problem is that the desired proportion of active ingredient release envisaged during the design of a pharmaceutical or nutraceutical composition may be altered by the patient's general living habits, negligence or by the patient's addictive behaviour in the use of ethanol or ethanol-containing beverages. In these cases, the pharmaceutical or nutraceutical form, which is actually designed only for aqueous media, is additionally exposed to a more or less intense ethanol-containing medium. As health authorities such as, for example, the Food and Drug Administration (FDA) are increasingly concerned with ethanol, resistance to ethanol may be an important registration requirement in the near future.

Since not all patients are aware of the risk or do not comply or are unable to comply with suitable warnings, recommendations or recommendations to take a controlled release pharmaceutical or nutraceutical form and an alcoholic beverage at the same time, there is a need for a controlled release pharmaceutical or nutraceutical composition, especially for gastric acid resistant ones, such that its mode of action is affected as little as possible by the presence of ethanol.

Conventional gastric resistant pharmaceutical or nutraceutical compositions, whether coated or uncoated, are generally not resistant to ethanol at all. It is therefore a problem of the present invention to provide a gastric acid resistant pharmaceutical or nutraceutical composition that is resistant to the influence of ethanol.

Especially gastric acid resistant or enteric formulated compositions are problematic. Such formulations are typically coated on the core with a gastric acid resistant coating layer (enteric coating layer) which has the following functions: the release of the pharmaceutical or nutraceutical active ingredient in the stomach at 2 hours will not exceed 10, 8 or possibly 5% respectively according to USP at ph 1.2. This function ensures that acid-sensitive pharmaceutical or nutraceutical active ingredients are prevented from being inactivated and that pharmaceutical or nutraceutical active ingredients that may irritate the gastric mucosa are not released in too high an amount. On the other hand in many cases the release of the pharmaceutical or nutraceutical active ingredient in the intestine according to the USP method at pH6.8 for one hour or less is designed to exceed at least 50, 60, 80% or more, respectively. The presence of ethanol in the gastric fluid at concentrations of 20, 30 or 40% (v/v) generally results in an increased release rate in the stomach. Due to the partitioning effect, the effect of ingested ethanol is not as important in the intestinal tract as in the stomach. Thus an effective prevention of the effects of ethanol should first prevent this undesired increase of the pharmaceutically or nutraceutically active ingredient in the stomach. It may furthermore be desirable to prevent that the influence of ethanol will not at least affect the release rate in ethanol-free media as fast as ph 6.8.

Several of the problems discussed herein are solved by a coating composition suitable for coating of pharmaceutical or nutraceutical dosage forms, comprising a core containing one or more pharmaceutical or nutraceutical active ingredients, wherein the coating composition comprises at least 20% by weight of an enteric core/shell polymer composition obtained by an emulsion polymerization process, wherein the core of the core/shell polymer composition is formed by a water-insoluble, cross-linked polymer or copolymer and the shell of the core/shell polymer composition is formed by an anionic polymer or copolymer.

Detailed Description

The present invention relates to a coating composition suitable for coating of pharmaceutical or nutraceutical dosage forms comprising a core comprising one or more pharmaceutical or nutraceutical active ingredients, wherein the coating composition comprises at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or 100% by weight of an enteric core/shell polymer composition obtained by an emulsion polymerization process, wherein the core of the core/shell polymer composition is formed by a water-insoluble, cross-linked polymer or copolymer and the shell of the core/shell polymer composition is formed by an anionic polymer or copolymer.

Food grade or pharmaceutical grade requirements

Suitable for coating of pharmaceutical or nutraceutical dosage forms will mean that the coating or binding composition will meet all general and specific food grade or pharmaceutical grade requirements, including regulatory and legal requirements, for pharmaceutical or nutraceutical dosage forms. Of course all other excipients used in the pharmaceutical or nutraceutical dosage forms described herein will also meet all general and specific food grade or pharmaceutical grade requirements, including regulatory and legal requirements, for pharmaceutical or nutraceutical dosage forms.

Coating composition

The present invention relates to a coating composition suitable for coating pharmaceutical or nutraceutical dosage forms, wherein the coating or binding composition comprises at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or 100% by weight of an enteric core/shell polymer composition obtained by an emulsion polymerization process, wherein the core is formed from a water-insoluble, cross-linked polymer or copolymer and the shell is formed from an anionic polymer or copolymer.

Aqueous dispersion

The enteric core/shell polymer composition may be present in the coating composition in the form of a solid phase in an aqueous dispersion having a solids content of from 1 to 60% by weight. This means that the aqueous polymer dispersion used for preparing the coating formulation may contain 1 to 70% by weight of the coating composition in solid phase and 30 to 99% by weight of the aqueous phase.

Powder or granules

The enteric core/shell polymer composition may be present in the coating composition in the form of a dry powder or granules. Compared to dispersions, powders or granules have the advantage of being of smaller weight and smaller volume and can be stored for a long time in the drying stage without the risk of coagulation or the risk of microbial contamination.

The solid can be separated from the aqueous dispersion by spray drying, freeze drying or coagulation to obtain a dry powder or granules. The powder or granules can be converted again into an aqueous dispersion by redispersion in water.

Emulsion polymerization process

In a typical emulsion polymerization process, the core in the form of core particles is first formed by polymerization of the monomers of the polymer or copolymer of the core. Subsequent polymerization of the monomers of the polymer or copolymer of the shell in the same reaction mixture produces a shell around the surface of the core particle.

In the emulsion polymerization process, the operation may be advantageously carried out by a monomer emulsion feed process or a monomer feed process, respectively. For this purpose, water is heated in the polymerization reactor to the reaction temperature. Surfactants and/or initiators may be added at this stage. The reactor is then fed-depending on the mode of operation-with an emulsion of the monomer, of the monomer mixture or of either. This dosed amount of (dotted) liquid may contain initiator and/or surfactant or the initiator and/or surfactant may be dosed in parallel.

Alternatively, all of the core monomers may be charged to the reactor prior to addition of the initiator. This process is commonly referred to as a batch process.

Chain transfer agents may be added to improve the stability of the process and the reproducibility of the molecular weight (Mw). Typical amounts of chain transfer agent may range from 0.05 to 1% by weight. Typical chain transfer agents may be, for example, 2-ethylhexyl Thioglycolate (TGEH) or n-dodecyl mercaptan (nDDM). However, the chain transfer agent is in many cases omitted without affecting the properties of the present invention.

It is also possible to combine the two processes by polymerizing a portion of the monomers in a batch process and then feeding the other portion.

The type of process and the mode of operation may be selected to obtain the desired particle size, sufficient dispersion stability, stable production process, etc., as is known to the expert in the art.

The average particle size of the polymer particles produced in the emulsion polymerization may vary from 10 to 1000, from 20 to 500 or from 50 to 250 nm. The average particle size of the polymer particles can be determined by methods well known to the skilled person, for example by means of laser diffraction. The particle size can be used2000 (Malvern) was determined by laser diffraction. This value can be the particle radius rMS [ nm ]]Expressed as half the median value of the volume-based particle size distribution, d (v, 50).

Emulsifiers which can be used are, in particular, anionic and nonionic surfactants. The amount of emulsifier used is generally not more than 5% by weight, based on the polymer.

Typical surfactants are, for example, alkyl sulfates (e.g., sodium lauryl sulfate), alkyl ether sulfates, sodium sulfosuccinate dicaprylate, polysorbates (e.g., polyoxyethylene (20) sorbitan monooleate), nonylphenol ethoxylates (nonoxynol) -9), and the like.

In addition to those initiators conventionally used in emulsion polymerization, for example per compounds such as Ammonium Peroxodisulfate (APS), redox systems such as sodium metabisulfite-APS-iron can also be used. Water-soluble azo-initiators may also be used and/or mixtures of initiators may be used. The amount of initiator is generally between 0.005 and 0.5% by weight, based on the weight of the monomers.

The polymerization temperature depends within certain limits on the initiator. For example, it is advantageous if APS is used, operating in the range of 60 to 90 ℃; polymerization is also possible if a redox system is used at lower temperatures, for example at 30 ℃.

Enteric core/shell polymer compositions

The core/shell polymer compositions of the present invention have enteric properties. This means that the core/shell polymer composition is gastric acid resistant, does not dissolve but swells at acidic pH values, e.g. at pH1 to 4, but dissolves more or less rapidly at higher pH values, e.g. at pH5.0 or higher. Due to the enteric properties, the core/shell polymer composition confers gastric resistance and a rapid release of the active ingredient in the intestinal tract to the pharmaceutical or nutraceutical dosage form, wherein said core/shell polymer composition is applied in the pharmaceutical or nutraceutical dosage form as a coating or as a binder. As a further advantage the core/shell polymer composition also imparts gastric resistance in the stomach in the presence of ethanol.

The core/shell polymer composition is obtained in at least two steps by an emulsion polymerization process. In a first procedure the core polymer particles are formed in the emulsion by polymerization of the monomers. In a second step the shell is polymerized on the core particles in the same emulsion by subsequent polymerization of the monomers.

The present invention relates to a core/shell polymer composition suitable as a coating or binder in a pharmaceutical or nutraceutical dosage form, wherein the core/shell polymer composition is obtained from an emulsion polymerization process, wherein the core is formed from a water-insoluble, cross-linked polymer or copolymer and the shell is formed from an anionic polymer or copolymer.

The present invention specifically discloses various possible combinations of any of the water-insoluble, crosslinked polymers or copolymers described herein as core polymers or copolymers with any of the anionic polymers or copolymers described herein as shell polymers or copolymers.

The polymer or copolymer of the core is crosslinked. Crosslinking means that the polymer or copolymer is at least partially polymerized from monomers containing two or more reactive groups or one or more reactive side groups capable of crosslinking linear polymer chains. The reactive groups or pendant groups capable of crosslinking the linear polymer chains may be vinyl groups or allyl groups. For example, monomers containing more than one vinyl group or containing one vinyl group and one or more allyl groups may be used. For example ethylene glycol-di-methacrylate (EGDMA) may be used as a crosslinking monomer.

As regards the crosslinked polymers, it is generally not possible to find solvents which dissolve them.

The polymer or copolymer of the shell is generally not crosslinked and thus may be linear.

Core/shell ratio

The weight of the core may be 10 to 95% of the total weight of the core/shell polymer composition.

The core/shell polymer composition may comprise, consist essentially of, or consist of 10 to 95, or 20 to 90, preferably 30 to 80 weight percent of the polymer or copolymer of the core.

The core/shell polymer composition may comprise, consist essentially of, or consist of a polymer or copolymer of from 5 to 90, or from 10 to 80, preferably from 20 to 70, weight percent of the shell.

The core and shell may add up to 100%. There is typically one core and one shell in the core/shell polymer composition. It is however also possible that more than one shell, i.e. two or more different shell polymers or copolymers, may be applied on one core polymer or copolymer.

It has been surprisingly found that the standard, non-core/shell enteric polymer coating can be replaced by a coating of the same thickness based on the disclosed core/shell polymer composition which does not impair the enteric properties. Furthermore, resistance to ethanol is improved. While the total amount of anionic groups in the coating is reduced. This has the further advantage that the maximum daily intake can be increased, with the amount of anionic groups generally being limited to the maximum daily intake.

Different micro-structural and physical behaviors

Due to the manner in which it is made, the core/shell polymer compositions of the present invention exhibit different microstructural and different physical behavior compared to a simple mixture of the same two polymers or copolymers in the same weight ratio. Since the polymer particles of the various core/shell dispersions contain both the core and the shell polymer, the two polymers are uniformly distributed from the outset. In contrast, as for the physical mixture of the two polymer dispersions, the particles of one polymer and the other polymer are randomly distributed; adjacent particles of the same polymer form larger domains.

This difference in microstructure can in some cases be visualized under light microscopy, wherein the core/shell polymer composition can exhibit a more uniform structure without visible phase separation. This difference in physical behavior can be shown by a more or less unique intermediate glass transition temperature compared to the two peaks of glass transition temperature of a simple mixture. The core/shell polymer composition of the present invention thus produces a more homogeneous mixture of the two polymers than can be obtained from a physically pure mixture or a simple mixture. This clearly results in a more uniform coating with the finer microstructure envisaged. There is less incompatibility between the two polymers. The coated pharmaceutical or nutraceutical drug form becomes more reliable in terms of active ingredient release behavior and more stable under storage conditions. A positive effect on tensile strength and a difference in film forming temperature can also be observed.

Core polymer or copolymer

Water-insoluble, crosslinked polymers or copolymers

Suitable water-insoluble, crosslinked copolymers for forming the core of the enteric core/shell polymer composition may be polymerized from crosslinked monomers alone or, preferably, from crosslinked and non-crosslinked monomers. The appropriate amount of crosslinking monomer may range from 0.1 to 100, 0.2 to 10, 0.2 to 5, preferably 0.3 to 3% by weight, calculated on the total amount of monomers used in the core polymer or copolymer.

Suitable water-insoluble, crosslinked copolymers for forming the core of the enteric core/shell polymer composition can be polymerized from 98 to 99.9, preferably 99.6 weight percent n-butyl acrylate (n-BA) and 0.1 to 2, preferably 0.4 weight percent ethylene glycol-di-methacrylate (EGDMA).

Suitable water-insoluble, crosslinked copolymers for forming the core of the enteric core/shell polymer composition can be polymerized from 99.6% Methyl Methacrylate (MMA) and 1.5% EGDMA.

Shell polymers or copolymers

Anionic polymers or copolymers

The anionic polymer or copolymer which may preferably be used as the shell of the enteric core/shell composition may be selected from (meth) acrylate polymers or copolymers or polyethylene polymers or copolymers.

Anionic polyethylene polymers

Suitable polyethylene polymers or copolymers may contain structural units derived from unsaturated carboxylic acids other than acrylic or methacrylic acid, exemplified by polyvinyl acetate phthalate or a copolymer of vinyl acetate and crotonic acid 9: 1.

Anionic (meth) acrylate copolymers

The anionic (meth) acrylate copolymers may comprise from 25 to 95, preferably from 40 to 95, in particular from 60 to 40,% by weight of free-radically polymerized C's of acrylic acid or methacrylic acid₁-to C₁₈Alkyl esters, preferably C₁-to C₈Or C₁-to C₄Alkyl esters and from 75 to 5, preferably from 60 to 5, in particular from 40 to 60,% by weight of (meth) acrylate monomers containing anionic groups.

The proportions mentioned generally add up to 100% by weight. However, it is also possible for small amounts in the range from 0 to 20 or 0 to 10, for example 1 to 5,% by weight of other monomers which are copolymerizable with ethylene, such as, for example, hydroxyethyl methacrylate or hydroxyethyl acrylate, to be present without this leading to impairment or modification of the basic properties. Preferably no other monomers capable of copolymerizing with ethylene are present.

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 anionic group-containing (meth) acrylate monomer is, for example, acrylic acid, preferably methacrylic acid.

Examples of suitable anionic (meth) acrylate copolymers

Suitable anionic (meth) acrylate copolymers may comprise, consist essentially of, contain or consist of the following polymerized units:

10 to 40% by weight of acrylic acid or methacrylic acid

10 to 80% by weight ofC of acrylic acid or methacrylic acid₄-to C₁₈-alkyl esters and optionally

0 to 60% by weight of another ethylene monomer.

C of acrylic acid or methacrylic acid₄-to C₁₈The alkyl esters are preferably selected from n-butyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, isodecyl methacrylate and lauryl methacrylate.

The other vinyl monomer is C which is not acrylic acid or methacrylic acid or acrylic acid or methacrylic acid₄-to C₁₈-monomers of alkyl esters. The other vinyl monomer may preferably be C of acrylic acid or methacrylic acid₁-to C₃-an alkyl ester which is methyl acrylate, ethyl acrylate, propyl acrylate, methyl methacrylate, ethyl methacrylate or propyl methacrylate. The other vinyl monomer may be hydroxyethyl methacrylate, hydroxypropyl methacrylate, poly (ethylene glycol) methyl ether acrylate, poly (ethylene glycol) methyl ether methacrylate, poly (propylene glycol) methyl ether acrylate, poly (propylene glycol) methyl ether methacrylate or styrene.

Preferably the anionic (meth) acrylate copolymer comprises, consists essentially of, or consists of polymerized units of:

10 to 40% by weight of acrylic acid or methacrylic acid

10 to 50% by weight of ethyl acrylate

10 to 80% by weight of C of acrylic acid or methacrylic acid₄-to C₁₈-alkyl esters and optionally

0 to 20 parts by weight of methyl methacrylate.

Preferably the anionic (meth) acrylate copolymer comprises, consists essentially of, or consists of polymerized units of:

20 to 40% by weight of methacrylic acid,

20 to 40% by weight of n-butyl methacrylate and

30 to 50% by weight of ethyl acrylate

Preferably the anionic (meth) acrylate copolymer comprises, consists essentially of, or consists of polymerized units of:

20 to 40% by weight of methacrylic acid,

30 to 50% by weight of 2-ethylhexyl acrylate,

15 to 40% by weight of ethyl acrylate and optionally

0 to 20% by weight of methyl methacrylate.

Preferably the anionic (meth) acrylate copolymer comprises, consists essentially of, or consists of polymerized units of:

from 10 to 40% by weight of methacrylic acid,

20 to 70% by weight of 2-ethylhexyl methacrylate and

10 to 50% by weight of ethyl acrylate.

Preferably the anionic (meth) acrylate copolymer comprises, consists essentially of, or consists of polymerized units of:

20 to 40% by weight of methacrylic acid,

20 to 50% by weight of 2-ethylhexyl methacrylate and

20 to 50% by weight of ethyl acrylate.

Preferably the anionic (meth) acrylate copolymer comprises, consists essentially of, or consists of polymerized units of:

from 10 to 35% by weight of methacrylic acid,

40 to 70% by weight of 2-ethylhexyl methacrylate and

10 to 30% by weight of ethyl acrylate.

Preferably the anionic (meth) acrylate copolymer comprises, consists essentially of, or consists of polymerized units of:

20 to 40% by weight of methacrylic acid,

20 to 40% by weight of isodecyl methacrylate and

40 to 50% by weight of ethyl acrylate.

Preferably the anionic (meth) acrylate copolymer comprises, consists essentially of, or consists of polymerized units of:

20 to 40% by weight of methacrylic acid,

20 to 40% by weight of lauryl methacrylate and

30 to 50% by weight of ethyl acrylate.

Other features of the (meth) acrylate copolymer,

other characteristics of the (meth) acrylate copolymer, in particular the (meth) acrylate copolymer described above, can be summarized as follows.

Preferably the (meth) acrylate copolymer can be characterized by an average glass transition temperature of 25 to 120 or 40 to 80 ℃ (determined by DSC according to DIN EN ISO 11357).

Preferably the (meth) acrylate copolymer can be characterized by a minimum film forming temperature (determined according to DIN ISO 2115) of 50 ℃ or lower.

Preferably the (meth) acrylate copolymer can be characterized by an average molecular weight Mw of 80.000 or higher as determined by Gel Permeation Chromatography (GPC).

Other suitable anionic (meth) acrylate copolymers

Fitting vaginaIonic (meth) acrylate copolymers are those composed of from 40 to 60% by weight of methacrylic acid and from 60 to 40% by weight of methyl methacrylate or from 60 to 40% by weight of ethyl acrylate (meth)L orTypes L100-55).

L is a copolymer of 50% by weight of methyl methacrylate and 50% by weight of methacrylic acid. The initial pH at which a particular active ingredient is released in intestinal fluid or simulated intestinal fluid may be designated pH 6.0.

L100-55 is a copolymer of 50% by weight of ethyl acrylate and 50% by weight of methacrylic acid.L30D-55 is a copolymer containing 30% by weightL100-55. The initial pH at which a particular active ingredient is released in intestinal fluid or simulated intestinal fluid may be designated pH 5.5.

Also suitable are anionic (meth) acrylate copolymers from 20 to 40% by weight of methacrylic acid and from 80 to 60% by weight of methyl methacrylate (meth)S type). The initial pH at which a particular active ingredient is released in intestinal fluid or simulated intestinal fluid may be designated pH 7.0.

Suitable (meth) acrylic acidsEster copolymers are those composed of from 10 to 30% by weight of methyl methacrylate, from 50 to 70% by weight of methyl acrylate and from 5 to 15% by weight of methacrylic acid: (FS type). The initial pH at which a particular active ingredient is released in intestinal fluid or simulated intestinal fluid may be designated pH 7.0.

FS is a copolymer of 25% by weight of methyl acrylate, 65% by weight of methyl acrylate and 10% by weight of methacrylic acid.FS30D is a mixture containing 30% by weight(iii) a dispersion of FS.

Also suitable are copolymers consisting of:

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

20 to 69% by weight of methyl acrylate and

0 to 40% by weight of ethyl acrylate and/or, where appropriate

From 0 to 10% by weight of other monomers capable of ethylene copolymerization,

provided that the glass transition temperature of the copolymer according to ISO11357-2, subsection 3.3.3 does not exceed 60 ℃. Such (meth) acrylate copolymers are particularly suitable for compressing pellets into tablets because of their good elongation at break properties.

Also suitable are copolymers consisting of:

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

5 to 30% by weight of methyl acrylate and

20 to 40% by weight of ethyl acrylate and

from more than 10 to 30% by weight of butyl methacrylate and, where appropriate

From 0 to 10% by weight of other monomers capable of ethylene copolymerization,

wherein the proportions of the monomers add up to 100% by weight,

with the proviso that the glass transition temperature (midpoint temperature T) of the copolymers according to ISO11357-2, subsection 3.3.3_mg) Is from 55 to 70 ℃. Copolymers of this type are particularly suitable for compressing pellets into tablets because of their good mechanical properties.

The above copolymers are composed in particular of the following free-radical polymerization units:

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

from 10 or more to 30, preferably from 15 to 25, particularly preferably from 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 glass transition temperature in this connection means in particular the midpoint temperature T according to ISO11357-2, section 3.3.3_mg. The measurements were carried out without addition of plasticizer, with a residual monomer content (REMO) of less than 100ppm, at a heating rate of 10 ℃/min and under nitrogen atmosphere.

The copolymers preferably consist essentially only of 90, 95 or 99 to 100% by weight of the monomers methacrylic acid, methyl acrylate, ethyl acrylate and butyl methacrylate in the abovementioned amount ranges.

However, it is possible, without this necessarily leading to impairment of the essential properties, for small amounts in the range from 0 to 10, for example from 1 to 5,% by weight of other monomers which are copolymerizable with ethylene, such as, for example, methyl methacrylate, butyl acrylate, hydroxyethyl methacrylate, vinylpyrrolidone, vinyl malonate, styrene, vinyl alcohol, vinyl acetate and/or derivatives thereof, to be additionally present.

Preparation of anionic (meth) acrylate copolymers

The anionic (meth) acrylate copolymers can be prepared in a manner known per se by free-radical polymerization of the monomers (see, for example, EP0704207a2 and EP0704208a 2) by residue polymerization of the monomers in the presence of polymerization initiators and optionally molecular weight regulators. The copolymers of the invention are preferably prepared by free-radical emulsion polymerization in the aqueous phase in the presence of anionic emulsifiers. Emulsion polymerization processes are well known in the art, for example as described in DE-C2135073.

The average molecular weight Mw (average molecular weight, determined for example by measuring the solution viscosity) of the anionic (meth) acrylate copolymers can be, for example, in the range from 80000 to 1000000 (g/mol).

Method for producing anionic (meth) acrylate copolymers

The anionic (meth) acrylate copolymer may be prepared by residue polymerization of monomers in the presence of a polymerization initiator. Molecular weight regulators may be added. The preferred polymerization method is emulsion polymerization.

Suitable core/shell combinations

Combination 1: core polymer C1 and shell polymer S1:

core polymer C1:

copolymer prepared from

95.0 to 99.9, preferably 99.6,% by weight of n-butyl acrylate (n-BA) and

0.1-5.0, preferably 0.4% by weight of ethylene glycol di-methacrylate (EGDMA)

Shell polymer S1:

copolymer prepared from

30 to 50, preferably 35 to 45, in particular 40,% by weight of Ethyl Acrylate (EA),

20 to 40, preferably 25 to 35, in particular 30,% by weight of 2-ethylhexyl methacrylate (EHMA) and

20 to 40, preferably 25 to 35, in particular 30,% by weight of Methacrylic Acid (MAS)

Release of pharmaceutically or nutraceutically active ingredients from a coated composition

According to USP, the release of the pharmaceutical or nutraceutical active ingredient is not more than 10, not more than 8 or not more than 5% after 2 hours in 0.1 mol HCl at ph1.2 with and without the addition of 20, 30 or 40% (v/v) ethanol under in vitro conditions.

According to USP, the release of the pharmaceutical or nutraceutical active ingredient under in vitro conditions at ph6.8 after 45 minutes or after 60 minutes in a buffered medium (phosphate buffered saline, ph6.8, european pharmacopoeia 4003200) is at least 50, at least 60, at least 80%.

Alternatively, for example whenWhen copolymers of the FS type are used as shell polymers, the pharmaceutical or nutraceutical active ingredients are present in a buffered medium according to USP after 45 minutes or after 60 minutes at pH7.2 under in vitro conditionsMay be at least 50, at least 60, at least 80%.FS type copolymers show that the release of a particular active ingredient begins in intestinal fluid or simulated intestinal fluid at about ph 7.0.

Thus the release of the pharmaceutical or nutraceutical active ingredient in a buffered medium after 45 minutes or after 60 minutes at ph6.8 or at ph7.2 under in vitro conditions according to USP may be at least 50, at least 60, at least 80%.

USP (USP = united states pharmacopeia) which can be preferably employed is USP32/NF27 (NF = national formulary), depending on monograph, instrument II, paddle, 50rpm for tablets or 50 to 100rpm for pills, paddle or basket (instrument I).

Core comprising a pharmaceutical or nutraceutical active ingredient

The core comprises one or more pharmaceutically or nutraceutically active ingredients as or as part of the core. The one or more pharmaceutical or nutraceutical active ingredients may be more or less homogeneously distributed in the matrix structure within the core structure or may form the core as a crystalline structure. Alternatively, the one or more pharmaceutical or nutraceutical active ingredients may be present as part of the core in the form of a layer on a carrier pellet. The core is thus an unfinished, coated or uncoated, but yet to be coated, pharmaceutical or nutraceutical dosage form.

The core, respectively the pharmaceutical or nutraceutical dosage form to be coated by the coating composition, may comprise or may contain neutral carrier pellets, such as sugar spheres or inert beads (non-pareils), on the outer layer of which the active ingredient is bound in a binder, such as lactose or polyvinylpyrrolidone.

Alternatively, the core may comprise pellets in the form of a polymer matrix in which the active ingredient is bound. The core may comprise uncoated pellets of crystallized active ingredient. The core may also comprise its own coating, such as a slow release coating. Such already coated cores may then be coated by the coating compositions described herein.

The core may be uncoated or may comprise a coating different from that obtained from the coating composition described herein. The core may be a coated pellet, e.g. a pellet with a slow release coating, an uncoated or coated tablet, an uncoated or coated micro-tablet or an uncoated or coated capsule. The core may also comprise a so-called "subcoat" as the outer layer.

The core comprises at least 80 or more, 90 or more, 95 or more, 98 or more, preferably 100% of the total amount of one or more pharmaceutical or nutraceutical active ingredients present in the gastric resistant pharmaceutical or nutraceutical dosage form.

In certain cases, it may be useful that the coating composition may comprise, in addition to the active ingredient present in the core, a partial amount, preferably less than 20, less than 10, less than 5 less than 2% by weight of the total amount of one or more pharmaceutical or nutraceutical active ingredients, for example to provide an initial dose of the active ingredient. In which case the coating composition functions as a binder or as a binder for the additional active ingredient. Preferably the coating composition comprises any active ingredient. Coating film

The coating suspension can be applied by spray coating or powder coating according to known methods. Typically the coated composition may be cured at elevated temperatures, for example at 40 ℃ or 60 ℃ for 24 hours after spray coating to provide reproducible and stable functional groups.

The polymer dry weight gain of the coating layer may have a surface area of at least 2.5, at least 3.5, at least 4, preferably 4 to 30, preferably 4 to 20, more preferably 5 to 18, or most preferably 10 to 18mg/cm 2. This may correspond to 2-60% polymer dry weight gain, related to the weight of the core. For coated tablets, the dry weight gain of the polymer in relation to the weight of the core (core: diameter or length about 1-25 or 1-10 mm) may be 2-30%. For coated pellets, the dry weight gain of the polymer in relation to the weight of the core (pellet core: diameter 0.1 to 1.5 mm) may be 10-60%.

The pellets are typically coated with at least 4% by weight of polymer based on the weight of the uncoated pellets (i.e. 4% polymer weight gain). Better protection of the active ingredient is obtained with thicker coatings weighted by 6%, 8% or 10% polymer.

Coatings of no more than 40% polymer weight gain are typically applied to the pellets as the time after which the coating layer dissolves begins to become too long. In many cases less than 30%, less than 25%, or less than 20% polymer weight gain is sufficient.

On tablets and capsules, typically at least 2mg of polymer per cm is coated²Coating the surface. In most cases at least 3mg, 4mg or 6mg of polymer per cm are applied²A surface. 40mg or more of polymer per cm²The amount of coating on the surface is almost never used; typically less than 30mg, less than 25mg or less than 20mg of polymer per cm is coated²A surface. Generally, greater coating thickness is required for capsules and oval tablets, while less coating is required for dosage forms that are more spherical.

Outer coating (Top Coat) and undercoating (Sub Coat)

The gastric resistant pharmaceutical or nutraceutical dose of the invention may further comprise a so-called "subcoat" or a so-called "outer coating" or both. The expressions subcoat and overcoat are well known to those skilled in the art.

The subcoating may be added as an outer layer of a core of a pharmaceutical or nutraceutical active ingredient below a layer of gastro-resistant (enteric) coating. The subcoating may have the function of separating potentially mutually incompatible core materials, such as active ingredients, from the materials of the coating layer. The subcoating has substantially no effect on the release profile of the active ingredient. The subcoat is preferably substantially water soluble, e.g., it may be composed of a material like Hydroxypropylmethylcellulose (HPMC) as a film former. The average thickness of the subcoat is very thin, e.g., no more than 15 μm, preferably no more than 10 μm.

The outer coating may be present over the enteric coating layer, and preferably may also be substantially water soluble. The outer coating may have the function of coloring the pharmaceutical or nutraceutical form or preventing environmental influences during storage, e.g. moisture. The outer coating may consist of a binder, for example a water soluble polymer such as a polysaccharide or HPMC, or a sugar compound such as sucrose. The outer coating may further contain high amounts of pharmaceutical or nutraceutical excipients such as pigments or glidants. The outer coating has substantially no effect on the release characteristics.

Pharmaceutical or nutraceutical active ingredients

Nutritional active ingredient

The present invention is preferably used in nutraceutical formulations.

A nutraceutical may be defined as a food extract which has a therapeutic effect on human health as claimed. Nutraceuticals are typically contained in pharmaceutical forms such as capsules, tablets or powders in prescribed doses. Examples of nutritional active ingredients are resveratrol from grape products as antioxidant, soluble dietary fibre products such as psyllium husk for reducing hypercholesterolemia, broccoli (sulfane) as a cancer health agent, and soybean or clover (isoflavones) for improving arterial health. Other examples of nutraceuticals are flavonoids, antioxidants, alpha-linoleic acid from linseed, beta-carotene from marigold petals or anthocyanins from berries (antocyanines). It is sometimes stated that nutraceuticals (nutraceuticals) are used synonymously as nutraceuticals.

A gastric resistant pharmaceutical or nutraceutical composition comprises a core containing a pharmaceutically or nutraceutically active ingredient. The pharmaceutical or nutraceutical active ingredient may be a pharmaceutical or nutraceutical active ingredient which may be inactivated by the influence of gastric juice at ph1.2 or which may irritate the gastric mucosa when released in the stomach.

Pharmaceutical active ingredient

The present invention also preferably applies to enteric coated dosage forms.

Preferred classes of drugs are, including but not limited to, those from the group that require a change from parenteral to oral administration to be considered and/or drugs with high potency (e.g. cytostatics, hormones, hormone receptor agonists, hormone receptor antagonists) and/or drugs with high side effects and toxicity problems (including prodrug metabolism; e.g. peptides, peptidomimetics, nucleotides, nucleosides, nucleoside analogues, taxanes)

The following drugs are particularly preferred

(Infliximab, Johnson)&Johnson, Schering-Plough, Mitsubishi Tanabe Pharma-Crohn's disease, rheumatoid arthritis),

(Etanercept, Wyeth-rheumatoid arthritis),

(Olanzapine), Eli Lilly and Company-psychosis),

(Quetiapine, AstraZeneca-schizophrenia),

herceptin(Trastuzumab (Trastuzumab), Roche, Genentech, Chugai Pharmaceutical-Breast cancer),

(escitalopram (Escitalo)pram), forest laboratories, h.lundbeck-depression, anxiety disorder),

glivec (Imatinib, Novartis-leukemia),

(Bevacizumab), Roche, Genentech-colorectal cancer),

(Docetaxel), Sanofi-Aventis-cancer),

(oxaliplatin, Sanofi-Aventis-colorectal cancer),

(Bupropion (Bupropion), GlaxoSmithKline, Biovail-Depression, Seasonal Affective Disorder (SAD)),

(Aripiprazole (Aripiprazole), Otsuka Pharmaceutical, Bristol-Myers Squibb-Psychosis, Depression),

(interferon beta-1 a, Biogen Idec-multiple sclerosis),

(Sildenafil, Pfizer-erectile dysfunction),

leuclin (Leuprolide), Takeda pharmaceutical, TAP Pharmaceuticals-prostate cancer),

(Ondansetron (Ondasetron), GlaxoSmithKline-nausea and vomiting),

runing(Anastrozole (Anastrozole), AstraZeneca-Breast cancer),

(Tacrolimus), Astellas Pharma-transplant rejection),

(Mycophenolatatemofetil, Roche, Chugai pharmaceutical-transplant rejection),

(Gemcitabine, Eli Lilly and Company-carcinoma），

(Duloxetine), Eli Lilly and Company-Depression, anxiety disorder),

(Fentanyl, Johnson)&Johnson-pain),

(Bicalutamide (Bicalutamide), AstraZeneca-prostate cancer),

(Tenofovir (Tenofovir) + Emtricitabine (Emtricitabine), Gilead Sciences-HIV infection),

(Tamsulosin (Tamsulosin), Boehringer Ingelheim-benign prostatic hypertrophy),

(Pregabalin, Pfizer-Neuropathy),

(Paroxetine, GlaxoSmithKline-Depression, anxiety disorders),

(Lopinavir (Lopinavir), Abbott Laboratories-HIV infection),

(Cetuximab (Cetuximab), Bristol-Myers Squibb, Merck KGaA-colorectal cancer),

(Goserelin (Goserelin), AstraZeneca-prostate cancer),

(Lamivudine) + Zidovudine (Zidovudine), GlaxoSmithKline-HIV infection),

(Tadalafil), Eli Lilly and Company, LillyIcos-erectile dysfunction),

(Atazanavir, Bristol-Myers Squibb-HIV infection),

(Methylphenidate, Johnson&Johnson-attention deficit hyperactivity disorder),

(Irinotecan (Irinotecan), Pfizer-colorectal cancer),

(Amphetamine (Amphetamine), fire Pharmaceuticals-attention deficit hyperactivity disorder),

(Sevoflurane (Sevoflurane), Abbott laboratories-anesthesia),

(Capecitabine, Roche, Chugai pharmaceutical-carcinoma),

freon(Letrozole (Letrozole), Novartis, Chugai pharmaceutical-Breast cancer),

(Tenofovir), Gilead Sciences-HIV infection),

(Erlotinib, Roche, Genentech-non-small cell lung cancer),

(Pemetrexed, Eli Lilly and Company-non-small cell lung carcinoma),

(Fentanyl, Cephalon-cancer pain),

(Lidocaine (Lidocaine), Endo Pharmaceuticals-pain),

(Paclitaxel (Paclixaxel), Bristol-Myers Squibb-carcinoma),

(Abacavir (Abacavir) + Lamivudine (Lamivudine) + Zidovudine (Zidovudine), GlaxoSmithKline-HIV infection),

(Abacavir (Abacavir) + Lamivudine (Lamivudine), GlaxoSmithKline-HIV infection),

venlafaxine(Effexor, Wyeth-antidepressants)

.., and their respective compound classes and/or drugs of various modes of action implied by the examples (as the latter are not only A Physicochemical (API) of the active pharmaceutical ingredient but also descriptive information of its physiological behaviour and pharmaceutical characteristics).

Therapeutic and chemical classes of drugs for enteric-coated pharmaceutical dosage forms are, for example, analgesics, antibiotics or anti-infectives, antibodies, antiepileptics, plant-derived antigens, antirheumatics, beta blockers, benzimidazole derivatives, beta blockers, cardiovascular agents, chemotherapeutic agents, central nervous system agents, digitosides, gastrointestinal agents, such as proton pump inhibitors, enzymes, hormones, liquid or solid natural extracts, oligonucleotides, peptide hormone proteins, therapeutic bacteria, peptides, proteins, proton pump inhibitors, (metal) salts such as aspartate, chloride, ortates, urological drugs, vaccines

Examples of acid labile, irritating or drug requiring controlled release may be: acamprosate (acamprosat), aescin, amylase, acetylsalicylic acid, epinephrine, 5-aminosalicylic acid, chlortetracycline, bacitracin (bacitracin), basalazine (balazazine), beta carotene, bicalutamide (bicalutamid) bisacodyl, bromelain (broomerain), budesonide (budesonide), calcitonin (calcein), carbamacipine, carboplatin (carboplatin), cephalosporins (cephalosporins), cetrorelix (cetrorelix), clarithromycin (clarithromycin), chloramphenicol, cimetidine (cimetidine), cisapride (cisaprilide), cladribine (cladribine), chlordiazepine (clozapine), cysteine (cysteine-8-cysteine), dexlanoline (diclofenac), dexlansoprazole (norfloxacin (diclofenac), dexlansoprazole (diclofenac), dihydrostreptomycin (dihydrostreptomycin), dimethicone (dimethicone), divalprex (dihydrospirorenone), duloxetine (duloxetine), enzymes, erythromycin, esomeprazole (esomeprazole), estrogens, etoposide (etoposide), famotidine (famotidine), fluorides, garlic oil, glucagon (glucogon), granulocyte colony stimulating factor (G-CSF), heparin (heparin), hydrocortisone (hydrocortisone), human auxin (hGH), ibuprofen (ibuprofen), ilaprazole (ilaprazole), insulin (insulin), interferon (interferon), interleukins, introns A, ketoprofen (ketoprofen), lansoprazole (lansoprazole), leuprolide acetate (leuprolide) lipase, lipoic acid, lithium, quinine (methacin), quinine (amantadine), amantadine (methacin), minomycin (methasone), oxymetazone (methasone (methazone), nitrofurantoin (nitrofuration), novobiocin (novobiocin), olsalazine (olsalazine), omeprazole (omeprazole), othathes, pancreatin (pancreatin), pantoprazole (pantoprazole), parathyroid hormone, paroxetine (parooxetine), penicillin, perprazole (perprazole), pindolol (pindolol), polymyxin (polymyxin), potassium, pravastatin (pravastatin), prednisone (prednisone), pregluatacin propagylamine (progabide), protist (pro-somatotatin), protease, quinapril (quinapril), rabeprazole (rabeprazole), ranitidine (ranitidine), ranolazine (ranolazine), reboxetine (reboxetine), rutin (ketostatin), growth hormone (valsartan), oxytocin (vasopressin), vasopressin (vasopressin), vasopressin (vasopressin, vasopressin (vasopressin, vasopressi, including their salts, derivatives, polymorphs, or mixtures or combinations of any of their species.

Pharmaceutical or nutraceutical excipient

The coating composition may comprise, consist essentially of, or consist of up to 80, up to 70, up to 60, up to 50, up to 40, up to 30, up to 20% by weight of any pharmaceutical or nutraceutical excipient. Thus the amount of enteric core/shell polymer and pharmaceutical or nutraceutical excipient may add up to 100% in the coating composition.

In some cases it may be useful that the coating composition may comprise in addition to the active ingredient in the core a partial amount, preferably less than 10% less than 5% less than 2% by weight of the total amount of one or more pharmaceutical or nutraceutical active ingredients, for example to provide a fast-releasing initial dose. In which case the coating composition acts as a binder or as a binder for the further part of the active ingredient. Thus in this case the amount of enteric core/shell polymer, pharmaceutical or nutraceutical excipient and one or more pharmaceutical or nutraceutical active ingredients may add up to 100% in the coating composition.

The coating composition may comprise up to 80, up to 70, up to 60, up to 50, up to 40, up to 30, up to 20% by weight of any pharmaceutical or nutraceutical excipient selected from antioxidants, brighteners, binders other than the core/shell polymers described herein, flavourings, flow aids, flavourings, glidants, penetration enhancers, pigments, plasticizers, polymers other than the core/shell polymers described herein, pore-forming agents or stabilizers.

Gastric acid resistant pharmaceutical or nutraceutical dosage form

The present invention relates to a gastric acid resistant pharmaceutical or nutraceutical dosage form comprising a core containing one or more pharmaceutical or nutraceutical active ingredients and a gastric acid resistant coating layer on the core, wherein the gastric acid resistant coating layer is applied in a coating process using a coating composition as described herein.

The gastric resistant pharmaceutical or nutraceutical dosage form of the invention is characterized by a release of the pharmaceutically or nutraceutically active ingredient which does not exceed 10, does not exceed 8 or does not exceed 5% after 2 hours in a medium according to USP at ph1.2 under in vitro conditions with and without the addition of 20% (v/v) ethanol.

The gastric resistant pharmaceutical or nutraceutical of the invention may further be characterized by a release of the pharmaceutically or nutraceutically active ingredient which is at least 50, at least 60, at least 80% after 45 minutes in a buffered medium according to USP at ph6.8 under in vitro conditions.

With reference to USP32/NF27 (NF = national formulary), instrument II, paddle, 50rpm for tablets, or 50 to 100rpm for pills, paddle or basket, depending on the monograph. Use as coating composition

The present invention relates to the use of a coating composition as described herein for coating a core of a pharmaceutical or nutraceutical dosage form to be coated, wherein said core comprises a pharmaceutical or nutraceutical active ingredient, wherein (the resulting coated core respectively) the coated pharmaceutical or nutraceutical dosage form shows the use of a binding composition with a release of the pharmaceutical or nutraceutical active ingredient of not more than 10% as an in vitro condition after 2 hours in a medium according to USP at ph1.2 with and without the addition of 20% (v/v) ethanol at in vitro conditions

The coating composition as described herein is preferably used as a binder for binding the pharmaceutical or nutraceutical active ingredient in the coating or in the core of the pharmaceutical or nutraceutical dosage form. When the coating composition is not used in a coating but is used as a binder in the core of a pharmaceutical or nutraceutical dosage form, as a binder or as a matrix former, it may be more accurately called a binding composition.

Release of pharmaceutical or nutraceutical active ingredients for adhesive compositions

The release of the pharmaceutical or nutraceutical active ingredient under in vitro conditions at ph1.2 does not exceed 10, does not exceed 8 or does not exceed 5% after 2 hours in a medium according to USP with and without the addition of 20, 30 or 40% (v/v) ethanol.

The release of the pharmaceutical or nutraceutical active ingredient under in vitro conditions at ph6.8 in a buffered medium according to USP after 45 minutes or after 60 minutes is at least 50, at least 60, at least 80%.

USP (USP = united states pharmacopeia) which can be preferably employed is USP32/NF27 (NF = national formulary), depending on monograph, instrument II, paddle, 50rpm for tablets, or 50 to 100rpm for pills, paddle or basket.

Core/shell polymer composition

The invention also relates to the core/shell polymer compositions described herein for use as a coating or binder in pharmaceutical or nutraceutical dosage forms.

The core/shell polymer composition is obtained from an emulsion polymerization process wherein the core is formed from a water-insoluble, crosslinked polymer or copolymer and the shell is formed from an anionic polymer or copolymer.

The present invention relates to a core/shell polymer composition suitable as a coating or binder in a pharmaceutical or nutraceutical dosage form comprising a core and an outer coating, wherein the core comprises one or more pharmaceutical or nutraceutical active ingredients and wherein the coating comprises a core/shell polymer composition, the core/shell polymer composition being obtained by an emulsion polymerization process, wherein the core of the core/shell polymer composition is formed by a water-insoluble, crosslinked polymer or copolymer and the shell is formed by an anionic polymer or copolymer. The core/shell polymer composition is thus part of a pharmaceutical or nutraceutical dosage form.

Similar to that described in WO2008/049657, the core/shell polymer composition of the present invention can be used as a binder and matrix former for an active ingredient contained in a delayed or extended release oral dosage form to minimize the acceleration or deceleration effect of the release of the active ingredient under in vitro conditions affected by ethanol.

Examples

Preparation of the Polymer Dispersion of the invention

The polymer was prepared in a1 liter round bottom flask equipped with a lid, anchor stirrer, baffles, reflux condenser, nitrogen feed line and temperature probe to monitor the temperature inside the reactor. A water bath equipped with a thermostat was used to control the reaction temperature.

The flask was charged with 653g of deionized water, 13.2g of sodium dodecyl sulfate solution (15% in water; Disponil SDS 15) and 6.5g of polysorbate 80 (TEGO SMO 80V). The reactor was flooded with nitrogen, the mixture was stirred with a stirrer and heated to an initial temperature of 82 ℃.

Two stable monomer emulsions were prepared for the core polymer and the shell polymer, respectively. A total of 280.0g of monomer was used, divided between the two flasks according to the desired ratio of core polymer to shell polymer. The monomer composition of each of the two emulsions was selected according to the table of the examples (see below). For each emulsion 3% by weight of deionized water based on the weight of the monomers was used.

According to the invention, the core monomer emulsion comprises a crosslinked monomer (ethylene glycol dimethacrylate).

In the examples given the shell monomer emulsion contains a chain transfer agent (2-ethylhexyl thioglycolate).

Comparative example (example 1) was prepared without the core emulsion; a total of 280.0g of monomers were used to prepare the emulsion, in which case the emulsion was not intended to form a shell but rather to form homogeneous particles.

As an example of the core-shell polymer composition of example 2-as shown in the Table of the examples-a core monomer emulsion was prepared with 83.7g of n-butyl acrylate, 0.3g of ethylene glycol dimethacrylate, and 2.5g of deionized water. The shell monomer emulsion was prepared from 58.6g of 2-ethylhexyl methacrylate, 58.6g of methacrylic acid, 78.3g of ethyl acrylate, 0.6g of 2-ethylhexyl thioglycolate (chain transfer agent) and 4.2g of deionized water.

Two initiators (used to prepare the core and shell polymers, respectively) were prepared by dissolving 0.12mol% ammonium persulfate (relative to the sum of the core and shell monomer emulsion monomers, respectively, used) in 5.0g of deionized water.

When the temperature inside the reactor reached 82 ℃, a solution of the initiator for the core polymer was added to the reactor. After two minutes, dosing of the core monomer emulsion at a dosage rate of 2g/min was started. The temperature inside the reactor was maintained at 82 ℃ by adjusting the temperature of the water bath. After all the monomer emulsion was added, the temperature was maintained at 82 ℃ for 10 minutes, after which the initiator solution of the shell was added to the reactor. After 2 minutes, dosing of the shell monomer emulsion at a dosage rate of 2g/min was started.

After all shell monomer emulsion was added, the temperature was held at 82 ℃ for 30 minutes, after which the reactor contents were allowed to cool to 20 ℃ and filtered through a 250 μm wire mesh (size),

Preparation of spray suspensions

8.8g triethyl citrate, 210.0g microfine talc and 1057g deionized water were charged to a vessel and homogenized for 15 minutes using an ULTRA TURRAX high performance disperser.

350.0g of this polymer dispersion (30% solids content) are stirred with a magnetic stirrer. After the talc dispersion was slowly poured into the polymer dispersion, stirring was continued for 60 minutes, after which the mixture was filtered through a 240 μm wire mesh.

Coating method

A MicroLab coater (Oystar Huttlin) was used to prepare the coating.

350g of diprophylline pellets (diameter 0.7-1.0 mm, 20% active content) were loaded into a MicroLab instrument and stirred with a low air supply.

The fluid bed temperature was raised to 23-26 c and the pellets were coated for 1.5 to 2.5 hours, up to a 10.5 or 17.5% weight gain in polymer (relative to the initial pellet weight due to the additional weight of polymer in the coating). The spray rate was slowly increased to a maximum of 2 g/min.

After the coating process, the pellets were stirred in the instrument for an additional 5 minutes for re-drying and curing. The coated pellets were then allowed to cool in the apparatus with a low air supply.

Table 1: monomer composition and core/shell ratio

MAA = methacrylic acid

EGDMA = ethylene glycol dimethacrylate

TGEH = 2-ethylhexyl thioglycolate

MA = methyl acrylate

EA = ethyl acrylate

n-BA = n-butyl acrylate

MMA = methyl methacrylate

n-BuMA = n-butyl methacrylate

EHMA = 2-ethylhexyl methacrylate

Table 2: properties of the core/Shell particles

	rMS[nm]	Vz in THF[mL/g]	Tg[℃]
				Example 1 (Compound)	49	n.d.	49
Example 2	51	81.5	77
				Example 3	51	92.4	68
Example 4	50	71.3	n.d.
				Example 5	51	n.d.	32
Example 6	48	50,7	68

n.d. no assay

Table 3: release of active ingredients

Analytical method

Particle size rMS [ nm ]

Particle size was determined by laser diffraction using a Mastersizer2000 (Malvern).

The value is indicated by the particle radius rMS [ nm ], which is half the median value of the volume-based particle size distribution d (v, 50).

Viscosity value Vz [ mL/g ]

The viscosity value Vz is usually used as a measure for the molecular weight. The viscosity number is determined in accordance with DIN EN ISO 1628-1.

A process-controlled viscosity measurement system (PVS, Lauda GmbH & co. kg) with a ubbeohde capillary (type Oc) was used.

The polymer was dissolved in THF at a concentration of 0,5g per 100mL of solvent. The temperature measured was 25 ℃.

Molecular weight Mw [ g/mol ]

The molecular weight was determined by Gel Permeation Chromatography (GPC). The molar mass calibration was based on poly (methyl methacrylate).

The conditions for the measurements were selected according to the disclosure of Martina Adler et al (e-polymers 2004, 055).

N, N-dimethylacetamide containing 6g/L acetic acid, 3g/L LiBr and 10g/L H₂O was used as the mobile phase at a flow rate of 1.0 ml/min. 4GRAM10 μm column equipment (pre-column,andcolumn-Polymer Standards Service, Mainz, Germany) was used as stationary phase.

Glass transition temperature Tg [ deg.C ]

The glass transition temperature Tg was determined by DSC in accordance with DIN EN ISO 11357. Typically between 10 and 12mg of sample is used, a heating rate of 20K/min; the temperature range is-40 ℃ to 140 ℃. The measurements were performed under nitrogen atmosphere. The evaluation was based on the second heating cycle, and the indicated values were average values over the glass transition interval.

Minimum film Forming temperature MFT [ deg.C ]

The lowest temperature at which the polymer-dispersion will form a polymer film upon evaporation of water is the minimum film-forming temperature (MFT). The MFT is a characteristic of the dispersion and-in particular-is influenced by the glass transition temperature and the particle size of the dispersed particles.

The minimum film-forming temperature has been determined according to DIN ISO2115 by applying the dispersion with a scalpel on a band heater under a defined temperature gradient. The MFT corresponds to crack-free film formation and is slightly above the lowest temperature of the whitening point (which is the temperature at which the polymer also appears whitish, since the film has not yet fully formed).

Release of active ingredients

The release characteristics were measured in a dissolution apparatus with 900mL of dissolution medium at a rotation speed of 100rpm (USP 32)<711>Dissolving out; type I: basket method). The temperature was 37 ℃ C. + -. 0.5 ℃. The dissolution medium was 0.1N hydrochloric acid (0.1N HCl) for 2 hours; the dissolution medium was then completely exchanged to pH6.8EP-buffer 4003200 (= phosphate-buffered saline: 8.5g NaCl, 1g KH)₂PO₄，2K₂HPO₄At 1L H₂In O). The amount of released API (diprophylline) was determined by UV-measurement.

The effect of ethanol was studied by replacing a portion of the hydrochloric acid with ethanol. Measurements of displacement (by volume) with 20% ethanol were performed.

The dissolution media did not contain any ethanol (in all cases) after total exchange to ph 6.8.

Claims (14)

1. A coating composition suitable for coating of pharmaceutical or nutraceutical dosage forms comprising a core comprising one or more pharmaceutical or nutraceutical active ingredients, wherein the coating composition comprises at least 20% by weight of an enteric core/shell polymer composition obtained by an emulsion polymerization process, wherein the core of the core/shell polymer composition is formed from a water-insoluble, cross-linked polymer or copolymer and the shell of the core/shell polymer composition is formed from an anionic polymer or copolymer.

2. Coating composition according to claim 1, wherein it comprises up to 80% by weight of pharmaceutical or nutraceutical excipients selected from antioxidants, brighteners, binders, flavors, flow aids, flavors, glidants, penetration enhancers, pigments, plasticizers, non-crosslinked polymers, pore-forming agents or stabilizers.

3. A coating composition according to claim 1 or 2, wherein it is present in the form of a solid phase in an aqueous dispersion having a solids content of from 1 to 60% by weight.

4. Coating composition according to one or more of claims 1 to 3, wherein it is present in the form of a dry powder or granules.

5. Coating composition according to one or more of claims 1 to 4, wherein the water-insoluble polymer or copolymer is selected from (meth) acrylate polymers or copolymers or polyethylene polymers or copolymers.

6. Coating composition according to one or more of claims 1 to 5, wherein the anionic polymer or copolymer is selected from (meth) acrylate polymers or copolymers or polyethylene polymers or copolymers.

7. Coating composition according to one or more of claims 1 to 6, wherein the coating composition comprises one or more pharmaceutically or nutraceutically active ingredients.

8. A gastric resistant pharmaceutical or nutraceutical dosage form comprising a core containing one or more pharmaceutical or nutraceutical active ingredients and a gastric resistant coating layer on the core, wherein the gastric resistant coating layer is applied in a coating process using a coating composition according to one or more of claims 1 to 7.

9. A gastric resistant pharmaceutical or nutraceutical dosage form according to claim 8, wherein the release of the pharmaceutically or nutraceutically active ingredient does not exceed 10% after 2 hours in a medium according to USP at pH1.2 with and without the addition of 20% (v/v) ethanol under in vitro conditions.

10. A gastric resistant pharmaceutical or nutraceutical composition according to claim 8 or 9, wherein the pharmaceutical or nutraceutical active ingredient is released at least 50% after 45 minutes in a buffered medium according to USP under in vitro conditions at ph6.8 or at ph 7.2.

11. Use of a coating composition according to claim 1 or 7 for coating a core of a pharmaceutical or nutraceutical dosage form, wherein the core comprises a pharmaceutical or nutraceutical active ingredient, wherein the resulting coated core shows a release of the pharmaceutical or nutraceutical active ingredient of not more than 10% under in vitro conditions after 2 hours in a medium according to USP at ph1.2 with and without the addition of 20% (v/v) ethanol.

12. Use of a coating composition according to claim 1 or 7 as a binder in the coating or in the core of a pharmaceutical or nutraceutical dosage form for binding pharmaceutical or nutraceutical active ingredients.

13. Core/shell polymer composition as defined in one or more of claims 1 to 7 for use as a coating or binder in pharmaceutical or nutraceutical dosage forms.

14. The core/shell polymer composition according to claim 13, wherein the weight of the core is from 10 to 95% of the total composition weight.