HK1165727B - Aqueous carbonated medium containing an amino(meth)acrylate polymer or copolymer - Google Patents

Description

Aqueous carbonation medium containing amino (meth) acrylate polymers or copolymers

Technical Field

The present invention relates to the field of aqueous solutions or dispersions containing amino (meth) acrylate polymers or copolymers to be used in pharmaceutical, nutraceutical or cosmetic formulations.

Background

Amino (meth) acrylate polymers or copolymers are well known for use as coating agents or binders, for example in the field of pharmaceuticals (US 4,705,695). The amino (meth) acrylate polymer or copolymer may, for example, consist of 30 to 80% by weight of C of acrylic or methacrylic acid₁-C₄-polymerized units of an alkyl ester and 70-20 wt% of an alkyl (meth) acrylate monomer having a tertiary amino group in the alkyl group. EUDRAGITE and EUDRAGITEPO is an example of these types of polymers or copolymers and consists of polymerized units of 25% by weight of methyl methacrylate, 25% by weight of butyl methacrylate and 50% by weight of dimethylaminoethyl methacrylate.

These kinds of polymers are soluble in organic solvents, but insoluble in pure or demineralized water. The amino (meth) acrylate polymer or copolymer is soluble in aqueous buffer media at less than pH 5.0, but is insoluble at higher pH values. Therefore, amino (meth) acrylate polymers or copolymers are often used to coat pharmaceutical compositions to achieve a taste-masking effect in the oral cavity, together with a rapid active ingredient release in the stomach. The amino (meth) acrylate polymer or copolymer may also show a positive effect on the storage stability of the pharmaceutical composition due to the prevention of moisture absorption.

Coatings with amino (meth) acrylate polymers or copolymers can be easily applied from organic solutions by spraying. However, organic solutions are nowadays increasingly being avoided due to general environmental and health considerations. Thus, aqueous dispersions of coating solutions are generally preferred over organic solutions.

In the case of amino (meth) acrylate polymers or copolymers, stable aqueous dispersions can be prepared by partially neutralizing the amino groups in the polymer or copolymer by addition of an acid (US 4,705,695). However, the addition of pure acids such as HCl may, for example, impair taste masking ability or a positive effect on storage stability. Sometimes, the use and addition of certain emulsifiers or fatty organic acids or alcohols in powder form can help overcome these problems.

WO02067906a1(US20030064036a1) for example describes coating and adhesive agents with improved storage stability, which essentially consist of:

(a) polymers or copolymers of acrylic or methacrylic acid C polymerized by free radicals₁-C₄-alkyl esters and other alkyl (meth) acrylate monomers comprising a functional tertiary amino group, said polymer or copolymer being in the form of a powder having an average particle size of 1-40 μm,

(b) 3-15% by weight, based on (a), of an emulsifier having an HLB value of at least 14,

(c) 5 to 50% by weight, based on (a), of C₁₂-C₁₈Monocarboxylic acids or C₁₂-C₁₈-a hydroxy compound.

One of the benefits of the invention is effective taste masking and reduced vapor transmission. The dispersion processing time for this inventive example was about 3-6 hours. However, the use of amino (meth) acrylate polymers or copolymers in powder form can sometimes cause dust-related problems. There is also a general tendency to at least avoid the addition of larger amounts of excipients.

Disclosure of Invention

Problem and solution

It is an object of the present invention to provide a stable aqueous form of an amino (meth) acrylate polymer or copolymer which avoids the problems described before.

This problem is solved by an aqueous medium containing an amino (meth) acrylate polymer or copolymer that is insoluble in demineralized water, characterized in that the medium has a content of an aqueous phase of at least 60% by weight and a content of solids comprising the amino (meth) acrylate polymer or copolymer of at most 40% by weight, wherein the aqueous phase is charged with a sufficient amount of carbon dioxide that causes the amino (meth) acrylate polymer or copolymer to be present in the medium in the form of a solute.

It has surprisingly been found that an aqueous medium carbonated with carbon dioxide can be used to achieve a solution or dispersion of an amino (meth) acrylate polymer or copolymer. It has been demonstrated that the amino groups are at least partially neutralized by the carbonic acid/bicarbonate salt dissolved in the aqueous phase and thus the amino (meth) acrylate polymer or copolymer becomes at least dispersed, partially dissolved or even completely dissolved or in the middle of these conditions.

This behavior has been identified by raman spectroscopic analysis which revealed the presence of protonated amino groups of the amino (meth) acrylate polymer in a carbonated solution of the polymer (at 1392 and 1406 cm)^-1The signal at (2) disappears and at 1396cm^-1Where a broad absorption peak occurs).

The carbonated aqueous medium containing amino (meth) acrylate polymers or copolymers of the present invention can be easily handled in a similar manner as organic solvent solutions. In this case, however, the organic solvent is not removed but the water is carbonated. This means that the dried coating made from the dispersion or solution of the invention will be more or less composed of pure amino (meth) acrylate polymer or copolymer, since carbon dioxide is removed together with the vapour. This is a considerable advantage over the aqueous dispersions known from the prior art, in which the acid or other excipient always remains with the dried amino (meth) acrylate polymer or copolymer. There is a balance of interactions between the amino (meth) acrylate polymer or copolymer and the carbon dioxide which remains in the stable range for a long time, for example at least 6 months or longer.

Detailed description of the invention

The invention relates to an aqueous medium containing an amino (meth) acrylate polymer or copolymer which is insoluble in demineralized water.

Water phase/water content/solids content

An aqueous phase in the sense of the present invention shall mean a liquid phase which is at least predominantly, substantially or almost or exactly 100% aqueous. Some amount of water may be replaced by a water-soluble fluid such as ethanol, acetone or isopropanol. This may be advantageous for the purpose of preventing microbial growth or for the purpose of improving solution properties (e.g. atomization) or end product properties. In the sense of the present invention, the aqueous phase may contain an amount of water-soluble or water-miscible fluid which is not higher than 40% (w/w), more preferably not higher than 30% (w/w), most preferably not higher than 20% (w/w). In any case, the resulting solution should not exhibit flammable properties. In the aqueous phase, water and water soluble fluid total 100%. Most preferably, the water of the aqueous phase consists of 100% water.

The medium may have an aqueous phase content of at least 60%, at least 70, at least 80 or at least 90%, and a solids content of at most 40, at most 30, at most 20 or at most 10% by weight. The solids content may be equal to the content of the amino (meth) acrylate polymer or copolymer. However, the solids content may also comprise amino (meth) acrylate polymers or copolymers and other excipients. Liquid, non-evaporative excipients having a boiling point greater than 100 ℃ should be considered to be in the solid phase. The aqueous phase and solids typically or substantially add up to 100%. The presence of carbon dioxide/carbonic acid in the medium or in the aqueous phase is negligible in the calculations.

Viscosity of the oil

The aqueous medium of the invention may be characterized in that the viscosity of the medium is 5-150, preferably 5-40, most preferably 8-15 mpa.s. In this viscosity range, the aqueous medium according to the invention can be used very well for spraying or as a binding solution or dispersion. Less preferred but also possible, especially when the solution is to be used as a binder, the viscosity may be much higher, e.g. more than 150 to 10,000 mpa.s. The viscosity may be according to ISO 3219: 1993-Plastics-Polymers/resins in the liquid state or as emulsions or dispersions with defined shear rate (Plastics-liquid or Polymers/resins in the form of emulsions or dispersions-determined using a rotational viscometer).

Carbon dioxide content/pH value

The aqueous phase is charged with a sufficient amount of carbon dioxide which renders the amino (meth) acrylate polymer or copolymer soluble or present in solute form in the medium due to the interaction between the carbon dioxide/carbonic acid/bicarbonate in the aqueous phase and the amino groups of said polymer or copolymer. "foot" shall mean sufficient or more.

The amount of carbon dioxide that must be added to make the amino (meth) acrylate polymer or copolymer soluble in the aqueous phase and the pH range in which the amino (meth) acrylate polymer or copolymer remains stable in the solute state depend on the amino (meth) acrylate polymer or copolymer itself. Factors influencing the solubility properties may be mainly the concentration of the polymer or copolymer and its overall monomer composition, in particular the amount of monomers having amino groups. Other factors such as molecular weight may also have an effect on solubility. However, with the knowledge of the present invention, the skilled person can easily adapt the appropriate amount of carbon dioxide that has to be added to the aqueous phase to render the different amino (meth) acrylate polymers or copolymers soluble, based on the following balance, and can find a suitable pH range in which certain amino (meth) acrylate polymers or copolymers remain stable in the solute state based on the balance described below:

the equilibrium constant for hydration at 25 ℃ is K_h＝1.70×10^-3: thus, most of the carbon dioxide is not converted to carbonic acid and remains as CO₂A molecule. In the absence of catalyst, equilibrium is reached rather slowly. Rate constant for forward reaction (CO)₂+H₂O→H₂CO₃) Is 0.039s^-1For the reverse reaction (H)₂CO₃→CO₂+H₂O) is 23s^-1. Carbonic acid is used for making soda (e.g., soda water) and the like.

Pure carbonic acid solution (or pure CO) at a given temperature₂Solution) is determined entirely by the partial pressure of carbon dioxide above the solution. To calculate this composition, the three different carbonate forms (H) must be considered₂CO₃、HCO₃ ^-And CO₃ ^2-) The above equilibrium between, and dissolved CO₂And H₂CO₃Has a constant K between_h＝[H₂CO₃]/[CO₂](see above) equilibrium of hydration, and dissolved CO₂And gaseous CO above the solution₂The following balance between:

wherein k is at 25 DEG C_H29.76atm/(mol/L) (Henry constant)

The corresponding equilibrium equation together with the relation and neutral condition results in a corresponding equation for six unknowns CO₂]、[H₂CO₃]、[H⁺]、[OH^-]、[HCO₃ ^-]And [ CO ]₃ ^2-]Six equations were obtained, indicating that the composition of the solution was completely determined. For [ H ]⁺]The equation obtained is cubic, and its numerical solution yields the following pH values and different species concentrations:

● it is seen that in the total pressure range, the pH is always well below the pKa₂So that CO is present₃ ^2-Concentration versus HCO₃ ^-The concentration is always negligible. In fact, CO₃ ^2-No quantitative role was played in this calculation (see comments below).

● for the passage of time, the pH is close to one of the pure waters (pH 7) and the dissolved carbon is essentially in HCO₃ ^-Form (a).

● for normal atmospheric conditions, a slightly acidic solution (pH 5.7) is obtained and the dissolved carbon is now essentially CO₂Form (a). From this pressure, [ OH ]^-]Becomes so negligible that the ionized portion of the solution is now H⁺And HCO₃ ^-An equimolar mixture of (a).

● typical for CO in soda drink bottles₂Pressure (about 2.5atm) to obtain a dissolved CO with a high concentration₂The more acidic medium (pH 3.7). These characteristics contribute to the sour and sparkling taste of these beverages.

Between 2.5 and 10atm, the pH value exceeds the pKa₁Value (3.60), while producing the predominant H at high pressure₂CO₃Concentration (relative to HCO)₃ ^-)。

A sufficient amount of carbon dioxide to render the amino (meth) acrylate polymer or copolymer soluble or present in solute form in the medium can be defined as at least sufficient to convert the amino (meth) acrylate polymer or copolymer from a dispersed state to a dissolved state when present in water. As a rough rule, an aqueous medium charged with carbon dioxide at 25 ℃ under atmospheric conditions (1 bar) contains sufficient carbonic acid to make the dispersed polymer soluble. The dissolved state is reached when the turbid dispersion has become clear and is stable at room temperature (approximately 25 ℃) and atmospheric pressure (1 bar) in the range of pH 5.5 to pH 8.0, pH 6.0 to pH 7.5, pH 6.7 to pH 7.4, pH 6.8 to pH 7.3.

As a rough rule, demineralized water which has been charged with carbon dioxide at 25 ℃ under atmospheric conditions contains a sufficient amount of carbonic acid when its pH value is between 4.0 and 5.5. In this state, carbon dioxide should be sufficiently charged into water to form an amino (meth) acrylate polymer or copolymer (EUDRAGIT) composed of polymerized units of 25% by weight of methyl methacrylate, 25% by weight of butyl methacrylate and 50% by weight of dimethylaminoethyl methacrylateE) Upon dissolution in water, at least 25% by weight of the copolymer is converted to become soluble.

Even more carbon dioxide can be charged into the water under pressure, for example 2-10 bar, so that a pH of about pH 3.5 can be reached. In this state, even higher amounts of up to 40% of the amino (meth) acrylate polymer or copolymer may be converted to become a solute in water.

When the amino (meth) acrylate polymer or copolymer is added to the feed water with agitation and becomes a solute, the pH increases and may be in the range of, for example, 5.5-8.0.

For example, when the amino (meth) acrylate polymer or copolymer consists of polymerized units of 20 to 30% by weight of methyl methacrylate, 20 to 30% by weight of butyl methacrylate and 60 to 40% by weight of dimethylaminoethyl methacrylate (EUDRAGIT)E-type), preferably the amino (meth) acrylate polymer or copolymer consists of polymerized units of 25% by weight of methyl methacrylate, 25% by weight of butyl methacrylate and 50% by weight of dimethylaminoethyl methacrylate (EUDRAGIT)E) When it is present in the medium in an amount of 12-22 wt.%, preferably 15 wt.%, and the medium is clarified from a pH of 6.7 to 7.3, preferably a pH of 6.8 to 7.2, a sufficient amount of carbon dioxide in the water may be present.

When the amount of carbon dioxide in water is reduced to a critical value due to the continuous discharge of carbon dioxide into the ambient air, it is presumed that the amount of neutralized amino groups in the amino (meth) acrylate polymer or copolymer becomes too low to maintain the amino (meth) acrylate polymer or copolymer in a dissolved state. This can be observed and indirectly characterized by an increase in the pH of the medium above a critical value. In particular cases, the critical pH range of the medium may be between pH 7.2 and 7.3. When the pH of the medium exceeds these values, the medium becomes increasingly turbid and the amino (meth) acrylate polymer or copolymer becomes insoluble and precipitates.

Amino (meth) acrylate polymers or copolymers

The carbonated aqueous medium may contain up to 40 wt%, up to 30 wt%, up to 25 wt% of the amino (meth) acrylate polymer or copolymer. From a practical point of view, a polymer or copolymer content of 12 to 22% by weight is quite suitable for handling, in particular for spraying.

The amino (meth) acrylate polymer or copolymer is preferably composed of C of acrylic acid or methacrylic acid₁-C₄-a copolymer of polymerized units of an alkyl ester and an alkyl (meth) acrylate monomer having a tertiary amino group in the alkyl group.

The carbonated aqueous medium preferably comprises or essentially comprisesOr C containing from 30 to 80% by weight of acrylic acid or methacrylic acid₁-C₄An amino (meth) acrylate copolymer consisting of polymerized units of an alkyl ester and 70 to 20% by weight of an alkyl (meth) acrylate monomer having a tertiary amino group in the alkyl group.

The carbonated aqueous medium preferably comprises or essentially comprises or contains an amino (meth) acrylate copolymer consisting of polymerized units of 20 to 30 wt.% methyl methacrylate, 20 to 30 wt.% butyl methacrylate and 60 to 40 wt.% dimethylaminoethyl methacrylate.

Amino (meth) acrylate copolymers

The copolymer component (a) may be a so-called "aminomethacrylate copolymer (USP/NF)", "basic butylated methacrylate copolymer (Ph. Eur)" or "aminoalkyl methacrylate copolymer E (JPE)", which are EUDRAGITAnd E type. The amino (meth) acrylate polymer or copolymer is preferably EUDRAGITA type E copolymer. Suitable (meth) acrylate copolymers are known, for example, from EP 0058765B 1.

The amino (meth) acrylate copolymer may be, for example, C of acrylic acid or methacrylic acid polymerized from 30 to 80% by weight of free radicals₁-C₄-alkyl esters and 70-20 wt% of (meth) acrylate monomers having a tertiary amino group in the alkyl group.

Suitable monomers having a functional tertiary amino group are described in detail in US 4705695, column 3, line 64 to column 4, line 13. Mention should be made in particular of dimethylaminoethyl acrylate, 2-dimethylaminopropyl acrylate, dimethylaminopropyl methacrylate, dimethylaminobenzyl acrylate, dimethylaminobenzyl methacrylate, (3-dimethylamino-2, 2-dimethyl) propyl acrylate, (dimethylamino-2, 2-dimethyl) propyl methacrylate, (3-diethylamino-2, 2-dimethyl) propyl acrylate, (diethylamino-2, 2-dimethyl) propyl methacrylate and diethylaminoethyl methacrylate.

Dimethylaminoethyl methacrylate is particularly preferred.

The content of monomers having tertiary amino groups in the copolymer can advantageously be between 20 and 70% by weight, preferably between 40 and 60% by weight. C of acrylic acid or methacrylic acid₁-C₄The proportion of alkyl esters is 70 to 30% by weight. Mention should be made of methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate.

Suitable amino (meth) acrylate copolymers can be obtained, for example, by polymerization of 20 to 30% by weight of methyl methacrylate, 20 to 30% by weight of butyl methacrylate and 60 to 40% by weight of dimethylaminoethyl methacrylate.

Particularly suitable commercial amino (meth) acrylate copolymers are formed, for example, from 25% by weight of methyl methacrylate, 25% by weight of butyl methacrylate and 50% by weight of dimethylaminoethyl methacrylate (EUDRAGIT)E100 or EUDRAGITE PO (powder form)). EUDRAGITE100 and EUDRAGITE PO is water soluble below about pH 5.0 and is therefore also soluble in gastric juice.

Excipient

The medium may contain water, carbon dioxide (carbon dioxide/carbonic acid/bicarbonate) and amino (meth) acrylate polymers or copolymers alone or may contain additional excipients commonly used in the pharmaceutical or nutraceutical or cosmetic field. These types of excipients are well known to those skilled in the art, but are not critical to the present invention.

It goes without saying that excipients which, due to their chemical nature or due to their concentration, can chemically interact with the amino (meth) acrylate polymer or copolymer and thus hinder the solubility of the amino (meth) acrylate polymer or copolymer should be excluded. Such undesirable chemical interactions may further hinder taste masking or moisture prevention effects. Of course, amino (meth) acrylate polymers or copolymers are not excipients in the sense of the present invention. Carbon dioxide is, of course, not an excipient in the sense of the present invention. However, polymers or copolymers other than amino (meth) acrylate polymers or copolymers may be used as excipients, as long as they are not critical to the present invention in the above-described sense. Anionic polymers or anionic (meth) acrylate copolymers that may interact with the amino (meth) acrylate polymer or copolymer may be excluded.

The carbonated aqueous medium is characterized in that it may contain excipients commonly used in pharmaceutical, nutraceutical or cosmetic products.

Preferably, the excipient is selected from the group consisting of antioxidants, whitening agents, flavoring agents, flow aids, fragrances, glidants (spacers), permeation enhancers, pigments, plasticizers, polymers, pore formers or stabilizers or combinations thereof.

The term "pharmaceutical, nutraceutical or cosmetic vehicle" is well known to those skilled in the art. Many excipients are commonly used in pharmaceutical, but also in the field of nutraceuticals or cosmetics, occasionally they are also referred to as conventional additives. Of course, all excipients or conventional additives employed must always be toxicologically acceptable and can be used in particular in foodstuffs or pharmaceuticals without risk to the consumer or patient.

Although the requirements are generally higher in the pharmaceutical field, there is a wide overlap of excipients for pharmaceutical purposes and those for nutraceutical or cosmetic purposes. In general, all pharmaceutical excipients can be used for nutraceutical or cosmetic purposes and at least many nutraceutical excipients also allow for pharmaceutical purposes. Excipients may be added to the formulations of the present invention, preferably during the manufacture of the granules or the mixing of the powders.

For practical reasons, pharmaceutical, nutraceutical or cosmetic excipients may be included, for example to avoid stickiness or to add colour. However, these excipients generally do not contribute or show little or no effect on the invention claimed herein itself. They can be used as processing aids and aim to ensure a reliable and reproducible preparation process and good long-term storage stability, or they achieve additional advantageous properties in pharmaceutical dosage forms. They are added to the polymer formulation prior to processing and may affect the permeability of the coating. This property can be used as an additional control parameter if necessary. Of course, all kinds of excipients used must of course be toxicologically safe and used in cosmetics, nutraceuticals or pharmaceuticals without risk to the consumer or patient.

Glidant/release agent:

release agents generally have lipophilic properties and are typically added to the spray suspension. They prevent agglomeration of the core during film formation. Preference is given to using talc, stearates of Mg or Ca, ground silica, fused silica, kaolin or nonionic emulsifiers having an HLB value of from 3 to 8. Preferred is Glycerol Monostearate (GMS). If the excipient is a glidant, it may be present in a concentration of 1 to 100% by weight, preferably 5 to 15% by weight, based on the amino (meth) acrylate polymer or copolymer.

Pigment:

pigments are only rarely added in soluble form. Usually, the oxide pigments of aluminum oxide or iron are used in dispersed form. Titanium dioxide is used as a whitening pigment. If the excipient is a pigment, it may be contained at a concentration of up to 200% by weight, based on the amino (meth) acrylate polymer or copolymer.

Plasticizer

The plasticizer effects a reduction in the glass transition temperature and promotes film formation via physical interaction with the polymer of the polymer mixture, depending on the amount added. Suitable materials typically have a molecular weight of 100-.

Examples of suitable plasticizers are alkyl citrates, glycerol esters, alkyl phthalates, alkyl sebacates, sucrose esters, sorbitan esters, diethyl sebacate, dibutyl sebacate and polyethylene glycols from 200 to 12000. Preferred plasticizers are triethyl citrate (TEC), acetyl triethyl citrate (ATEC), diethyl sebacate and dibutyl sebacate (DBS). Esters which are normally liquid at room temperature, such as citrates, phthalates, sebacates or castor oil, should also be mentioned. Esters of citric acid and sebacic acid (sebinic acid) are preferably used. C is added in a concentration of 5 to 25% by weight, preferably 5 to 15% by weight, based on the amino (meth) acrylate polymer or copolymer₁₂-C₁₈Monocarboxylic acids, particularly stearic acid, appear to reduce water vapor permeability.

The addition of the plasticizer to the formulation can be carried out in a known manner, either directly in aqueous solution or after thermal pretreatment of the mixture. Mixtures of plasticizers may also be employed. If the excipient is a plasticizer, it may be contained in a concentration of up to 50% by weight, preferably 2 to 25% by weight, based on the amino (meth) acrylate polymer or copolymer.

Most preferably, triethyl citrate, dibutyl sebacate and/or stearic acid are contained.

Plasticizers, such as triethyl citrate, dibutyl sebacate, may be included in relatively low amounts of 0.5-10 or 1-5% by weight.

Storage of

In order to avoid the risk that the solute amino (meth) acrylate polymer or copolymer becomes insoluble again and precipitates, the emission or disappearance of carbon dioxide from the aqueous medium should be prevented. Thus, the carbonated aqueous medium may preferably be stored in an open or closed container under a carbon dioxide atmosphere. Preferred containers are made of polymeric materials or metals to avoid carbon dioxide diffusion or leakage. Preferred containers are made of polyethylene, polypropylene or polyethylene terephthalate. In such a container, the aqueous medium of the invention can be stored in a stable form for up to several months or even longer without precipitation of the amino (meth) acrylate polymer or copolymer taking place. If the container is opened, the contained medium can generally be used in a stable form for further coating or bonding processes for at least several hours. If the remaining medium remains in the container, it is advisable to add carbon dioxide gas before closing again and storing it.

Method of producing a composite material

The invention discloses a method for preparing carbonated aqueous medium, which comprises the following steps: charging carbonic acid into the aqueous phase and dissolving therein an amino (meth) acrylate polymer or copolymer which is insoluble in pure water but soluble in the carbonic acid-charged water.

The method may be characterized by: the aqueous phase is charged with carbonic acid up to the saturation point by contacting the carbonic acid in gaseous form with water under atmospheric conditions or at a pressure of up to 10, preferably 2-8 bar. Suitable processing temperatures may be in the range of 10-60 ℃.

The method may be characterized by: the aqueous phase was carbonated to the saturation point as follows: the carbonic acid in gaseous form is brought into contact with the aqueous phase in a pressure reactor at a pressure of 100-1000 mbar, the pressure is reduced to normal conditions and subsequently the amino (meth) acrylate polymer or copolymer is dissolved in the carbonated aqueous phase with stirring until the polymer or copolymer is completely dissolved.

Use/application

The present invention discloses the use of an aqueous medium comprising an amino (meth) acrylate polymer or copolymer as a coating or binding solution for spraying or binding a pharmaceutical composition, preferably a pharmaceutical composition containing an active ingredient in the form of pellets, granules, mini-tablets, tablets or capsules, or a nutraceutical or cosmetic composition. Use as a coating solution should include use as a sub-coating or top-coating in combination with other coatings.

Nutritional product

Nutraceuticals may be defined as food extracts that are required to have a medical effect on human health. Nutraceuticals are usually contained in a prescribed dose in a medical form such as capsules, tablets or powders. Examples of nutraceuticals are resveratrol from grape products as antioxidant, soluble dietary fibre products such as flaxseed shells for reducing hypercholesterolemia, broccoli (sulfane) as cancer protective agent and soybean or clover (isoflavonoids) for improving arterial health. Other examples of nutraceuticals are flavonoids, antioxidants, alpha-linoleic acid from linseed, beta-carotene from marigold petals or anthocyanin from berries. Sometimes, the expression "nutraceuticals" is used synonymously with nutraceuticals.

Cosmetic preparation

Cosmetics are substances used to enhance or protect the appearance or odor of the human body. Typical cosmetic active ingredients may include vitamins, phytochemicals, enzymes, antioxidants and essential oils. Cosmetics may include skin care creams, lotions, powders, perfumes, lipsticks, fingernail and toenail polishes, eye and face cosmetics, permanent waving agents, colored contact lenses, hair dyes, hair sprays and gels, deodorants, baby products, bath oils, bubble baths, bath salts, butter, and many other types of products. Their use is common, particularly among women, but also by men. A sub-group of cosmetics is called "make-up", which mainly refers to colored products intended to change the appearance of the user. Many manufacturers differentiate decorative cosmetics from care cosmetics. The term "cosmetic" shall include both topical application forms, such as the so-called cosmeceuticals, and oral ingestion forms, such as the so-called nutritional cosmetics.

Detailed Description

Examples

The copolymer used: EUDRAGITE and EUDRAGITE PO

EUDRAGITE is a copolymer consisting of 25% by weight of methyl methacrylate, 25% by weight of butyl methacrylate and 50% by weight of dimethylaminoethyl methacrylate. EUDRAGITE is in the form of particles. EUDRAGITThe E PO is in powder form.

Example 1 (E1): carbonating EUDRAGITSmall laboratory scale manufacture of E solution under Normal conditions

465g of water are poured into a1 liter PE beaker. After 15g of TEC was dissolved in water at 1000Rpm using a conventional stirrer with dissolver plate (diameter: 5 cm). Using an Ultra Turrax disperse 75g EUDRAGIT at 22,000rpmE100 granule (1-3mm diameter) for 5 min. Then, 3.5g of polydimethylsiloxane (simethicon) dispersion (5%) was added, and finally 600g of water was added. The dispersion was carbonated over the liquid under normal conditions, temperature (25 ℃) and pressure (1013 mbar) for 24h, with stirring at 500rpm using a conventional stirrer with a dissolver plate. A weakly turbid solution was obtained. Containing 12.5% EUDRAGITThe viscosity of the solution of E (amount before carbonation) was 5.6mPa s at 25 ℃. The pH of the freshly prepared carbonated solution was 6.75. The solution was filled in 1 liter polyethylene terephthalate (PET) bottles with polyethylene stoppers.

Example 2 (E2): carbonating EUDRAGITModerate-scale (20% -wt.) manufacture of E solution under pressure

2.4kg of water was poured into a 5 l beaker. 600g of EUDRAGIT were then dispersed during 15min at 2000rpm using a conventional stirrer with a dissolver plate (diameter: 5cm)And E PO. 3kg of the suspension are poured with CO₂Supplied 6.4 liter stainless steel reactor. The reactor was closed and the CO was maintained at 5.0 bar₂The paddle stirrer was set at approximately 150rpm under pressure. After 15 minutes the rotation speed was increased up to about 350 rpm. During the entire process time (about 7h), CO is introduced every half hour₂The pressure was adjusted to about 5 bar (minimum pressure was 3.6 bar). The final product was a clear, slightly viscous yellowish solution. Subsequently, the pressure was reduced to atmospheric pressure (about 2 hours), and the product was poured into 1 liter PET bottles. The final yield was 2800g of 20 wt.% EUDRAGITE, solution. The pH was 6.8 and the viscosity was 14mPa · s at 25 ℃.

Example 3 (E3): carbonating EUDRAGITModerate-scale (30% -wt.) manufacture of E solution under pressure

2.8kg of water are poured with CO₂Supplied to a 6.4 liter reactor. Then, 1.2kg of EUDRAGIT were added with stirring at 300rpm with a paddle stirrer (7cm diameter)And E100. The reactor was closed and the paddle stirrer was set to about 550rpm and the CO was added₂The pressure was set to 5.0 bar. CO was added every half hour during the entire process time of 6h at 25 deg.C₂The pressure was adjusted to 5 bar (minimum pressure was 3.4 bar). Subsequently, the pressure was reduced to atmospheric pressure (about 1 hour), and the product was poured into 1 liter PET bottles. The bottle was immediately closed due to foam formation. The final yield was 3.5 kg. The viscosity was 138 mPas at 23 ℃.

Example 4 (E4): EUDRAGIT of E2 and E3Comparison of pH values of E-carbonatate solutions

The solutions of E2 and E3 were filled into 30ml glass bottles closed with screw caps. Obtaining 10% w/w EUDRAGIT by diluting a 20% E2 solution with waterE carbonatate solution. At each measurement time, the sampling flask was opened for no more than 3min and the pH electrode was immersed in the open solution with moderate stirring. During storage in a refrigerator at 2-8 ℃, no precipitation was observed. However, EUDRAGIT is observed after the pH reaches a value of about 7.3 to 7.5 or moreE, precipitation of particles. Whenever the sampling bottle is opened for measurement, a slight overpressure can be visually identified (sounding like the opening of a soda bottle), which indicates a small amount of CO₂Release from solution. The results are described in table 1. The higher the concentration of polymer, the lower the pH at which the first indication of precipitation of polymer can be identified.

TABLE 1

Dry particles were found in the solution, the majority of the solution remained clear

Example 5 (E5): the actual approach is as follows: EUDRAGIT in an open containerViscosity measurement and pH of E-carbonate solutions

Under practical conditions, such as those used in spray applications, it is common practice to soak the spray solution from an open container, typically from a bottle, for about 2-4 hours. Thus, if EUDRAGITThe E-carbonate solution remained stable in the open bottle container with no sign of precipitation for 4 hours, and it should be tested.

200g of 20% (w/w) EUDRAGIT from example 2The E-carbonatate solution was poured into a 250ml glass bottle that was left open, as typically occurred during the coating test. A pH electrode connected to a pH meter and a temperature sensor were inserted into the liquid and stirred using a stirrer equipped with a dissolver plate (diameter 3cm) at approximately 540rpm (500-The pH was measured and maintained for 4 h. 20ml samples were collected in parallel and used at 25 ℃ and 100s using a rotational viscometer^-1At a shear rate of (c). 20% EUDRAGITThe viscosity of the E-carbonator solution tends to decrease by evaporation of carbon dioxide, resulting in a higher pH. However, no sign of precipitation could be identified, which is consistent with a pH of 7.12 after 4 hours, which is below the expected precipitation point of about 7.3. The results are described in table 2.

TABLE 2

Time, min	0	60	120	180	240
						Viscosity, mPas	11.80	10.21	8.69	8.43	8.06
pH	6.80	6.91	6.97	7.04	7.12

Comparative example 6 (C6): organic EUDRAGITProduction of E100 solution

3.400g of acetone, 5.100g of isopropanol and 250g of water were poured into a 15 l stainless steel vessel and stirred at room temperature using a conventional paddle stirrer (diameter 8 cm). Dividing into several portions and adding 1.250g EUDRAGITE100 is added to the solvent mixture. The stirring intensity was adjusted to avoid sedimentation of undissolved granules. After about 45 minutes, the solid material turned into a clear yellowish solution. The polymer content was 12.5%. The viscosity was 12 mPas (25 ℃).

Comparative example 7 (C7): containing EUDRAGITProduction of an aqueous Dispersion of EPO, stearic acid and sodium lauryl sulfate (so-called Standard formulation)

1416g of water were poured into a 3 liter beaker and 20g of SDS were added by setting the stirring speed at approximately 5900rpm using a rotor-stator dispersion unit, followed by 30g of stearic acid. After 1 minute of stirring, 200g of E PO were gradually poured in and the dispersion was allowed to mix properly: the speed was first increased to about 6500rpm until about 7400rpm was reached. Once the dispersion appeared homogeneous, it was stirred for a further 30 minutes: once foam formation begins to increase, the speed is reduced to avoid too much foam. The dispersion was allowed to stand until the foam disappeared (about 4 hours). The solids content of the dispersion was 15%, the yield was 100%, the pH of the solution was 9.3, and the viscosity of the yellowish/greenish milky dispersion was 10mPa s (25 ℃).

Example 8 (E8): comparison of Water vapor Permeability of membranes made from solutions of E2 and C6

EUDRAGIT 56.25g E2The carbonated solution was mixed with 1.13g of water and 2.5% by weight (0.28g) of triethyl citrate (TEC) with stirring with a conventional stirrer at 200rpm for 25min, based on the polymer. A clear yellowish solution with a pH of 6.8 is obtained.

2.5 wt% (0.313g) TEC, based on polymer, was dissolved in 100g C6 of organic solution. These two solutions were stable for several weeks without precipitate formation and formed transparent flexible films after drying. The water vapour permeability values of the two formulations were measured and found to be comparable (E2: 342+/-22 and C6: 324+/-23 g/m)²/d)。

The water vapour permeability of the membrane can be analysed by measuring the diffusion of water vapour through the polymer membrane according to the gravimetric water vapour permeability method described in DIN 53122. The humidity at 23 ℃ selected is 85% relative humidity according to DIN 53122, climate D as described in section 8.2.

Example 9 (E9): addition of stearic acid to EUDRAGIT from E2Effect of the Water vapor Permeability of membranes made from E-carbonatate solutions

25.13g of water was added to 56.25g E2 of EUDRAGITIn a carbonated solution. Then, 1.13g stearic acid (10 wt%, based on polymer) was added and dissolved with stirring at 900rpm for about 1h, i.e. until a clear yellowish coloration with a pH of 7.1 was observedThe color solution and after drying a transparent flexible film was formed. The water vapor permeability of the dry film is reduced to 227+/-12g/m in comparison with the film obtained in E8²/d。

Comparative example 10 (C10): EUDRAGIT from C7 (Standard formulation) with the addition of TECWater vapor permeability of membranes made from E dispersions

Based on the polymer, 2.5% TEC was added to the dispersion made as described in C7. 30g were dried on a glass plate at room temperature. After drying overnight, a milky white flexible film was obtained. The water vapor permeability of the membrane was 229+/-24g/m²/d。

Example 11 (E11): sedimentation and redispersion tests in the presence of 10% by weight of the glidant Glycerol Monostearate (GMS)

The addition of glidants such as GMS is important in practical terms to avoid stickiness. However, it is well known that glidants can cause undesirable side effects such as phase separation followed by settling or floating. These undesirable effects may be more or less harmless if the sediment can be redispersed. Therefore, EUDRAGIT of E2 should be testedThe stability of the carbonate solution to sedimentation in the presence of GMS and if sedimentation is to occur, whether such sedimentation can be redispersed.

20.79g of water and 0.15g of Tween were added80 (4% by weight, based on the polymer) are dissolved in a 250ml bottle (A), the top is covered with aluminum foil and the solution is heated up to 70 ℃ with magnetic stirring (600 rpm). Subsequently, 0.38g of GMS (10% by weight, based on the polymer) was added and the stirring speed was increased up to 900rpm, while the dispersion was slowly cooled.

37.5g of EUDRAGIT manufactured in E2The E carbonate solution was poured into another bottle (B) together with 0.19g TEC (2.5 wt% based on polymer) and, once closed, stirred at 600rpm for 10 min. Then, 0.75g stearic acid (10 wt%, based on polymer) was added with stirring at 900rpm for about 1h, i.e. until a clear yellowish solution was observed.

Glycerol-containing monostearate/Tween Once obtained from bottle A80 at a temperature of between 20 and 30 ℃ and mixing it with EUDRAGITThe E bicarbonate solution was poured together into bottle B and stirred at 700rpm for 1 hour. The pH of the white, turbid, fine dispersion obtained was 6.93.

After 1 week, the dispersion (containing 10% glycerol monostearate) showed slight phase separation, but no settling. This slight phase separation disappears after redispersion by simple inversion of the bottle.

Example 12 (E12): sedimentation and redispersion tests in the presence of 5% by weight of the glidant Glycerol Monostearate (GMS)

E12 was carried out in the same manner as in example E11, except that 5% by weight of GMS was used. After 24 hours, the dispersion (containing 5% by weight of glycerol monostearate) showed phase separation with slight settling. After redispersion by multiple switching of the bottles, the phase separation and sedimentation disappeared.

Example 13 (E13): use of EUDRAGIT containing GMS and TEC on bitter quinidine sulfate pelletsCoating test of E-carbonate solution

EUDRAGIT-containing pellets were produced as described in example E11Spray dispersions of E carbonate solution, GMS and TEC, except that stearic acid and Tween were absent80. Using a conventional fluidized bed coating system with a bottom spray device, 100g of quinidine sulfate pellets (1 mm to 1.2mm in diameter) were sprayed with 7.5% EUDRAGITE (on a dry matter basis). The parameters are listed in table 3. The final weight of the obtained free-flowing pellets was 106.65g, corresponding to a theoretical yield of 98.7%. As a result, in the absence of stearic acid and Tween80, a smooth coating is obtained. The taste of the coated pellets is neutral.

TABLE 3

Batch size [ g ]]	100
		Air flow [ m ]3/h]	15
Pressure of atomization [ bar ]]	0.5
		Microclimate [ Bar ]]	0.4
Spraying time [ min ]]	25
		Inlet air temperature of [ deg.C]	41-47
The temperature of the product is [ deg.C]	26-32
		Temperature of discharged air [ ° c]	28-29
Humidity of discharged air [% ]]	18-50
		Pump scale [ rpm ]]	2.5-6.5
Spraying rate [ g/min ]]	1.0-2.7

Comparative example 14 (C14): containing EUDRAGITEUDRAGIT of EPO HCl and TECPreparation of E solution

50g of water are poured into a beaker and 15g of EUDRAGIT are addedE PO while stirring with a paddle stirrer at 800 rpm. During stirring, 0.375g of TEC (2.5% based on the polymer) was added. Once the dispersion appeared homogeneous, 20g of 1 mole hydrochloric acid (HCl) were added and they were all stirred at the same speed for another 40 minutes. At the end a slightly yellowish turbid solution was observed. The pH of the solution was 6.7 and 6g of HCl 1M were added again in order to further neutralize EUDRAGITE; then 10g of water was also poured to reach the amount of 100g of solution. After stirring at 600rpm for 3min, the final pH of the obtained yellowish and clear solution was 6.6. The film made from this solution is transparent and flexible and again soluble in distilled water. The film material had an unpleasant bitter-like taste after 1 minute.

Example E15: from EUDRAGITE-carbonatate manufacturing film

30g EUDRAGIT with 2.5% TEC added, manufactured as in example E2E hydrogen carbonate. The solution was dried on a glass plate at room temperature overnight. The film is transparent, flexible and insoluble in distilled water. The taste of the membrane material after drying has a neutral taste.

Example E16: EUDRAGIT coated with the coating obtained from examples E2, E9, C6 and C7Theophylline pellets of the dispersion/solution of E were compared for theophylline release according to the pharmacopoeia at pH 6.8.

With EUDRAGIT from examples E2, E9, C6 and C7E Dispersion/solution, examples13 the coated pellet. Carrying out different EUDRAGIT's in a dissolution testing apparatus according to USP apparatus 2E dissolution test of coated theophylline pellets. 150mg of each sample was added to a 900ml glass container containing 700ml of 0.1M HCl. The liquid was stirred at a blade speed of 150rpm and at 37 ℃. Dissolution in buffer pH 6.8, n-3 was also analyzed using the same equipment conditions. The collected samples were analyzed at 270nm using an on-line UV-photometry. All pellet formulations showed 100% theophylline release after a maximum of 10 minutes at 37 ℃ in 0.1M HCl.

The results of theophylline release at a buffer pH of 6.8 are described in table 4. E9 and C7 show similar rapid release behavior (see e.g. 60min values). This is significant because the water vapor permeability value of the dry film of E9 is only 227g/m²And d. Thus, stearic acid is directed to EUDRAGITThe addition of the E-carbonator solution combines rapid active ingredient release with low water vapor permeability. C6 (organic solution) showed the slowest release. E2 is in between.

Table 4: spray test on theophylline pellets

Description of the drawings: STA ═ stearic acid, SDS ═ sodium lauryl sulfate,% -% by weight%

Claims (14)

1. Aqueous medium comprising an amino (meth) acrylate polymer or copolymer which is not soluble in demineralised water, characterised in that the medium has a content of an aqueous phase of at least 60% by weight and a content of solids comprising the amino (meth) acrylate polymer or copolymer of at most 40% by weight, wherein the aqueous phase is charged with a sufficient amount of carbon dioxide which causes the amino (meth) acrylate polymer or copolymer to be present in the medium in the form of a solute, wherein the viscosity of the medium is from 5 to 150 mpa.s.

2. Aqueous medium according to claim 1, characterized in that the pH of the medium is 6.7-7.4.

3. Aqueous medium according to claim 1 or 2, characterized in that the amino (meth) acrylate polymer or copolymer content is 10 to 20% by weight.

4. Aqueous medium according to claim 1 or 2, characterized by containing pharmaceutical or nutraceutical excipients.

5. Aqueous medium according to claim 4, characterized in that the pharmaceutical or nutraceutical excipient is selected from the following classes: antioxidants, whitening agents, coloring agents, flavoring agents, glidants, permeation enhancers, plasticizers, pore formers, or stabilizers.

6. Aqueous medium according to claim 5, characterized by containing triethyl citrate and/or stearic acid.

7. Aqueous medium according to claim 1 or 2, characterized in that the amino (meth) acrylate polymer or copolymer consists of 30 to 80% by weight of C of acrylic or methacrylic acid₁-C₄-polymerized units of an alkyl ester and 70-20 wt% of an alkyl (meth) acrylate monomer having a tertiary amino group in the alkyl group.

8. Aqueous medium according to claim 7, characterized in that the amino (meth) acrylate polymer or copolymer consists of polymerized units of 20 to 30% by weight of methyl methacrylate, 20 to 30% by weight of butyl methacrylate and 60 to 40% by weight of dimethylaminoethyl methacrylate.

9. Aqueous medium according to claim 1 or 2, characterized in that it is stored in a container under an atmosphere of carbon dioxide.

10. Aqueous medium according to claim 1 or 2, characterized in that it is stored in a container made of polyethylene or polyethylene terephthalate.

11. Process for the preparation of an aqueous medium according to any one of claims 1 to 10 by: charging carbonic acid into the aqueous phase and dissolving therein an amino (meth) acrylate polymer or copolymer which is insoluble in pure water but soluble in the aqueous phase charged with carbonic acid.

12. Process according to claim 11, characterized in that the aqueous phase is charged with carbonic acid up to the saturation point by contacting the carbonic acid in gaseous form with the aqueous phase at 25 ℃ and atmospheric conditions or at a pressure of up to 10 bar.

13. Process according to claim 11 or 12, characterized in that the aqueous phase is charged with carbonic acid up to the saturation point by: the carbonic acid in gaseous form is brought into contact with the aqueous phase in a pressure reactor at a pressure of 100-1000 mbar, said pressure is reduced to normal conditions, and subsequently the amino (meth) acrylate polymer or copolymer is dissolved in the carbonated aqueous phase with stirring until the polymer or copolymer is completely dissolved.

14. Use of an aqueous medium according to any one of claims 1 to 10 as a coating or binding solution for spraying or binding a pharmaceutical or nutraceutical or cosmetic composition in the form of pellets, granules, tablets or capsules.