WO2002003967A1

WO2002003967A1 - Film-coating composition based on cellulose derivatives and sugar alcohols

Info

Publication number: WO2002003967A1
Application number: PCT/IB2001/001168
Authority: WO
Inventors: Johannes Respondek
Original assignee: Societe dExploitation de Produits pour les Industries Chimiques SEPPIC SA
Current assignee: Societe dExploitation de Produits pour les Industries Chimiques SEPPIC SA
Priority date: 2000-07-07
Filing date: 2001-07-03
Publication date: 2002-01-17
Anticipated expiration: 2003-01-07
Also published as: DE10033023A1; AU2001267765A1

Abstract

The invention relates to a film-coating composition which comprises at least one cellulose derivative and at least one sugar alcohol. The film-coating composition is particularly suitable for producing coatings or coverings in the sector of pharmaceuticals, foodstuffs and agricultural products.

Description

Film-coating composition based on cellulose derivatives and sugar alcohols

The invention relates to a film-coating composition based on cellulose derivatives and sugar alcohols with which it is possible in particular to produce coatings or colorings in the sector of pharmaceuticals, foodstuffs and agricultural products.

Film formers are used, for example, for coating (also called "enveloping") solid pharmaceutical forms (e.g. tablets, capsules), foodstuffs (e.g. chewing gum, breakfast cereals), agricultural products (e.g. seed, fruits) and the like. A substrate onto which a film coating is applied is also referred to hereinafter as "core". Film formers are applied in dissolved or dispersed form to such a core, and a coherent film remains on the core after evaporation of the solvent or dispersant. The objectives pursued with the application of film coatings varies depending on the area of application. Film coatings on pharmaceutical forms are intended, for example, to provide temporary protection from the spatial surroundings and thus avoid adverse effects on the substrate, e.g. through atmospheric oxygen, moisture, light, heat or gastric juice. It is possible thereby, for example, to ensure controlled delivery of active ingredient by employing, where appropriate, a coating which is resistant to gastric juice and soluble in the small intestine and which protects the active ingredient and the pharmaceutical form from inactivation. In food technology, film coatings likewise have a protective function (e.g. suppression of penetration of moisture or loss of flavor). Besides the protective function it is also possible to confer on the core the color type of their appearance for their identification. It is also possible, for example, to mask an unpleasant or bitter taste.

Film formers commonly employed are polymers which are sprayed as solution or dispersant onto the core to be coated. One disadvantage of polymers is, however, that they generally lead even in very low concentrations to a high viscosity of the solution or dispersion and have high tackiness. It is therefore possible for processing problems to arise in the spraying step, so that the concentration of the polymeric film former in the coating solution or dispersion, and thus also the processing speed, must be reduced in order to produce a coherent, uniform film on the core.

In order to be able to employ coating dispersions with larger contents of film-forming solids than in conventional polymer coating systems, EP-A-0 551 700 describes a dry film-coating composition for use in the area of pharmaceuticals, foods, confectionery, agricultural feed products and the like, which comprises a dry mixture of a cellulose powder and lactose and contains where appropriate a plasticizer and/or a pigment. Partial replacement of the polymeric film former by f lactose makes it possible to adjust larger solids contents in aqueous coating suspensions, while the viscosity remains the same, resulting in shorter spraying times and thus lower production costs than with conventional polymer solutions. Further results of the inclusion of lactose are an improved adhesion of the film coating to the substrate, less absence of a coherent, uniform film on the substrate surface, an improved photostability of organic pigments and natural dyes and a reduced permeability to moisture. The use of lactose in film-coating compositions has the disadvantage, however, that this filler has moderate solubility in water and is virtually insoluble in ethanol and other organic solvents. In addition, lactose is often not completely inert because of the reactivity of its carbonyl group. Characteristic carbonyl reactions may lead to incompatibilities with certain active ingredients (e.g. amines) and instabilities (e.g. easy oxidizability, discolorations to Muillard reactions). Finally, lactose intolerance is found to be increasing in some population groups. It is therefore an object of the present invention to avoid the prior art disadvantages detailed above and provide an improved dry film coating composition which affords a solution or dispersion which has a high solids content without leading to a higher viscosity interfering with further processing (e.g. spray processes) and leads, after evaporation of the solvent or dispersant, to improved ad- hesion of the dry film coating to a core and to an increase in the photostability of added colored pigments and/or dyes.

This object is achieved by a film-coating composition which comprises a) at least one cellulose derivative and b) a least one sugar alcohol. The film-coating composition of the invention preferably comprises, based on its final composition, a) 14 to 54 % by weight of cellulose derivative. b) 14 to 54 % by weight of sugar alcohol and c) where appropriate, other conventional additions.

The film-coating composition of the invention particularly comprises, based on its final composition, a) 25 to 40 % by weight of cellulose derivative, b) 20 to 40 % by weight of sugar alcohol, where a mass content of the cellulose derivative of from 28 to 35 % by weight and a mass content of the sugar alcohol of from 25 to 35 % by weight is most preferred. Said cellulose derivatives a) are cellulose derivatives acceptable in film- coating compositions. Examples thereof are methylcellulose, ethylcellulose, hy- droxymethylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxyethylmethylcellulose (HEMC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (Na-CMC), carboxymethyl- sulfoethylcellulose, hydroxyethylmethylcarboxymethylcellulose and cellulose acetate phthalate. Hydroxypropylmethylcellulose (HPMC), methylcellulose, hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC) or mixtures thereof are preferred. Preferred cellulose derivatives are those whose 2% by weight aqueous solutions have a viscosity (rotational viscometer, determined by the German Pharmacopeia method) of from 1 to 100 mPa-s, in particular from 3 to 50 mPa-s, and the most preferred cellulose derivatives have a solution viscosity (2% by weight aqueous solution) of from 5 to 20 mPa-s. Examples thereof are the hydroxypro- pylmethylcellulose (HPMC) currently available under the proprietary name Phar- macoat 606 (6 mPa-s) and Pharmacoat 615 (15 mPa-s) or the methylcellulose currently available under the proprietary name Methocel A 15 (15 mPa-s).

The sugar alcohols b) mentioned are, for example, sugar alcohols acceptable in the pharmaceutical, cosmetic or foodstuffs sector, with preference for sor- bitol, mannitol, maltitol, xylitol, lactitol, isomalt (Palatinit^®) or mixtures thereof.

The film-coating composition of the invention preferably comprises, based on its final composition, as further conventional additions c) to 40% by weight of plasticizer, i particular from 5 to 25 % by weight, with a mass content of from 5 to 20 % by weight being most preferred. It is possible to employ for this any plasti- cizer customary in film-coating compositions. Those preferably used are polyethylene glycol (PEG), polypropylene glycol (PPG), glycerol, ethylene glycol, propyl- ene glycol, miglylol, glycerol triacetate, triethyl citrate, liquid paraffin or mixtures thereof.

Preferred polyethylene glycols (PEG) and polypropylene glycols are those having an average molecular mass of from 100 to 20 000 g/mol, in particular of from 200 to 8 000 g/mol, with a molecular mass range of from 400 to 4 000 g/mol being most preferred. Compounds of this type are currently available, for example, under the proprietary name Macrogol.

The film-coating composition of the invention additionally comprises, based on its final composition, as further conventional addition c) to 60% by weight, in particular 2 to 40 % by weight, of colored pigment and/or dye, with a mass content of from 20 to 30 % by weight being most preferred. Conventional inorganic and/or organic pigments of synthetic or natural origin are suitable as colored pigment, e.g. titanium dioxide, iron oxide pigments (calculated as Fe₂0₃) or laked colored pigments (e.g. FD&C lakes or D&C lakes). The colored pigment has an average particle diameter (determined by the Coulter counter method) in a range of from 0.1 to 100 μm, preferably from 0.5 to 20 μm, and in particular from 2 to 10 μm.

Dyes which can be used are the synthetic or natural dyes normally employed in pharmaceuticals, cosmetics and foodstuffs. Examples thereof are indigo, carmine, quinoline yellow, orange yellow S, curcumin, riboflavin and cochi- neal.

It is further preferred to add to the film-coating composition of the invention, based on its final composition, as further customary addition c) up to 50% by weight, preferably 2 to 35 % by weight, of talc, with a mass content of from 5 to 20 % by weight being most preferred. Talc has, according to the invention, an average particle diameter (determined by the Coulter counter method) in a range of from 0.5 to 50 μm, preferably from 1 to 10 μm, and in particular from 2 to 5 μm.

In another preferred embodiment, the film-coating composition of the invention comprises, based on its final composition, as further customary addition c) up to 10% by weight, in particular 1 to 8 % by weight, of gelatin, with a mass content of from 2 to 5% by weight being most preferred.

The film-coating composition of the invention is a dry preparation, meaning a composition in which the individual components are present only or predominantly in solid form and no solvent or dispersant is present. Such a dry prepara- tion may be a powder or may be granulates

Such a dry preparation may be preferably dissolved or dispersed in water. Such a dry preparation may also be dissolved or dispersed in an organic solvant or in a mixture of an organic solvent and water and wherein the organic solvent is more particularly ethanol, acetone, isopropanol or a mixture of two or more thereof, so that the resulting solution or dispersion can be applied (e.g. by spraying) to a core using special coating machines (coaters). After evaporation of the solvent or dispersant, a film coating is formed on the surface of the core.

The solution or dispersion of the invention, which is prepared from the dry preparation mentioned, has a solids content in a range from 5 to 35 % by weight, preferably from 10 to 30 % by weight, and in particular from 15 to 25 % by weight.

In addition, the solution or dispersion of the invention has a viscosity

(20°C, rotational viscometer) in the range from 50 to 1 000 mPa-s, preferably from

100 to 500 mPa-s, and in particular from 300 to 300 mPa-s. The organic solvents mentioned are organic solvents acceptable in film- coating solutions or dispersions, e.g. ethanol, acetone, isopropanol and the like. The use of organic solvents is necessary in particular when, for example, cores containing substances sensitive to hydrolysis are to be coated. The film-coating composition of the invention may, besides the components already mentioned, comprise other additives normally employed in film-coating compositions. These include, for example, dispersants, leveling agents, wetting agents, emulsifiers, binders, non-stick agents, fillers, polishing agents, gloss improvers, pH regulators, preservatives, surfactants, antifoams, disintegrants (for increasing the dissolution rate) and other aids.

The film-coating composition of the invention can be produced as dry preparation by mixing together and/or comminuting the individual components in any sequence. It is also possible in this connection to use special mixing and/or comminution processes (e.g. grinding, stirring, kneading, trituration) employing mechanical forces.

The dry preparation of the film-coating composition of the invention may also be modified by other processes, e.g. granulation, compaction, extrusion and/or spray agglomeration.

The film-coating composition of the invention can be dissolved or dis- persed as dry preparation or in modified form (e.g. as granules) in water and/or organic solvent by mechanical stirring in a suitable stirring apparatus. Although it is preferred to prepare a solution or dispersion as the film-coating composition of the invention by combining the complete dry preparation with the solvent or dispersant, it is also possible to mix each one of the components mentioned succes- sively in any sequence with the solvent or dispersant.

It is additionally possible to prepare from the solution or dispersion of the film-coating composition of the invention by wet granulation a dry preparation of film-coating composition which is then mixed again with water and/or organic solvent in order to obtain a coating solution or dispersion. The film-coating composition of the invention can be used for coating tablets, capsules, moldings, foodstuffs, agricultural products or the like.

A solution or dispersion of the film-coating composition of the invention can be sprayed onto any core in special coating machines (coaters), the core preferably being a molding, a tablet, a capsule, a food product, a crystal, a plant seed or a fruit.

Evaporation of the solvent or dispersant results in an article which comprises a core and, as coating, a film coating which is produced from the film- coating composition of the invention. It is moreover possible also to apply two or more coatings or coverings to a core.

The mass ratio of core to the film-coating composition of the invention in the article is in the range from 10:1 to 100:1, preferably from 10:1 to 50:1 , and in particular from 20: 1 to 40: 1.

The film coating has according to the invention a thickness in a range from 10 to 100 μm, preferably from 20 to 100 μm, and in particular from 30 to 80 μm.

Film coatings of this type are surprisingly distinguished by a distinctly stronger adhesion to a core. It is also possible to increase the photostability of the added pigments and/or dyes. The film coating of the invention additionally provides protection from the spatial environment (e.g. atmospheric oxygen, moisture, light, heat or gastric juice). This makes it possible where appropriate to ensure controlled delivery of active ingredient by a film coating which is resistant to gastric juice and soluble in the small intestine. The film coating of the invention can be also suppress a loss of flavor if it is applied, for example, to foodstuffs. In addition, it is also possible to provide the cores with a color to improve their appearance or their identification. An addition possibility is, for example, to mask an unpleasant or bitter taste. In contrast to the use of polymeric film formers on their own, it is possible distinctly to increase the solids content of a solution or disper- sion prepared from the film-coating composition of the invention (dry preparation), without contributing to a considerable increase in the viscosity, resulting in higher processing speeds, e.g. for spraying.

Among the above mentioned sugar alcohols, lactitol was found to be the best one. Dry coating compositions containing lactitol are more stable under hu- mid conditions than coating compositions containing sorbitol or xylitol. That is why, film - coating compositions as decribed above and containing lactitol as sugar alcohol, are a prefered mode of the subject - matter of the present patent application.

The following examples illustrate the present invention.

Film-coating compositions of the invention with the following formulas were prepared : Exam le 1

Example 4

Example 7

Example 10

Exam le 11

Exam le 12

Exam le 14

The dry preparations detained in examples 1 to 16 were produced by a combination of intimate grinding, trituration and mixing of polymers, sugar alco- hols, pigments and other additives in suitable grinding and mixing equipment.

The above dry preparations were dissolved or dispersed in a concentration of up to 25% by weight in water, with the solids content of the finished solution or dispersion depending essentially on the processing conditions (e.g. temperature, spraying equipment, amount of air, pressure) necessary for producing film coatings for coverings.

The aqueous solutions or dispersions were prepared by placing the total amount cold water in a stirred vessel equipped with a simple stirrer device (e.g. IKA stirrer). The stirring speed was initially adapted so that a vortex formed in the filled container without drawing in air. While stirring, the dry preparation was put as quickly as possible in the stirred vessel by introducing it where possible into the vortex. This was intended to avoid constituents of the dry preparation floating. As addition of the dry preparation continued the viscosity of the stirred solution or dispersion rose such that it was necessary to increase the stirring speed in order to obtain a vortex. After complete addition of the total amount of the dry preparation, the stirring speed was reduced so that a vortex was no longer formed. It was then stirred for a further 45 minutes, during which the polymeric components of the dry preparation completely dissolved and a fine dispersion was obtained. Film coatings or coverings were produced using the above aqueous dispersions by employing special coating machines called coaters (e.g. from Hϋttlin Technologie & Design, Glatt Driam or Lδdige). If coating dispersions with high mass contents of pigments are employed, the dispersion should be stirred gently throughout the spraying time in order to prevent the pigments settling out. The film coatings were characterized by producing isolated films and assessing their color, adhesion to various surfaces, ultimate tensile strength, elasticity and dissolution in water.

Claims

1. A film-coating composition, characterized in that it comprises a) at least one cellulose derivative and b) at least one sugar alcohol.

2. A film-coating composition as claimed in claim 1, characterized in that it comprises, based on its final composition a) 14 to 54 % by weight of cellulose derivative, b) 14 to 54 % by weight of sugar alcohol and c) where appropriate other conventional additions.

3. A film-coating composition as claimed in claim 2, characterized in that it comprises, based on its final composition, a) 25 to 40 % by weight of cellulose derivative, b) 20 to 40 % by weight of sugar alcohol.

4. A film-coating composition as claimed in claim 1 , 2 or 3, characterized in that the cellulose derivative is hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose or a mixture of two or more thereof.

5. A film-coating composition as claimed in claim 1, 2, 3 or 4, characterized in that the cellulose derivative has a solution viscosity (2% by weight aque- ous solution) of from 1 to 100 mPa-s, in particular of from 3 to 50 mPa-s.

6. A film-coating composition as claimed in any of the preceding claims, characterized in that the sugar alcohol is sorbitol, mannitol, maltitol, xylitol, lactitol, isomalt or a mixture of two or more thereof.

7. A film-coating composition as claimed in any of the preceding claims, characterized in that the sugar alcohol is lactitol.

8. A film-coating composition as claimed in any of the preceding claims, characterized in that if comprises, based on its final composition, as further conventional addition up to 40% by weight, in particular 5 to 25 % by weight, of plas- ticizer.

9. A film-coating composition as claimed in claim 8, characterized in that the plasticizer is polyethylene glycol, polypropylene glycol, glycerol, ethylene glycol, propylene glycol, miglyol, glycerol triacetate, triethyl citrate, liquid paraffin or a mixture of two or more thereof.

10. A film-coating composition as claimed in any of the preceding claims, characterized in that it comprises, based on its final composition, as further conventional addition up to 60% by weight, preferably 2 to 40% by weight, of colored pigment and/or dye. - 3.4 -

11. A film-coating composition as claimed in any of the preceding claims, characterized in that the colored pigment and/or dye is titanium dioxide, an iron oxide pigment, a laked colored pigment, indigo, carmine, quinoline yellow, orange yellow S, curcumin, riboflavin, cochineal or a mixture of two or more thereof.

12. A film-coating composition as claimed in any of the preceding claims, characterized in that it comprises, based on its final composition, as further conventional addition up to 50% by weight, in particular 2 to 35 % by weight, of talc.

13. A film-coating composition as claimed in any of the preceding claims, characterized in that it comprises, based on its final composition, as further con- ventional addition up to 10% by weight, in particular 1 to 8 % by weight, of gelatin.

14. A film-coating composition as claimed in any of the preceding claims, characterized in that it is dissolved or dispersed in water.

15. A film-coating composition as claimed in claim 13, characterized in that it is dissolved or dispersed in an organic solvent or a mixture of an organic soivent and water and wherein the organic solvent is more particularly ethanol, acetone, isopropanol or a mixture of two or more thereof.

16. A process for preparing a film-coating composition as claimed in any of claims 1 to 15, characterized in that the components are mixed together and/or comminuted in any sequence.

17. The process as claimed in claim 16, characterized in that the film- coating composition is dissolved or dispersed in water and/or organic solvent.

18. The process as claimed in claim 16 or 17, characterized in that the film-coating composition is modified by granulation, compaction, extrusion and/or spray agglomeration.

19. The use of the film-coating composition as claimed in any of claims 1 to 15 or prepared as claimed in any of claims 16 to 18 for coating tablets, capsules, moldings, foodstuffs or agricultural products.

20. A film coating, characterized in that it is produced from a composition as claimed in any of claims 1 to 15 or prepared as claimed in any of claims 16 to 18.

21. An article, characterized in that it comprises a core and a film coating as claimed in claim 20 as coating.

22. An article as claimed in claim 21 , characterized in that it comprises as core a molding, a tablet, a capsule, a food product, a crystal, a plant seed or a fruit.