Capsule shell comprising a core-shell polymer and a cellulose

Abstract

A capsule shell contains 40 to 99% by weight of a core-shell polymer and 1 to 60% by weight of a cellulose. The core-shell polymer contains 50 to 90% by weight of a core, containing polymerized units of 65 to 75% by weight of ethyl acrylate and 25 to 35% by weight of methyl methacrylate; and 10 to 50% by weight of a shell, containing polymerized units of 45 to 55% by weight of ethyl acrylate and 45 to 55% by weight of methacrylic acid.

Claims

1. A capsule shell, comprising: a mixture of: (a) 40 to 99% by weight of a core-shell polymer, wherein the core-shell polymer comprises 50 to 90% by weight of a core, comprising polymerized units of 65 to 75% by weight of ethyl acrylate and 25 to 35% by weight of methyl methacrylate, and wherein the core-shell polymer comprises 10 to 50% by weight of a shell, comprising polymerized units of 45 to 55% by weight of ethyl acrylate and 45 to 55% by weight of methacrylic acid, and (b) 1 to 60% by weight of a cellulose; wherein an aqueous dispersion comprising water, and 10-40% by weight of the mixture, shows a viscosity, measured with a Brookfield viscometer, spindle 1, at 20 C. in the range of 25 to 3,000 mPa*s.

2. The capsule shell according to claim 1, wherein the cellulose shows a viscosity when measured as a 2% by weight aqueous dispersion at 20 C. with a Brookfield viscometer, spindle 1, in the range of 1 to 3 mPa*s.

3. The capsule shell according to claim 1, comprising 95 to 99% by weight of the core-shell polymer, and 1 to 5% by weight of the cellulose, wherein the cellulose shows a viscosity when measured as a 2% by weight aqueous dispersion at 20 C. with a Brookfield viscometer, spindle 1, in the range of more than 3 and up to 6 mPa*s.

4. The capsule shell according to claim 1, wherein the cellulose is a hydroxypropyl methyl cellulose.

5. The capsule shell according to claim 1, wherein a thickness of a wall of the capsule shell is from about 80 to 250 m.

6. The capsule shell according to claim 1, wherein the capsule shell is a capsule body or a capsule cap.

7. The capsule shell according to claim 1, wherein the core-shell polymer comprises 70 to 80% by weight of the core, and 20 to 30% by weight of the shell.

8. A hard shell capsule, comprising: two matching capsule shells according to claim 1.

9. The hard shell capsule according to claim 8, wherein the hard shell capsule is closed and contains a filling comprising a biologically active ingredient.

10. A process for preparing a capsule shell according to claim 1, the process comprising: a) providing the core-shell polymer in the form of an aqueous polymer dispersion A, b) providing the cellulose in the form of an aqueous polymer dispersion B, c) mixing the polymer dispersion A and the polymer dispersion B into a mixed aqueous polymer dispersion, d) dipping a moulding pin, that has an inner complementary form of the capsule shell at its end, with this end into the mixed polymer dispersion, e) withdrawing the moulding pin from the mixed polymer dispersion and drying a polymer dispersion on the moulding pin to form a film, which has the form of the capsule shell, and f) removing the capsule shell from the moulding pin.

11. The process according to claim 10, wherein the aqueous polymer dispersion A in a) comprises 25 to 35% by weight of the core-shell polymer.

12. The process according to claim 10, wherein the mixed aqueous polymer dispersion comprises the aqueous polymer dispersions A and B at a ratio of A:B from 99:1 to 40:60.

13. The process for preparing a capsule shell according to claim 10, wherein the mixed aqueous polymer dispersion of step c) shows a viscosity, measured with a Brookfield viscometer, spindle 1, at 20 C. in the range of 25 to 3,000 mPa*s.

14. The capsule shell according to claim 1, wherein in the core-shell polymer, the core comprises polymerized units of 70% by weight of ethyl acrylate and 30% by weight of methyl methacrylate.

15. The capsule shell according to claim 1, wherein the cellulose is hydroxypropyl methyl cellulose and has a viscosity when measured as a 2% by weight aqueous dispersion at 20 C. with a Brookfield viscometer, spindle 1, in the range of about 1.5 to 2.5 mPa*s.

16. An aqueous dispersion, comprising: water, and 10 to 40% by weight of a composition, and 1 to 60% by weight of a cellulose, wherein the composition comprises 40 to 99% by weight of a core-shell polymer, comprising 50 to 90% by weight of a core, comprising polymerized units of 65 to 75% by weight of ethyl acrylate and 25 to 35% by weight of methyl methacrylate, wherein the core-shell polymer comprises 10 to 50% by weight of a shell, comprising polymerized units of 45 to 55% by weight of ethyl acrylate and 45 to 55% by weight of methacrylic acid, and wherein the aqueous dispersion shows a viscosity, measured with a Brookfield viscometer, spindle 1, at 20 C. in the range of 25 to 3,000 mPa*s.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) Hard Shell Capsules and Capsule Shells

(2) Hard shell capsules for pharmaceutical or nutraceutical purposes are well known to a skilled person. A hard shell capsule is a two-piece encapsulation capsule comprising of two capsule shells, called the capsule body and the capsule cap. A capsule shell in the sense of the invention is therefore a capsule body or a capsule cap. The capsule body and cap material is usually made from a hard and sometimes brittle polymeric material. A hard shell capsule comprises a body and a cap. Body and cap are usually of a one end open cylindrical form with a closed rounded hemispherical form on the opposite end. The shape and size of the cap and body are matching such that the body can be pushed telescopically with its open end into the open end of the cap, resulting in a tightly closed hard shell capsule.

(3) A capsule shell in the sense of the invention is therefore a capsule body or a capsule cap. A hard shell capsule comprises two matching capsule shells, which are the capsule body and the capsule cap. A biologically active ingredient, which may be a pharmaceutical active ingredient or a nutraceutical active ingredient, may be filled into the capsule body. The capsule body may then be closed by adding the capsule cap, resulting in a closed hard shell capsule according to the invention. The disintegration of the hard shell capsule respectively the release of the active ingredient is dependent on the polymeric composition of the capsule shell material, especially on the ratio between the core-shell polymer and the cellulose as described. A wide spectrum of different release profiles from slightly delayed release over enteric USP-conform release and strongly delayed release may be realized depending on the desired use.

(4) The capsule body and the capsule cap usually comprise a potential overlapping matching area (overlap area) outside the capsule body and inside the capsule cap, which partially overlaps when the capsule is closed in the pre-locked state and totally overlap in the final-locked state. When the capsule cap is partially slid over the overlapping matching area of the capsule body, the capsule is in the pre-locked state. When the capsule cap is totally slid over the overlapping matching area of the capsule body, the capsule is in the final-locked state.

(5) The maintenance of the pre-locked state or of the final-locked state is usually supported by snap-in locking mechanisms of the capsule body and the capsule cap such as matching encircling notches or dimples, preferably elongated dimples. Usually dimples are preferred for fixing the body and the cap in the pre-locked state. As a non-binding rule, the matching area of dimples is smaller than the matching area of encircling notches. Thus, snapped-in dimples may be snapped-out again by applying less forces than those that would be necessary to snap-out a snapped-in fixation by matching encircling notches.

(6) Hard shell capsules are commercially available in different sizes. Hard shell capsules are usually delivered as empty containers with the capsule body and capsule cap already positioned in the pre-locked state and on demand as separate capsules halves, bodies and caps. Pre-locked hard shell capsules may be provided to a capsule-filling machine, which performs the opening, filling and closing of the capsule into the final-locked state. Usually hard shell capsules are filled with dry materials, for instance with powders or granules comprising a biologically active ingredient, which may be an active pharmaceutical ingredient or an active nutraceutical ingredient.

(7) Core-Shell Polymer

(8) The capsule shell as disclosed is comprising a mixture of 40 to 99% by weight of a core-shell polymer and 1 to 60% by weight of a cellulose.

(9) The core-shell polymer is comprising 50 to 90, preferably 70 to 80% by weight of a core, comprising polymerized units of 65 to 75% by weight of ethyl acrylate and 25 to 35% by weight of methyl methacrylate, and 10 to 50, preferably 20 to 30% by weight of a shell, comprising polymerized units of 45 to 55% by weight of ethyl acrylate and 45 to 55% by weight of methacrylic acid.

(10) A suitable core-shell polymer is EUDRAGIT FL 30 D-55 (Evonik Nutrition & Care GmbH, Darmstadt, Germany), which is a commercially available 30% by weight aqueous dispersion of a copolymer from a two-stage emulsion polymerization process, with a core of about 75% by weight, comprising polymerized units of 70% by weight of ethyl acrylate and 30% by weight of methyl methacrylate, and a shell of about 25% by weight, comprising polymerized units of 50% by weight of ethyl acrylate and 50% by weight of methacrylic acid.

(11) Suitable core-shell polymers that are usually derived from two-stage emulsion polymerization processes and their synthesis are well-known for instance from WO2012/171575A1.

(12) Pharmaceutically or Nutraceutically Acceptable Excipients

(13) Optionally up to 50% by weight of pharmaceutically or nutraceutically acceptable excipients such as pigments, coloring agents or separating agents, such as Mg stearate, talc or glycerol monostearate, may be added. However, usually less than 25, preferably less than 10% by weight or no excipients at all are added. The core-shell polymer, the cellulose and, if present, the optional excipients may add up to 100%. Pharmaceutically or nutraceutically acceptable excipients, are excipients well known to the skilled person in pharmacy, galenics or nutrition technology, are classified as harmless to the human or animal health and allowed to be used in pharmaceutical or nutraceutical compositions.

(14) Cellulose

(15) The capsule shell, which can be either a capsule cap or a capsule body, comprises 1 to 60% by weight of a cellulose.

(16) Preferably, the capsule shell is comprising 40 to 99% by weight of the core-shell polymer, and 1 to 60% by weight of a cellulose, wherein the cellulose shows a viscosity when measured as a 2% by weight aqueous dispersion at 20 C. with a Brookfield viscometer, spindle 1, in the range of about 1 to 3, preferably of about 1.5 to 2.5 mPa*s.

(17) The capsule shell may also comprise 95 to 99% by weight of the core-shell polymer, and 1 to 5% by weight of a cellulose, wherein the cellulose shows a viscosity when measured as a 2% by weight aqueous dispersion at 20 C. with a Brookfield viscometer, spindle 1, in the range of about more than 3 and up to 6, preferably of about 4 to 5.5 mPa*s.

(18) Preferably, the capsule shell is comprising 40 to 99% by weight of the core-shell polymer, and 1 to 60% by weight of a cellulose, wherein the cellulose shows a viscosity when measured as a 2% by weight aqueous dispersion at 20 C. with a Brookfield viscometer, spindle 1, of 1 to 3, preferably of 1.5 to 2.5 mPa*s.

(19) The capsule shell may also comprise 95 to 99% by weight of the core-shell polymer, and 1 to 5% by weight of a cellulose, wherein the cellulose shows a viscosity when measured as a 2% by weight aqueous dispersion at 20 C. with a Brookfield viscometer, spindle 1, of more than 3 and up to 6, preferably of 4 to 5.5 mPa*s.

(20) The cellulose may be a water-soluble cellulose, preferably a water-soluble cellulose of low viscosity, most preferred a hydroxypropyl methyl cellulose. A suitable, commercially available cellulose is for instance METHOCEL Premium VLV.

(21) A low viscosity cellulose may be defined as a cellulose which shows a viscosity, when measured as a 2% by weight aqueous dispersion at 20 C. with a Brookfield viscometer, spindle 1, in the range of 1 to 6, preferably from 1.5 to 5.5 mPa*s.

(22) Aqueous Dispersion

(23) Disclosed is also an aqueous dispersion comprising water and 10 to 40% by weight of a composition comprising 40 to 99% by weight of a core-shell polymer, comprising 50 to 90% by weight of a core, comprising polymerized units of 65 to 75% by weight of ethyl acrylate and 25 to 35% by weight of methyl methacrylate, and 10 to 50% by weight of a shell, comprising polymerized units of 45 to 55% by weight of ethyl acrylate and 45 to 55% by weight of methacrylic acid, and 1 to 60% by weight of a cellulose.

(24) Preferably, the aqueous dispersion shows a viscosity, measured with a Brookfield viscometer, spindle 1, at 20 C. in the range of 25 to 3,000, preferably 150 to 2,800 mPa*s.

(25) Dimension of Capsule Shells/Capsules

(26) The capsule shell as disclosed may have a thickness of the capsule shell wall of from about 80 to 250, preferably from about 100 to 220 m. The capsule shell as disclosed may have a thickness of the capsule shell wall of from 80 to 250, preferably from 100 to 220 m.

(27) A capsule shell as disclosed may be a capsule body or a capsule cap. Usually, the capsule body is longer than the capsule cap. The outside overlapping area of the capsule body can be covered by the capsule cap in order to dose or to lock the capsule. In the closed state the capsule cap covers the outside overlap area of the capsule body either in a pre-locked state or in a final-locked state. In the final-locked state, the capsule cap covers the outside overlap area of the capsule body in total, in the pre-locked state, the capsule cap overlaps the outside overlapping area of the capsule body only partially. The capsule cap can be slid over the capsule body to be fixed in usually one of two different positions in which the capsule is closed either in a pre-locked state or in a final-locked state.

(28) Within the context of the invention, a dosed capsule may show a total length in the range from about 5 to 50 mm. The diameter of the capsule cap (upper part) may be in the range from about 4 to 12 mm. The diameter of the capsule body (lower part) may be in the range from about 2 up to 10 mm. The length of the capsule cap may be in the range from about 4 to 20 mm and that of the capsule body in the range from 8 to 30 mm. The fill volume may be between about 0.1 and 2 ml.

(29) Capsules may be divided, for example, into standardized sizes from 000 to 5.

(30) A closed capsule of size 000 has, for example, a total length of about 28 mm, a diameter of the upper part of about 9.9 mm and a diameter of the lower part of about 9.5 mm. The length of the upper part is about 14 mm, that of the lower part of about 22 mm. The fill volume is about 1.4 ml.

(31) A closed capsule of size 5 has, for example, a total length of about 10 mm, a diameter of the upper part of about 4.8 mm and a diameter of the lower part of about 4.6 mm. The length of the upper part is about 5.6 mm, that of the lower part of about 9.4 mm. The fill volume is about 0.13 ml.

(32) Hard Shell Capsule

(33) A hard shell capsule comprises two matching capsule shells, the capsule body and the capsule cap (or simply addressed as body and cap). The term matching shall mean that the capsule body and the capsule cap have dimensions that allow (usually after filling), that the capsule cap can be slid over the capsule body, usually in a locked position, to result in a tightly closed hard shell capsule. A closed hard shell capsule may contain a filling comprising a biologically active ingredient, which may be an active pharmaceutical ingredient or an active nutraceutical ingredient.

(34) Dissolution Behavior

(35) The dissolution or disruption behavior of a filled and closed capsule may be simulated by a rather simple steel ball fall test. The rather simple test correlates well with more elaborate dissolution tests with filled and closed capsules. For this purpose, films of about 100 m thickness are prepared from the different aqueous dispersions. The films of about 100 m thickness are comparable to a typical capsule wall thickness. Each film may then be horizontally and tightly fixed between two plastic rings (inner diameter about 1.9 cm), separating the space between the two plastic rings. A pH 1.2 medium or a pH 6.8 buffer respectively (each according to USP, for instance USP 31) is filled into the void volume formed by the wall of the upper plastic ring and with the film as bottom. A steel ball (diameter about 1.1 cm, weight about 5.4 g) is added to simulate mechanical stress in the stomach or in the intestine on the film. The time until the steel ball breaks through the film may then be measured (s. also for instance the film disintegration test as described in WO2014018279A1, p. 8-9, and as described in European Pharmacopeia, seventh Edition, 2011, disintegration of Tablets and Capsules).

(36) Films with a steel ball break-through time in pH 1.2 medium of 1 to 30 min allow the manufacture of capsule shells for hard shell capsules, which disintegrate in a mode from fast to slightly delayed.

(37) Films with a steel ball break-through time in pH 1.2 medium of more than 1 hour and a disintegration time in pH 6.8 buffer of less than 45 min allow the manufacture of capsule shells for hard shell capsules, which disintegrate in a USP-conform mode for enteric protection.

(38) Films with a steel ball break-through time in pH 1.2 medium more than 1 hour and a disintegration time at pH 6.8 buffer of more than 45 min or up to 3 to 5 hours allow the manufacture of capsule shells for enteric protected hard shell capsules, with a strongly delayed disintegration profile.

(39) Process for Preparing a Capsule Shell

(40) Disclosed is a process (dip-moulding process) for preparing a capsule shell by the steps a) providing the core-shell polymer in the form of an aqueous polymer dispersion A, b) providing the cellulose in the form of an aqueous polymer dispersion B, c) mixing the polymer dispersions A and B to a mixed aqueous polymer dispersion (optionally pharmaceutically or nutraceutically acceptable excipients may be added as described before), d) dipping a moulding pin, that has the inner complementary form of the capsule shell at its end with this end into the mixed polymer dispersion, e) withdrawing the moulding pin from the polymer dispersion and drying the polymer dispersion on the moulding pin to form a film, which has the form of the capsule shell, f) removing the capsule shell from the moulding pin.

(41) The aqueous dispersion A in step a) may comprise 25 to 35% by weight of the core-shell copolymer.

(42) The mixed aqueous dispersion in step c) may comprise 15 to 40% by weight of the core-shell copolymer, the cellulose and optionally pharmaceutically or nutraceutically acceptable excipients.

(43) The mixed polymer dispersion in step c) may show a viscosity, measured with a Brookfield viscometer, spindle 1, at 20 C. in the range of 25 to 3,000, preferably from 250 to 2,800 mPa*s.

(44) Optionally, post-processing steps such as cutting the length or post-drying may be added as known by a skilled person in the art.

EXAMPLES

(45) Polymers

(46) EUDRAGIT FL 30 D-55 (Evonik Nutrition & Care GmbH, Darmstadt, Germany) is a 30% by weight aqueous dispersion of a copolymer from a two-stage emulsion polymerization process, with a core of about 75% by weight, comprising polymerized units of 70% by weight of ethyl acrylate and 30% by weight of methyl methacrylate, and a shell of about 25% by weight, comprising polymerized units of 50% by weight of ethyl acrylate and 50% by weight of methacrylic acid.

(47) The viscosity of EUDRAGIT FL 30 D-55 that was measured in a 30% by weight aqueous dispersion at 20 C. with a Brookfield viscometer spindle 1 is approximately 10 mPa*s.

(48) METHOCEL Premium VLV is a very low viscosity hydroxypropyl methyl cellulose.

(49) The viscosity of METHOCEL Premium VLV was measured as a 2% by weight aqueous dispersion at 20 C. with a Brookfield viscometer, spindle 1, in the range of about 2 mPa*s.

(50) METHOCEL Premium E5 is a low viscosity hydroxypropyl methyl cellulose.

(51) The viscosity of METHOCEL Premium E5 was measured as a 2% by weight aqueous dispersion at 20 C. with a Brookfield viscometer, spindle 1, in the range of 5 mPa*s.

(52) Preparation of the Cellulose Solution

(53) 800 g of water were heated up to 80 C. 200 g of METHOCEL Premium VLV were added slowly, while stirring with a blade agitator. The suspension was cooled down to 20 C. while continuously stirring. METHOCEL Premium VLV dissolves during the cooling phase and a very high viscose solution is formed.

(54) The viscosity of the 20% METHOCEL Premium VLV solution was measured at 20 C. with a Brookfield viscometer, spindle 3, in the range of 10,000 mPa*s or more (10,000 to 12,000 mPa*s).

(55) 850 g of water were heated up to 80 C. 150 g of METHOCEL Premium E5 were added slowly, while stirring with a blade agitator. The suspension was cooled down to 20 C. while continuously stirring. METHOCEL Premium E5 dissolves during the cooling phase and a very high viscose solution is formed.

(56) The viscosity of the 15% METHOCEL Premium E5 solution was measured at 20 C. with a Brookfield viscometer, spindle 3, in the range of 3,000 mPa*s or more (3,000 to 3,500 mPa*s).

(57) Preparation of the Mixed Dispersions

(58) With the help of a blade agitator, EUDRAGIT FL 30 D-55 was mixed with the according amount of METHOCEL solution to form the following aqueous dispersions.

(59) EUDRAGIT FL 30 D-55/METHOCEL Premium E5 polymer ratios:

(60) TABLE-US-00001 TABLE 1 EUDRAGIT FL 30 D-55 polymer/ METHOCEL Premium E5 (w/w) Viscosity mPa*s 90:10 >10,000 98:2 500

(61) Due to the viscosity the ratio 90:10 is not suitable to prepare a film or as dipping solution for capsule manufacturing.

(62) EUDRAGIT FL 30 D-55/METHOCEL Premium VLV polymer ratios:

(63) TABLE-US-00002 TABLE 2 EUDRAGIT FL 30 D-55 polymer/ METHOCEL Premium VLV (w/w) Viscosity mPa*s 50:50 2500 70:30 1030 90:10 280 98:2 50

(64) The viscosity of all ratios is suitable to prepare a film or as dipping solution for capsule manufacturing.

(65) Preparation of the Films

(66) With the help of a doctor blade, a Teflon board was coated with the suitable dispersions and dried at room temperature. The thickness of the resulting films was approximately 100 m.

(67) Test Procedure/Steel Ball Fall Test

(68) The resulting films were tested according to WO2014018279A1 and as described in European Pharmacopeia (Seventh Edition, 2011, disintegration of Tablets and Capsules). Therefore, the films were fixed between 2 tubs (1.9 cm inner diameter). A steel ball (diameter 1.1. cm, weight 5.4 g) was placed on top of the film and the corresponding media was charged into the upper tube. The break-through time of the steel ball was measured.

(69) Results: The results are summarized in table 3

(70) TABLE-US-00003 TABLE 3 Break-through times of 100 m films in the steel ball fall test pH 1.2 pH 6.8 Remark EUDRAGIT FL 30 D-55 Polymer/ METHOCEL Premium VLV (w/w) 50:50 Ca. 1 min Ca. 1 min Fast disintegrating 70:30 Ca. 20 min Ca. 2 min Slightly delayed 80:20 >17 h Ca. 8 min USP-conform enteric 85:15 >17 h Ca. 20 min 90:10 >17 h Ca. 25 min 98:2 >17 h Ca. 3 h Strongly delayed EUDRAGIT FL 30 D-55 Polymer/ METHOCEL Premium E5 (w/w) 90:10 n.a. n.a. Viscosity too high to manufacture a film 98:2 >17 h Ca. 3 h Strongly delayed