HK1060060A - Pectin film compositions - Google Patents

Description

Pectin film compositions

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The present invention relates to a film composition comprising pectin, at least one additional film-forming polymer and a setting system for use in pharmaceutical, veterinary, food, cosmetic or other products, such as films for packaging food, lavender or jelly, preferably for pre-dosed formulations (e.g. soft or hard capsules).

The pectin composition is preferably used for the manufacture of hard capsules for use in pharmaceutical and veterinary applications. The pectin content of the composition imparts enteric properties to such capsules, and the at least one further film-forming polymer enhances the mechanical properties of the hard capsules. The combination with a setting system allows the film-forming composition of the invention to be used to produce enteric capsules by conventional dip moulding processes.

The use of conventional dip moulding equipment for the production of gelatin capsules enables the production of enteric capsules of the same size and properties, which can be used with conventional filling equipment for gelatin capsules.

Enteric materials have a pH-dependent solubility. They are insoluble under gastric conditions (simulated by pH 1.2) and soluble under intestinal conditions (simulated by pH 6.8). Typically, these materials are polymers containing carboxyl groups, such AS Cellulose Acetate Phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMC-AS), acrylic copolymers, pectin or alginate.

Enteric properties of pharmaceutical compositions are typically achieved by coating the enteric material on, for example, pellets, pills, tablets, or hard or soft capsules.

Enteric film compositions for use in hard capsules are described, for example, in US 4138013. The film-forming composition for dip molding consists of: (1) ammonium salts of hydroxypropylmethylcellulose and cellulose acetate phthalate polymers, or (2) ammonium salts of gelatin and methacrylic acid and methacrylate ester copolymers. However, it has been found that the capsules prepared according to the above-mentioned techniques have the disadvantages of poor solubility in intestinal fluids, high content of organic solvents, insufficient stability and diffusion problems.

The improved process is described in EP-A-0056825, wherein the film composition contains ｃA film-forming polymer such as ｃA cellulose ester or cellulose ether ester, ｃA plasticizer, ｃA tackifying substance such as ｃA high viscosity cellulose ether, and ｃA defoamer.

Conventional hard capsules are produced from gelatin by a dip moulding process. The method is based on the setting capacity of a hot gelatin solution upon cooling. On fully automated industrial hard gelatin capsule machines, the mold probe is dipped into a hot gelatin solution, the probe is removed from the solution, inverted, the gelatin solution (gel) remaining on the probe is allowed to dry, the capsule shell is peeled off, and finally the capsule cap and capsule body are cut and pre-bonded. The intermediate setting of the gelatin solution on the mould probe after dipping is a critical step of the process. Otherwise, the gelatin solution will flow down to form capsules with uneven wall thickness and unacceptable properties.

Another enteric film composition is described in US4365060, which contains mixed esters of alkyl-, hydroxyalkyl-, or hydroxyalkylalkyl-cellulose esterified with succinic anhydride and an aliphatic monocarboxylic anhydride. However, solutions of these compositions do not have any setting ability and therefore cannot be used in dip molding processes on an industrial scale.

JP- ｃA-58138458 describes ｃA method in which ｃA mold probe is immersed in an aqueous solution of hydroxypropyl-methyl-cellulose alkali metal acetate succinate and gelatin, and then immersed in an aqueous solution of an acid. However, in this composition, the gelatin content is too low to provide sufficient setting ability to the impregnation solution.

Surprisingly, we have found that a film composition based on pectin as enteric material and at least one second film-forming material and a setting system has sufficient setting capacity for the industrial production of hard capsules.

Pectin has excellent enteric properties. A lower pectin content of 5-25%, preferably 10-20% by weight in the composition is sufficient to obtain a capsule film with enteric properties. Surprisingly, the capsules of the present invention can resist dissolution in an in vitro disintegration test at pH 1.2 for at least 2 hours and readily dissolve at pH 6.8 (greater than 80% after 45 minutes under USP dissolution conditions).

Aqueous solutions of prior art film-forming compositions must be prepared under alkaline conditions and are therefore very unstable. The composition of the present invention overcomes this disadvantage because the pectin used as enteric material is water soluble and the solution is therefore very stable.

Another advantage of pectin is that pectin itself has the properties of a coagulant, as described below.

Similar to other enteric materials, pectin has the disadvantage of being brittle if used alone or in large amounts in the film forming polymer. Surprisingly, we have found that this problem can be solved by adding to the film-forming composition at least one other film-forming material, which can be generally selected from all pharmaceutical and/or food quality grade water-soluble film-forming materials. Suitable are, for example, gelatin; amylopectin starch; polyvinyl alcohol; modified starches such as hydroxypropylated starch or hydroxyethylated starch; cellulose ethers such as hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose or hydroxyethylmethylcellulose; and mixtures thereof.

In addition to improving the mechanical properties of the capsule film, the addition of a second film-forming material also increases the solid material content in the dip molding solution of the film composition.

The pectin content is in the range of 5-60%, preferably 10-40% by weight of the film composition and the second film-forming material content is in the range of 40-95%, preferably 50-85% by weight.

Particularly preferred are pectins with a low methoxyl content (LM pectins) wherein the degree of esterification of the carboxyl groups by methanol is less than 50%.

The content of the film-forming composition in the dipping solution used in the capsule production process is 15-40% by weight.

In order to produce enteric capsules by an industrial dipping method, it is necessary that the dipping solution has sufficient setting ability. Surprisingly, we have found that pectin, in addition to its enteric properties, can be present in divalent cations such as Ca⁺⁺Or Mg⁺⁺Provides sufficient setting properties in the presence of (c). Divalent salts, e.g. CaCl₂The content in the impregnation solution is preferably 100-5000ppm (0.01-0.5% by weight), which means 0.04-2% by weight of the final film composition. During the preparation of the solution, the formation of concentration peaks of divalent salts must be avoided. Local high concentrations of divalent salts will result in the formation of a thermodynamically irreversible local pectin gel.

The setting properties of the film-forming solution of the invention can also be achieved or modified by adding other gelling agents, preferably polysaccharides such as carrageenan or gellan. It has been found that the addition of small amounts of such additional gelling agents provides sufficient setting ability. The content of gelling agent in the impregnation solution is preferably 0.05-2% by weight, which means 0.2-8% by weight of the final film composition.

The temperature of the solution during the impregnation process is also important for the setting properties of the impregnation solution. The temperature should preferably be above 50 ℃ and depends on the pectin content. It has been found that the temperature of the impregnation solution must be increased with increasing pectin content.

In another aspect, the compositions of the present invention may contain additional pharmacologically or food acceptable colorants in an amount ranging from 0 to 10% based on the weight of the final film composition.

In another aspect, the compositions of the present invention may contain additional pharmacologically or food acceptable plasticizers or flavoring agents.

Finally, the film forming solution of the present invention may be used to encapsulate enteric capsules. This prevents the capsule from leaking or the capsule cap and body from separating in gastric juice.

The following examples and experiments are presented to illustrate the production of hard enteric capsules and their enteric properties from a composition of the dipping solution of the present invention.

Example 1

At room temperature, 2.5 g CaCl were dissolved in 3.9 kg deionized water₂(0.05% by weight of the final infusion solution) and 100 g of glycerol (plasticizer, 2%), then 200 g of LM pectin (4%) and 800 g of hydroxypropyl starch (16%) were dispersed. The mixture was then heated to 95 ℃ to solvate all components with stirring. After defoaming by slowing down the stirring, the solution was equilibrated at 60 ℃.

The solution was poured into the dipping pan of a laboratory machine of a conventional hard gelatin capsule production facility. The infusion solution was maintained at 60 ℃, and a naturally clear grade 0 hard enteric capsule was made according to conventional methods, having the same size specification as a conventional hard gelatin capsule. The final capsule had a film composition of 16.3% pectin, 65.3% hydroxypropyl starch, 8.1% glycerol, 0.20% CaCl₂And 10% moisture (by weight).

Example 2

At room temperature, 200 g of LM pectin were dispersed in 2.0 kg of deionized water, and the mixture was then heated to 85 ℃ to solvate the pectin. After defoaming by slowing down the stirring, the solution was equilibrated at 60 ℃.

2.5 kg of 32% aqueous gelatin solution were prepared by a conventional method for producing hard gelatin capsules. 11.75 g of 20% CaCl₂The aqueous solution was added to the gelatin solution and then left to stand at 60 ℃ to defoam.

The two solutions were mixed under gentle stirring to avoid the formation of bubbles. The solution thus prepared (containing 4.25% by weight of pectin, 17.0% by weight of gelatin and 0.05% by weight of CaCl) was then concentrated₂) Pouring into the dipping pan of a laboratory machine of a conventional hard gelatin capsule production facility. The infusion solution was maintained at 45 ℃ to produce a naturally clear grade 0 hard enteric capsule according to conventional methods, which had the same size specification as a conventional hard gelatin capsule.

The final capsule had a film composition of 16.9% pectin, 67.4% gelatin, 0.20% CaCl₂And 15.5% moisture (by weight).

Example 3

250 g of polyethylene glycol 400, which had been preheated at 60 ℃ were added at 60 ℃ to 4.7 kg of the solution prepared in example 2, containing 4.25% pectin, 17.0% gelatin and 0.05% CaCl, with gentle stirring₂。

Naturally clear hard gelatin capsules were prepared as described in example 2. The final capsule had a film composition of 13.9% pectin, 55.8% gelatin, 17.4% PEG400 and 0.20% CaCl₂And 12.7% moisture (by weight).

Example 4

At room temperature, 3.85 kg of gellan gum and 150 g of LM pectin were dispersed in 2.0 kg of deionized water, and the mixture was heated to 85 ℃ for solvation. After defoaming, the solution was equilibrated at 60 ℃.

2.66 kg of an aqueous gelatin solution containing 32% by weight of gelatin were prepared by a conventional method for producing hard gelatin capsules and equilibrated at 60 ℃.

The two solutions were mixed and debubbled. The final solution contained 3.12% by weight pectin, 17.7% by weight gelatin and 0.08% by weight gellan gum.

Grade 0 natural hard enteric capsules were prepared in the same manner as in the above examples, with the infusion solution maintained at 55 ℃. The film composition of the final capsule was 12.8% pectin, 72.4% gelatin and 0.33% gellan gum and 14.5% moisture (by weight).

The enteric properties of all capsules were evaluated by in vitro disintegration and solution experiments according to UPS XXIIII: the first 2 hours were in simulated gastric fluid (pH 1.2) and then simulated intestinal fluid (pH 6.8). No enzyme was used in these experiments.

Capsules were filled with lactose containing 0.1% indigo (FD & C blue N ° 2) in disintegration experiments or with acetaminophen in vitro dissolution experiments. The capsules were then coated with the same solutions as used during capsule preparation for each example, respectively. The encapsulation of the capsule prevents the separation of the capsule cap from the capsule body in the disintegration test.

The results of the disintegration experiments are listed in table 1 and the results of the dissolution experiments are listed in figure 1.

TABLE 1

Result of disintegration

Capsule	Disintegration time
				pH＝1.2	pH＝6.8
Example 1	Greater than 2 hours	10.6 minutes
			Example 2	Greater than 2 hours	3.5 minutes
Example 3	Greater than 2 hours	2.5 minutes
			Example 4	Greater than 2 hours	4.8 minutes

The experiments performed showed that all capsules had excellent gastric resistance and they remained intact after 2 hours at pH 1.2.

The capsules of examples 1-3 dissolved very rapidly after entering a buffer at pH 6.8. The capsules of example 4 dissolved slightly more slowly. Using an additional coagulometer will make it possible to simulate the dissolution pattern under intestinal conditions.

Claims (16)

1. A film composition comprising:

a) the pectin is added with the water to be added,

b) a second film-forming polymer, and

c) a solidification system.

2. A film composition according to claim 1 wherein the second film-forming polymer is selected from gelatin; amylopectin starch; polyvinyl alcohol; hydroxypropylated starches, hydroxyethylated starches; hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose; or mixtures thereof.

3. A film composition according to claim 1 wherein the pectin is present in an amount of 5-60%, preferably 10-40%, and the second polymer is present in an amount of 60-95%, preferably 50-85%.

4. A film composition according to claim 1 wherein the setting system consists of pectin and a salt of a divalent cation.

5. A film composition according to claim 4 wherein the divalent cation salt is selected from magnesium or calcium salts.

6. A film composition according to claim 1 wherein the setting system consists of pectin and an additional setting agent selected from carrageenan or gellan gum or mixtures thereof.

7. A film composition according to claim 1 which contains additional colouring and/or flavouring agents.

8. A film composition according to claim 1 which contains an additional plasticiser.

9. An aqueous film-forming solution of a composition according to claim 1 for use in the production of hard enteric capsules.

10. A solution according to claim 9, comprising the film-forming composition according to claim 1 in an amount of 10 to 50% by weight, preferably 15 to 40% by weight, based on the weight of the aqueous solution.

11. A solution according to claim 9 containing a salt of a divalent cation in an amount of 0.01 to 0.5% by weight based on the weight of the aqueous solution.

12. Solution according to claim 11, characterized in that the salt of a divalent cation is a magnesium and/or calcium salt.

13. An aqueous solution according to claim 9, which contains an additional coagulant selected from carrageenan or gellan gum in an amount of 0.05 to 2% by weight of the aqueous solution.

14. Use of the aqueous solution according to claim 9 for the production of hard enteric capsules by a dip moulding process.

15. A process for producing hard enteric capsules by a dip moulding process from an aqueous solution containing 10 to 50% by weight of the film-forming composition of claim 1 at a temperature of 40 to 70 ℃ using conventional hard gelatin capsule production equipment.

16. Use of the aqueous solution according to claim 9 for a process of encapsulation of enteric capsules.