FR2783832A1 - Compositions for manufacture of pharmaceutical capsules comprise hydroxy propylated starch and hydrocolloid plus cation hardening system - Google Patents

Abstract

Film-forming compositions comprise a hydroxy propylated starch and a hardening system. The hardening system may be a hydrocolloid plus a cation, optionally with a sequestering agent. Suitable hydrocolloids include polysaccharides such as alginates, agar gum, carob gum, carrageenan, tara gum, gum arabic, ghatti gum, Khaya grandifolia gum, gum tragacanth, karaya gum, pectin, arabin, xanthan, gellan, starch, Konjac mannan, galactomannan, or funoran. Exocellular polysaccharides may also be used. Gellan gum and \=k-carrageenan are the preferred hydrocolloids. The cations used may be those of K, Na, Li, NH4, Ca, or Mg. Sequestering agents that may be incorporated into the compositions include acids and their salts such as EDTA, acetic acid, boric acid, citric acid, edetic acid, gluconic acid, lactic acid, phosphoric acid, and tartaric acid, metaphosphates, dihydroxy ethyl glycine, lecithin, and beta -cyclodextrin. The compositions preferably contain 88 - 98% hydroxy propylated starch, 2 - 12% water, 0.01 - 10% polysaccharides, and 0.001 - 5% cations. Other components that may be present include plasticizers (0 - 40%), and colors (0 - 10%)

Description

MODIFIED STARCH FILM COMPOSITIONS

  The invention relates to compositions obtained from modified starches such as starch ethers, more particularly hydroxypropylated starch ("HPS" for hydroxy-propylated starch) for use in pharmaceutical, veterinary, food, cosmetics or others such as films for packaging food, aspics or jellies, preferably for pre-dosed formulations such as soft or hard capsules. The hard capsules obtained by the present invention are similar to the hard gelatin capsules (HGC, English acronym for

"hard gelatin capsules").

  A second embodiment of the invention is the use of the modified starch compositions for the manufacture of hard capsules by a conventional immersion molding process as normally used in the manufacture of capsules

in classic hard gelatin.

  For the industrial manufacture of pharmaceutical capsules, gelatin is

  particularly preferred for its gelling, film-forming and surfactant properties.

  The manufacture of hard gelatin capsules by an immersion molding process takes full advantage of these gelling and film-forming capacities. Such capsules are made by immersing molding needles in hot gelatin solution, removing the needles from the gelatin solution, curing the gelatin solution adhering to the needles by cooling, drying and detaching the needles from the needles. shells thus formed. Curing the solution on the molding needles after immersion is the critical step for

  obtaining a uniform thickness of the capsule shell.

  Attempts to manufacture capsules with materials other than gelatin have been made, in particular with modified cellulose. Successful industrial examples are capsules made of hydroxypropyl methylcellulose

  (IIPMC). HPMC capsules show many advantages over HGC.

  However, HPMC is a significantly more expensive raw material than gelatin. Starch is another abundant natural polysaccharide that is renewable, biodegradable and inexpensive. Due to its limited film-forming property and poor mechanical properties, its success in this area is more limited. A unique industrial example (US-4,738,724) are starch capsules made by injection molding, but such capsules have much higher shell thicknesses and a different shape which requires filling and filling equipment.

specific closure.

  US-4,026,986 describes the manufacture of IPS capsules by an immersion molding process. However, due to the lack of the curing property of the HPS solution, the immersion time is long (20 seconds) and

  therefore, it did not lead to a commercial process.

  Contrary to expectations, we have found that the addition of a very small amount of a curing system, preferably consisting of hydrocolloids, particularly polysaccharides, gives the IIPS solution an appropriate curing property which results in that hard HPS capsules can be made by the process of dipping hard gelatin capsules in

conventional operating conditions.

  The object of the invention is therefore to obtain compositions based on HPS for use in pharmaceutical, veterinary, food, cosmetic or other products such as films for packaging food, aspics or jellies. , preferably for containers of predosed formulations such as flexible or hard capsules and in which the HPS compositions have, in

  aqueous solution, sufficient hardenability.

  The first subject of the invention is compositions based on HPS for

  improve and adjust the mechanical properties of films for various applications.

  We have found that adding a plasticizer to the formulation can significantly improve the flexibility of the IPS film. The plasticizer or the mixture of plasticizers is chosen from polyethylene glycol, glycerol, sorbitol, sucrose, glucose syrup, fructose, dioctyl sodium sulfosuccinate, triethyl citrate, tributyl citrate,

  1,2-propylene glycol, glycerol mono-, di- or triacetates or natural gums.

  Preferred are glycerol, polyethylene glycol, propylene glycol, citrates and combinations thereof. The amount of plasticizer depends on the final application. For hard film formulations as for hard capsules, the plasticizer is present in an amount of 0 to 20%, preferably 10 to 20%. A higher content, 20 to%, is preferred for flexible film formulations such as for flexible capsules. We have also found that it is possible to further improve the mechanical properties of the film by combining the IIPS with other water-soluble polymers or polysaccharides. Preferred examples are pectin, alginates,

  polyvinyl alcohol and high molecular weight polyethylene glycol.

  The second object of the present invention consists in obtaining an adequate hardenability of the HIPS solution depending on the objectives of the process. The addition of a curing system, preferably based on polysaccharides, to the HPS solutions makes it possible to adapt specific and desired gelation properties to a chosen process (film formation or immersion molding such as the manufacture of capsules hard in HPS by a conventional immersion process). For the manufacture of hard capsules by an immersion molding process, it is extremely important that the film-forming HPS solution remaining on the molding needles after immersion is prevented from running down the needles. Otherwise, the film obtained will not have the thickness

uniform desired.

  With the compositions of the present invention, we can manufacture hard HPS capsules with the same equipment and the same range of operating conditions as those used for the manufacture of conventional hard gelatin capsules. In addition, the capsules made from compositions of the present invention have the same dimensional characteristics and allow the use of existing filling machines and do not require a

  new specific equipment for the filling process.

  The concentration of IIPS in the immersion solution is included in a

  range from 10 to 60%, preferably in the range from 20 to 40% by weight.

  The curing system consists of a hydrocolloid or mixtures

  hydrocolloids and may additionally contain cations and / or sequestering agents.

  Suitable hydrocolloids or mixtures leading to synergistic properties can be chosen from natural algae, natural seed gums, natural plant exudates, natural fruit extracts, biosynthetic gums, gelatins, starches or treated cellulosic materials.

  biosynthetically, polysaccharides being preferred.

  The preferred polysaccharides are alginates, agar gum, guar gum, locust bean gum, carrageenan, tara gum, gum arabic, ghatti gum, khaya grandifolia gum, tragacanth gum, karaya gum , pectin, arabine, xanthan, gellan, starch, Konjac mannan, galactomannan, funoran and other exocellular polysaccharides. Are

  preferred are the exocellular polysaccharides.

  The preferred exocellular polysaccharides are xanthan, acetane, gellan or welane, rhamsane, furcelleran, succinoglycan, scleroglycan, schizophyllan,

  tamarind gum, curdlane, pullulan, dextran.

  The preferred hydrocolloids are kappa-carrageenane, or gellan gum or combinations such as xanthan with carob gum or

xanthan with the Konjac mannan.

  Among the curing systems mentioned above, kappa-carragenane systems with cation and gellan gum with cation are specifically preferred. They lead to high gel resistances to low

  concentrations and have excellent compatibility with HIPS.

  The amount of the hydrocolloid is preferably in the range of 0.01 to 5% by weight and particularly preferably between 0.03 to I% in the

aqueous HPS solution.

  The cations are preferably chosen from K +, Na +, Li +, NH4 +, Ca ++ or Mg ++, for kappa-carrageenane K +, NH4 + or Ca ++ is preferred. The amount of cations is preferably less than 3%, in particular from 0.01 to 1% by weight in

the aqueous solution of HPS.

  The preferred sequestering agents are ethylene diamine tetraacetic acid, acetic acid, boric acid, citric acid, edetic acid, gluconic acid, lactic acid, phosphoric acid, acid tartaric and their salts, metaphosphates, dihydroxyethylglycine, lecithin or beta-cyclodextrin or their combinations. Particularly preferred is ethylene diamine tetraacetic acid or its salts or citric acid or its salts. The amount is preferably less than 5%, preferably 0.01 to 3%, and preferably in particular between 0.01 to I% by weight

of the immersion solution.

  The HPS compositions of the invention contain, according to another aspect, in addition coloring agents, acceptable at the pharmaceutical or food level, in the range of 0 to 10% relative to the weight of the film. The coloring agents can be chosen from azo dyes. quinophthalone, triphenylmethane, xanthene or indigooid, iron oxides or hydroxides, titanium dioxide or natural dyes or their mixtures. Examples are patent blue V, brilliant acid green BS, red 2G, azorubine, culvert 4R, amaranth, red D + C 33, red D + C 22, red D + C 26 , red D + C 28, yellow D + C 10, yellow 2G, yellow FD + C 5, yellow FD + C 6, red FD + C 3, red FD + C 40, blue FD + C 1, blue FD + C 2, green FD + C 3, glossy black BN, carbon black, iron oxide black, iron oxide red, oxide oxide yellow iron, titanium dioxide, riboflavin, carotene, anthocyanins, turmeric, extract

  cochineal, chlorophyllin, canthaxanthin, caramel or betanin.

  The HPS capsules of the invention can be coated using an appropriate coating agent such as cellulose acetate phthalate, polyvinyl acetate phthalate, methacrylic acid gelatins, hypromellose phthalate, l hydroxypropyl methyl cellulose phthalate, hydroxyalkyl methyl cellulose phthalates

  or mixtures thereof in order to obtain, for example, enteric properties.

  The HPS capsules of the invention can be used for the manufacture of containers for obtaining unit dosage forms, for example for agrochemicals, seeds, herbs, food products, products

  colors, pharmaceuticals, flavorings and the like.

  The IIPS capsules of the invention can be used when a release of the filling product is to take place at low temperature such as temperature

  ambient, which is not possible with gelatin capsules.

  The capsules can be produced by sealing the halves of capsules with at least one layer of the composition of the invention. The sealing of

  halves of capsules can be made by a liquid melting process.

  The film-forming solution of the invention can also be used for

encapsulation of microcapsules.

  In the film-forming composition of the invention, the content of hydroxypropylated starch is from 88 to 98% by weight, the water content is from 2 to 12% by weight, the content of polysaccharides is from 0.01 to 10%, from preferably from 0.05 to 5% by weight, and

  the cation content is 0.001 to 5%, preferably 0.01 to 3% by weight.

  The following examples and tests illustrate the manufacture of HPS capsules and their properties: Example 1: Manufacture of HPS capsules comprising 15% of plasticizer 1.5 kg of HPS powder are mixed with 25 g of kappa-carragenane. To 3.21 kg of stirred demineralized water is added 0.5 g of potassium acetate (0.01% by weight in the solution) and 265 g of glycerol (5.3% in solution and 15% in the capsule), followed by the addition of the above mixture (30% HIPS and 0.5% carrageenan in the solution). After good dispersion of the HPS, the dispersion is heated to 90 ° C. with slow stirring, then kept under strong stirring for 10

  minutes to ensure good solubilization of the components.

  The HIPS solution thus prepared is demulsified with slow stirring and then poured into an immersion tank of a pilot machine of equipment for manufacturing conventional hard gelatin capsules. By maintaining the IPS immersion solution at 60 ° C, natural transparent hard HIPS size 0 capsules are produced according to the conventional process with the same characteristics

  dimensional than conventional hard gelatin capsules.

  Results of disintegration tests (according to USP XXIII 1995- <701> Disintegration): First leakage time 21 seconds Total disintegration time 263 seconds Example 2: Manufacture of HPS capsules comprising 10% PVA and 10% plasticizer Mix 1 , 4 kg of HPS powder with 10 g of kappa-carragenane and 175 g of PVA (the PVA has a viscosity of 0.33 Pascal hg / ms (33 cps) at 4% and 20 C). To 3.21 kg of demineralized water with stirring, 5 g of potassium acetate (0.10% by weight in the solution) and 175 g of glycerol (3.5% in solution and 10% in the capsule) are added. ), followed by the addition of the above mixture (28% HPS, 0.20% carrageenan and 3.5% PVA in solution). After good dispersion of the HPS, the dispersion is heated to 90 ° C. with slow stirring, then it is kept under strong stirring for 30 minutes in order to ensure good solubilization of the products. The HPS solution thus prepared is demulsified with slow stirring and then poured into an immersion tank of a pilot machine of equipment for manufacturing conventional hard gelatin capsules. By maintaining the HPS solution bath at 60 ° C., natural transparent hard capsules of size 0 are produced according to the conventional process with the same dimensional characteristics as the

  classic hard gelatin capsules.

  Decay test results First leak time: 51 seconds Total decay time 225 seconds

Claims (28)

  1.- Film-forming compositions consisting of hydroxypropylated starch and a hardening system.   2. Film-forming compositions according to claim 1, in which the   curing system consists of hydrocolloids and cations.   3. Film-forming compositions according to claim 1, in which the   hardening system contains, if necessary, sequestering agents.   4. Film-forming compositions according to claim 1, in which the content of hydroxypropylated starch is from 88 to 98% by weight, the water content is from 2 to 12% by weight, the content of polysaccharides is from 0.01 to 10. %, preferably 0.05 to% by weight and the cation content is from 0.001 to 5%, preferably from 0.01 to 3% in weight.   5. Film-forming compositions according to claim 1, in which the   hydrocolloids of the hardening system are chosen from polysaccharides.   6. Film-forming compositions according to claim 1, in which the hydrocolloids of the curing system are chosen from alginates, agar gum, guar gum, locust bean gum, carrageenan, tara gum, gum arabic, ghatti gum, gum from Khaya grandifolia. tragacanth gum, karaya gum, pectin, arabine, xanthan, gellan, starch, Konjac mannanle, galactomannan or funoran.   7. Film-forming compositions according to claim 1, in which the hydrocolloids of the curing system are chosen from exocellular polysaccharides. 8. Film-forming compositions according to claim 1, in which the hydrocolloids of the curing system are chosen from xanthan, acetane, gellan, welane, rhamsane, furcelleran, succinoglycan, scleroglycan,   schizophyllan, tamarind gum, curdlane, pullulan or dextran.   9. Film-forming compositions according to claim 1, in which the hydrocolloids of the curing system are chosen from gellan gum. or kappa-carragenane.   10. Film-forming compositions according to claim 1, in which the sequestering agent or the mixture of optional sequestering agents of the curing system is chosen from ethylene diamine tetraacetic acid, acetic acid, boric acid, citric acid, edetic acid, gluconic acid, lactic acid, phosphoric acid, tartaric acid, or their salts, metaphosphates,   dihydroxyethylglycine, lecithin or beta-cyclodextrin.   1. Film-forming compositions according to claim 10, in which the sequestering agent or the mixture of sequestering agents is chosen from ethylene acid.   tetraacetic diamine or its salts or citric acid or its salts.   12. Film-forming compositions according to claim I to I 1, further containing plasticizers in a range of about 0 to 40% relative to the weight of the composition. 13. Film-forming compositions according to claim 12, in which the plasticizer or the mixture of plasticizers is chosen from polyethylene glycol, glycerol, sorbitol, sucrose, glucose syrup, fructose, dioctylsodium.   sulfosuccinate, triethyl citrate, tributyl citrate, 1,2propylene glycol, mono-   glycerol di- or triacetates or natural gums.   14. Film-forming compositions according to claims 1 to 13, containing   besides coloring agents in the range of about 0 to 10% based on the weight of the composition.   15. Film-forming compositions according to claim 14, in which the coloring agent or the mixture of coloring agents is chosen from azo dyes, quinophthalone, triphenylmethane, xanthene or indigo, oxides or hydroxides   iron, titanium dioxide or natural dyes.   16. Film-forming compositions according to claim 15, in which the coloring agent or the mixture of coloring agents is chosen from patent blue V, brilliant acid green BS, red 2G, azorubine, culvert 4R, l amaranth, red D + C 33, red D + C 22, red D + C 26, red D + C 28, yellow D + C 10, yellow 2G, yellow FD + C 5, FD + C 6 yellow, FD + C 3 red, FD + C 40 red, blue   FD + C 1, blue FD + C 2, green FD + C 3, glossy black BN.   17. Film-forming compositions according to claim 14, in which the coloring agent or the mixture of coloring agents is chosen from carbon black, iron oxide black, iron oxide red, yellow d oxide, titanium dioxide, IA riboflavin, carotene, anthocyanins, tumor, cochineal extract,   chlorophyllin, canthaxanthin, caramel or betanin.   18.- Containers for unit dosage forms for agrochemicals, seeds, herbs, food products, coloring products, pharmaceuticals or   flavors made from the compositions according to claims 1 to 17.   19. A container according to claim 18, which is a pharmaceutical capsule.   20.- Containers according to claim 18 or 19, characterized in that they have a coating.   21. Coating containers according to claim 20, in which the coating is chosen from cellulose phthalate acetate, polyvinyl acetate phthalate, methacrylic acid gelatins, hypromellose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxyalkyl-miethyl-cellulose phthalates or their mixtures.   22.- Microcapsules encapsulated in film-forming compositions according to the claims I to 17.   23.- Capsules according to claim 18 or 19, characterized in that the half   capsules are sealed with one or more layers of the composition according to the claims I to 17.   24.- Capsules according to claim 18 or 19, characterized in that the   capsule halves are sealed by a liquid melting process.   25.- Capsules according to claim 18 or 19, characterized by a release   filling product at low temperature such as at room temperature.   26.- Aqueous solutions of compositions according to claims I to 17 for the manufacture of capsules.   27.- Aqueous solutions according to claim 26 containing hydroxypropylated starch in an amount of 10 to 60%, preferably 20 to 40% by weight, hydrocolloids in an amount of 0.01 to 5%, preferably 0, 03 to I% by weight, and cations in an amount of 0.001 to 3%, preferably 0.01 to I% by weight of the aqueous solution.   28.- Aqueous solutions according to claims 26 or 27 containing the case   if necessary sequestering agents in an amount of less than 5%, preferably   0.01 to 3% and particularly preferably 0.01 to I% of the aqueous solution.   29.- Use of the aqueous solutions according to Claims 26 to 28 for the   manufacture of hard capsules in an immersion molding process.   30.- Manufacture of hard capsules from aqueous starch solutions   hydroxypropylated according to claims 26 to 28, in a process of molding by   immersion with gelatin capsules equipment and operating parameters hard classic.