Stringer, Ian James (35 Walker Close, Clayford, Kent DA1 4SR, GB)
Green, Linda Ann (9 Oakhill Road, Orpington, Kent BR6 0AE, GB)
Stringer, Ian James (35 Walker Close, Clayford, Kent DA1 4SR, GB)
| 1. | A powder coating material for the production of capsules by electrostatic powder deposition, which comprises hydroxypropyl cellulose and stearic acid. |
| 2. | A powder coating material as claimed in claim 1, wherein the stearic acid is present in an amount from 1 to 15% by weight of the powder. |
| 3. | A powder coating material as claimed in claim 1 or claim 2, wherein the hydroxypropyl cellulose is present in an amount from 15 to 90% by weight of the powder. |
| 4. | A powder coating material as claimed in any one of claims 1 to 3, wherein the material includes a vinyl pyrrolidone/vinyl acetate copolymer. |
| 5. | A powder coating material as claimed in claim 4, wherein the copolymer is present in an amount no more than 75% by weight of the powder. |
| 6. | A powder coating material as claimed in any one of claims 1 to 5, wherein the material includes an aminoalkyl methacrylate polymer. |
| 7. | A powder coating material as claimed in claim 6, wherein the aminoalkyl methacrylate polymer is present in an amount no more than 80% by weight of the powder. |
| 8. | A powder coating material as claimed in any one of claims 1 to 7, wherein the material includes a sugar alcohol. |
| 9. | A powder coating material as claimed in claim 8, wherein the sugar alcohol is present in an amount no more than 15% by weight of the powder. |
| 10. | A powder coating material as claimed in any one of claims 1 to 9, wherein the material includes opacifier and/or colourant. |
| 11. | A powder coating material as claimed in claim 10, wherein the opacifier and/or colourant present constitute no more than 20% by weight of the powder. |
| 12. | A powder coating material as claimed in any one of claims 1 to 11, wherein the material includes a disintegrant. |
| 13. | A' powder coating material as claimed in claim 12, wherein the disintegrant is present in an amount of no more than 10% by weight of the powder. |
| 14. | A powder coating material as claimed in any one of claims 1 to 13, wherein the material includes a plasticiser other than stearic acid. |
| 15. | A powder coating material as claimed in claim 14, wherein the amount of plasticiser is such that the total of stearic acid and other plasticiser together are no more than 15% by weight of the powder. |
| 16. | A powder coating material as claimed in claim 1 which comprises : 15 90% by weight hydroxypropyl cellulose 1 15% by weight stearic acid 0 30% by weight opacifier and/or colourant 0 15% by weight sugar alcohol 0 75% by weight vinyl pyrrolidone/vinyl acetate copolymer 0 80% by weight aminoalkyl methacrylate polymer 0 10% by weight disintegrant 0 10% by weight plasticiser other than stearic acid, the total of stearic acid + other plasticiser together being no more than 15% by weight. |
| 17. | A powder coating material as claimed in any one of claims 4 to 16, wherein the material comprises stearic acid, hydroxypropyl cellulose and at least 2, more especially at least 3, of the other specified components. |
| 18. | A powder coating material as claimed in claim 1, which comprises : 15 90% by weight hydroxypropyl cellulose, 1 15% by weight stearic acid and at least 1, preferably at least 2, more especially 3 or more, of the following further components (i) to (vi) (i) opacifier in an amount of from 5 to 30% by weight and/or colourant in an amount of from 0.5 to 15% by weight, provided that, when both are present, the maximum amount of opacifier and colourant is 30% by weight; (ii) sugar alcohol in an amount of from 2 to 15% by weight; (iii) vinyl pyrrolidone/vinyl acetate copolymer in an amount of from 10 to 75% by weight; (iv) aminoalkyl methacrylate polymer in an amount of from 20 to 80% by weight; (v) disintegrant in an amount of from 2 to 10% by weight; (vi) plasticiser other than stearic acid in an amount of from 2 to 10% by weight, provided that the maximum amount of stearic acid and other plasticiser is 15% by weight; all percentages being based on the total weight of the powder. |
| 19. | A powder coating material as claimed in any one of claims 1 to 18, wherein the stearic acid is present in an amount of no more than 12%, preferably no more than 10%, by weight of the powder. |
| 20. | A powder coating material as claimed in any one of claims 1 to 19, wherein the stearic acid is present in an amount of at least 2%, preferably at least 3%, more especially at least 5%, by weight of the powder. |
| 21. | A powder coating material as claimed in any one of claims 1 to 20, wherein the hydroxypropyl cellulose is present in an amount of no more than 85% by weight of the powder. |
| 22. | A powder coating material as claimed in any one of claims 1 to 21, wherein the hydroxypropyl cellulose is present in an amount of at least 20% by weight of the powder. |
| 23. | A powder coating material as claimed in claim 22, wherein the hydroxypropyl cellulose is present in an amount of at least 60% by weight of the powder. |
| 24. | A powder coating material as claimed in any one of claims 6 to 22, wherein the material includes aminoalkyl methacrylate polymer in an amount of at least 20% by weight of the powder. |
| 25. | A powder coating material as claimed in any one of claims 1 to 23, wherein any aminoalkyl methacrylate polymer is present in an amount of no more than 20% by weight of the powder. |
| 26. | A powder coating material as claimed in any one of claims 1 to 24, wherein any aminoalkyl methacrylate polymer is present in an amount of no more than 60%, preferably no more than 50%, by weight of the powder. |
| 27. | A powder coating material as claimed in any one of claims 1 to 26, wherein any vinyl pyrrolidone/vinyl acetate copolymer is present in an amount of no more than 65%, preferably no more than 60%, by weight of the powder. |
| 28. | A powder coating material as claimed in any one of claims 4 to 27, wherein the material includes vinyl pyrrolidone/vinyl acetate copolymer in an amount of at least 10%, preferably at least 20%, by weight of the powder. |
| 29. | A powder coating material as claimed in any one of claims 1 to 28, wherein any sugar alcohol is present in an amount of no more than 10%, preferably no more by 8%, more especially no more than 5%, by weight of the powder. |
| 30. | A powder coating material as claimed in any one of claims 6 to 29, wherein the material includes a sugar alcohol in an amount of at least 2% by weight of the powder. |
| 31. | A powder coating material as claimed in any one of claims 8 to 30, wherein the material includes xylitol or sorbitol as sugar alcohol. |
| 32. | A powder coating material as claimed in any one of claims 1 to 31, wherein any opacifier and/or colourant is (are) present in an amount of no more than 15%, prefably no more than 10%, by weight of the powder. |
| 33. | A powder coating material as claimed in any one of claims 10 to 32, wherein the material includes titanium dioxide as opacifier. |
| 34. | A powder coating material as claimed in claim 33, wherein the material includes titanium dioxide in an amount of at least 5% by weight of the powder. |
| 35. | A powder coating material as claimed in any one of claims 1 to 34, wherein any colourant is present in an amount of no more than 5%, preferably no more than 2.5%, by weight of the powder. |
| 36. | A powder coating material as claimed in any one of claims 10 to 35, wherein the material includes colourant in an amount of at least 0.5% by weight of the powder. |
| 37. | A powder coating material as claimed in any one of claims 1 to 36, wherein any disintegrant is present in an amount of no more than 8% by weight of the powder. |
| 38. | A powder coating material as claimed in any one of claims 12 to 37, wherein the material includes a disintegrant in an amount of at least 2% by weight of the powder. |
| 39. | A powder coating material as claimed in any one of claims 12 to 38, wherein the disintegrant is sodium starch glycolate or cross carmellose sodium. |
| 40. | A powder coating material as claimed in any one of claims 1 to 30, wherein any plasticiser other than stearic acid is present in an amount of no more than 5%, preferably no more than 3%, by weight of the powder. |
| 41. | A powder coating material as claimed in any one of claims 14 to 40, wherein the material includes plasticiser other than stearic acid in an amount of at least 2%. |
| 42. | A powder coating material as claimed in any one of claims 14 to 41, wherein the plasticiser other than stearic acid is triethyl citrate or polyethylene glycol. |
| 43. | A method for the production of a capsule, which comprises the electrostatic application of a powder coating material as claimed in any one of claims 1 to 42 to a shaped substrate, treating the powder to form a capsule shell, removing the capsule shell from the substrate, filling the capsule shell and assembling a capsule from the filled shell and a further such shell prepared in the same manner. |
| 44. | A method for the production of capsule shells or capsules, which comprises electrostatically applying a powder coating material as claimed in any one of claims 1 to 42 to a plurality of shaped substrates, treating the powder to form a continuous coating layer on each of the shaped substrates, and removing the shaped coating layers from the substrates to provide hollow capsule shells, constituting capsule bodies and capsule caps, and optionally filling the capsule bodies and assembling capsules from the filled capsule bodies and the capsule caps. |
| 45. | A method as claimed in claim 43 or claim 4A1 wherein a glidant powder is applied on top of releasing agent on to the substrate prior to application of the powder coating material. |
| 46. | A method as claimed in any one of claims 43 to 45, wherein lecithin is applied to the substrate as releasing agent prior to application of the powder coating material. |
| 47. | A method as claimed in claim 46, wherein lecithin is applied as a solution in fractionated coconut oil. |
| 48. | Use of lecithin for application to a substrate as a releasing agent, prior to electrostatic application of a coating material for subsequent removal from the substrate. |
| 49. | An electrostatic coating process in which lecithin is applied to a substrate as releasing agent, a powder coating material is deposited thereon by electrostatic means, the coating material is treated to form a fused film layer, the coating being removable from the substrate as a layer, and optionally the layer is removed from the substrate. |
| 50. | A process as claimed in claim 49, wherein the powder material comprises biologically active material. |
| 51. | A process as claimed in claim 50, wherein the coating is removable to provide an individual dosage form. |
| 52. | A process as claimed in claim 50, wherein individual dosages are prepared by subdivision of the coated substrate. |
| 53. | A process as claimed in claim 50, wherein the active coating layer is removed from the substrate and the layer is divided into individual dosages. |
| 54. | A process as claimed in claim 49, wherein a capsule shell is prepared by electrostatic powder deposition. |
| 55. | A process as claimed in any one of claims 49 to 54, wherein a glidant powder is applied on top of a lecithin prior to application of the powder coating material. |
| 56. | A process as claimed in any one of claims 49 to 55, wherein lecithin is applied as a solution in fractionated coconut oil . |
This invention relates to formulations for production of capsule shells and capsules, more especially, but not exclusively, for use in the fields of pharmaceuticals and foods or food supplements.
The mass production of medicines, food supplements and other compounds in predefined doses has become an important part of the health care and other industries. Many of these doses are provided inside a hard or soft gelatin or cellulose capsule. Such a capsule may be easier to administer to a patient when compared to tablets, and the capsules may be readily produced by a mass production manufacturing facility. Capsules are also more easily transported by patients than are bulk liquids, since only the required number of doses are needed. Moreover, in comparison with compressed solid tablets or bulk liquid preparations, incorporation of an active ingredient in a capsule can permit more accurate delivery of a unit dose, an advantage which becomes especially important when relatively small amounts of the active ingredient must be delivered.
Traditionally, mammalian gelatin has been the material of choice for producing the capsule envelope for both soft and hard-shell capsules. Although gelatin is useful for its rapid gelling ability, excellent film-forming properties and ability to impart oxygen impermeability, it has disadvantages, for example its high cost, limited availability and, at times, variation in properties between
batches. Accordingly, a number of patent specifications, for example US 6,375,981 and US 6,337,045, describe the use of alternative compositions, water-soluble cellulose ethers or modified starch compositions, for capsule formation. However, commercial manufacturing methods for capsules, whether gelatin-based or cellulose-based, are complicated and expensive.
Our patent application PCT/GB2004/002742 discloses a novel method for the production of a capsule shell, wherein the capsule shell is prepared by electrostatic powder deposition on a substrate. A capsule shell is prepared by electrostatic powder deposition, filled and capped to provide a finished capsule.
We have now found a range of formulations that are especially suitable for the preparation of capsules by electrostatic powder deposition.
As mentioned in PCT/GB2004/002742, powder material for producing capsules by electrostatic deposition should include a component which is fusible to form a film coating, and various suitable materials, both polymeric and non-polymeric, are mentioned.
All capsule compositions presently on the market utilise hydroxypropyl methylcellulose (HPMC) as the film- former and binder. However, we have developed a range of compositions based on hydroxypropyl cellulose as film-former and binder. Hydroxypropyl celllulose (HPC) is water-soluble and provides a suitably flexible capsule, and has improved properties in capsule formulations for electrostatic powder deposition processes.
As mentioned in the PCT/GB2004/002742 mentioned above, powder material for electrostatic powder deposition preferably also includes a material having a charge-control function, and various charge-control agents are listed. PCT/GB2004/002742 discloses that that functionality may be incorporated into a polymer structure, as in the case of aπunonio-methacrylate polymers, for example those sold under the name Eudragit, and/or, for a faster rate of charging, may be provided by a separate charge-control additive. Examples of suitable charge-control agents are given.
The application PCT/GB2004/002742 mentions also the use of ethyl citrate and polyethylene glycol (PEG) as plasticiser in capsule formulations. Surprisingly, we have found that the plasticiser stearic acid, unlike other plasticisers such as ethyl citrate and PEG, acts also as a charge-control agent; its use also provides improved flexibility to the capsules . The use of stearic acid in cap,sule formulation has not previously been described.
Accordingly, the present invention provides a powder coating material for the production of capsules by electrostatic powder deposition, which comprises HPC and stearic acid.
Advantageously, the content of HPC is at least 15% by weight, preferably at least 20% by weight, of the powder and often at least 60% by weight, and usually is no more than 90% by weight, for example no more than 85% by weight, of the powder.
Preferably, stearic acid is present in an amount of at least 1% by weight of the powder, especially at least 2%, for example at least 3%, often at least 5%, by weight, and
usually no more than 15% by weight. Amounts no more than 12% by weight are common. Powders containing 5 to 10%, or substantially 5% or substantially 10%, by weight stearic acid should especially be mentioned.
Powder coating materials that are treatable on a substrate to form a film coating and processes for their use in electrostatic powder deposition are disclosed, for example, in WO 96/35413, WO 98/20861, WO 98/20863 and WO 01/57144, and PCT application PCT/GB2004/00274 discloses materials suitable for electrostatic powder deposition processes to produce capsule shells. However, none of these specifications discloses a powder coating material comprising HPC and stearic acid.
Often the powder material of the invention includes an opacifier and/or a colourant, depending on the appearance required. Titanium dioxide is an especially useful opacifier, providing white colour and having good hiding power and tinctorial strength. If present, titanium dioxide is usually used in an amount of no more than 30%, preferably no more than 20%, more especially no more 15%, and especially it constitutes no more than 12%, more especially no more than 10%, by weight of the powder material. Often, if used, the minimum is, for example, 5%, and amounts of in the range of 5 to 10%, or substantially 5% or substantially 10%, by weight should especially be mentioned. Any colourant may, for example, constitute no more than 15%, preferably no more than 5%, more especially no more than 2.5%, by weight of the powder. If used, a suitable minimum is for example 0.5%, by weight. Usually, however, the powder material contains, for example, from 0 to 30%, preferably no more than 20%, more especially no more than 15%, by weight of titanium dioxide or colourant or of titanium dioxide plus colourant together,
colourant being present usually in an amount of from 0 to 15%, preferably 0 to 5%, by weight, especially 0 to 2.5%, of the powder material.
A sugar alcohol, for example xylitol, lactitol, sorbitol, galactitol or maltitol, may, if desired, also be used to promote solubility. Preferably, if present, xylitol is used in an amount of no more than 15% by weight, more especially no more than 10% by weight, more especially no more than 8%, for example substantially 5% or less, by weight. A suitable minimum is, for example, 2% by weight. Sugar alcohols are fusible components and are highly soluble, being added therefore to improve disintegration. Xylitol and sorbitol should, for example, be mentioned in particular.
A further possible component is, for example, a vinyl pyrrolidone/vinyl acetate (VP/VA) copolymer, which is fusible and acts as film-former, and provides water-solubility. Vinyl pyrrolidone/vinyl acetate copolymers are known, and, for example, polymers having a VPrVA ratio of 20:80, 30:70, 40:60, 50:50, 60:40 and 70:30 are available commercially. The 60:40 copolymer, for example, which copolymer has been cleared for pharmaceutical use, gives considerably improved results in comparison with vinyl pyrrolidone itself, and formulations containing vinyl pyrrolidone/vinyl acetate copolymer have a smoother and more glossy appearance and a greater tensile strength than formulations based on HPC as the main or sole film-former. Preferably, if present, the copolymer is used in an amount of no more than 75% by weight, especially no more than 65% by weight, more especially no more than 60% by weight, for example no more than 50% by weight, of the powder. A suitable minimum is, for example, 10% by weight, especially 20% by weight, more especially 25% by weight. A range of 20 or 25 to 50%, for example
substantially 25% or substantially 45%, should especially be mentioned.
The powder material may, if desired, further contain a fusible, film-forming aminoalkyl methacrylate polymer, which has charge-control properties, more especially the acid- soluble, low melting, aminoalkyl methacrylate copolymer sold under the trade name Eudragit E. Eudragit E is excellent for instant-release coatings and has very good properties for electrostatic coating (melt flow, charge and resistivity) . Aminoalkyl methacrylate polymer is especially useful when acid-solubility, rather than water-solubility, is required, and a suitable minimum is, for example, 20% by weight, and amounts of, for example, substantially 35% or substantially 50% by weight should especially be mentioned. Preferably, the polymer is used in an amount of no more than 80% by weight, for example no more than 60% by weight. Combinations of the film-formers Eudragit E, VP/VA copolymer and HPC in the respective amounts 35%, 35%, 20% and 50%, 20%, 22% should especially be mentioned. When water-solubility is required, in general, no more than 20% by weight of aminoalkyl methacrylate polymer, and often none, will be used. Amounts up to 10%, for example up to 5%, should especially be mentioned. The use of Eudragit E results in a harder capsule, but on its own would lead to brittle capsules, but flexibility is ensured by its use together with stearic acid and HPC or HPC+VP/VA combinations, the VP/VA copolymer being used to improve strength. In comparison with capsules prepared from a combination of HPC, Eudragit E and other plasticiser, formulations including stearic acid provide more flexibility and shinier capsules.
The powder material of the invention may, if desired, include a disintegrant, for example sodium starch glycolate
or cross carmellose sodium. Preferably, if present, a disintegrant is used in an amount of no more than 10% by weight, more especially no more than 8% by weight, for example substantially 5% by weight, of the powder. A suitable minimum is, for example, 2% by weight. With thin capsule walls, however, the need for a disintegrant is less.
Further possible addition includes, for example, an additional plasticiser, e.g. triethyl citrate or PEG, for example polyethylene glycol 6000. If used, additional plasticiser (i.e. other than stearic acid) may be present, for example, in an amount of at least 2%, for example up to 5%, especially up to 3%, and the total plasticiser, including stearic acid, is preferably no more than 15%, especially no more than 12%, more especially no more than 10%, for example no more than 5%, by weight of the powder.
Accordingly, more especially, the present invention provides a powder coating material comprising:-
15 - 90% by weight HPC
1 - 15% by weight stearic acid
0 - 30% by weight in total, titanium dioxide and/or colourant 0 0 -- 1 155%% by weight xylitol or other sugar alcohol
0 - 75% by weight vinyl pyrrolidone/vinyl acetate copolymer
0 - 80% by weight aminoalkyl methacrylate polymer
0 - 10% by weight disintegrant 0 - 10% by weight plasticiser other than stearic acid, the total of stearic acid + other plasticiser together being no more than 15% by weight.
More especially, the material comprises HPC and stearic acid and at least one, preferably at least two, more especially at least three, other materials mentioned.
Powder materials comprising 15 - 90% by weight HPC,
1 - 15% by weight stearic acid and at least 1, preferably at least 2, more especially 3 or more, of the following further components (i) to (vi) (i) opacifier in an amount of from 5 to 30% by weight and/or colourant in an amount of from 0.5 to 15% by weight, provided that, when both are present, the maximum amount of opacifier and colourant is 30% by weight; (ii) sugar alcohol in an amount of from 2 to 15% by weight; (iii) vinyl pyrrolidone/vinyl acetate copolymer in an amount of from 10 to 75% by weight;
(iv) aminoalkyl methacrylate polymer in an amount of from 20 to 80% by weight;
(v) disintegrant in an amount of from 2 to 10% by weight; (vi) plasticiser other than stearic acid in an amount of from 2 to 10% by weight, provided that the maximum amount of stearic acid and other plasticiser is 15% by weight should especially be mentioned.
Good film strength is an important consideration for capsules, and formulations of the invention show good dry film strength, and good film flexibility, and can be used to produce instant-release capsules, dissolving in water or in acid. In comparison with the manufacture of capsules based on HPMC, the use of formulations of the present invention
allows a quicker and easier manufacture of capsules, with more formulation flexibility.
Preferably, the powder material has a glass transition temperature (Tg) in the range of 4O 0 C to 180°C, e.g. in the range 40 to 12O 0 C. Advantageously, the material has a Tg in the range of 50 0 C to 100 0 C. A preferred minimum Tg is 55°C, and a preferred maximum Tg is 70 0 C. Accordingly, more advantageously, the material has a Tg in the range of 55°C to 7O 0 C.
Advantageously, the powder material is prepared by melt compounding the components of the powder material. Melt compounding gives a very intimate blend so that after extrusion and milling the particles produced contain all the different component materials. Melt compounding may be carried out, for example, in a twin-screw extruder at a temperature in the range of from 100 to 140 0 C, preferably from 120 to 13O 0 C. Other methods may alternatively be used to obtain even dispersion and content uniformity in the resulting capsule.
After melt compounding, the material is micronised and advantageously classified to obtain the desired particle size. Preferably, at least 50% by volume of the particles of the material have a particle size no more than lOOμrα.
Advantageously, at least 50% by volume of the particles of the material have a particle size in the range of 5μm to 40μm. More advantageously, at least 50% by volume of the particles of the material have a particle size in the range of 8 to 25μm, for example substantially lOμm.
Powder having a narrow range of particle size should especially be mentioned. Particle size distribution may be quoted, for example, in terms of the Geometric Standard Deviation ("GSD") figures dgo/dso or dso/dio where dgo denotes the particle size at which 90% by volume of the particles are below this figure (and 10% are above) , dio represents the particle size at which 10% by volume of the particles are below this figure (and 90% are above) , and d 5 o represents the median particle size. Advantageously, the median (d 50 ) is in the range of from 5 to 40μm, for example from 10 to 25μm. Preferably, dgo/d 5O is no more than 2.5, often no more than 1.5, especially the range of from 1.2 to 1.5, especially 1.3 to 1.4, the particle sizes being measured by laser measurement systems, for example by Malvern particle size analyser. Thus, for example, the powder may have d 50 = lOμm, dgo = 13μm, dχo = 7μm, so that dgo/dso = 1.3 and dso/dio = 1.4.
A flow aid may, if desired, be added to the powder material before use. Flow aid is present at the outer surface of the powder particles to reduce the cohesive and/or other forces between them. Suitable flow aids (which are also known as "surface additives") are, for example, colloidal silica; metal oxides, e.g. fumed titanium dioxide, zinc oxide or alumina; metal stearates, e.g. zinc, magnesium or calcium stearate; talc; functional and non-functional waxes; and polymer beads, e.g. poly-methyl methacrylate beads, fluoropolymer beads and the like. Such materials may also enhance tribocharging. A mixture of flow aids, for example silica and titanium dioxide, should especially be mentioned. The powder material may contain, for example, 0 to 1% by weight, advantageously no more than 0.5%, e.g. no more than 0.25%, by weight of surface additive flow aid, calculated on the powder of the invention plus additive.
The electrostatic application of powder material to a substrate is known. Methods have already been developed in the fields of electrophotography and electrography and examples of suitable methods are described, for example, in Electrophotography and Development Physics, Revised Second Edition, by L.B. Schein, published by Laplacian Press, Morgan Hill California.
Preferably powder is deposited electrostatically on a shaped substrate, and then treated to form a continuous layer on the substrate, for example by IR and/or convection heating, and the coating layer is removed to provide a hollow capsule shell. Subsequently, the capsule itself is assembled, generally from two such capsule shells, which may conveniently be referred to as capsule body and capsule cap. Before assembly the capsule body is filled, for example with liquid, powder or other solid material, and the cap fitted to the body. A capsule cap is usually smaller than its capsule body, for example about half its length, although it may be of the same size and shape. However, a capsule may also be assembled using a capsule shell (capsule body) prepared by electrostatic powder deposition and provided with a cap by some other means.
A shaped substrate may be, for example, in the shape of a rod, for example about 5mm in diameter, more especially for the production of conventionally shaped pharmaceutical capsules, but the capsules may be a different shape suitable for their mode of use, and appropriately shaped moulds should be used as substrates.
More especially, a substrate may be a metal substrate, for example steel; a metal support provides an excellent
substrate for electrostatic deposition because of its high conductivity.
Preferably the substrate (s) is (are) treated with a releasing agent prior to application of the powder coating material. Releasing agents are known in the literature. In general, such materials provide lubrication for release but should not penetrate the coat during fusion. Application PCT/GB2002/002742 discloses the use of an oil, paraffin, talc. PTFE, heavy paraffin liquid or polyethylene glycol, e.g. PEG 300, as releasing agent, and such releasing agents or mixtures thereof may be applied prior to deposition of a powder coating material of the invention.
We have now found that good results can be obtained by application of a liquid releasing agent such as oil, paraffin, heavy paraffin liquid of PEG, followed by application of talc or PTFE or other glidant powder to act as releasing agent.
We have also found that particularly advantageous results may be obtained by the use of lecithin as releasing agent. Lecithin dissolved in fractionated coconut oil (capric triglyceride) , for example as sold under the trade name Migliol 810, is especially suitable.
Accordingly, the present invention provides the use of lecithin for application to a substrate as a releasing agent, prior to electrostatic application of a coating material for subsequent removal from the substrate.
The invention also provides the use of lecithin for the manufacture of a releasing agent for application to a
substrate to which a coating material is to be applied to form a coating removable as a layer from the substrate.
More especially the lecithin is used in the production of pharmaceutical products, although use in the production of non-pharmaceutical dosage forms should also be mentioned.
WO 98/20863 describes the coating of a substrate for the production of wafers or similar pharmaceutical products, by the electrostatic application of active coating material, more especially powder material, to the substrate to form an active coating layer, wherein the active coating layer is removable from the substrate. The active coating layer may be removable to provide an individual solid dosage form, or individual dosages may be prepared by sub-division of the coating layer, before or after removal of that layer from the substrate.
There should especially be mentioned use of lecithin, or liquid releasing agent followed by glidant powder, as releasing agent in this process of WO 98/20863, the text of which is herein incorporated by reference.
More especially, lecithin is applied to the substrate as releasing agent, if desired a glidant powder is applied, the coating material is applied as a powder; and the powder is converted more especially by fusing to a coherent layer removable as a layer from the substrate.
Thus, the present invention also provides an electrostatic coating process in which lecithin is applied to a substrate as releasing agent, a powder coating material is deposited thereon by electrostatic means, the coating material is treated to form a fused film layer, the coating
being removable from the substrate as a layer, and optionally the layer is removed from the substrate.
A process in which the coating material includes biologically active material, preferably pharmaceutically active material, should especially be mentioned.
More especially the lecithin is used as releasing agent in the production of capsules by electrostatic powder deposition, as detailed for example in patent application PCT/GB2004/002742.
Accordingly, the present invention further provides a method for the production of a capsule shell, wherein the capsule shell is prepared by electrostatic powder deposition, lecithin being applied as releasing agent before the electrostatic powder deposition process.
Preferably the lecithin is used as releasing agent in capsule production by electrostatic powder deposition using a powder coating material of the invention.
The present invention also provides a method for the production of a capsule, which comprises the electrostatic application of a powder coating material of the invention to a shaped substrate, optionally after prior application of releasing agent, more especially lecithin, treating the powder to form a capsule shell, removing the capsule shell from the substrate, filling the capsule shell and assembling a capsule from the filled shell and a further such shell prepared in the same manner.
The present invention further provides a method for the production of capsule shells or capsules, which comprises
electrostatically applying a powder coating material of the invention to a plurality of shaped substrates, optionally after prior application of releasing agent, more especially lecithin, treating the powder to form a continuous coating layer on each of the shaped substrates, and removing the shaped coating layers from the substrates to provide hollow capsule shells, constituting capsule bodies and capsule caps, and optionally filling the capsule bodies and assembling capsules from the filled capsule bodies and the capsule caps.
Preferably, lecithin is applied as releasing agent to the shaped substrates, prior to application of the powder coating material .
Suitable methods for assembling capsules are known in the literature. For example, the two halves may be pressed or squeezed together until they are frictionally locked. A particular assembling process with closing and ejection pins is for example, disclosed in US 6,546,702. The capsules may also if desired be heat-sealed. The seal should of course be suitable for the capsule purpose.
The filling material may be any material that can be apportioned into individual units, and is often a biologically active material, that is, a material that increases or decreases the rate of a process in a biological environment. The biologically active material more especially is a material that is physiologically active, especially for use in medicine, but it may also, for example, be for use in nutrition (for example a vitamin, nutritional supplement, pre-measured food ingredient such as flavouring, or confectionery) . Preferably, the capsules are for pharmaceutical use. Where the capsule is to be taken orally
or otherwise, the powder material should of course be pharmaceutically acceptable.
Other biologically active filling material may be, for example, for use in agriculture or pest control (for example a fertiliser, pesticide, herbicide or repellent) , and other non-pharmaceutical capsules may be filled, for example, with material for use in bathing or washing, for example liquid soaps, foaming agents, perfumes, detergents, enzymes, bleach, or water or fabric softeners or rinse aids.
A coating layer formed on the substrate may be, for example, from 70 to 200μm. Increasing the coating thickness will in general provide further capsule strength. Usually one layer is applied but, if desired, one or more layers may be applied, each being fused before application of further powder, to provide a thickness of, for example, at least 200μm. Alternatively, using a low charge to mass ratio and a large particle size powder, for example about 30μm, may allow the production of a thicker capsule shell from a single layer.
Preferably the powder material is electrostatically charged and an electric field is present in the region of the shaped substrate to cause the powder material to be deposited on the shaped substrate. For example, the powder material may be electrostatically charged with a sign of one polarity, an electric potential of the same polarity may be maintained in the region of a source of the powder material, and the substrate may be maintained at a lower, earth or opposite potential. For example, the powder material may be electrostatically charged and a potential of the same sign may be maintained in the region of a source of the powder material and the substrate may be maintained at earth
potential. The powder material may have a permanent or temporary net charge. Any suitable method may be used to charge the powder material. Advantageously, the electrostatic charge on the powder material is applied by triboelectric charging (as is common in conventional photocopying) or corona charging. The use of a charge- control agent encourages the particle to charge to a particular sign of charge and to a particular magnitude of charge.
The electric field is preferably provided by a bias voltage that is a steady DC voltage. Preferably, an alternating voltage, which is substantially higher than the DC voltage, is superimposed on the bias voltage. The alternating voltage preferably has a peak to peak value greater than, and more preferably up to twice, the peak value of the DC bias voltage. The DC bias voltage may be in the range of 100V to 2,000V and is preferably in the range of 200V to 1,200V. The alternating voltage may have a peak to peak value of the order of 5,000V and may have a frequency in the range of 0.1 to 3 kHz, more especially 250 to 1000 Hz.
Achievement of good and even coating is facilitated if the spacing between the source of powder material and the substrate is relatively small, that is less than 10mm.
Preferably the spacing is in the range of 0.3mm to 5mm and more preferably between 0.5mm to 5mm.
The application of the powder material may be continued for a pre-determined time, sufficient to obtain the desired coating thickness such that a good balance between capsule strength and solubility is achieved. Thus, for example, application may be carried out for a period in the range of
from 10 to 100 seconds, especially from 15 to 30 seconds, for example 15 or 30 seconds.
Alternatively, the method may include the steps of: applying a bias voltage to generate an electric field between a source of the powder material and the substrate; applying the electrostatically charged powder material to the substrate, the powder material being driven onto the substrate by the interaction of the electric field with the charged powder material and the presence of the charged powder material on the substrate serving to build up an electric charge on the substrate and thereby reduce the electric field generated by the bias voltage between the source of powder material and the substrate, and continuing the application of the electrostatically charged powder material to the substrate until the electric field between the source of powder material and the substrate is so small that the driving of the powder material by the electric field onto the substrate is substantially terminated.
Using such a method promotes even coating of the substrate even when the spacing of some parts of the substrate from the source of powder material differs from the spacing of other parts. That is of particular advantage when the substrate is in the shape of a rod with a rounded end. Furthermore the method promotes even coating regardless of the rate at which powder is deposited on the substrate and may be employed when there is relative movement between the substrate and the source of powder material during deposition. In a case where the thickness of one layer of coating is not as great as the final thickness required, one or more other coating layers may be deposited and, if
desired, the DC bias voltage increased for the deposition of the further layer (s) .
An electrostatically conducting shield may be provided around part or all of the substrate. For example, in the case where the substrate is in the shape of a rod, the electrostatically conducting shield may be disposed closely around, and may or may not be spaced from, the rod, at a distance from the end of the rod. The shield may be maintained at an electric potential more similar to that of the powder material than to that of the substrate. We have found that by providing an electrically conducting shield closely around the substrate and maintaining the shield at a potential more similar to that of the source of powder material than to that of the substrate, a physical and electrostatic barrier can be created and it becomes possible to confine the application of powder to the substrate and to coat a region of the substrate uniformly as far as a limit defined by the shield. Thus a well-defined limit to the coating can be obtained. Where the substrate is a rod and the shield extends circumferentially around the rod, the limit to the coating may be defined at a predetermined axial distance from the end of rod.
The spacing of the shield from the substrate is preferably less than lmm and is preferably uniform. It may, for example, be in the range of 0.1 to 3mm, for example 0.1 to 0.15mm.
The electrically conducting shield may comprise an electrically conducting element covered wholly or partly by a layer of insulating material. The provision of a layer of insulating material, which is preferably thin, prevents
accidental electrical contact being made between the substrate and the shield.
The potentials of the electrically conducting shield and the charge powder material are preferably of the same sign.
In the case where powder material is applied to a plurality of shaped substrates, a common shield may be provided around part or all of the substrates. For example, where the substrates are in the shapes of rods the shield may have a plurality of holes through each of which the end of a respective rod projects.
Selection of the physical arrangement to be employed for coating of the substrate is dependent upon the shape of the substrate to be coated. For example, it is possible to provide a plurality of separate sources of powder material to coat a single substrate and/or to provide sources of complex shapes and/or to provide electric fields of complex shapes. It is also possible to arrange for the source of powder material and/or the substrate to move during the application of the powder material. In the case where the substrate is a rod of circular cross-section, the source of powder material may be positioned at a radial spacing from the rod alongside the end portion of the rod and the rod may be rotated relative to the source of powder material. In such a case, if the rod is about 5mm diameter, then the centre of the end of the rod may be about 2.5mm further from the source of powder material than the circumferential portion of the rod. Such a difference in spacing need not, however, result in uneven coating, especially if application of the powder material is continued until the electric field between the source of material and the substrate is substantially cancelled. Another possibility is to provide the source of
powder material on the longitudinal axis of the rod beyond the end of the rod.
Further details of suitable methods and apparatus are described in WO 96/35516, WO 01/43727, WO 02/49771, WO 03/061841 and WO 04/24339, the texts of which are incorporated herein by reference.
As mentioned in PCT/GB2004/002742, an apparatus for the production of a capsule shell may include a substrate, a source of charged powder material and a voltage source for applying a bias voltage between the source of powder material and the substrate to generate an electric field therebetween such that powder material is applied to the substrate.
A plurality of substrates, in the form of a plurality of rotatable rods, may be provided and the rods may be arranged to be rotated by a common drive arrangement. The rods are preferably detachably mounted on respective mounting members that are arranged to be rotated by the common drive arrangement.
After application, the powder coating may be converted into a coherent film by heating, preferably by infra-red radiation, but other forms of electromagnetic radiation or convection heating may be used. Usually the change in the coating upon heating will simply be a physical change. The powder material may be heated to a temperature above its softening point, and then allowed to cool to a temperature below its Tg to form a continuous solid coating. It may, for example, be heated to a temperature of 150 to 300°C, for example for 90 to 180 seconds. Preferably, the powder material is fusible at atmospheric pressure at a temperature of less than 250°C eg less than 200°C, and most commonly below
15O 0 C, and often at least 8O 0 C, for example in the range of from 120 to 140 0 C.
By way of example of the production of capsule shells, an apparatus suitable for the application of powder material of the invention to a substrate to form a capsule shell will now be described with reference to the accompanying drawings, in which:
Fig. IA is a schematic side view of the apparatus;
Fig. IB is a schematic side view of a modified part of the apparatus;
Fig. 1C is a schematic side view showing a particular arrangement of a powder material source that may be employed in the apparatus of Fig. IA or Fig. IB;
Fig. ID is a schematic side view showing another particular arrangement of a powder material source that may be employed in the apparatus of Fig. IA or Fig. IB; and
Fig. 2 is a schematic sectional side view of part of a modified form of apparatus.
Referring first to Fig. IA, a substrate comprises the end portion of a solid steel rod 1 of circular cross-section. The rod has a hemispherical end 2. A shield 3 in the form of a flat plate with a circular hole 4 is provided and is disposed with the end portion of the rod 1 projecting through the hole 4. Thus the shield 3 closely surrounds, but is spaced from, the rod 1.
A source 5 of charged powder material is provided alongside the end portion of the rod 1 at an even radial spacing from the rod. The source 5 has an elongate outlet 6, schematically illustrated in Fig. IA, from which the powder material is supplied.
The shield 3 has an electrically insulating base 7 and an electrically conducting layer 8 supported on the base 7.
A voltage source 9 is connected to apply a potential to the powder material source 5 and also to the electrically conducting layer 8 of the shield 3. As previously described, the potentials applied may comprise both DC bias potential and an AC potential. The rod 1 is earthed. In an alternative embodiment, the voltage source and shield are not connected.
An infra red heater 10 is also provided alongside the rod 1.
In use after the rod has been coated with a suitable releasing agent, preferably lecithin, the rod 1 is rotated by means not shown, as indicated by the arrow in Fig. IA and charged powder is made available at the powder material source 5. The voltage source 9 establishes an electric field between the powder material source 5 and the rod 1 with the result that powder is driven onto the end portion of the rotating rod 1, including the hemispherical end 2 of the rod. The shield 3 shapes the electric field such that powder is deposited along the rod up to the shield 3 but not beyond, and a well-defined circumferential edge to the powder deposition is thereby defined. Application of powder is continued until powder ceases to transfer across from the source 5 to the rod 1 because the charged powder deposited on
the rod 1 has so reduced the electric field between the powder source 5 and the rod, or until the desired transfer time has elapsed.
Once the application of powder is complete, the infra red heater 10 is switched on to heat the powder material deposited on the rod 1 and convert it into a continuous layer. The material is then allowed to cool and is then removed from the rod, providing a hollow capsule shell.
Fig. IB shows an alternative arrangement for the shield and the parts shown in Fig. IB are referred by the same reference numerals as in Fig. IA but with the suffix "b" added where the parts are arranged differently. Thus it will be seen that the shield 3b of Fig. IB is of generally cylindrical shape surrounding the rod 1. The shield 3b has an outer electrically conducting cylindrical layer 8b and an inner electrically insulating cylindrical base 7b. In Fig. IB the base 7b is shown slightly spaced from the rod 1 but it may be in contact with the rod 1 and indeed the shield 3b may be fixed to the rod 1 and rotates with the rod. Although not shown, it will be understood that the layer 8b is electrically connected to a voltage source 9 in the same manner as in the arrangement of Fig. IA and the operation of the modified arrangement according to Fig. IB is substantially the same as that of Fig. IA.
The powder delivery source 5 may be of a kind known per se. For example, WO 02/49771 describes an apparatus that may be employed and shows in Fig. 1 a powder source having a roller Ia from which charged powder is supplied. Fig. 1C illustrates one possible orientation of the roller Ia of WO 02/49771 to the rod 1. In Fig. 1C the roller Ia of WO 02/49771 is shown without its associated apparatus and is
referenced 11a. It will be seen that the axis of the roller 11a is perpendicular to the axis of the rod 1, that the periphery of the roller 11a is alongside the side of the rod 1 and that the rod 1 is rotated. It will be understood that the other parts of the apparatus (not shown in Fig. 1C) may ¬ be as shown in Fig. IA or Fig. IB. In operation powder leaves the region of the roller 11a adjacent to the side of rod 1 and is deposited along the exposed length of the rod 1.
Fig. ID shows an alternative orientation of the roller 11a and the rod 1. In this case the axis of the roller 11a is perpendicular to the axis of the rod 1, but the periphery of the roller 11a is alongside the end of the rod 1. In this case the rod 1 need not be rotated. Powder from the roller 11a tends first to coat the adjacent end of the rod 1 but thereafter coats the more distant parts of the rod 1. Again it will be understood that the other parts of the apparatus (not shown in Fig. ID) may be as shown in Fig. IA or Fig. IB; it will be understood that, if necessary, the shape and/or position of the heater 10 can be adjusted to avoid the heater and the roller 11a obstructing one another.
Whilst the apparatus shown is suitable for producing only one capsule shell at a time, it should be understood that by providing many rods and moving them and/or providing a plurality of sources of powder material and/or heaters, it is possible to adapt the apparatus to generate many capsule shells at a time.
Fig. 2 shows a rig that may be employed to coat a plurality of rods at one time. In the drawing five rods 1 are shown but it will be understood that a much greater number may be provided, if desired. Each rod 1 is detachably located in a socket 21 at one end of a mounting member 22.
The other end of each mounting member 22 is received in a drive assembly 23 where it is rotatably mounted in a bearing block 24 and has a toothed gear portion 25. The toothed gear portion of adjacent mounting members mesh with one another and there is also provided an additional toothed gear portion 25a connected to a rotary drive (not shown) . Thus, operation of the rotary drive causes rotation of each of the mounting members 22, with adjacent members rotating in opposite directions. It will be appreciated that one or more static or travelling powder sources, corresponding to the source 5 shown in Fig. 1 can be provided along the sides of the rods 1 as shown in Fig. 1C and a heater and/or shield can be provided as shown in Figs. IA or IB. A shield may be provided around each rod 1 in the region designated 26 in Fig. 2.
If desired, one or more additional rows of mounting members may be provided alongside the row shown in Fig. 2. If more than one additional row is provided then it is necessary either for the powder to be applied from the ends of the rods or for a sufficiently large space to be left between rows to accommodate an appropriate powder source .
In one particular example of the invention, using an apparatus of the kind shown schematically in Fig. 1C, coating was carried out under the following conditions:
Speed of rotation of rod 1: 35 rpm
Gap between rod 1 and roller 11a (minimum) : 10 mm Potential of roller 11a : -3000V
Coating time: 90 seconds
In another particular example of the invention, again using an apparatus of the kind shown schematically in Fig. 1C, coating was carried out under the following conditions:
Speed of rotation of rod 1: 35 rpm
Gap between rod 1 and roller 11a (minimum) : 2 mm Potential of roller 11a : -1000V
Coating time: 90 seconds
In each case the rod 1 was maintained at earth potential and after application to the rod 1, the coating was exposed to a fuser at a temperature of 25O 0 C for a time of for example 90 or 180 seconds.
Capsules produced in these examples had wall thicknesses of 150~200μm and a length in the range of 10 to 30μm.
The following Examples illustrate the invention
Examples
Example 1
Formulation
42.5% Hydroxypropyl cellulose
42.5% Vinyl pyrrolidone/vinyl acetate copolymer
5.0% Stearic acid
5.0% Titanium dioxide 5.0% Polyethylene glycol 3000
The hydroxypropyl cellulose used in this and subsequent Examples was the commercial grade with lowest softening point.
Powder Manufacture
The components were blended using a high speed pharma mixer and the blend was then passed through a twin screw compounder using a temperature of 120°C in the mixing zone. The material was cooled using a chilled roll and then size- reduced using a hammer mill. The material was then micronised and classified to produce a powder of mean particle size of lOμm with a GSD of 1.7.
Capsule manufacture
The powder was used to produce capsules using the following method:
Five pins were mounted as shown in Fig 2. Two sets of pins were used, one to produce the caps and one to produce the bodies of the capsules .
A release agent was applied by hand using a swab, covering the exposed pin surface evenly. The release agent consisted of 1.5g of lecithin dissolved in 30 ml of Miglyol.
Pins were positioned approximately 5mm from the powder source. Pins were coated using the following conditions:
Pin rotation speed: 35 rpm DC voltage: + 1200V AC voltage: 2400V Coating time: 30-45 seconds
The pins were moved to a position below a hot air fuser and heated under an air temperature of 250°C for 90 seconds.
The capsule shells were removed from the pins by hand when cool and trimmed using a blade: the bodies were trimmed to approximately 18 mm length, and the caps were trimmed to approximately 9 mm length
Satisfactory capsules were obtained.
Capsule Performance
Average weight of a complete capsule (body + cap) : 71.5 mg Average capsule body thickness: 110 μm Capsules disintegrated in water within 5 minutes
Example 2
60.0% Hydroxypropyl cellulose
25.0% vinyl pyrrolidone/vinyl acetate copolymer
5.0% Titanium dioxide
5.0% Polyethylene glycol 3000 5.0% Stearic acid
The powder formulation was produced and capsules were produced as detailed in Example 1.
The vinyl pyrrolidone/vinyl acetate copolymer used here and below was the 60:40 commercially available product of ISP Global Technologies, Kentucky, or BASF Fine Chemicals. Satisfactory capsules were obtained.
Capsules disintegrated in water in < 10 mins
Comparative Example
Formulation
60.0% Hydroxypropyl cellulose
25.0% vinyl pyrrolidone/vinyl acetate copolymer
5.0% Titanium dioxide
5.0% Polyethylene glycol 3000 5.0% Sorbitol
The powder formulation was produced as described in Example 1 and the method for capsules production as detailed in Example 1 was followed. However the electrostatic properties of this powder were poor and, hence, although capsules could be produced, the variation in capsule weight and wall thickness was unacceptable.
Capsules disintegrated in water in < 5 mins
The following further examples of formulations of the invention are manufactured and used for producing capsules as in Example 1.
Water-soluble Capsule Formulations
Formulation 3 85% HPC 10% stearic acid
5% titanium dioxide
Formulation 4 66% HPC 14% vinyl pyrrolidone/vinyl acetate copolymer
5% sodium starch glycolate 10% stearic acid 5% titanium dioxide
Formulation 5 66% HPC 14% vinyl pyrrolidone/vinyl acetate copolymer
5% xylitol 10% stearic acid 5% titanium dioxide
Formulation 6 60% HPC
25% vinyl pyrrolidone/vinyl acetate copolymer 10% stearic acid
5% titanium dioxide
Formulation 7 80% HPC 5% xylitol
10% stearic acid 5% titanium dioxide
The HPC-based formulations formed flexible capsules that dissolve in water in approximately 5 minutes.
Acid-soluble Capsule formulations
Formulation 8 35% Eudragit E
37% vinyl pyrrolidone/vinyl acetate copolymer 20% HPC
3% stearic acid
5% titanium dioxide
Formulation 9 35% Eudragit E
35% vinyl pyrrolidone/vinyl acetate copolymer 20% HPC
5% stearic acid
5% titanium dioxide
The Eudragit E used is manufactured by Rohm and available from Degussa.
The formulations based on Eudragit E formed harder (non- flexible) capsules that dissolve in 0.1 M HCl.