Patent 6,783,768

Method of coating a substrate which is a belt, sheet, film, or tape, comprising applying an active coating material to the substrate to form an active coating layer, the active coating material comprising biologically active material. The active coating material is applied electrostatically as a powder and, after the active coating material is applied, the active coating material is fused to form an active film layer. The active coating material is removable from the substrate as a wafer comprising the active film layer.

Description of the Invention

The present invention relates to methods of coating by substrates, to apparatus for coating substrates and to coated substrates for pharmaceutical use. In particular, but not exclusively, the invention relates to the coating of pharmaceutical substrates to produce solid dosage forms.

BACKGROUND OF THE INVENTION

It is to be understood that the term "solid dosage form" is to be interpreted in a broad sense as covering a wide variety of pharmaceutical products. Thus the term covers pharmaceutical products to be taken orally, for example, pharmaceutical tablets of conventional shape as well as capsules and spherules and tablets of unconventional shape. The term also covers pharmaceutical products not taken orally, for example, a pessary, a bougie, a suppository or a patch for application to the skin. Also, where reference is made to "pharmaceutical substrate" it is to be understood that the term covers the substrates of the solid dosage forms indicated above. The term "solid dosage form" does not, however, include pharmaceutical products such as small pellets and granules, for example small pellets which are filled into capsule shells for administration and granules which are compressed to form tablets; such pellets or granules are not themselves each solid dosage forms but rather, when combined together in a capsule or tablet, define in combination a solid dosage form.

It will be understood that the term "active material" and "active component" used throughout the specification includes material which is biologically active and will comprise one or a mixture of pharmaceutical materials. The pharmaceutical materials include those materials which are administered for the prevention and/or treatment of disease.

Active materials are conventionally administered in the form of tablets.

In a conventional method of producing a pharmaceutical tablet, a mixture containing the biologically active ingredient together with diluents such as lactose and other ingredients is mixed and portions of the mixture are formed into discrete tablets by, for example, pressing samples of the mixture.

A problem with the method of producing tablets described above is that, due to inhomogeneity of the mixture from which the tablet cores are made, the amount of active ingredient in the resulting tablet cores varies from one tablet to the next. While that is a problem for all types of tablet core produced in that way, it is a particularly serious problem when the amount of active ingredient in each core is low, for example for active compounds of high activity. In that case a small absolute variation in the percentage amount of active ingredient in the cores corresponds to a significant variation in the dose contained in each tablet which is clearly most undesirable.

In one known method, a coating solution containing active material is applied to the surfaces of small beads using conventional spray coating techniques, for example by spraying the coating solution towards the beads as they are tumbled in a revolving drum. The coated beads are filled into capsule shells for administration. Such a method is not appropriate for use where accuracy in the amount of the active material applied to the cores is required because there is little control over the amount of coating material applied to each core using that method.

Active components are often administered in tablet form. As indicated above, conventional tablets include a small amount of active component and a large amount of diluent such as lactose so that the tablet is a convenient size. The tablet is a convenient way for the active component to be administered because each tablet contains a predetermined metered dose of the active material.

However, some patients find the taking of tablets difficult, for example because of their size or because of the presence of the other ingredients in the tablet composition. Thus an alternative dosage form would be desirable.

GB 1 561 100 describes the coating of a web with material containing an active ingredient. The coated web is processed to internalize the active coating by, for example, lamination and winding to provide a dosage form.

It is an object of the invention to overcome or mitigate one or more of the above mentioned disadvantages.

In accordance with the invention, there is provided a method of coating a substrate, the method including the steps of applying an active coating material to the substrate to form an active coating layer, the active coating material comprising biologically active material, wherein the active coating layer is removable from the substrate.

In accordance with the invention, the active material is applied as a coating to a substrate from which it can be removed.

In one alternative embodiment of the invention, the coating material is applied directly onto a surface of the coating apparatus, the coating formed in the process being removed from the apparatus as a wafer containing the active material.

In a second alternative embodiment of the invention, the coating material is applied onto a substrate, the coating being removed from the substrate as a wafer, for example by a patient prior to the administration of the material. The substrate may be, for example, a sheet comprising plastics material, for example low adhesion plastics material.

The surface of the substrate may be precoated with one or more coating layers.

Preferably, the active coating material is applied electrostatically. There are various advantages in applying coating materials electrostatically, for example, reduction in waste of coating material, improved coating efficiency and improved coating weight uniformity.

In one alternative of the invention, the active coating material is applied in the form of a dry powder.

Advantageously, at least 90% by weight of the particles of the active coating material have a particle size less than 200 .mu.m.

Advantageously, at least 90% by weight of the particles of the active coating material have a particle size between from 1 to 200 .mu.m. Preferably, at least 90% by weight of the particles of the active coating material have a particle size between from 1 .mu.m to 100 .mu.m. The term "particle size" refers to the equivalent particle diameter of the particles and may be measured using, for example, laser light diffraction. The particle size of the powder is an important factor in powder coating techniques. If the particles of the powder are very small, the powder will often be too cohesive for successful powder application using many powder coating techniques. However, large particles can be disadvantageous because they are often more difficult to coat onto a surface and, if the coating material is to be fused after application to the surface, longer fusing times may be required, leading to increased risk of damage to the substrate and to the active component.

Where reference is made to by weight of particles, for example the by weight of particles having a particular size, the particles will also preferably have that by volume of particles of that size.

Alternatively, the coating material may be applied in the form of a liquid.

Advantageously, the active coating material further includes one or more excipients. The formulation will usually consist of the active component and a mixture of excipients that will aid in the coating of the material. The formulation may also include other components, for example, colorants and/or flavourings and/or agents to control the rate of release of the active component.

Advantageously, the substrate is conveyed through a region adjacent to a source of the active coating material. That allows the method to be continuous.

In one advantageous embodiment of the invention, the method comprises supporting the substrate adjacent to the source of the active coating material with a surface of the substrate maintained at such a different electric potential from that of the active coating material that the application of the electric potential causes the active coating material to move from the source of the active coating material towards the substrate, a surface of the substrate becoming coated with the active coating material.

Preferably, the substrate is supported from above and the powder moves from the source upwards towards a lower surface of the substrate.

Preferably, the substrate is charged when the substrate is adjacent the source of the active coating material. Alternatively, or in addition, the source of active coating material may be charged.

The method may further include the step that after the active coating layer is applied the active coating material is treated to form an active film coating secured to the surface of the substrate. Where the coating material is in the form of a powder material, the treatment advantageously comprises a heating step, preferably by infra red radiation, but other forms of electromagnetic radiation may be used. Usually, the change in the coating upon heating will simply be a physical change from a powder to a liquid and then, on cooling, to a solid coating, but there are other possibilities: for example, the powder coating may comprise a polymer which is cured during the treatment step, for example by irradiation with energy in the gamma, ultra violet or radio frequency bands, to form a cross-linked polymer coating.

The method may further include the step of applying a cover coating layer onto the active coating layer to form a cover coating layer such that the active coating layer is substantially completely covered by the cover coating layer.

The active coating material applied to the surface of the substrate might not be treated to form an active film coating. A cover coating layer applied subsequently over the active coating material could be used to seal the active coating on the surface of the substrate.

Where the coating material is in the form of a liquid, the treatment advantageously comprises drying the coating material with a heater although other methods could be used.

The coating material containing the active component is susceptible to damage at high temperatures and it is therefore particularly important that the temperature of treatment is dot high. Advantageously, the temperature of treatment is less than 250^oC., preferably less than 200^oC. and more preferably less than 150^oC. Where the higher treatment temperatures are used, the duration of the treatment is advantageously short to reduce the possibility of damage of the coating material.

Preferably, the cover coating material is applied electrostatically. The cover coating material may be in the form of a powder. The cover coating material may also include active material. The active material in the cover coating may be the same as or different from the active material in the active coating layer.

Advantageously, at least 90% by weight of the particles of the cover coating material have a particle size between from 1 to 200.mu.m.

Preferably, the substrate is conveyed through a region adjacent to a source of the cover coating material.

In one advantageous embodiment of the invention, the method comprises supporting the substrate adjacent to the source of the cover coating material with a surface of the substrate maintained at such a different electric potential from that of the cover coating material that the application of the electric potential causes the cover coating material to move from the source of the cover coating material towards the substrate, a surface of the substrate becoming coated with the cover coating material.

Advantageously, the substrate is supported from above and the powder moves from the source upwards towards a lower surface of the substrate.

Preferably, the substrate is charged when the substrate is adjacent to the source of the cover coating material. Alternatively, or in addition, the source of cover coating material may be charged.

Advantageously, the method further includes the step that after the cover coating layer is applied the cover coating material is treated to form a film coating secured to the surface of the substrate. The treatment of the cover coating layer may be similar to that of the active coating layer described above.

In an embodiment of the invention the active coating layer covers only part of a surface of the substrate. In that embodiment, the cover coating layer may cover only part of a surface of the substrate, or alternatively may cover the whole surface of the substrate.

The cover coating layer may be applied by depositing powder which thereafter forts a layer over the active coating layer or by applying a preformed sheet or film over the active coating layer.

The method may further include the step of applying a further coating material to a surface of the substrate to form a further coating layer. The further coating material may include biologically active material, the further coating layer forming a further active coating layer and the method may further include the step of applying a further cover coating material onto the further active coating layer to form a further cover coating layer such that the further active coating layer is substantially completely covered by the further cover coating layer.

Thus substrates having two or more different active components may be produced. The cover coating material covering the first active coating may be different from that covering the second active coating so that the rate of release of the first active component may be different from that of the second active component. Alternatively, the two active components maybe the same and the cover coatings may be the same or different materials. One or more of the cover coating materials may contain active material.

Advantageously, the method is continuous. In practice, there are considerable advantages in being able to operate the coating process continuously rather than as a batch process.

Advantageously, the active coating material is applied to a part of a surface of the substrate, the active coating layer forming a first active coated region on the surface of the substrate. Where, for example, a plurality of coating layers are to be applied to each substrate, each coating layer forms a coated region on a part of the substrate.

Thus the method may include the further step of applying a second active coating layer onto a surface of the substrate, the second active coating layer forming a second active coated region on a surface of the substrate.

Preferably, the method further includes the step of applying a cover coating material onto the active coating layer to form a cover coating layer such that the active coating layer is substantially completely covered by the cover coating layer and such that the cover coating layer is removable from the substrate. Depending on the nature of the cover coating material, the cover coating layer may be removable together with the active coating layer or may be removable separately. The cover coating layer provides a cosmetic coating and may also protect the active coating material. The cover coating material may also include active material which may be the same as or different from the active material of the active coating layer. The cover coating may comprise a preformed film or sheet of material which is applied over the active coating.

Where more than one active coating layer is applied to the substrate, the method preferably further includes the step of applying a second cover coating layer onto the second active coating layer to form a second cover coating layer such that the second active coating layer is substantially completely covered by the second cover coating layer, the second cover coating layer being substantially separate from the first cover coating layer.

The invention also provides a method of coating a plurality of coating regions onto the surface of a substrate, the method comprising the steps of:

(a) applying active coating material to a surface of the substrate to form a plurality of active coating regions on the surface comprising active coating layers, the active coating material including biologically active material

(b) applying cover coating material to a surface of the substrate to form a plurality of cover coating regions, the cover coating regions forming layers of cover coating material, each active coating region being substantially completely covered by a cover coating region, such that each region of active coating and cover coating is removable from the surface of the substrate.

Advantageously, the method further includes the step of removing that active coating layer from the substrate to form a wafer comprising active material. Each wafer may comprise a single dose of active component. Alternatively, the wafer may be subsequently cut to form wafer portions, each wafer portion including substantially a dose of active material.

Where reference is made to the quantity of active coating material being substantially equal to a dose of the active material, it will be understood that the quantity may be a fraction of the single standard dose, for example 1/2 or 1/3 of a single standard dose of the active material. It will be understood that the quantity of active material will depend on the active component used and the number of solid dosage forms to be taken by the patient for each dose. Where more than one layer of the active coating material is to be applied to each substrate, the quantity of active component in each layer will be chosen accordingly.

The invention also provides apparatus for coating a substrate according to a method as described above.

The first aspect of the invention also provides an apparatus for coating a substrate, the apparatus comprising:

(a) a source of active coating material,

(b) support means for supporting a substrate adjacent to the source of the active coating material such that the active coating material forms an active coating layer on a surface of the substrate.

Advantageously, the apparatus further comprises:

(d) means for conveying the substrate having the active coating layer to a position adjacent to the source of cover coating material such that the cover coating material forms a cover coating layer which substantially completely covers the active coating layer.

The apparatus advantageously includes means for applying the active coating material and/or the cover coating material electrostatically. As indicated above, the coating material may be applied in the form of a dry powder or in the form of a liquid.

Advantageously, the substrate comprises a conveyor belt.

Advantageously the apparatus further includes means for applying a charge to the source of active coating material. The charge can be adjusted to change the amount of coating material applied to the substrate.

Advantageously, the apparatus further includes charging means for applying a charge to the substrate. The charge may be applied using a corona charge wire adjacent to the substrate or by arranging a charged plate adjacent to the substrate. The charged substrate attracts coating material from the source onto the surface of the substrate. Thus it is possible to obtain a very thin uniform layer of coating material on the substrate surface.

Preferably, the source is arranged below the conveyor.

Also provided by the present invention is an apparatus for coating a substrate, the apparatus comprising:

(a) a source of coating material

(b) means for moving the substrate relative to the source of coating material,

(c) means for applying an active coating material onto a surface of the substrate to form a plurality of active coating regions,

(d) means for applying a cover coating material onto the surface of the substrate to form a plurality of cover coating regions such that each active coating region is substantially completely covered by a cover coating region, the coating materials being applied such that the active coating material is removable from the surface of the substrate.

The invention also provides a coated substrate comprising an active coating layer on a surface of the substrate, the active coating layer including biologically active material and in which the active coating layer is removable from the surface of the coated substrate.

In one embodiment of the invention, each active coating layer comprises a quantity of biologically active material which is substantially equal to one dose or, for example, one half dose of the biologically active material. It will be understood that the quantity of active component will depend on the active material used and the required dose.

Alternatively the active coating layer may subsequently be cut into small portions.

Preferably, the substrate further includes a cover coating layer on a surface of the substrate, the cover coating layer substantially completely covering the active coating layer in which the cover coating layer is removable from the surface of the substrate. As indicated above, the cover coating layer may be removable separately from the active coating layer.

The substrate may include a plurality of active coating layers forming active coating regions on a surface of the substrate.

Preferably, each active coating region includes a cover coating region comprising a layer of cover coating material in which each active coating region is substantially completely covered by a cover coating region.

In one alternative embodiment of the present invention, for example where the active coating material is applied as a liquid, the active coating material is applied as a metered dose to a surface of the substrate. to form an active coating layer on the surface.

Very accurate application of the coating material on each surface can be obtained.

This is to be contrasted with the known methods where coating material is sprayed towards the cores. In that case the amount of coating material applied to each substrate depends on many factors all of which would require close control if accurate application is to be achieved. It will be understood that whilst reference is made to applying a metered dose, that should not be taken to imply that there is necessarily any measurement of the amount of material applied. A metered volume of liquid may be applied to each substrate.

Advantageously, a predetermined number of droplets of active coating material are applied to the surface of the substrate. Thus where the droplets are of the same size, the number of droplets applied to the substrate surface determines the amount of active material applied. By altering the number of droplets applied, the apparatus can easily be adapted to apply the required quantity of active material.

Advantageously the coating method is such that the coefficient of variation of the quantity applied to each substrate or region of the substrate is not more than 15%.

As indicated above, where the coating material includes active material, the accuracy and reproducibility of the application of the material to the substrates is of particular importance. For known spraying techniques such as those described above, the coefficient of variation can be 50% or more. Whilst that is acceptable where the coating is a cosmetic coating, it is not acceptable where the coating contains active material. Preferably the coefficient of variation is not more than 10%, and most preferably 3% or less.

Advantageously, the active coating material is applied in the form of individual liquid droplets which are propelled from the supply directly towards a surface of the substrate.

As indicated above, where the material is applied as a plurality of individual droplets, it is more simple to alter the dose of active material applied to the substrate by changing the number of droplets applied. Thus advantageously, the number of droplets applied is controllable.

An ink jet head may be used in the coating of the substrates with active coating material. A conventional ink jet head, for example those used for ink jet printers, can be used to apply an easily controllable amount of material from the head onto a substrate.

In one embodiment of the invention, the area of the surface of the substrate covered by the active coating layer is less than 40% of the total surface area of the substrate. The area covered by the active coating layer may be less than 25% of the total surface area of the substrate. The active coating may form a plurality of small coated regions on the surface of the substrate.

Thus the active coating layer may cover only apart of the exposed surface of the substrate.

Where the quantity of active material to be administered using each solid dose is small, as indicated above, it is advantageous for the proportion of active component in the active coating material to be large.

By covering a smaller proportion of the surface of the substrate, a smaller amount of coating material may be used. Thus the proportion of active component in the coating material may be increased.

The active coating material may be applied to a plurality of individual regions of the surface of the substrate.

The invention also provides a method of coating a substrate, the method comprising applying an active coating material to a surface of the substrate to form an active coating layer, the active coating material comprising biologically active material, applying a cover coating over the exposed surfaces of the active coating layer and dividing the substrate to form substrate portions, each substrate portion including substantially one dose of the active material.

The invention also provides a pharmaceutical solid dosage form comprising a substrate and an active coating layer covering less than 25% of the surface area of the substrate the active coating layer comprising biologically active material.

The coating layer may be shaped, for example to form a pattern, a picture, symbols, letters or numerals.

The invention also provides a wafer for administration to a patient, the wafer comprising biologically active material and having a thickness of less than 2 mm. Preferably the thickness is less than 1 mm.

The invention further provides an intermediate product for use in producing a plurality of solid dosage forms, the intermediate product comprising a substrate and an active coating layer deposited on the substrate, the amount of active coating material deposited on a given area of the substrate being controlled such that the product can subsequently be divided into portions with each portion containing a predetermined amount of active coating material, each predetermined amount being one dose of the active material.

In accordance with a further aspect of the invention, there is provided a method of coating a substrate, the method comprising applying an active coating material to a surface of the substrate to form an active coating layer, the active coating material comprising biologically active material, applying a cover coating layer over the exposed surfaces of the active coating layer and dividing the layered product to form layered portions, each layered portion including substantially one dose of the active material.

In accordance with the further aspect of the invention, the active coating material can be such that it is not removed from the substrate. For example, the active material might be applied to an edible film which can be administered orally.

It will be understood that the method of coating may further include features of the method of the first aspect of the invention described herein. Furthermore, it will be appreciated that the apparatus and coating materials described in respect of the first aspect of the invention could be used in the method in accordance with the further aspect of the invention, with minor modifications where necessary.

Claim 1 of 118 Claims

What is claimed is:

1. A method of coating substrate which is a belt sheet, film, or tape, the method comprising the step of preparing a pharmaceutical product by applying an active coating material to the substrate to form an active coating layer, the active coating material comprising biologically active material, wherein the active coating material is applied electrostatically as a powder, and, after the active coating material is applied, the active coating material is fused to form an active film layer, wherein the active coating material is removable from the substrate as a wafer comprising the active film layer, and wherein the active coating layer is divided into portions

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