HK1037975B - Two-piece capsule for receiving pharmaceutical preparations for powder inhalers - Google Patents

Description

Two-part capsule for containing a pharmaceutical preparation for a powder inhaler

The present invention relates to a new two-part capsule for containing pharmaceutical preparations for powder inhalers.

Prior Art

Capsules containing pharmaceutical preparations are commonly used for the treatment and diagnosis of diseases. The capsule may be administered orally or may be used in a specific medical device such as a powder inhaler. Generally, a capsule is composed of two parts, a capsule body and a capsule lid, which are telescopically inserted into each other. However, multi-part capsules are also known. Capsules are generally composed of gelatin, particularly hard gelatin. In certain specific applications, the capsule occasionally contains a water-soluble synthetic substance that is readily digestible by humans so as to release the active ingredient at a specific site in the gastrointestinal tract upon oral administration. Examples of various capsule materials are listed below.

EP 0143524 discloses a two-part capsule material which is readily digestible by humans, preferably gelatin.

EP 0460921 describes capsules consisting of chitosan and starch, cereal flour, oligosaccharides, methacrylic acid-methacrylate, methacrylic acid-ethyl acrylate, hydroxypropylmethylcellulose acetate, succinate or phthalate. These capsule materials are characterized by their contents being released only after reaching the large intestine.

GB 938828 discloses capsules for radioactive materials for use in therapy or diagnosis. The capsule comprises water-soluble gelatin, methylcellulose, polyvinyl alcohol or water-soluble non-toxic thermoplastic.

The materials used are generally not very resistant to humidity in the air, and therefore also indicate that the pharmaceutical quality of the contents cannot be guaranteed in all climatic zones. In particular, the capsules customary in climate zone 4(30 ℃/70% relative atmospheric humidity) cannot be used.

Two-part capsules that are particularly suitable for use in powder inhalers and that are not intended for oral administration are not known in the prior art. Capsules for powder inhalers contain the same material as that used for oral administration, usually hard gelatin. However, the use of these materials in powder inhalers is not perfect.

The object of the present invention is to provide a capsule that is more suitable for this particular situation of a powder inhaler.

The capsules used to date in powder inhalers have various disadvantages due to their composition. The materials used to construct the capsules therefore change their properties due to ambient atmospheric humidity and/or often do not have sufficient intrinsic stability. As a result, such capsules cannot be used in high atmospheric humidity climatic zones 4, since the capsule material absorbs moisture to such an extent that the intrinsic stability is severely impaired and/or moisture penetrates into the interior of the capsule. This can affect the drug stability of the capsule contents. The materials also have different disadvantages at different stages during the manufacture of the capsule to its use, which may affect the suitability of the capsule as a carrier for pharmaceutical preparations, the manner in which the contents are administered, the destructiveness of the contents and/or the use of the capsule in certain areas. Another disadvantage of conventional capsule materials is that, in particular, the capsules are usually produced by applying a layer of mould release agent, which tends to bind to the powdered substance. In the case of capsules for inhalation this leads to difficulties in accurately measuring out the fine fraction to be passed into the lungs.

It is a further object of the present invention to propose a capsule for a powder inhaler which does not suffer from the problems of the conventional capsules mentioned above.

Description of the invention

The present invention relates to a capsule which can increase the safety of a pharmaceutical preparation for a powder inhaler and a capsule which carries a pharmaceutical preparation for a powder inhaler, and has an improved applicability to a powder inhaler. The capsules are made of water-insoluble hydrophobic synthetic materials which do not in themselves significantly affect the pharmaceutical quality of their contents, and furthermore improve their availability in terms of their function, durability and/or their climatic region, and are advantageous at various stages during their manufacture to use.

According to the invention, the capsule is formed of two parts, a capsule body and a capsule lid, which are joined together to form a stable closed space of limited volume, which can be used to contain a pharmaceutical preparation. The capsule size selected is one that can be adapted to powder inhalers using capsules in general, such as described in patent document DE 3345722 (inhaller Ingelheim M), EP 0591136 (inhaller Ingelheim) or in published german patent application DE 4318455 ("HandiHaler").

Detailed description of the invention

In one embodiment, the synthetic material of the capsule is not digestible by humans, so that the active ingredient is not released when the capsule is taken orally. Its advantage is no damage to health. This is particularly suitable for young children or the elderly.

Preferably, the synthetic material used can be processed by injection molding or blow molding and/or the synthetic material does not require the use of a release agent when processed into a capsule lid or body, which would attach the contents to the capsule wall. This has the advantage that there is no need to clean the inside of the lid or body to remove the release agent in order to comply with government regulations (e.g. according to DAB (german pharmacopoeia)), which regulations have restrictions on the use of release agents on direct packaging containers.

In a preferred embodiment of the invention, the synthetic material does not have a significant capacity to adsorb pharmaceutical chemicals, in particular particles of a size that can reach the lungs, so that the entire contents of the capsule can be released when the capsule is used in the aforementioned inhaler. This has the advantage that the dose can be correctly dosed, in particular for the part of the fine powder that can reach the lungs.

In another embodiment, the synthetic material from which the capsule is made has a Shore D hardness of 65 to 73. A material with such hardness will not disintegrate when it is pierced or cut, but at the same time it is so strong that the resulting hole will not reclose. The advantage of this material is that no fragments are pressed out of the capsule when the capsule is opened, pierced or cut in the powder inhaler, while it is inhaled simultaneously with the inhalation of the powder.

In a particular embodiment, the synthetic material capsule is extremely stable so as to withstand forces of up to 15N along its longitudinal or transverse axis. This has the advantage that the capsule is more pressure resistant during manufacture, filling, packaging, shipping etc.

In another embodiment, the capsule wall has a vapor transmission rate of less than 1.3X 10^-14kg/(m²sPa), preferably 1.5X 10^-16To 2X 10^-16kg/(m²sPa). The advantage of this property is that the capsule contents can remain moisture-tight in geographical areas of high air humidity.

In a preferred embodiment, the synthetic material is polyethylene, in particular high-density polyethylene, polycarbonate, polyester, polypropylene or polyethylene terephthalate.

In a preferred embodiment, the cap and body are cylindrical with a circular cross-section and a spherical convex (practically hemispherical) closed end, both of which are formed of high density polyethylene.

The capsules according to the invention can be used in all types of powder inhalers where the formulation is administered by inhalation in capsule form.

In a preferred embodiment, the lid and body of the capsule are cylindrical like each other, each containing an inherent, closed jacket with an open end and a closed end. The cap and capsule are sized and shaped so that the body of the capsule is telescopically urged with the open end of the body toward the open end of the cap to tightly engage the cap with the body.

In a particular embodiment, both the lid and the body have an interlocking means, which has the advantage of allowing a temporary and/or final closure of the capsule.

In this embodiment, the cover has a plurality of point-like projections on the inner surface thereof and the body has a plurality of larger point-like recesses on the outer surface thereof, the arrangement being such that the projections and recesses engage one another when the capsule is closed. Conversely, the protrusion may be located on the outer sleeve of the body and the recess on the inner sleeve of the cap. Preferably the arrangement is such that the protrusions or recesses each form a ring or spiral around the sleeve. In addition to the dot-shaped protrusion and recess design, the ring-shaped protrusion and recess can be continuously formed around the body or the cover.

In a particular embodiment, the one or more projections surround the body or the lid and are designed such that the projections of the lid are in close proximity to the projections of the body when the capsule is closed.

In the above-described embodiments of the annular recesses and/or projections, the recesses and/or projections may be continuous or intermittent.

In yet another embodiment, the projections are formed on the outside of the open end of the body and the apertures are formed adjacent the open end of the lid, such that when the capsule is closed the projections of the body fit within the apertures formed in the lid. The projections are designed so that the lid can be opened at any time without damaging the capsule or, once closed, without being destroyed.

In a further embodiment, the outer side of the body is designed with a projection around the capsule body, which projection is perpendicular to the axis of connection between the lid parts. The protrusion functions as a stopper of the capsule when it appears on the outside of the body to prevent the cover from being detached from the body. The area between the body open end and the protrusion corresponds to the area where the cover can be pushed over the body. The protrusion is located on the body in a position that allows the cover to be advanced sufficiently for close, good contact between the cover and the body. The protrusion cannot be located directly on the open side of the body. The side of the bulge facing the open end of the body forms a vertical edge on the outer wall of the body such that the lid cannot be pushed over the bulge when closed. The side of the protrusion facing the closed end of the body may be designed to be almost a right-angled edge or taper towards the closed end. The advantage of forming the edges at an approximate right angle is that the capsule can be loosely placed into the capsule holder, while the tapering projections are adapted for the tight fit required. The projections may be continuous or intermittent.

In a preferred embodiment, the projection tapers towards the closed end of the body and the face facing the open end is perpendicular to the body of the capsule. The height of the rim so formed does not rise above the lid rim when the capsule is in the closed position, thereby providing a planar interface from the lid to the body.

The thickness of the lid wall and body wall may be different throughout the capsule area. Therefore, the thickness of the wall in the arc area of the cover and the body or the position of the convex point of the body is generally larger than that of the capsule wall in the straight line area. In one embodiment, the wall thickness of the cover and body is 0.1 to 0.5 mm.

In one possible embodiment, the outer side of the capsule forms a small protrusion section, while in another embodiment there are three or more ridges parallel to the longitudinal axis of the capsule. These devices have the advantage that when the capsule is used in the aforementioned capsule inhaler, it is not damaged or broken when it is removed from the capsule holder. The ridges or raised nubs may be disposed on the outside of the entire capsule or only a portion thereof. On the other hand, it may also be present only in the area of the lid or in a partial area of the body, in a region that is also visible when the capsule is closed. The ridges are parallel to the longitudinal axis of the capsule and ensure that the capsule can be held vertically in the aforementioned capsule holder. When the capsule has a circular cross-section, the ridges are preferably arranged such that the cross-section of the capsule is not rotationally symmetrical along its central axis. In this embodiment the ridge may only be present in the part of the capsule body that is visible when the capsule is closed. This embodiment may prevent the capsule from getting stuck in the capsule holder. In a particular embodiment in which there are no protrusions but ridges present in the body part of the capsule that are visible when the capsule is closed, the ridges are designed so that one end faces the open end of the body to perform the function of protrusions, i.e. as a barrier for the lid when it comes into contact with the body.

In yet another embodiment, the sandwich of the lid and body has a cross-section of a hollow cylinder of circular, oval, triangular, quadrilateral, hexagonal, octagonal or polygonal shape when the respective upper half is open and the lower half is closed. The closed underside may be planar or rounded. An advantage of the angled embodiment is that it may be less space consuming than a round embodiment, for example, when stored.

In one embodiment, the capsule has a degree of expansion (ratio of the distance from the body closed end to the lid closed end to the diameter of the capsule when closed) greater than 1, in one embodiment the degree of expansion of the capsule is 1 and in another embodiment the degree of expansion of the capsule is less than 1. The latter has the advantage that the capsule body has a larger mouth opening when filled.

In the embodiment with an extension degree of 1, the lid and body are designed such that the capsule is spherical in shape after closing, which has the advantage that the capsule can be automatically loaded into the powder inhaler from the storage container.

In order to provide a good seal between the lid and the body after closure, the body may be welded, bonded or wrapped at the intersection of the body and the lid, thus reducing the vapor transmission rate to one tenth. Alternatively, the entire capsule may be coated with a protective film.

In another preferred embodiment, the gap may be sealed with a filler. A suitable filler to fill the gap in this way is a pharmaceutically acceptable filler such as gastric soluble acrylic resin (Eudragit). Such fillers may be filled into the gap as a solution or suspension in a suitable (preferably highly volatile) solvent. Suitable solvents include chlorofluorocarbons such as dichloromethane, chloroform, fluorocarbons, alcohols such as methanol, ethanol, propanol, isopropanol, alkanes such as propane, hexane, heptane, ketones such as acetone, esters such as ethyl acetate, ethers such as dimethyl ether or diethyl ether, or other liquids known in the art (particularly volatile liquids) which may be suitable for use in solution or suspension, and which do not attack the capsule material, do not chemically react with the pharmaceutical composition or alter its availability. The nature and concentration of the solution or suspension containing the filler must be such that sufficient filler is delivered to the interstices, leaving the filler in the interstices as a tight seal after the solvent has evaporated, and not so viscous that it can penetrate or be drawn into the capsule by capillary action.

Preferably, for closing the gap is a solution of gastric soluble acrylic resin (Eudragit) and acetone.

From the description it can be seen that the capsule according to the invention is suitable for containing any powdered pharmaceutical formulation suitable for inhalation. In one particular application, the capsule contains cromolyn, reproterol (reproterol), beclomethasone (beclomethasone), terbutaline (terbutaline), salbutamol (salbutamol), albuterol (salmeterol), ketotifen (ketotifen), ipratropium (orciprenaline), fluticasone (fluticasone), insulin, ipratropium (ipratropium), dexamethasone (dexamethone), meprolyn (bambuterol), tiotropium (tiotropium), budesonide (budesonide), phenomenol (phenoterol), clenbuterol (clenbuterol), prednisolone (prednisolone), prednisone (predfenone), prednisolone (predfenoxymethone), prednisolone (hylol), prednisolone (prednisolone), or other salts thereof, or mixtures thereof, which are suitable for inhalation.

In a preferred embodiment, the capsule contains ipratropium bromide or tiotropium bromide.

Description of the drawings

The figures show, by way of example, various specific embodiments of the capsule according to the invention, but are provided only for illustrating the invention and not for limiting its scope.

Fig. 1 shows the simplest embodiment of a capsule according to the invention in a side section.

Fig. 2a and 2b show different embodiments of the capsule with a tapering protrusion, each in a side cross-section.

Figure 3 shows an embodiment of the capsule with angular projections in a side section.

Figure 4 shows in side cross-section an embodiment of a capsule having a body with a gradually narrowing protrusion and an angular recess in the body and lid.

Fig. 5 is a front view of an embodiment of the capsule having a body with a gradually narrowing protrusion and an annular recess in the body and the lid.

Fig. 6 is a front view of an embodiment of the capsule having a body with a gradually narrowing protrusion and a body and a lid with a point-like depression or protrusion.

Figure 7 shows in front a particular embodiment of a capsule having a body with a gradually narrowing protrusion and having a point-like projection on the body and a point-like hole in the lid.

Fig. 8 is a front view of a capsule having ridges on its body.

Figure 9 shows the capsule of figure 7 in a parallel cross-section.

Fig. 10a, 10b and 10c show embodiments of capsules each having a different cross-section.

The specific embodiment of the spherical capsule is not shown here.

In fig. 1, a capsule 1 according to the simplest embodiment of the invention is shown in cross-section. The capsule 1 has a lid 2 and a body 3 which are nested one within the other in a nested manner. The cover 2 has the same shape as the body 3 and is rounded at its lower side 4.

Figure 2a shows a cross section of an embodiment wherein a protrusion 5 is provided on the body 3 of the capsule 1, which gradually narrows towards the closed end of the capsule. The side of the projection 5 facing the open end of the capsule body is substantially perpendicular to the body. The area defined by the rim thus formed is the extent to which the capsule lid 2 is nested.

Another embodiment is shown in fig. 2 b. The embodiment shown by cross-section differs from the embodiment of fig. 2a in that the wall thickness of the capsule lid 2 or body 3 is not uniform over the entire capsule but differs in individual part-areas. Furthermore, there is an arcuate recess at the arcuate lower end portion 4 of the cover or body.

Fig. 3 presents an embodiment in which the protrusions 5 are located on the body almost at right angles to the upper and lower halves of the body. The embodiment of fig. 4 represents a further extension of fig. 2a, wherein it is more desirable when the body 3 or the lid 2 forms an annular recess 7 or 6 such that the capsule 1 is closed.

Fig. 5 shows a front view of the embodiment shown in cross-section in fig. 4.

Fig. 6 shows a further variant of the invention in front view, with punctiform depressions 8 and 9.

Figure 7 shows another variant of the capsule 1 in which the projection 10 is located adjacent the open end of the body 3 and the aperture 11 is located adjacent the open end of the lid, so that the projection 10 will engage the aperture 11 when the capsule is closed.

Fig. 8 shows the appearance of a particular embodiment of the capsule 1, wherein the ridges 12 are located in the body 3.

Fig. 9 shows the body 3 in the embodiment of fig. 7 in cross section. The cross-section shows that the three ridges 12 are not rotationally symmetrical about the central axis of the body. FIGS. 10a, 10b, and 10c show capsules having square, triangular, and octagonal cross-sections, respectively.

Claims (16)

1. A capsule for a pharmaceutical preparation for a powder inhaler, the capsule comprising a capsule body and a capsule lid, both of which are formed from the same material and which, when joined, form a stable closed space having a fixed volume, characterised in that the capsule material is a water-insoluble hydrophobic synthetic material.

2. Capsule according to claim 1, characterized in that the thickness of the walls of the capsule lid and body is 0.1 to 0.5 mm.

3. Capsule according to claim 1 or 2, wherein the capsule can withstand external forces applied up to 15N in its longitudinal and transverse axes.

4. Capsule according to claim 1, 2 or 3, characterized in that the shore D hardness of the synthetic material is 65 to 73.

5. Capsule according to claim 1, 2, 3 or 4, characterized in that the capsule wall has a vapor transmission rate of less than 1.3 x 10^-14kg/(m²sPa)。

6. Capsule according to any of the preceding claims, wherein the capsule wall has a vapor transmission rate of 1.5 x 10^-16To 2X 10^-16kg/(m²sPa)。

7. Capsule according to claim 1, 2, 3, 4 or 5, characterized in that the synthetic material is polyethylene, polycarbonate, polyester, polypropylene or polyethylene terephthalate.

8. Capsule according to claim 7, characterized in that the synthetic material is polyethylene.

9. A capsule according to claim 1, 2, 3, 4, 5, 6, 7 or 8, wherein the capsule lid has one or more projections or recesses provided therein and the capsule body has one or more recesses or projections provided therein, the projections or recesses being arranged so as to interengage with the recesses when the capsule is closed.

10. Capsule according to one of the preceding claims, wherein the projection is annular around the outer surface of the body and perpendicular to the axis of connection of the body and the lid, the edge of the projection facing the open end of the body and being at approximately right angles to the outer wall of the body.

11. Capsule according to one of the preceding claims, wherein the capsule body and the capsule lid are both made of high density polyethylene and are both shaped as circular-section cylinders with a circular arc-shaped closed end, so that the capsule has an extension (ratio of the distance from the closed end of the body to the closed end of the lid to the diameter of the capsule when closed) of more than 1.

12. Capsule according to any of the preceding claims, wherein the intersection, or gap, of the capsule body and lid is sealed by welding, gluing, wrapping or covering with a protective film.

13. Capsule according to any of claims 1 to 12, wherein the intersection of the capsule body with the lid, or the gap, can be sealed by filling with a pharmaceutically acceptable filler.

14. Capsule according to claim 13, characterized in that the filler is a gastric soluble acrylic resin.

15. Use of a capsule according to any preceding claim for containing a pharmaceutical formulation suitable for inhalation purposes which comprises a pharmaceutical formulation of cromolyn, meprobamate, beclomethasone, terbutaline, albuterol, meprobamate, ipratropium, fluticasone, ipratropium, dexamethasone, meprobamate, tiotropium, budesonide, meprobamate, dichloramine, prednisolone, methylprednisolone, formoterol, nedocromil, salts or mixtures thereof or other cortisone formulations or atropine derivatives.

16. Use of a capsule according to one of the preceding claims in a powder inhaler.