Capsules for inhalers

FIELD: medicine.

SUBSTANCE: in capsule, in accordance with the invention, at least, one hollow space is surrounded by wall. At least, part of wall includes polymer mixture, which contains, at least, one adsorbent. Polymer mixture contains, at least, thermoplastic material, preferably polyolefin, more preferably, polyethylene or polypropylene. Adsorbent is selected from group, consisting of silica gels, zeolites, alumosilicates, molecular sieves, active coal, oxides of alkali-earth metals, calcium sulfate. Capsule is intended for packing compositions for inhalation.

EFFECT: invention allows to prolong stability of medication compositions.

28 cl, 8 dwg

 

The invention relates to a capsule as primary packaging, in particular to pharmaceutical compositions for inhalation. Proposed according to the invention the capsule is a one-piece integral part of the ready-to-use powder inhaler.

The level of technology

Treatment aimed at pulmonary inhalation aerosol therapy plays an important role in the treatment of many lung diseases. Along with sprays of liquids containing biologically active substances, often use powder inhalers for the introduction of the powdered compositions of biologically active substances.

In the field of powder inhalers known devices with single doses and multiple doses. In the case of powder inhalers with usual doses, the dosage can be realized in the form of at least cylindropuntia capsules, which contain the powder composition. Powder compositions contain biologically active substance in micronized form (with a particle size of about 1-5 microns) and often one or more auxiliary substances. If you use the capsule as a vessel, then its in powder inhalers before implementation inhalation opened by piercing, crushing or cutting, so that the powder could move out of the capsule due to the inhalation of the patient is and was formed supported by the air spray, which the patient inhales. Depending on the device it may contain one or more capsules together or each capsule when using insert into the machine individually.

Preferably applicable in powder inhaler capsules consist of two or more parts, and preferably have a size of 3. This powder inhaler, for example, a nebulizer brand HandiHafer®, which is described, for example, in European patent 1342483.

Packing in capsule prescribed for inhalation powder composition is decisive for the quality of the product and the suitability for use for the purpose of inhalation. Typically, when this powder for inhalation comes directly into contact with the material of the capsule, so you need to take into account quality criteria in relation to the primary packaging. If necessary, the primary packaging can surround the second external protection, secondary packaging means that you want to remove before use. Secondary packing means in this case, as a rule, completely surrounds the primary packing means. Secondary packaging means, in particular use when the primary packing means gives no time or unlimited sufficient protection from, for example, humidity or other is their external influences. Such secondary packaging means can consist, for example, the film "cases" of aluminum foil (blisters, etc.).

In such cases, as a rule, secondary packing means is first removed before the closed capsule is inserted into the powder inhaler. Then there's the capsule is opened by appropriate means of the powder inhaler.

The selection of suitable material for capsules is determined by two factors: first, the material should be known to perform a protective function. Secondly, the material must be such that it was possible to give a capsule necessary for use in a powder inhaler form and that it could perform its intended her function. If HandiHalers®the capsule should be such that the powder could be removed according to the produced by the inhalation of the patient to the Bernoulli effect.

Capsules for powder inhalers usually consist of solid gelatin, cellulose derivatives, starch, starch derivatives, chitosan, and so forth, however, also known capsules of synthetic materials such as polyethylene, polycarbonate, polyesters, polypropylene or polyethylene terephthalate, and the like.

So far the materials have the disadvantage that they both directions permeable to moisture in the air. The poet is there is a need to improve the ability of the capsules to maintain stable powder for inhalation. In addition, the materials, such as gelatin, are sensitive to humidity and too much dryness can break down. In wet conditions they, on the other hand, are adhesive, thereby deteriorating the effective filling and/or capsules, for example, in the inhalers. In addition, you can specify how difficult to create a suitable or stable holes in the capsule to release the powder. A certain part of the powder may remain stuck to the wall of the capsule and, therefore, not be used for therapeutic effect after inhalation. Summarizing, it should be noted that the mechanical and physico-chemical properties are known in the prior art products, including products by using the above synthetic materials are not completely satisfactory.

Description of the invention

One of the main tasks of the capsule is to protect biologically active substances, as well as the whole composition for inhalation, from biological, chemical or physical changes. A physical change when it referred in particular changes that can alter receiving a given dose of fine particles. The term "dose of fine particles" see dose, which may reach the lung of the patient. The last effect of the interaction micronized cha is TIC biologically active substances with each other, as well as interaction with auxiliary substances. Currently, it is shown that especially due to changes in the degree of humidity inside the package, these interactions may increase so that the dose of fine particles is clearly reduced. Such changes include the penetration of water into the packaging is exactly the same as removing water from the interior of the package.

Therefore, the main task of packaging is maintaining a constant chemical composition of the atmosphere within the package to prevent physical or chemical changes in the composition of biologically active substances, respectively, the stable compositions for inhalation. In this regard, there are, on the one hand, short-installed stability, which should have a composition for inhalation during the time period of the actual application ("stability"), that is, the retrieval time capsule from under additional protective packaging (secondary packaging), the introduction of an inhaler, until opening the capsules and inhalation of powder for inhalation, and, on the other hand, long-term stability, i.e. stability, which should be provided until the composition for inhalation secure unopened protective packaging (secondary packaging). Task infusion is his invention, next is getting a capsule which can be manufactured in a simple manner, with improved protective action in respect of the composition of biologically active substances, and also have favorable mechanical and physical-chemical properties and which is devoid of the disadvantages of the prior art.

The solution to this problem was found because the capsules, which are used, for example, in the HandiHaler®, made from material including a polymer blend in which you have entered at least one adsorbent.

In this surprisingly discovered that the preservation of the powder compositions for inhalation can have a positive impact on the distribution of small particles and may even increase the proportion of fine particles obtained doses. When it was found that it can significantly extend long-term stability of the composition of the medicinal product, as well as to increase the stability when using".

The present invention therefore relates to capsules that you can use along with a powder inhaler and which, as such, are an integral part ready-to-use powder inhaler. When this capsule can be pre-entered into the apparatus and placed in the apparatus when applied individually by hand.

Task capsules and used for its production m the material preferably is to slow down and, if necessary, to minimize the exchange of gaseous matter, especially water vapor, between its interior and the surrounding environment.

Another challenge is finding a material for the capsule, which is suitable for the manufacture of capsules preferably of size 3 that can be used in the inhaler of Bernoulli.

The next task is to get the capsules suitable for extraction from the inhaler of the total mass and mechanical stability. This takes into account the density of gelatin or polyethylene.

Detailed description of the invention

The invention relates to a capsule, in particular for packaging compositions for inhalation in which at least one hollow space surrounded by a wall, wherein at least a portion of the wall comprises a polymer mixture which contains at least one adsorbent.

The form proposed according to the invention the vessel is set according to the intended application, for example, according to the type of the powder inhaler. Preferably, in the case of proposed according to the invention of the vessel we are talking about a two-part capsule, and both parts Telescopable can vdvinut'sâ each other so as to form a capsule with inner closed hollow space. E is om the floor space is a composition for inhalation. The preferred proposed according to the invention the capsule cylindrophinae shape with rounded ends. Only after opening the capsule in the inhaler pharmaceutical composition can be removed through the process of inhalation. The capsule preferably is an integral part of the ready-to-use inhaler.

In this regard, the term "confined space" means closed by the walls of the hollow space from which, not without opening it, may leave the powder.

The term "composition for inhalation" this preferably means a pharmaceutical powder composition, which consists of an easily sprayable powder particles of biologically active substances in size (median aerodynamic diameter) of less than 100 micrometers, preferably from 1 micrometer to 15 micrometers, further preferably from 1 micrometer to 5 micrometers. Additionally, the pharmaceutical composition may contain an easily flowable, powder carrier, for example lactose, with an average particle size <500 μm, preferably <200 μm, particularly preferably <100 μm, as well as other excipients to improve respisense.

The expression "one-piece integral part of the ready-to-use inhaler" means that the inhaler is a dry capsule that corresponds to the public, element, without which it is impossible, therefore, is not provided, the load inhaler composition of the medicinal product (composition for inhalation) for the purposes of inhalation. Capsule in the ready state (ready for commissioning) can be firmly connected with the inhaler, so that it cannot be removed without destruction or without damage to the pump, or it is related to inhaler free from destruction by way, respectively, of a demountable manner.

The concept of "ready-to-eat" means proposed according to the invention the vessel is inserted into the inhaler. This can be done already at the factory or capsule is inserted into the inhaler patient. If necessary, the vessel is mechanically opened by the structural components of the inhaler and/or transferred to the nebulizer in place of extract. The sequence of these stages can also be changed.

Using the proposed according to the invention capsules composition for inhalation is better protected against the penetration of undesirable substances, in particular of moisture from the external environment than is the case known from the prior art, comparable capsules.

Proposed according to the invention the capsules contain a polymer mixture with the adsorbent, that is, at least part of the capsule is made of such material. According to the pre is respectful, offer in accordance with the invention, a variant implementation, the capsule is completely or essentially consists of a polymer mixture with the adsorbent, i.e., polymer mixture containing at least one adsorbent.

In the present description uses the term "adsorbent" to refer to a component that is able to respond, respectively, to interact with chemical junk in the capsule (i.e. near pharmaceutical composition) component, which has an affinity to the adsorbent and which is likely to hold the adsorbent. Although based on different reaction mechanisms, the term "adsorbent" and "absorbent" in the present description use ravnoznachen and interchangeable.

As the adsorbent is preferably possible to use any material that has the ability to adsorb moisture or other way to extract moisture from the surrounding atmosphere, or any material capable of adsorbing, or otherwise extracted from ambient air other (unwanted) chemical components, which are without limitation subject to the oxygen, carbon dioxide, carbon monoxide, amines, aldehydes, epoxides and alcohols.

In the present description and in the following claims, the term "adsorbent", according to the SNO preferred variant implementation, also use identical with the concept of "drier" or "drying agent". Not exhaustive examples of suitable adsorbents include, among others, silica gels, drying, respectively, adsorbing moisture or water clay, aluminosilicates, as zeolites or bentonites, molecular sieves, active carbon, oxides of alkaline-earth metals, calcium sulfate, or mixtures thereof.

According to the preferred offer in accordance with the invention, a variant implementation, the adsorbent includes at least one dehydrating agent. Not exhaustive examples of the preferred drying means are silica gel, aluminosilicates, as bentonites or zeolites, molecular sieves and/or calcium sulfate.

Proposed according to the invention the capsules improve the suitability of the filled capsules in respect of their functionality, stability, respectively, stability during storage, including contained in the pharmaceutical composition. In particular, they prevent the negative effects of moisture or other harmful chemical components in the pharmaceutical composition and the material of the capsule, as well as the adhesion of the walls of the capsules due to the high humidity.

Then, unexpectedly found that the presence of at least one adsorbent, respectively, the drying means in the floor of the dimensional mixture preferably allows the perforation, cutting, respectively, opening the walls of the capsules in a different way, especially with studs or devices for cutting/opening, which use, for example, in conventional powder inhalers, and avoid the destruction or fragmentation of capsules. Thus, the adsorbent also has an effect on the mechanical properties of polymer mixtures in comparison with the polymer mixture without adsorbent. It suddenly allows manufacturing of capsules, which have superior barrier properties, and also have the necessary strength and permeability, for example, by means of thorns or devices for cutting/opening you can create a hole in the wall of the capsule, which is large enough and stable to effectively release the powdered pharmaceutical composition. Also unexpectedly found that in the case of proposed according to the invention capsules less pronounced, or even it can completely avoid the problem of partial or full re-close the hole after it has been created by the cutting or perforation of the capsule wall with studs or devices for cutting and opening, however, before the release of the powder from the capsules. Assume, without limiting the scope of protection of the invention that this positive effect is reduced to effect the Yu of the adsorbent on the mechanical and physical properties of the polymer mixture. Thus, the proposed according to the invention capsules combine stable and optimal protection powder compositions with improved vswobozdaemoe pharmaceutical compositions, also in case of other conventional ways of opening the capsule, for example, when disengaging the two parts of the capsule.

Preferably, in the polymer mixture of the adsorbent is justiciary adsorbent. The adsorbent, thus, may be preferably in granular or powder form. However, in the framework of the invention are also suitable polymeric adsorbents.

According to a particularly preferred are proposed in accordance with the invention a variant implementation, the polymer mixture contains, in terms of wt.% with respect to the total weight of the mixture, of at least 5 wt.%, preferably, at least 10 wt.%, in particular, between about 10 wt.% and 50 wt.%, the adsorbent. In General, in case of greater wall thickness more than about 0.4 mm, use a slightly higher content of the adsorbent, for example, in the range of 10 wt.% up to 80 wt.% In the case of the thinner walls of the capsules, preferably, less than about 0.4 mm, the polymer mixture preferably contains less than 50 wt.% adsorbent.

Needless to say, the duration and intensity of protection Packed in the capsule pharmaceutical the songs from harmful chemical components, as moisture, can be set, for example, varying the amount of adsorbent in the polymer mixture. Also the adsorption capacity and kinetics of adsorption can be installed at the expense of the type of adsorbent. Further, due to the properties of the polymer mixture, additional additives, the content of the polymer, the wall thickness of the capsule and method used for making the walls of the capsules, you can set its barrier function. You can also match the specific surface area of exchange between the external and the internal atmosphere of the capsule.

According to the preferred offer in accordance with the invention, the variant of implementation of the used polymer mixture (polymer structure) contains at least one thermoplastic material. Suitable thermoplastic materials are, in General, all materials with thermoplastic properties, for example, a polymer derived from a single monomer, a copolymer of two or more monomers, a mixture of two or more polymers derived from a single monomer, a mixture of two or more copolymers, or a mixture of at least one polymer, which is derived from a single monomer, and at least one copolymer.

According to a particularly preferred are proposed in accordance with the invention a variant implementation, the COI is leseman thermoplastic material is polyethylene or polypropylene. According to another offer in accordance with the invention, a variant implementation, you can use polystyrene, in particular, when the desired welding (e.g. ultrasonic welding) parts of the capsule. May be preferred polyamides, for example, when desirable, especially thin-walled capsules. To establish a few "softer" properties can be used, for example, the silicones.

Not exhaustive examples of the polymers (thermoplastic materials) of the individual monomers include: polystyrene, polyolefins, especially polyethylene and polypropylene, polyacrylates, polymethacrylates, polyimides, polycarbonates, polyethersulfones, polyamides, polyesters, and polyvinylchloride. Not exhaustive examples of the copolymers include copolymers of ethylene and acrylate modified polymers and copolymers based on maleic anhydride, and grafted copolymers. If using one copolymer or a mixture, it is preferable to use a combination, which consists of monomers or polymers having (at least) chemical total Monomeric unit. For example, it is possible to use a thermoplastic material that contains a linear low density polyethylene (LLDPE), low density polyethylene (LDPE) and a copolymer of ethylene and vinyl acetate, where each of the comp the components include ethylene as monomer units.

According to a possible offer in accordance with the invention, a variant implementation, the polymer mixture contains no elastomer or contains only a small amount of it. Found that in many cases can most clearly to reduce the phenomenon of re-welding the holes created in the wall of the capsule to release pharmaceutical composition. According to alternative implementation, the polymer mixture contains, however, at least one elastomer, and also in this case, the properties containing the adsorbent polymer mixtures are particularly preferred for the primary packaging and release of powdered pharmaceutical compositions. The elastomer can be, for example, from the group consisting of the best choice rubber (SBR), copolymers of type a styrene-ethylene-butadiene-styrene (SEBS), butyl rubber, ethylene-propylene rubber (EPR), ethylene propylene diene monomer rubber (diene monomer (EPDM) and a copolymer of ethylene and vinyl acetate (EVA) and copolymers of butadiene and Acrylonitrile.

The preferred materials are processed by injection molding or blow molding of plastic. In addition, suitable plastics, for processing which does not require any adhesive lubricant to retrieve items from a form, which the traveler may cause adhesion of the filler to the wall. This has the advantage that the inner part of the vessel does not need to be cleaned of adhesive lubricant for extracting the product from the mold, to satisfy, for example, official regulations restrict the use of adhesive residue to extract the product from the form for the primary packaging means.

According to the preferred offer in accordance with the invention, a variant implementation, the polymer composition may contain or consist of 5-85 wt.%, at least a polymer, in particular at least a thermoplastic material, and 5-85 wt.%, at least adsorbent.

The relative concentration of thermoplastic material and the adsorbent can be varied as a function of the used thermoplastic material and the used adsorbents, preferably, within the above area. According to a particularly preferred variant implementation, the polymer mixture with the adsorbent contains polyethylene, especially high density polyethylene (HDPE), and about 20-50 wt.%, in particular, 20-40 wt.%, at least justicialismo adsorbent or drying means.

The adsorbent has a maximum particle size of preferably less than 50 μm, in particular less than 40 μm, particularly preferably less than 25 μm, measured with the NGOs, as a maximum of 2% of the residue on the sieve. The average particle size, determined by the method of diffraction of laser beams (Malvern, according to the manufacturer's instructions, measurement in air) is between about 0.5 μm and 50 μm, preferably between 0.5 μm and 40 μm, in particular between 1 μm and 20 μm, further preferably between 1 μm and 10 μm.

According to the preferred offer in accordance with the invention, a variant implementation, the wall thickness of the capsules is at least between about 0.05 mm and 2 mm, particularly between about 0.1 mm and 1.1 mm, further preferably between 0.1 mm and 0.5 mm was Found that such wall thickness, as a rule, leads to sufficient stability of the composition of biologically active substances in the proposed according to the invention the capsule, and also contributes to a favorable vswobozdaemoe.

Further, it is found that according to the preferred offer in accordance with the invention, a variant implementation, the ratio of the maximum particle size of the adsorbent to the wall thickness of the capsules should be between 0.01 and 0.2, in particular between 0.02 and 0.1, as this is found particularly favorable stability with very good vswobozdaemoe compositions of biologically active substances.

According to the preferred offer in accordance with the invention is arianto implementation the basic mixture with at least one polymer and at least one adsorbent is prepared in the usual way, in which the polymer (thermoplastic material) is heated to obtain a melt, add the adsorbent (as we have not yet introduced), and other conventional additives and stirred, after which the mixture can be converted into a granulate and stored in this form. This granulate can then be used to obtain the desired structure (capsule), for example, by extrusion molding, in particular, however, by injection molding.

According to the preferred offer in accordance with the invention, the variant of implementation, at least one adsorbent uniformly distributed across the wall thickness of the capsule or its parts produced from the polymer mixture with at least one adsorbent. In the case of this variant implementation of the polymeric mixture can be viewed as monolithic.

According to another preferred variant implementation proposed in the invention, at least one adsorbent, there is, near the surface of the wall of the capsule, respectively, the polymer mixture is in a higher concentration than in its inner region. Accordingly, the used polymer mixture has at least the area of migration on the surface of the capsule wall and an internal region, and m is ximala concentration, at least adsorbent within the zone of migration, at least twice higher than the maximum concentration, at least, of the adsorbent in the inner region. In many cases it favorably against the barrier function of the wall of the capsule. Such polymer structures are described, for example, in PCT/FR03/03465 or PCT/IB2004/004403. Their corresponding description is included in the description by reference.

In General, according to a possible variant of implementation of the present invention, in the framework of the present invention is also possible, however, to use any polymer mixture with an adsorbent, for example, described in U.S. patent 5432214, 5911937, 4665050; European patents 0432438 or 0400460. Their disclosure is included in the description by reference.

As already mentioned, the used polymer materials with the adsorbent may contain additional organic or inorganic additives (additives)such as fibers, stabilizers, dyes, pigments, leavening agents, or combinations of these, or other additives known from the processing of plastics. Preferably, the amount of these additional substances reduce to a minimum amount. According to one preferred variant implementation, the polymer mixture with the adsorbent contains at least one absorbent fibrous component, in which W is STI, overabsorbed fiber, for example, from a polyacrylate. According to another offer in accordance with the invention, a variant implementation, the polymer mixture do not use any absorbent fiber (capillary fibers).

According to a preferred variant implementation, the drying synthetic material has no pronounced adhesion to chemical pharmaceutical substances, in particular to particles suitable for lung size, so when you use a vessel in the inhaler may be released all the contents of the capsule. This ensures exact dosage, especially suitable for lightweight fine particles of the pharmaceutical composition.

Further information about the possible polymer mixtures or possible processing, can be obtained from the above-mentioned prior art, particularly from a European patent application A-0599690 and PCT/IB2004/004403.

According to one variant of implementation, the vessel wall may contain areas with different composition of the polymer/adsorbent. The latter, for example, in the case of capsules, which consist of several different parts.

According to some variants of implementation, the wall of the capsule comprises at least two layers, one inner and at least one lying on it, the outer layer. In the morning the layer forms a direct wall of the hollow space, and thus is in contact with the composition for inhalation. In this case, one of the two layers may consist of a polymer mixture with the adsorbent, and the other layer of pharmacologically neutral material. It is also possible sandwich structure, in which case the outer layer forms the first barrier against moisture, the middle layer consists of a polymer adsorbent and the inner layer consists of a pharmacologically neutral material. Any other sequence of layers. Suitable pharmacologically neutral materials known to the expert and include (along with used according to the invention the polymer mixtures with at least one adsorbent), for example, polymer blend or synthetic materials, such as polyethylene, polypropylene or polystyrene.

The materials of the individual layers can be chosen in such a way that they are connected to each other not at the molecular level or that they are connected to each other at the molecular level.

According to another another variant implementation, the vessel wall outside cover containing the adsorbent polymer mixture, which is formed of a sealed tightly sealed surface. This option has the advantage that with the application of adsorption, in particular, the drying compacted layer also possible joints, which may form a wall of cavitate. This option prigoginian in the case of a two-part capsules.

Preferred according to the invention the capsule is composed of two parts of the capsule. Such capsules preferably consist of two, Telescopable dvigausciesya each other parts, the main part of the capsule (the main part) and cap of the capsule (cap), which can thus be connected to each other, which formed a stable closed hollow space of a certain volume, which contains the pharmaceutical composition. Capsule size is such that it can be inserted, for example, in normal, equip capsules powder inhalers.

According to a particularly preferred variant implementation, the cap and the main part of the capsules are in the form of a cylinder with a circular cross section and convex, almost polusharovidnye closed ends.

According to one preferred variant implementation, the capsule consists of drying synthetic material with a shore hardness D from 60 to 80, preferably from 65 to 73.

Preferably, such that the capsule is so stable that along the longitudinal axis or transverse axis it can withstand a force of up to 10 N, further preferably up to 15 N. The advantage is that the capsule is better suited to the loads that act on the capsule in the manufacture, filling, packaging, transportation is rtirovki etc.

According to a preferred variant implementation, the cap and the main part of the capsules have mutually similar cylindrophinae form consisting of a single closed shell, respectively, closed and open side. The shape and size of the cap and the capsule is such that the main part of the capsule with its open end Telescopable can vdvinut'sâ in the open end of the cap is that the cap is firmly connected with the main part of the capsule.

According to a special variant of implementation, the cap and the main part of the capsule is equipped with closure devices that are advantageous for temporary and/or final welding capsules.

According to such a variant implementation, the inner shell of the cap are tochkoobraznye convexity and the outer casing of the main part of the capsule are several large tochkoobraznye depressions that are located so that when the closure capsule convexity sink in deeper. Alternatively, the bumps may be formed on the outer shell of the main part of the capsule and recesses can be formed on the inner shell of the cap. Preferred location, in which case bulges or depressions are located, respectively, koltseobrazno or a spiral shell. Instead techcoop the heat form the protuberances and recesses they can also continuously koltseobrazno "circumnavigate" the shell of the cap, accordingly, the main part of the capsule.

According to one variant of implementation, the inner shell of the cap and the outer casing of the main part of the capsule is formed of one or more koltseobrazno going bulges such that in the closed position of the capsule bulge of the cap is located, respectively, near the bulge of the main part of the capsule.

According to the options exercise with these annular grooves and/or bumps they can be solid or preryvayuscheesya.

According to a further variant of the implementation on the outer side of the main part of the capsule around the open end of the formed bumps in the cap around the open end of the formed holes so that the convexity of the main part of the capsule in the closed position of the capsule sink into the hole of the cap. Convexity can be such that the cap at any time can be opened without damage or, however, the capsule after a single closure can be opened without destruction.

According to the following variant of implementation, on the outer side of the main part of the capsule is formed of a protrusion that is perpendicular to the connecting axis between the cap and the main part of the capsule around the main part of the capsule. The ledge serves as a stop for the cap when the cap is supplied on top of the main part of the capsule, to prevent perforation of the cap main part of the capsule. The region between the open end of the main part of the capsule and the protrusion corresponds to the region of the main part of the capsule, which can hang the cap. The protrusion localized in the main part of the capsule so that the cap may be a little hang on the main part of the capsule to facilitate durable closure between the cap and the main part of the capsule. That is, the projection is, for example, not directly on the open side of the main part of the capsule. The side of the ledge, which is located at the open end of the main part of the capsule, has the appearance of perpendicular ribs on the outer side of the main part of the capsule so that the cap when the closure cannot hang above the ledge. The side of the ledge, which is located at the closed end of the main part of the capsules may be made in the form of an almost rectangular ribs or may be more flat to the closed end of the main part of the capsule. The nearly rectangular ribs may be an advantage in the case of a free fitting capsule in the holder capsules, a variant of the flat ledge with a solid fit. The protrusion may be continuous or interrupted.

According to one preferred variant implementation, the ledge constantly becomes flatter to the closed end of the base h is STI capsules and its side oriented to the open end of the main part of the capsule is located perpendicular to the main part of the capsule. The height thus obtained rib such that the rib in the closed state of the capsule is not higher than the cap of the capsule, and the transition from the cap of the capsule to the main part of the capsule is smooth.

The wall thickness of the cap and the main part of the capsules can vary in the General area. Thus, the wall thickness, as a rule, in rounded areas of the cap or the main part of the capsule or in the place of the main parts of the capsule in which is formed a protrusion is greater than in areas where the walls are straight. According to one variant of implementation, the walls of the cap and the main part of the capsules have a thickness of from 0.1 mm to 0.5 mm

According to a further variant of implementation, on the outside of the capsule are thickening, according to another variant implementation, there are three or more ribs that run parallel to the longitudinal axis of the capsule. The advantage of these devices is that of the mounting device for capsules, which are used, for example, in the above-mentioned powder inhaler, the capsule can be removed so that it is not damaged or does not open. Rib or thickening can walk across the outside of the capsule or cover only a part of it. Alternatively, they who may be formed only on the cap or only in the main part of the capsule, which in the closed state of the capsule is visible from the outside. Ribs run parallel to the longitudinal axis of the capsule and contribute to the fact that the capsule is fixed vertically in the specified mounting device for capsules. In the case of circular cross-section capsules ribs are preferably arranged so that the cross-section of the capsule has no rotational symmetry around its center axis. According to such a variant implementation, the ribs can be formed only in the area of the main part of the capsule, which is visible in the closed state of the capsule. In the event of such option exercise prevents jamming of the capsule in the holder capsules.

Under option exercise without hanging, but with the ribs in the main part of the capsule, which is visible in the closed state of the cap, the ribs are formed so that oriented to the open end of the main part of the capsule ends of the ribs perform the task of projection, namely, to serve as a stop for the cap when the Association of a cap with the main part of the capsule.

In the following embodiment describes the shell of the cap and the main part of the capsule, hollow cylinder with a circular, oval, three-, four-, six-, eight - or polygonal cross-section, and the corresponding upper side is open, and the bottom side is closed. Closed the lower side may be flat or convex. Form implementation corners have, for example, the advantage that they can be placed sparingly.

According to one variant of implementation, the elongation of the capsule (the distance from the closed end of the main part of the capsule to the closed end of the cap relative to the diameter when closed capsule) is greater than 1, according to another variant implementation, the elongation is equal to 1 and, according to yet another variant implementation, the elongation is less than 1. The latter has the advantage that the main part of the capsule has a larger hole to fill.

If one of the options for the implementation of the extension is equal to 1, the cap and the main part of the capsule is made so that a closed capsule has the shape of a ball, which, in turn, can be an advantage for automatic loading inhaler capsule from the tank.

To achieve, in the case of filled capsules in a closed state, a better seal between the cap and the main part of the capsule, the joint between the cap and the main part of the capsule for sealing is possible to weld, glue or wrap, which considerably reduced the permeability to water vapor. It is preferable for the welding of the cap and the main part of the capsule. Alternatively, the entire cap can cover the solid protective film. The latter may b the th of preferred according to the invention material. In this case, the capsule itself may be of a material which contains no adsorbent.

According to a further preferred variant implementation, the gap can be closed by a filler. As a filler for such filling a gap suitable pharmaceutically acceptable excipients as, for example, Eudragit (Eudragit), a family of polymers based on methacrylic acid and esters of methacrylic acid. This filler is in the form of a solution or suspension in a suitable, preferably volatile, the solvent can be entered into the gap.

According to the invention such capsules are suitable containers for inhalers, which are known, for example, under the trade names HandiHaler®, Spinhaler®, Rotahaler®, Aerolizer®, Flowcaps®, Turbospin®, AIR DPI®, Orbital®, and/or are described in the patent Germany 3345722, European patent 0591136, the Federal Republic of Germany patent 4318455, International application WO-91/02558, the application for French patent A-2146202, application for a U.S. patent And is 4069819, European patent 666085, U.S. patent 3991761, International application WO-99/45987.

The preferred invention relates to the combination of an inhaler for the inhalation of powdered medicaments and proposed according to the invention the capsule, in particular two-part capsules cylindrophinae shape with rounded ends, and the inhaler is characterized by a) open the th up stenobrachius lower part, which floor has two opposite window and on the edge of the hole of the first hinge element; b) a plate which closes the opening of the lower part and has a second hinged element; (C) inhalation chamber for receiving the capsules, which are constructed perpendicular to the plane of the plate located on the lower part of the side plate and which includes moving from spring to the head, and the head is equipped with two sharp needles; (d) upper part with an inlet tube and a third hinge element, and (e) a cap that has a fourth hinge element, and the hinge elements of the bottom plate, the upper part and the cover are connected to each other.

However, preferably it is about the inhaler brand HandiHaler®.

Another aspect of the present invention relates to a secondary packaging means containing at least the capsule, as described in this context, and secondary packing means preferably is water resistant and, further, preferably, at least partially, includes aluminum foil (e.g., blisters).

Another aspect of the present invention relates to the drying of small quantities suitable for inhalation compositions of medicines. And it is found that proposed under the breath is retenu capsules not only able to prevent or slow the entry of moisture into capsules, so at the expense of the capsules becomes available dewatering method suitable for inhalation compositions medicines, but also that using the proposed according to the invention the capsules can be dried suitable for inhalation compositions medicines with little residual moisture. Particularly suitable compositions of medicines in the amount of up to 50 mg, preferably up to 30 mg, particularly preferably up to 15 mg, and highly preferably, up to 10 mg of the Degree of humidity may be, for example, up to 5 wt.% of the composition. Data refer to capsules of size 3. They and other suitable dimensions capsules are described in more detail in the examples.

Finally, a further aspect of the present invention relates to the use of polymer mixtures, as described here (with at least one adsorbent), to obtain a capsule, as described here.

Examples

Capsules of size 3 was obtained as follows.

The polymer mixture with the adsorbent contains 67 wt.% high density polyethylene (HDPE), 3 wt.% copolymer of ethylene and vinyl acetate (EVA) (elastomer) and 30 wt.% synthetic zeolite (molecular sieve 4A, the maximum particle size of 20 μm). First manually preparing a preliminary mixture of HDPE and EVA. It is mixed with a synthetic zeolite in co-rotating twin screw extras is Dere. The mixture is transferred in the form of a granulate. The granulate, if not immediately processed for storage can be packaged in aluminum foil to exclude moisture. The granulate is processed by injection molding into capsules of size 3, and a melt flow index (MFI) is set to about 18 and use the injection channel with a diameter of 0.6 mm According to the second variant, the polymer mixture with the adsorbent contains 66 wt.% high density polyethylene (HDPE), 3 wt.% EVA (elastomer), 30 wt.% synthetic zeolite (molecular sieve 4A, the maximum particle size of 20 μm) and an additional 1 wt.% synthetic overabsorbed fiber of polyacrylate.

Received capsules filled with 5,5 mg water-sensitive composition and then subjected to welding the upper and lower parts of the capsule with each other. Thus obtained capsules store open, therefore, without further secondary packaging, at a temperature of 40°C and relative humidity of 75%. After different periods of time inhalation fraction of particles (mass fraction of particles with an aerodynamic size less than 5 microns) is measured when removing powder inhaler. As a powder inhaler using an apparatus of the type HandiHaler® (WO-94/28958), inhalation share is measured using a cascade impactor at a flow rate of 39 l/m is N.

As a result, found that the "stability" of the composition in capsules, which consist of the usual material without the addition of molecular sieves, can be extended from 1 day to at least 9 days. As stability when using the" you have to understand the period of time between removing the capsule from the packaging (e.g. blister packs) and the use of capsules in the process of inhalation. In this time capsule must have sufficient stability to protect it contains biologically active substance, for example, from moisture. It is of great importance especially in the case of inhalers with multiple doses.

Proposed according to the invention, the capsules preferably have the following dimensions:

a) the length of the main parts of capsules: 22,2±0.46 mm; 20,22±0.46 mm; 20,98±0.46 mm; 18,4±0.46 mm; 16,61±0.46 mm; 15,27±0.46 mm; 13,59±0.46 mm; 12,19±0.46 mm; 9,3±0.46 mm;

b) the length of the cap capsules: 12,95±0.46 mm; 11,74±0.46 mm; 11,99±0.46 mm; of 10.72±0.46 mm; 9,78±0.46 mm; 8,94±0.46 mm; 8,08±0.46 mm; 7,21±0.46 mm; 6,2±0.46 mm;

C) the outer diameter of the main parts of capsules: of 9.55 mm; 8,18 mm; of 7.36 mm; 7,34 mm; 6,63 mm; 6,07 mm; 5,57 mm; of 5.05 mm; 4,68 mm;

d) the outer diameter of the caps of the capsules: to 9.91 mm; 8,53 mm; 7,66 mm; of 7.64 mm; 6,91 mm, 6.35 mm; of 5.83 mm; 5,32 mm; 4,91 mm;

(e) the total length of the closed capsules: 26,1±0.3 mm; 23,3±0.3 mm; and 24.2±0,3; 21,7±0.3 mm; and 19.4±0.3 mm, 18,0±0.3 mm; 15,9±0.3 mm; 14,3±0.3 mm; 11,1±0.3 mm;

f) the volume of capsules: 1,37 ml; 0.9 ml; 0,78 ml to 0.50 ml; and 0.37 ml of 0.30 ml of 0.21 ml of 0.13 ml

Following the invention shall be explained more by using blueprints

Figure 1 presents the easiest option to implement the proposed according to the invention the capsule 1 in cross section. Capsule 1 consists of a cap 2 and the main part of the capsule 3, which Telescopable inserted into each other. The cap 2 and the main part of the capsule 3 have the same shape and have a convex bottom side 4.

On figa presents in cross section an implementation option, in case of which the main part 3 of the capsule 1 is formed tab 5, which narrows to the closed end of the main part of the capsule. Oriented to the open end of the main part of the capsules side is a ledge 5 which is almost perpendicular to the main part of the capsule. Thus the formed edge limits the scope of the main part of the capsule, whereby the cap 2 can move Telescopable.

Another variant implementation presented on fig.2b. The cross section shows that this implementation differs from that presented in FIGU the fact that the wall thickness of the cap 2, respectively, of the main part of the capsule 3 is not across the field made the same, and changes to individual subareas. Additionally, the convex bottom side 4 of the cap, respectively, of the main castigatory have vagotomy curve at the highest point.

On figs and 2d presents the caps of the capsules with protuberances on the inner shell 6. On five presents an additional embodiment of the main part of the capsule, which differs from that of figure 1, 2A and 2b wall thickness.

Figure 3 presents an implementation option, a protrusion 5 located at the main part of the capsule is nearly rectangular as the top of the main part of the capsule, and also to its lower side.

An implementation option according to figure 4 represents a further development of option implementation according figa, in the case of which for the best of the closure capsule 1 is formed an annular recess, respectively, the bulge 6, respectively, 7 in the cap 2, respectively, of the main part of the capsule 3.

Figure 5 presents a front view of a variant of implementation, shown in figure 4 in cross-section view.

Figure 6 presents a further variant of the invention with dotted recesses 8 and 9 as the front view.

Figure 7 shows a variant of the capsule 1, in the case of which the main part of the capsule 3 near the open end of the formed bumps 10 and the cap 2 around the open end of the formed holes 11 so that the convexity 10 when the closure capsule sink into the holes 11.

On Fig presents an implementation option of the capsule 1 from the outside, in case the E. of which the main part of the capsule 3 is formed by ribs 12.

Capsules, which are presented on the figures, according to one variant of implementation, can be produced from the proposed according to the invention material, particularly polyethylene, with a dehydrating agent. According to another variant implementation, the capsule is made from polymer and then veneer on the syringe-machine this material. According to the following alternative implementation, the capsule is then wrapped or laminated with metal foil, e.g. aluminum foil.

1. Capsule packaging compositions for inhalation in which at least one hollow space surrounded by a wall, wherein at least a portion of the wall comprises a polymer mixture which contains at least one adsorbent, where the adsorbent is capable of adsorbing moisture or other undesirable chemical components selected from such as oxygen, carbon dioxide, carbon monoxide, amines, aldehydes, epoxides and alcohols.

2. The capsule according to claim 1, characterized in that it is formed of at least two Telescopable inserted into each other cylindropuntia individual elements, and the capsule is a one-piece integral part of the ready-to-use powder inhaler.

3. The capsule according to claim 1 or 2, characterized in that at least part of the wall predominantly, sushestvuete consists entirely of polymer blends, at least one adsorbent.

4. The capsule according to claim 1, characterized in that the polymer mixture contains at least a thermoplastic material selected from the group consisting of polystyrene, polyolefins, in particular polyethylene and polypropylene, polyacrylates, polymethacrylates, polyimides, polycarbonates, polyethersulfones, polyamides, polyesters and PVC; the best choice rubber (SBR), copolymers of type a styrene-ethylene-butadiene-styrene (SEBS), butyl rubber, ethylene-propylene rubber (EPR), ethylene propylene diene monomer rubber (diene monomer (EPDM)copolymer of ethylene and vinyl acetate (EVA), copolymers of ethylene and acrylate or butadiene and Acrylonitrile;
modified maleic anhydride polymers and copolymers; graft copolymers.

5. The capsule according to claim 4, characterized in that thermoplastic material includes at least a polyolefin, particularly preferably polyethylene or polypropylene.

6. The capsule according to claim 1, characterized in that the absorbent is in the form of particles, in particular with a maximum particle size of less than 50 μm, in particular less than 40 μm, particularly preferably less than 20 microns.

7. The capsule according to claim 1, characterized in that the wall thickness of the capsule is in the range of values between approximately 0.05 mm and 2 mm, particularly between about 0.1 mm and 1.1 mm,further preferably between 0.1 mm and 0.5 mm

8. The capsule according to claim 1, characterized in that the ratio of the particle size of the absorbent to the wall thickness of the capsules is between 0.01 and 0.2, in particular between 0.02 and 0.1.

9. The capsule according to claim 1, characterized in that the adsorbent is chosen from the group consisting of silica gels, zeolites, dewatering, respectively, adsorbing moisture or water clays, aluminosilicates, as zeolites or bentonites, molecular sieves, active carbon, oxides of alkaline earth metals, calcium sulfate and mixtures thereof.

10. The capsule according to claim 1, characterized in that the adsorbent, which is at least dehydrating agent, preferably selected from silica gel, aluminosilicates, as bentonites, molecular sieves and/or calcium sulphate.

11. The capsule according to claim 1 or 4, characterized in that the polymer mixture, respectively, of thermoplastic material is chosen from the group consisting of a polymer derived from a single monomer, a copolymer of two or more monomers, a mixture of two or more polymers derived from a single monomer, a mixture of two or more copolymers, and mixtures of at least one polymer, which is derived from a single monomer, and at least one copolymer.

12. The capsule according to claim 1 or 4, characterized in that the polymer mixture, respectively, of thermoplastic material is of FDS is th a mixture of, at least one polymer derived from a single monomer, and at least one copolymer, where, preferably, at least the copolymer thermoplastic material has a total Monomeric unit of the polymer, in particular a mixture of two copolymers with at least one common monomer unit.

13. The capsule according to claim 1, characterized in that the wall of the capsule of the polymer mixture with at least one adsorbent has at least the area of migration on at least the surface of the capsule wall and an internal region, and the maximum concentration of the adsorbent within the zone of migration, at least twice higher than the maximum concentration of the adsorbent in an inner scope.

14. The capsule according to claim 1, characterized in that the wall of the capsule is made homogeneous polymeric mixture with at least one adsorbent and is a monolithic structure.

15. The capsule according to claim 1, characterized in that the wall of the capsule is made of two or more layers, in particular two or three layers.

16. Capsule 15, characterized in that the wall of the capsule has one internal and at least one lying on it the outer layer and the inner layer forms a direct wall of the hollow space capsules, and one of the two layers consists of a polymer mixture, is less than the least one adsorbent, and the other layer of pharmacologically neutral material.

17. Capsule 15, characterized in that the wall of the capsule comprises a sandwich structure, in which case the outer layer forms a barrier against moisture, the middle layer consists of a polymer mixture with at least one adsorbent and the inner layer consists of a pharmacologically neutral material.

18. The capsule according to claim 1, characterized in that the polymer mixture contains plasticizers, stabilizers, dyes or pigments.

19. The capsule according to claim 1, characterized in that the capsule is a two-part capsule, having closed the form of a cylinder with rounded closed ends, which is formed by the main part of the capsule, which Telescopable is inserted into the cap of the capsule.

20. The capsule according to claim 1, characterized in that the capsule consists of a main part of the capsule and cap of the capsule walls have a thickness of from 0.1 to 0.5 mm.

21. The capsule according to claim 19 or 20, characterized in that the joints between the main part of the capsule and the cap is closed by welding.

22. The application of the polymer mixture according to claim 1 for the manufacture of capsules.

23. Inhaler containing at least one capsule according to any one of claims 1 to 21.

24. Secondary packing means containing at least one capsule according to any one of FG1-21.

25. The method of drying a pre-dosed quantities suitable for inhalation powders with a residual moisture content up to 5 wt.% in quantities of up to 50 mg, preferably up to 30 mg, particularly preferably up to 15 mg and, in the highest degree, preferably up to 10 mg, characterized in that the powder is stored in a capsule according to claims 1 to 21.

26. The method according A.25, characterized in that the capsule is surrounded by a secondary packaging tool.

27. The method according to p, characterized in that the secondary packing means is water resistant.

28. The method according to p or 27, characterized in that the secondary packing means is a blister, which at least partially includes an aluminum foil.



 

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