Hpmc capsules with reduced powder retention

Abstract

Hydroxypropyl methylcellulose (HPMC) capsules containing a small amount of CaCl2 and a method for making the HPMC capsules, which exhibit reduced powder retention when used in a dry powder inhaler (DPI).

Description

[0001] The present invention discloses a hydroxypropyl methylcellulose (HPMC) capsule containing a small amount of CaCI2 and a method for preparing said HPMC capsule, which exhibits a reduced powder retention when said HPMC capsule is used in a dry powder inhaler (DPI). BACKGROUND

[0002] Capsules are used in the pharmaceutical industry to allow oral administration of a drug or to allow administration of a powder for inhalation. In the latter case, the capsule is pierced using a suitable inhalation device and the powder is inhaled through the mouth or sometimes through the nose.

[0003] US 2015 / 0231344 A1 discloses a dry powder inhaler system comprising a HPMC capsule filled with a powder formulation containing a micronized active ingredient and a single dose dry powder inhaler device especially adapted for said capsule.

[0011] It is mentioned that after inhalation a certain amount of the drug will still be present in the capsule.

[0004] US 5,626,871 discloses capsules for intratracheal bronchial administration of the powder contained in these capsules. As disclosed in example 17, the capsules are produced from HPMC, a gelling agent, carrageenan, and a gelling aid added as KCI, K + constitutions.

[0005] HPMC is a gelling polymer compared to conventional film forming polymers like gelatin and vice versa: HPMC can be completely dissolved at ambient like temperatures and gels only at elevated temperatures, whereas gelatin gels at ambient like temperatures and dissolves at elevated temperatures. HPMC capsules produced using conventional gelling techniques, i.e. at ambient like temperatures, require a gelling agent in order to gel at such ambient like temperatures.

[0006] Typical gelling agents are known to the skilled person and can be gellan gum, carrageenan, konjac gum, xanthan gum and guar gum, etc.

[0007] Gelling agents are often used in combination with a gelling aid, which is often a cation, like potassium or calcium. The gelling aid enhances the gelling ability of the gelling agent.

[0008] CN 189 846 851 A discloses such HPMC capsules, which are prepared using conventional gelling techniques with the help of a gelling agent. The gelling agents are gellan gum in examples 1, 2 and 3 and konjac gum in examples 4, 5 and 6. Further gelling agents are mentioned in the description in

[0012] .

[0009] Cations in the form of their salts, like potassium salts and in particular calcium salts, disclosed in the examples are used as gelling aids.

[0010] CN 106 166 143 B discloses such HPMC capsules, which are prepared using conventional gelling techniques with the help of a gelling agent. The gelling agents mentioned in the examples are gellan gum, carrageenan and pectin.

[0011] The cations disclosed in the examples in the form of their salts, such as potassium salts and in particular calcium salts, act as coagulation promoters, i.e. as gelling aids.

[0012] In examples 17-21, US 5 626 871 A discloses such HPMC capsules, which have been prepared using conventional gelling techniques with the help of a gelling agent. The gelling agent mentioned is carrageenan.

[0013] The potassium disclosed in examples 17-21 in the form of its potassium chloride salt acts as a gelling aid.

[0014] US 2019 / 0321301 A1 discloses acid-resistant capsules, which comprise pectin and a divalent cation, such as calcium chloride, in the capsule shell.

[0015] US 2017 / 0087092 A1 discloses a high-performance manufacturing method for a hard capsule shell, which is prepared with HPMC 2906 instead of calcium chloride.

[0016] None of the documents cited above, whether used alone or in combination, gives any impetus to change the DPI application from a HPMC capsule containing a gelling agent to a HPMC capsule without a gelling agent, let alone to use a small amount of CaCI2 in a HPMC capsule without a gelling agent.

[0017] Gelling agents can have an adverse effect on the performance of the capsules, for example, the presence of a gelling agent in a HPMC capsule can interfere with components in the dissolution medium, such as ions, or in particular cations, etc., resulting in a change and difference in the dissolution profile. This is not desirable.

[0018] The second method of gelling HPMC is the thermal gelling method, in which the HPMC is gelled at high temperatures above the gelling point of the HPMC. In the thermal gelling method, no gelling agent is required.

[0019] It was found that pure HPMC capsules show less favorable powder retention properties compared to HPMC capsules containing a gelling agent.

[0020] There is a need for such a HPMC capsule which does not contain any gelling agent while showing at least comparable average powder retention properties compared to HPMC capsules containing a gelling agent to exclude any differences in dissolution properties caused by any ions or the interaction of said ions with the gelling agent in the dissolution medium. Furthermore, the mechanical properties need to be acceptable for the production of the capsules and their use.

[0021] Moreover, parameters important for the functioning of the capsule in the intended use, i.e. in a DPI device, should be met, like the piercing and opening of the capsule should work as required. Thus, for example, the piercing force needs to open the capsule efficiently without breakage or breakage at least minimal.

[0022] Surprisingly, the problem was solved without a gelling agent by adding a certain amount of CaCI2to the shell material of the HPMC capsule. As shown in Example 4 and Figure 3 The average powder retention properties shown are superior to the average powder retention properties of pure HPMC capsules and at least comparable to the average powder retention properties of HPMC capsules containing a gelling agent, in some cases even better. The mechanical properties in the impact test as shown in Example 3 are comparable to the mechanical properties of pure HPMC capsules. The piercing test as shown in Example 5 shows better performance than HPMC capsules containing a gelling agent.

[0023] Abbreviations and definitions used in this specification

[0024] API active pharmaceutical ingredient

[0025] cP centipoise, in SI units (1 cP = 10 -3 Pa-s = 1 mPa-s) one centiPoise or one milliPascal-seconds (mPa-s)

[0026] DPI dry powder inhaler

[0027] HPMC hydroxypropyl methylcellulose, also known as hypromellose, cellulose, 2-hydroxypropyl methyl ether; cellulose hydroxypropyl methyl ether, [9004-65-3].

[0028] The definition of hypromellose used in this invention can be found in the following document:

[0029] US Pharmacopeia

[0030] Document type: USP and NF

[0031] DocId: 1_GUID-6A0B0F3C-FA70-433C-AD55-2020BBC64718_4_en-US

[0032] Printed from: https: / / online.uspnf.com / uspnf / document / 1_GUID-6A0B0F3C-FA70-433C-AD55-2020BBC64718_4_en-US

[0033] 2020USPC

[0034] Page information:

[0035] USP43-NF38-2279

[0036] USP42-NF37-2229

[0037] USP41-NF36-2105

[0038] RH relative humidity: As used herein, the term "relative humidity" means the ratio of the actual water vapor pressure at a given temperature to the water vapor pressure at the same temperature when air is saturated with water. The skilled person is aware of many techniques for humidity measuring instruments, all of which will give essentially the same RH value.

[0039] wt% weight percent or percent by weight SUMMARY

[0040] The subject of the present invention is a capsule shell CAPSSHELL comprising HPMC and CaCl2;

[0041] The amount of CaCl2 comprised in the CAPSSHELL is comprised between 3Ό00 ppm and 9Ό00 ppm based on the weight of the HPMC comprised in the CAPSSHELL;

[0042] The CAPSSHELL does not contain a gelling agent;

[0043] The CAPSSHELL does not contain a combination of a gelling agent and a gelling aid. BRIEF DESCRIPTION OF DRAWINGS

[0044] The present invention will be described again with reference to the accompanying drawings, in which:

[0045] Figure 1: shows SEM pictures of residual powder on the inner surface of a capsule after emptying the powder from the capsule under the action of a DUSA device; the film forming polymer of the capsule shell is HPMC and the capsule shell contains CaCl2

[0046] Figure 2 : shows SEM pictures of residual powder on the inner surface of a capsule after emptying the powder from the capsule under the action of a DUSA device; the film forming polymer of the capsule shell is HPMC and the capsule shell does not contain CaCl2

[0047] Figure 3 : shows a graphical representation of the PR values versus the LOD in the data of Table 3. DETAILED DESCRIPTION

[0048] A CAPSSHELL is a capsule shell filled with a powder comprising a substance selected from the group consisting of an active pharmaceutical ingredient, a drug, and mixtures thereof. A CAPSSHELL is a capsule for pharmaceutical or healthcare applications.

[0049] The HPMC and CaCl2 are contained in the capsule shell itself, i.e. in the wall that actually builds the capsule shell. Another word for "builds" can be "constitutes" or "forms". The HPMC is the film forming substance that actually builds the wall, i.e. that builds the capsule shell itself; the CaCl2 is contained in the HPMC, i.e. the CaCl2 is contained in the wall.

[0050] The HPMC and CaCl2 as referred to in the present invention do not mean that they are contained in the content of the capsule shell, i.e. in the powder that is filled into the capsule shell, such as a drug in powder form, etc.

[0051] Suitable HPMC is commercially available.

[0052] The methoxyl content of the HPMC can be 27.0% to 30.0% (w / w).

[0053] The hydroxypropoxyl content of the HPMC can be 4.0% to 12.0% (w / w).

[0054] Preferably, the methoxyl content of the HPMC can be 27.0% to 30.0% (w / w) and the hydroxypropoxyl content 4.0% to 12.0% (w / w).

[0055] In the present invention, the content of the methoxyl and the hydroxypropoxyl of the HPMC is expressed according to the US Pharmacopeia, as the US Pharmacopeia reference is cited herein.

[0056] There are different types of HPMC. The HPMC can for example be selected from the group consisting of:

[0057] HPMC 2910 containing about 7.0% to 12.0% hydroxypropyloxy and about 28.0% to 30.0% methoxy;

[0058] HPMC 2906 containing about 4.0% to 7.5% hydroxypropyloxy and about 27.0% to 30.0% methoxy;

[0059] HPMC 2208 containing about 4.0% to 12.0% hydroxypropyloxy and about 19.0% to 24.0% methoxy; and

[0060] HPMC 1828 containing about 23.0% to 32.0% hydroxypropyloxy and about 16.5% to 20.0% methoxy.

[0061] The HPMC in the CAPSSHELL can be one type of HPMC, but also a mixture of different types of HPMC.

[0062] In one embodiment, the HPMC can be HPMC 2906, HPMC 2910 or a mixture thereof.

[0063] The CAPSSHELL can contain 3'500 ppm to 9'000 ppm, preferably 4'000 ppm to 9'000 ppm, more preferably 4'500 ppm to 9'000 ppm, even more preferably 4'750 ppm to 9'000 ppm, especially 5'000 ppm to 9'000 ppm, more especially 6'000 ppm to 9'000 ppm, more especially 6'000 ppm to 8'000 ppm, in particular 6'000 ppm to 7'000 ppm, more in particular 6'000 ppm to 6'500 ppm of CaCI2, wherein the ppm are based on the weight of the HPMC included in the CAPSSHELL.

[0064] The CAPSSHELL can contain 3'500 ppm to 7'000 ppm, preferably 4'000 ppm to 7'000 ppm, more preferably 4'500 ppm to 7'000 ppm, even more preferably 4'750 ppm to 7'000 ppm, especially 5'000 ppm to 7'000 ppm, more especially 6'000 ppm to 7'000 ppm, even more especially 6'000 ppm to 6'500 ppm of CaCI2, wherein the ppm are based on the weight of the HPMC included in the CAPSSHELL.

[0065] In another embodiment, the CAPSSHELL can contain 3'500 ppm to 6'500 ppm, preferably 4'000 ppm to 6'500 ppm, more preferably 4'500 ppm to 6'500 ppm, even more preferably 4'750 ppm to 6'500 ppm, especially 5'000 ppm to 6'500 ppm, more especially 6'000 ppm to 6'500 ppm of CaCI2, wherein ppm is based on the weight of HPMC comprised in the CAPSSHELL.

[0066] The CAPSSHELL can contain 70 wt% or more, preferably 80 wt% or more, more preferably 90 wt% or more, even more preferably 95 wt% or more, especially 97.5 wt% or more, more especially 99 wt% or more, even more especially 99.3 wt% or more, in particular 99.35 wt% or more of HPMC, wherein wt% is based on the weight of the dry CAPSSHELL.

[0067] The upper limit of HPMC is 99.65 wt%, wherein wt% is based on the weight of the dry CAPSSHELL.

[0068] In one embodiment, the dry CAPSSHELL consists of HPMC and CaCI2.

[0069] In one embodiment, the CAPSSHELL consists of HPMC, CaCI2and residual water, preferably wherein the amount of CaCI2is based on the weight of HPMC contained in the CAPSSHELL as disclosed herein and all embodiments thereof.

[0070] In one embodiment, the dry CAPSSHELL consists of 99.4 wt% to 99.35 wt% of HPMC and 0.6 wt% to 0.66 wt% of CaCI2, wherein the amounts of HPMC and CaCI2add up to 100 wt%, wherein wt% is based on the weight of the dry CAPSSHELL.

[0071] In one embodiment, the CAPSSHELL is a hard capsule shell.

[0072] The wall thickness of the CAPSSHELL is known to the skilled person, typical values can be about 100 micrometer, typical ranges can be 60 micrometer to 150 micrometer.

[0073] Typical sizes of the CAPSSHELL are known to the skilled person and can be expressed for example with size 00, 0, 1, 2 or 3.

[0074] The CAPS SHELL contains residual water. The residual water can come from the production process of making the CAPS SHELL using a water-containing mixture, thus the water in the CAPS SHELL is typically residual water that remains in the CAPS SHELL after drying, and can also come from the atmospheric humidity, essentially the air humidity, around the CAPS SHELL. The typical content of residual water in the CAPS SHELL is 14 wt% or less, preferably 10 wt% or less, more preferably 9 wt% or less, even more preferably 7 wt% or less; wt% based on the weight of the CAPS SHELL.

[0075] The typical range of residual water content in the CAPS SHELL can be 0 wt% to 14 wt%, preferably 1 wt% to 14 wt%, even more preferably 2 wt% to 14 wt%, especially 2 wt% to 10 wt%, more especially 2 wt% to 9 wt%, even more especially 2 wt% to 7 wt% of water; wt% based on the weight of the CAPS SHELL.

[0076] In one embodiment, the CAPS SHELL does not contain a gelling agent GEL AGE or a combination of a gelling agent GEL AGE and a gelling aid GEL AID.

[0077] Gelling agents GEL AGE, and combinations of gelling agents GEL AGE and gelling aids GEL AID for capsule manufacturing are known to the skilled person.

[0078] Typical gelling agents GEL AGE are known to the skilled person, such as agar gum, guar gum, locust bean gum (carob gum), carrageenan gum, pectin, xanthan acid, gellan gum, konjac gum or gelatin.

[0079] Typical gelling aids GEL AID that can be used in combination with a gelling agent GEL AGE are known to the skilled person and can be cations, such as K + , Na + , Li + , NH4 + , Ca 2+ or Mg 2+ .

[0080] In addition to HPMC and CaCI2, the CAPS SHELL can comprise one or more additives ADD, ADD can be a viscosity modifier, an antifoam aid, a plasticizer, a lubricant, a colorant, a solvent, a solvent aid, a surfactant, a dispersant, a solubilizer, a stabilizer, a flavoring agent, a sweetener, an absorbent, an adsorbent, an adhesion agent, an antioxidant, an antibacterial agent, a preservative, a drying agent, a flavoring agent, a fragrance, a pH adjuster, a binder, a wetting agent, a disintegrant, a controlled release agent, an acid, a salt or a mixture thereof.

[0081] Typical ADDs can be viscosity modifiers, antifoam aids, plasticizers, colorants, surfactants, dispersants, antioxidants, pH modifiers, wetting agents, acids, salts or mixtures thereof.

[0082] Preferred ADDs can be viscosity modifiers, antifoam aids, plasticizers, colorants, surfactants, dispersants, antioxidants, pH modifiers, wetting agents, salts or mixtures thereof.

[0083] The plasticizer can be glycerol, propylene glycol, sorbitol or lecithin. To avoid excessive softness, the content of plasticizer should not be too high, such as at most 2 wt%, preferably at most 1 wt%, wt% based on the weight of the dry CAPS SHELL.

[0084] The colorant can be a pigment, such as Ti02, or a dye.

[0085] A typical amount of pigment or dye can be 0.01 wt% to 10 wt%, preferably 0.01 wt% to 5 wt%, more preferably 0.01 wt% to 2.5 wt%, even more preferably 0.01 wt% to 1 wt%, wt% based on the weight of the dry CAPS SHELL.

[0086] The dispersant can be sodium lauryl sulfate, sorbitol or lecithin.

[0087] The antioxidant can be ascorbic acid.

[0088] The acid can be acetic acid.

[0089] A typical amount of acid can be 0.025 wt% to 0.75 wt%, preferably 0.04 wt% to 0.6 wt%, wt% based on the weight of the HPMC.

[0090] A possible content of any ADD in the CAPS SHELL can be 0.025 wt% to 29.65 wt%, preferably 0.04 wt% to 22 wt%, wt% based on the total weight of the dry CAPS SHELL.

[0091] In one embodiment, the dry CAPS SHELL consists of HPMC, CaCl2and a colorant.

[0092] In one embodiment, the dry CAPS SHELL consists of HPMC, CaCl2and a pigment.

[0093] In one embodiment, the CAPS SHELL consists of HPMC, CaCl2, residual water and optionally a pigment, preferably wherein the possible amount of CaCl2is based on the weight of the HPMC contained in the CAPS SHELL as disclosed herein and all embodiments thereof;

[0094] In case the pigment is contained in the CAPSSHELL, then preferably wherein the amount of HPMC is based on the weight of the dry CASPSHELL as disclosed herein and all embodiments thereof.

[0095] A further subject matter of the present application is a process for preparing a CAPSSHELL, wherein the CAPSSHELL is formed by a process PROCFORMCAPS for forming a capsule shell from a mixture DIPMIX, DIPMIX is a water containing CaCl2and HPMC;

[0096] wherein the CAPSSHELL is defined as herein and all embodiments thereof.

[0097] Preferably, the CaCl2is present in DIPMIX in form of an aqueous solution thereof.

[0098] Preferably, the HPMC is present in DIPMIX in form of an aqueous solution thereof.

[0099] The skilled person also refers to DIPMIX as melt.

[0100] PROCFORMCAPS can be any conventional method for forming a capsule shell known to the skilled person, like extrusion molding, injection molding, casting or dip molding, preferably dip molding.

[0101] Dip molding can also be referred to as dip coating.

[0102] A CAPSSHELL made by dip molding comprises two parts of the capsule shell, said two parts are referred to as cap and body. The two parts are also often referred to as two halves, but said two parts do not necessarily need to be of the same size and each of said two parts does not necessarily need to be exactly half of the size of the CAPSSHELL. The cap and the body are two separate parts. When connected together, said two parts form a capsule or capsule shell, which can be empty or filled. The words "capsule" and "capsule shell" are often used interchangeably. The term shell generally refers to a capsule shaped polymer forming a membrane, which again forms the wall of the shell, that is to say, again forms the shell, thus the capsule shaped polymer is also referred to as shell. The cap can be obtained by a mold pin having a corresponding geometry complementary to the desired shape of said cap. The body can be formed by a mold pin having a corresponding geometry complementary to the desired shape of said body. By using a corresponding mold pin in dip molding, the cap or the body can be obtained.

[0103] Thus, the CAPSSHELL can comprise two parts, a cap and a body. The cap and the body are telescopically joined to provide the CAPSSHELL. Typically, the cap and the body each have two regions: a dome-shaped region, which is the closed end of the cap or the body, respectively; and a substantially cylindrical region, which extends from the dome-shaped region and terminates at the open end of the cap or the body, respectively.

[0104] The substantially cylindrical region of the cap, or at least a portion thereof, is telescopically joined with the substantially cylindrical region of the body, or at least a portion thereof. Essentially, the body is inserted into the cap, or vice versa. This insertion is typically a sliding of the cap over the body, or vice versa. Typically, the cap is slid over the body. Thereby the substantially cylindrical region of the body, or at least a portion of this region of the body, is located inside the substantially cylindrical region of the cap, or at least inside a portion of this region of the cap. Thus, the substantially cylindrical regions of the cap and the body are slid over each other, as the case can be. Thus, typically the body is inserted into the cap, i.e. the body is slid into the cap. The telescopically joining occurs coaxially with respect to the longitudinal axis of the cap and the body.

[0105] The telescopically joined cap and body are thus the capsule.

[0106] It is required to provide a DPIMIX for dip molding.

[0107] The dip molding comprises the following steps:

[0108] (1) dipping a mold pin for a first half of a CAPSSHELL into a DIPMIX;

[0109] (2) withdrawing the mold pin from the DIPMIX while allowing a film to form on the mold pin;

[0110] (3) drying the film on the mold pin, thereby providing the first half of a CAPSSHELL; and

[0111] (4) removing the half of the CAPSSHELL from the mold pin;

[0112] wherein CAPSSHELL and DIPMIX are as defined herein and all embodiments thereof.

[0113] The CAPSSHELL comprises two parts, which are referred to as a cap and a body of the CAPSSHELL.

[0114] Steps (1) to (4) are done with both a pin shaped to provide the cap and a pin shaped to provide the body.

[0115] Steps (1) to (4) need to be performed in the order in which they are presented.

[0116] After the two parts of the CAPSSHELL have been prepared, the two parts are joined to each other to form the capsule.

[0117] The length of the half capsule shell removed from the pin can still be longer than the target length of the desired half capsule shell, in which case the half capsule shell on the pin and after removal from the pin represents an unprocessed part and is cut to size to provide the desired half capsule shell of the desired length.

[0118] The pin can have a high temperature PINTEMP for dip molding. In one embodiment, the pin has a high temperature when it is dipped into the DIPMIX, and when the film dries on the pin after dipping.

[0119] The PINTEMP can be 1.0°C or more, preferably 5°C or more, more preferably 10°C or more, than the gel temperature of the DIPMIX. The PINTEMP can have an upper limit of 95°C.

[0120] The PINTEMP can be selected according to the desired capsule size.

[0121] The PINTEMP can have a typical range of 45°C to 95°C, preferably 45°C to 80°C, more preferably 45°C to 70°C, even more preferably 50°C to 70°C, especially 50°C to 65°C.

[0122] Accordingly, the pin can be pre-heated to the desired PINTEMP prior to step (1).

[0123] The temperature of the DIPMIX, DIPMIXTEMP, during dipping of the pin into the DIPMIX can be at most 1.0°C, preferably 10°C to 1.0°C, more preferably 6°C to 1.0°C, even more preferably 6°C to 2°C, below the gel temperature of the DIPMIX.

[0124] As an example for HPMC grade 2906, the DIPMIXTEMP can be 10°C to 29°C, preferably 15°C to 29°C, more preferably 20°C to 29°C.

[0125] Drying of the film on the pin can be done by air drying. The drying can be done at a high temperature, where the temperature is higher than the gel temperature of the DIPMIX.

[0126] Accordingly, the air temperature used for drying can be higher than the gel temperature of the DIPMIX.

[0127] The air temperature used for drying the film on the pin can be 45°C to 90°C, preferably 45°C to 80°C.

[0128] Typically, step (3) has a duration of 5 minutes to 60 minutes.

[0129] Typically, step (3) is performed at a RH of 20% to 90%, preferably 20% to 70%, more preferably 20% to 60%.

[0130] In a preferred embodiment, the drying is performed as disclosed in WO 2008 / 050205 Al.

[0131] The DIPMIX comprises HPMC and CaCI2 in an amount based on the weight of the dry DIPMIX, which corresponds to the amount of HPMC and CaCI2 in the dry CAPS SHELL based on the weight of the dry CAPS SHELL as defined herein.

[0132] The DIPMIX can comprise 15 wt% to 25 wt%, preferably 17 wt% to 23 wt%, more preferably 17.5 wt% to 22.5 wt% of HPMC, wt% based on the weight of the DIPMIX.

[0133] The concentration of HPMC in the DIPMIX can be chosen to obtain a DIPMIX viscosity measured at a temperature of 10 °C to 1.0 °C below the gelling temperature of the DIPMIX of 1 '000 mPa * s to 3'000 mPa * s, preferably 1 '200 mPa * s to 2'500 mPa * s, more preferably 1 '600 mPa * s to 2'000 mPa * s.

[0134] The amount of CaCI2 in the DIPMIX corresponds to the content of CaCI2 in the dry CAPS SHELL based on the weight of the HPMC in the DIPMIX.

[0135] The DIPMIX can be prepared by mixing a mixture CCMIX (CCMIX is a mixture of CaCI2 and water) with a mixture HPMCMIX (HPMCMIX is a mixture of HMPC in water).

[0136] The CCMIX can comprise 15 wt% to 25 wt%, preferably 17.5 wt% to 22.5 wt% of CaCI2, wt% based on the weight of the CCMIX.

[0137] The HPMCMIX can comprise 15 wt% to 25 wt%, preferably 17.5 wt% to 22.5 wt% of HPMC, wt% based on the weight of the HPMCMIX.

[0138] The amounts of HPMC MIX and CCMIX and their concentrations and the amounts of HPMC and CaCl2 are calculated and selected in a manner to provide the amounts of CaCl2 and HPMC in DIP MIX that are desired in order to provide the amounts of CaCl2 and HPMC in CAPS SHELL that are desired.

[0139] The amounts of CaCl2 and HPMC in dry DIP MIX correspond to the respective amounts in dry CAPS SHELL.

[0140] CCMIX can be prepared by mixing MIXCC of CaCl2 with water.

[0141] HPMC MIX can be prepared by mixing MIXHPMC of HPMC with water.

[0142] The temperature of the water can be higher than room temperature, preferably higher than 60°C, more preferably higher than 70°C. The optimal temperature can be determined by the skilled person. Mixing HPMC with water at a temperature higher than 60°C provides a dispersion of HPMC in water. The dispersion can be cooled to a temperature of 10°C to 20°C to achieve dissolution of the HPMC.

[0143] The gelation temperature of any solution of HPMC in water, such as HPMC MIX or DIP MIX, can be determined by measuring the viscosity of the solution upon stepwise heating. The temperature at which the viscosity starts to increase sharply is considered the gelation temperature. As an example, for a concentration of about 19 wt% in water, the gelation temperature of any HPMC of the present invention meeting the USP definition of HPMC type 2906 is between about 30°C and 40°C. As a further example, for a concentration between about 15 wt% and 25 wt% in water, the gelation temperature of HPMC of the present invention meeting the USP definition of HPMC of about 6% hydroxypropoxy content is between about 30°C and 40°C.

[0144] A further subject-matter of the present invention is a CAPS SHELL filled with a formulation FILL FORM comprising an active ingredient ACTING R, which can be selected from the group consisting of an active pharmaceutical ingredient, a drug, and mixtures thereof;

[0145] wherein CAPS SHELL is as defined herein and all embodiments thereof.

[0146] FILL FORM can have the form of a powder.

[0147] A further subject-matter of the present invention is the use of a CAPS SHELL for filling with FILL FORM, wherein CAPS SHELL and FILL FORM are as defined herein and all embodiments thereof.

[0148] FILLFORM can comprise ACTINGR in an amount of 0.05 wt% to 100 wt%, preferably 0.5 wt% to 90 wt%, more preferably 1 wt% to 50 wt%, even more preferably 5 wt% to 30 wt%, wt% based on the weight of the dry FILLFORM.

[0149] Examples of drugs or APIs that are candidates for ACTINGR to be filled into the CAPSSHELL are those commonly used in DPI applications and known to the skilled person, such as from the following classes: mucolytics, bronchodilators, corticosteroids, xanthine derivatives, leukotriene antagonists, proteins or peptides, and mixtures thereof.

[0150] A further subject matter of the present application is the use of a CAPSSHELL in a dry powder inhaler, wherein the CAPSSHELL is as defined herein and all embodiments thereof.

[0151] For such use of a CAPSSHELL in a dry powder inhaler, the CAPSSHELL filled with FILLFORM in the form of a capsule is used in a dry powder inhaler for dispensing FILLFORM during the action of the dry powder inhaler. The action of the dry powder inhaler on the CAPSSHELL releases FILLFORM from the CAPSSHELL. The release of FILLFORM provides the patient with FILLFORM for inhalation.

[0152] A further subject matter of the present application is a dry powder inhaler having a CAPSSHELL inserted in said dry powder inhaler, preferably wherein the CAPSSHELL is filled with FILLFORM, wherein the CAPSSHELL and FILLFORM are as defined herein and all embodiments thereof.

[0153] Examples

[0154] Materials, apparatus, methods and further abbreviations used in this specification

[0155] CC calcium chloride as calcium chloride dihydrate, CaCI2.2H2O, CAS 10035-04-8, product 22317.297, titration 99.8%, from VWR International bvba, 3001 Leuven, Belgium

[0156] HPMC Hydroxypropyl Methylcellulose, also known as Hypromellose, grade 2906, METHOCEL® FS Premium LV Hydroxypropyl Methylcellulose, The Dow Chemical Company, SWITZERLAND, 29.5% methoxyl, 6.2% hydroxypropoxyl

[0157] The lactose blend can be obtained in the form of Respitose ML001 from DFE Pharma, 47568 Goch, Germany, a quality of lactose for inhalation: d10 or 4 microns, D50 of 49 microns and d90 of 169 microns, particle size distribution data obtained from Murphy, Seamus. (2014). UNDERSTANDING THE AFFECT OF DPI DEVICE AND LACTOSE TYPE ON THE OUTPUT FROM A DEVICE. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 27. A16-A16.

[0158] LOD Loss on Drying

[0159] Equipment

[0160] 1 Mettler Toledo AB204 balance

[0161] 1 Memmert U40 drying oven

[0162] 1 aluminium container

[0163] Procedure

[0164] To measure LOD, do the following :

[0165] Weigh 1 + / - 0.001 g of capsule material in a pre-weighed aluminium container

[0166] Place the container in a drying oven set to a temperature of 100-105°C and cover the container with a wire mesh

[0167] Stored and dried at a temperature of 100 to 105°C for 18 hours

[0168] Cooled in a desiccator equipped and then weighed after a maximum of 30 minutes

[0169] The loss of weight on drying was calculated as a percentage of the original weight

[0170] If necessary, repeated 3 times and the accuracy of the LOD determination was assessed.

[0171] PR Powder retention

[0172] SD Standard deviation

[0173] SML Sorbitan monolaurate, Glycomul L KFG (non-GMO) / SCHL-470LB, acid value 6, color Gardner 1963 16, hydroxyl value 358, saponification value 165, water content according to KF 1.3 of Lonza, 3930 Visp, Switzerland

[0174] RF10 SOLEC(TM) RF-10 standard rapeseed lecithin liquid, acid value 28.60, acetone insolubles 62.80%, Solae Europe, S.A., 2, 1218 Le Grand Saconnex, Switzerland

[0175] Tube tester Capsugel, = in-house development:

[0176] Method:

[0177] The breaking and elastic behavior of the capsules was measured by their resistance to the impact test on the tube.

[0178] Procedure

[0179] 1. The capsules were stored for five days before the test in the desiccator.

[0180] The available storage conditions were: 10% RH, 23% RH, 33% RH, 45% RH

[0181] 50 capsules were stored in each case in an open box. This was then closed to avoid any exchange of moisture with the surrounding atmosphere.

[0182] 2. The capsules were placed horizontally on a flat surface.

[0183] 3. Place 100 g of weights in the tube.

[0184] 4. Place the tube on the capsule and push the latch to release the weights.

[0185] 5. Test 50 capsules.

[0186] After equilibration at the selected RH, store using a closed box and do not remove every 50 capsules at the same time (to avoid reabsorption of any humidity).

[0187] Record the number of broken bodies, caps or capsules (bodies and caps).

[0188] The tube tester and test method are disclosed in M. Sherry Ku et al., “Performance qualification of a new hypromellose capsule: Part I. Comparative evaluation of physical, mechanical and processability quality attributes of Vcaps and gelatin capsules”, International Journal of Pharmaceutics, Volume 386, Issues 1-2, 15 February 2010, Pages 30-41, Chapter 2.5. Mechanical strength evaluation and gelatin capsules).

[0189] Balance XPE205DR, Mettler-Toledo AG

[0190] Friability tester Friability / attrition tester TAR from ERWEKA GmbH, 63225 Langen, Germany

[0191] DUSA Dose Unit Sampling Equipment, a device for testing inhalation products, equipped with a critical flow controller, product model name TPK 2000, HCP5 vacuum pump, filter PALL FLEX 47 mm and DFM 2000 flowmeter, Copley Scientific, also known as DDU (Dose Delivered Uniformity) equipment for dry powder inhalers of Copley Scientific

[0192] SEM (Scanning Electron Microscope) FlexSEM 1000

[0193] Example 1: Preparation of CC Melt

[0194] Step 1: Preparation of HPMC Melt (HPMCMIX)

[0195] List of compounds for preparing HPMC melts:

[0196] HPMC: 20.55wt%

[0197] Water 79.45 wt%

[0198] HPMC melt is prepared by filling a container with water containing HPMC and mixed at 80°C to 85°C. The container is then cooled to 10°C to 20°C to dissolve the HPMC. After maintaining this temperature at 10°C to 20°C for one hour, the HPMC melt is heated to and maintained at 29°C for further use.

[0199] Step 2: Preparation of CaCl2·2H2O (CCMIX) solution

[0200] Add CaCl2·2H2O to water at 80°C while stirring at 200 rpm.

[0201] Step 3: Preparation of CC Melt (DIPMIX)

[0202] CC melt is a mixture of HPMC melt prepared according to step 1 and CaCl2·2H2O solution prepared according to step 2.

[0203] The CaCl2·2H2O solution is mixed with the HPMC melt prepared according to step 1, thereby providing the CC melt.

[0204] Three types of CC melt CC-A were prepared in this manner. * Melt, CC-A ** The fourth melt, CC-A melt, was prepared in this manner, along with CC-B melt. The amounts of these CC melts are given in Table 1.

[0205]

[0206]

[0207] CaCl2 MW = 110.98 g / mol

[0208] CaCl₂·2H₂O MW = 147.01 g / mol

[0209] CaCl2 weight:

[0210] CC-A: 503.41 g * (110.98 / 147.01) = 380.03 g

[0211] CC-A*: 503.41 g * (110.98 / 147.01) = 380.03 g

[0212] CC-A**: 497.05 g * (110.98 / 147.01) = 375.23 g

[0213] CC-B: 59.59 g 20 wt% = 11.918 g CaCl2.2H2O

[0214] 11.918 g * (110.98 / 147.01) = 9.0 g

[0215] ppm of CaCl2 based on the weight of HPMC + CaCl2:

[0216] CC-A: 380.03 g / (57'540 g + 380.03 g) * 1'000'000 = 6'561 ppm

[0217] CC-A * : 380.03 g / (59'820 g + 380.03 g) * 1'000'000 = 6'313 ppm

[0218] CC-A ** : 375.23 g / (49'530 g + 375.23 g) * 1'000'000 = 7'519 ppm

[0219] CC-B: 4'500 g 20.55 wt% = 924.75 g HPMC

[0220] 9.0 g / (924.75 g + 9.0 g) * 1'000'000 = 9'639 ppm

[0221] ppm of CaCl2 based on the weight of HPMC:

[0222] CC-A: 380.03 g / 57'540 g * 1'000'000 = 6'605 ppm

[0223] CC-A * : 380.03 g / 59'820 g *1'000'000 = 6'353ppm

[0224] CC-A ** 375.23g / 49'530g * 1'000'000 = 7'576ppm

[0225] CC-B: 9.0g / 924.75g * 1'000'000 = 9'732ppm

[0226] Example 2: Preparation of CC shells and CC capsules, and HPMC shells and HPMC capsules

[0227] The corresponding CC melt CC-A prepared according to Example 1 * CC-B and the HPMC melt prepared according to step 1 of Example 1 were used for conventional molding impregnation, i.e., by impregnating a stainless steel mold pin at a temperature of 55°C into the corresponding CC melt or HPMC melt at a temperature of 29°C, respectively, to produce CC shells and HPMC shells in the form of capsule halves (body and cap) with a capsule size of 3 and a target weight standard (capsule weight of 47 + / - 3 mg). A film was formed on the mold pin. The film on the mold pin was dried once for 15 to 20 minutes at 50°C to 60°C and 30% RH to 40% RH, and then dried a second time for 30 minutes at 50°C to 60°C and 25% RH to 30% RH, respectively, to obtain CC capsule halves and HPMC capsule halves, respectively.

[0228] Capsules are always assembled by connecting a cap to a body.

[0229] Example 3: Capsule Testing - Mechanical Properties

[0230] The fracture behavior of the capsules prepared according to Example 2 was measured by the resistance of their impact test using a tube tester. In preparation for the test, the capsules were stored in a desiccator for five days under four different storage conditions: 10% RH, 23% RH, 33% RH, and 45% RH, to obtain capsules with different levels of rupture (LOD). Fifty capsules were tested for each RH value, and the number of broken bodies or broken caps was recorded. The percentage of broken capsules is presented in Table 2.

[0231]

[0232] (1) The values ​​in Table 2 represent the mean ± standard deviation of the three individual tests.

[0233] When the amount of CaCl2 is too high, the mechanical properties deteriorate.

[0234] Example 4: Capsule Test - Powder Retention Rate in Capsules (PR)

[0235] To determine the residual powder in the capsules, a DUSA apparatus from Copley Scientific was used. Ten capsules prepared according to Example 2 were filled with 25 + / - 1 mg of lactose blend. These ten lactose blend filled capsules were placed in a 25 ml volume plastic bottle with a lid and tumbled 100 times in a friabilator TAR. The DUSA device was used to empty the capsules. The setup was adapted according to the USP Pharmacopea guideline section 601, entitled “Sampling the Delivered Dose from Dry Powered Inhalers”, Apparatus B; two pumps were used with a flow parameter of 100 L / min and a suction time of 2.4 seconds in order to match the 4 L air volume drawn from the inhaler as required by the cited USP Pharmacopea guideline section 601. The weight of the filled powder (Wpowder) was recorded for each of the ten capsules. The weight of the powder before (Wempty) and after (Wemptied) the use of the DUSA device to empty the capsules was determined. PR is the percentage of residual powder and is determined by the equation EQ1:

[0236] EQ1: PR% = 100 * [(Wemptied - Wempty) / Wpowder]

[0237] The results are expressed as the average value and standard deviation SD of 3 samples, tested on each of the total of 10 capsules, and are given in Table 3:

[0238]

[0239] ( * ) The capsule samples at LOD 5.0 to 5.5 were obtained without prior equilibration by any storage in a desiccator at the defined RH, instead of letting them stand at the RH at which they were present in the laboratory (about 50% RH) and at a temperature of about 22°C, and the given LOD is the LOD obtained by this treatment.

[0240] Figure 3 A graphical representation of the PR values in the Table 3 data versus the LOD is shown. The individual values are shown in black and the average values in grey.

[0241] ▲ Triangle: by CC-A * Capsules made from melt are represented by triangles.

[0242] • Circle: Capsules made from CC-A Melt ** Capsules made from Melt are indicated by a circle.

[0243] ■ Square: Capsules made from CC-B Melt are indicated by a square.

[0244] ♦ Diamond: Capsules used in US 5,626,871 Example 17 (medical hard capsules consisting essentially of hydroxypropyl methylcellulose [composition: 93 parts by weight of hydroxypropyl methylcellulose, "TC-5R" produced by Shinetsu Kagaku; 1 part by weight of carrageenan; 1 part by weight of potassium chloride; 5 parts by weight of water]) are indicated by a square.

[0245] o Circle: HPMC capsules are indicated by a triangle.

[0246] Results:

[0247] • Compared to capsules made from CC-A Melt * Melt and CC-A Melt ** HPMC capsules show the highest average PR values compared to capsules made from Melt.

[0248] • Compared to capsules with gelling agent used in US 5,626,871 Example 17 * Melt and CC-A Melt ** Capsules made from CC-A Melt show comparable or better PR values.

[0249] • Compared to capsules made from HPMC Melt * Melt and CC-A Melt ** Capsules made from CC-A Melt consistently show lower average PR values.

[0250] Example 5: Capsule testing - SEM imaging of capsule inner surface after DUSA test

[0251] CC-A Melt with LOD 4.5 to 5.0 prepared according to Example 2 and stored in a desiccator at 50% RH as described in Example 4 * Capsules and HPMC capsules were also tested using powders obtained by purchasing publicly available drugs in the form of capsules filled with powder at a pharmacy and extracting this powder and filling it into capsules. The capsules were then emptied under the action of the DUSA equipment as described in Example 4 and any residual powder was determined by visual inspection. Visual inspection showed that CC-A * Capsules contained significantly less powder content compared to HPMC capsules.

[0252] PR of HPMC capsules was 0.6% and CC-A *The PR of the capsules was 0.11%.

[0253] Figure 1 SEM pictures of the residual powder on the inner surface of a capsule after emptying the powder from the capsule under the action of a DUSA device. The film-forming polymer of the capsule shell was HPMC, and the capsule shell contained CaCl2. * SEM pictures of the residual powder on the inner surface of a capsule after emptying the powder from the capsule under the action of a DUSA device. The film-forming polymer of the capsule shell was HPMC, and the capsule shell contained CaCl2.

[0254] Figure 2 SEM pictures of the residual powder on the inner surface of a capsule after emptying the powder from the capsule under the action of a DUSA device. The film-forming polymer of the capsule shell was HPMC, and the capsule shell contained CaCl2.

[0255] Obviously, Figure 1 The number of powder particles shown is much lower than Figure 2 The number of powder particles shown is much lower than

[0256] Example 6: Capsule test - puncture test

[0257] Capsules made from CC-A * Puncture tests were performed with capsules made from CC-A

[0258] Puncture test protocol:

[0259] • The capsules (N=15) were equilibrated in the desiccators at 23% RH and 45% RH for 5 days.

[0260] • The puncture test was performed using a RSOl dry powder inhaler by Plastiape (Plastiape S.p.a. con socio unico, Osnago, Italy).

[0261] • The capsules were placed inside the inhaler chamber and punctured by pushing both side needles of the inhaler onto the capsule at the same time.

[0262] Once punctured, the capsules were visually inspected one by one and the capsules that did not meet the requirements were identified, i.e. the capsules whose cap was not pierced or the cap or some parts of it were detached, thus leading to the risk of depositing some capsule particles together with the powder in the patient's body by inhalation.

[0263] The sorted capsules were counted and expressed as a percentage of the total number of capsules analyzed, the results are given in Table 6.

[0264]

[0265] Compared to the capsules with gelling agent used in US 5,626,871 Example 17, the capsules from CC-A * Melt and CC-A ** Capsules made from the melt showed significantly better performance in the puncture test, no out-of-spec capsules were observed.

[0266] Comparative examples with additives

[0267] Preparation of additive melts and capsules thereof

[0268] Two other additives were tested as a replacement for CaCI2.2H2O.

[0269] The additives were:

[0270] • Sorbitol monolaurate SML

[0271] • Rapeseed lecithin RF10

[0272] The content of the additive in the respective melt was 5000 ppm relative to the weight of the HPMC, and the respective melt was prepared according to the procedure of Example 1, with the difference that step 2, and the amounts are given in Table 4, and in step 3, the respective dispersion of the additive was used instead of the CaCI2.2H2O solution.

[0273] Step 2: Preparation of dispersant for the additive

[0274] The additive was added to water and homogenized by Ultra-Turrax, IKA T25 at a speed of 8000 to 9000 rpm for 5 minutes.

[0275] The SML dispersion was left to stand until the foam had disappeared before adding to the HPMC melt, whereas the RF10 dispersion was used directly without the need for standing as no foam was formed.

[0276]

[0277] Preparation of additive melts provided the following two melts: RF10 melt and SML melt. With these two additive melts, additive capsule shells were then prepared according to the dip-molding method as described in Example 2.

[0278] Tests performed on additive capsules prepared from additive melts - powder retention PR in the capsules

[0279] The PR of the additive capsules having an LOD (%) of 5.0 to 5.5 was tested according to the method described in Example 4. As described in the Note below * ), an LOD of 5.0% to 5.5% was obtained. Table 5 shows the PR values.

[0280]

Claims

1. A capsule shell CAPSSHELL comprising HPMC and CaCl2; Based on the weight of HPMC included in CAPSSHELL, the amount of CaCl2 included in CAPSSHELL is between 3,000 ppm and 9,000 ppm. CAPSSHELL contains no gelling agents; or CAPSSHELL does not contain a combination of gelling agents and gelling aids. The gelling agent mentioned above is selected from the group consisting of: agar gum, guar gum, locust bean gum, carrageenan, pectin, xanthan acid, gellan gum, konjac gum, and gelatin; and The gelling aid is cationic.

2. The CAPSSHELL according to claim 1, wherein The HPMC is selected from the following group: HPMC 2910 contains 7.0% to 12.0% hydroxypropoxy and 28.0% to 30.0% methoxy. HPMC 2906 contains 4.0% to 7.5% hydroxypropoxy and 27.0% to 30.0% methoxy. HPMC 2208 containing 4.0% to 12.0% hydroxypropoxy and 19.0% to 24.0% methoxy; and HPMC 1828 contains 23.0% to 32.0% hydroxypropoxy and 16.5% to 20.0% methoxy.

3. The CAPSSHELL according to claim 1, wherein The HPMC has a methoxyl content of 27.0% to 30.0% (w / w).

4. The CAPSSHELL according to claim 1 or 2, wherein The HPMC has a hydroxypropoxy content of 4.0% to 12.0% (w / w).

5. The CAPSSHELL according to claim 1 or 2, wherein The HPMC is HPMC 2906, HPMC 2910, or a mixture thereof.

6. The CAPSSHELL according to claim 1 or 2, wherein CAPSSHELL contains 3,500 ppm to 9,000 ppm of CaCl2, where the ppm is based on the weight of HPMC included in CAPSSHELL.

7. The CAPSSHELL according to claim 1 or 2, wherein CAPSSHELL contains 4,000 ppm to 9,000 ppm of CaCl2, where the ppm is based on the weight of HPMC included in CAPSSHELL.

8. The CAPSSHELL according to claim 1 or 2, wherein CAPSSHELL contains 70 wt% or more HPMC, where the wt% is based on the weight of dried CAPSSHELL.

9. The CAPSSHELL according to claim 1 or 2, wherein CAPSSHELL includes one or more additives (ADDs) selected from the group consisting of viscosity modifiers, defoamers, lubricants, colorants, dispersants, flavoring agents, absorbents, adsorbents, antioxidants, antibacterial agents, pH adjusters, wetting agents, disintegrants, controlled-release agents, or mixtures thereof.

10. The CAPSSHELL according to claim 1 or 2, wherein Dry capshillell consists of HPMC and CaCl2.

11. The CAPSSHELL according to claim 1 or 2, wherein The dried CAPSSHELL consists of 99.4 wt% to 99.35 wt% HPMC and CaCl2, wherein the total amount of HPMC and CaCl2 is 100 wt%, and the wt% is based on the weight of the dried CAPSSHELL.

12. The CAPSSHELL according to claim 1 or 2, wherein Dry capshillell consists of HPMC, CaCl2 and colorant.

13. The CAPSSHELL of claim 1, wherein the gelling agent is selected from the group consisting of: K + Na + Li + NH4 + Ca 2+ and Mg 2+ .

14. The CAPSSHELL according to claim 1 or 2, wherein CAPSSHELL includes one or more additives (ADDs) selected from the group consisting of solvents, solvent auxiliaries, or mixtures thereof.

15. The CAPSSHELL according to claim 1 or 2, wherein CAPSSHELL includes one or more additives, wherein the additive is a solubilizer.

16. The CAPSSHELL according to claim 1 or 2, wherein CAPSSHELL includes one or more additives, said additives being selected from the group consisting of acids, salts, or mixtures thereof.

17. The CAPSSHELL according to claim 1 or 2, wherein CAPSSHELL includes one or more additives (ADDs) selected from the group consisting of stabilizers, desiccants, flavoring agents, binders, or mixtures thereof.

18. The CAPSSHELL according to claim 1 or 2, wherein CAPSSHELL includes one or more additives, wherein the additive is a surfactant.

19. A method for preparing CAPSSHELL, wherein CAPSSHELL is formed by the process PROCFORMCAPS, which is a mixture of water containing CaCl2 and HPMC, used to form capsule shells. CAPSSHELL is defined as in claim 1.

20. The method for preparing CAPSSHELL according to claim 19, wherein PROCFORMCAPS are extrusion molding, injection molding, casting, or dip molding.

21. The method for preparing CAPSSHELL according to claim 19 or 20, wherein PROCFORMCAPS are dip-molded.

22. The method for preparing CAPSSHELL according to claim 21, wherein... The impregnation molding process includes the following steps: (1) Dip the mold pin for the first half of CAPSSHELL into DIPMIX; (2) Remove the mold pin from DIPMIX while allowing a film to form on the mold pin; (3) Dry the film on the mold pin to provide the first half of CPASSHELL; as well as (4) Remove the first half of the CAPSSHELL from the mold pin; Wherein CAPSSHELL is as defined in claim 1, and DIPMIX is as defined in claim 19; And among them CAPSSHELL consists of two parts, referred to as the cap and body of CAPSSHELL; Steps (1) to (4) are accomplished using both a pin shaped to provide the cap and a pin shaped to provide the body.

23. A capshillell filled with a formulation comprising the active ingredient ACTINGR. CAPSSHELL is defined as in any one of claims 1 to 18.

24. A use of CAPSSHELL for filling with FILLFORM, wherein CAPSSHELL is as defined in claim 1, and FILLFORM is as defined in claim 23.

25. Use of CAPSSHELL in a dry powder inhaler, wherein CAPSSHELL is as defined in any one of claims 1 to 18 and 23.

26. A dry powder inhaler having a CAPSSHELL inserted into the dry powder inhaler, wherein the CAPSSHELL is as defined in any one of claims 1 to 18 and 23.

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