HPMC capsules with reduced powder retention

Abstract

The present invention discloses hydroxypropyl methylcellulose (HPMC) capsules containing low amounts of CaCl that exhibit reduced powder retention when used in dry powder inhalers (DPIs), and methods for making them.

Description

Background Art

[0001] The present invention discloses hydroxypropyl methylcellulose (HPMC) capsules containing a small amount of CaCl2, which exhibit reduced powder retention when used in a dry powder inhaler (DPI), and methods for making them.

[0002] Capsules are used in the pharmaceutical industry to enable oral administration of drugs or to administer inhalable powders. In the latter case, the capsules are pierced using a suitable inhalation device, and the powder is inhaled through the mouth or sometimes through the nose.

[0003] US2015 / 0231344A1 discloses a dry powder inhaler system comprising HPMC capsules filled with a powder formulation containing a micronized active ingredient, and a single-dose dry powder inhaler device specifically adapted to said capsules. In

[0011] , it is mentioned that some amount of drug will be present in the capsule after inhalation.

[0004] US5,626,871 discloses capsules for use in bronchial administration of powders contained in these capsules. The capsules are composed of HPMC, the gelling agent carrageenan, and the gelling aid K added as KCl, as disclosed in Example 17. + and.

[0005] HPMC is a polymer that gels reversely compared to conventional film-forming polymers such as gelatin. HPMC can dissolve completely at ambient-like temperatures and gel only at high temperatures, while gelatin gels at ambient-like temperatures and dissolves at high temperatures. HPMC capsules manufactured using conventional gelling techniques performed at ambient-like temperatures require a gelling agent to gel at such ambient-like temperatures.

[0006] Typical gelling agents are known to those skilled in the art and can be, for example, gellan gum, carrageenan, konjac gum, xanthan gum, and guar gum.

[0007] Gelling agents are often used in combination with gelling aids, which are usually cations such as potassium or calcium. Gelling aids enhance the gelling ability of the gelling agent.

[0008] CN189 846 851A discloses such HPMC capsules prepared with the help of a gelling agent using conventional gelling techniques. The gelling agent is 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 potassium salts, specifically calcium salts, as disclosed in the examples, function as gelling aids.

[0010] CN106 166 143B discloses such HPMC capsules prepared with the help of a gelling agent using a conventional gelling technique. The gelling agents mentioned in the examples are gellan gum, carrageenan, and pectin.

[0011] The cations in the form of potassium salts, specifically calcium salts, as disclosed in the examples, function as coagulants, which are gelling aids.

[0012] US5 626 871A discloses such HPMC capsules prepared with the help of a gelling agent using conventional gelling techniques in Examples 17-21. The gelling agent mentioned is carrageenan.

[0013] Potassium chloride, which is potassium in the form of its salt disclosed in Examples 17-21, functions as a gelling aid.

[0014] US2019 / 0321301A1 discloses an acid-resistant capsule containing divalent cations such as pectin and calcium chloride within a capsule shell.

[0015] US2017 / 0087092A1 discloses a high-performance manufacturing method for rigid capsule shells prepared with HPMC2906 instead of calcium chloride.

[0016] None of the above documents, individually or in combination, provide any incentive to change the DPI application from HPMC capsules containing a gelling agent to HPMC capsules without a gelling agent, much less to use small amounts of CaCl2 in HPMC capsules without a gelling agent.

[0017] Gelling agents can have detrimental effects on capsule performance. For example, the presence of a gelling agent in an HPMC capsule can interfere with the components in the dissolution medium, such as ions, specifically cations, or may result in altered or different dissolution profiles. This is undesirable.

[0018] A second method exists for gelling HPMC, which is a thermal gelling method in which HPMC is gelled at a temperature exceeding its gelation point. In the thermal gelling method, a gelling agent is not required.

[0019] It was found that pure HPMC capsules exhibit less desirable powder retention characteristics compared to HPMC capsules containing a gelling agent.

[0020] To eliminate differences in solubility caused by interactions between arbitrary ions or interactions with the gelling agent of the dissolution medium, there was a need for HPMC capsules without a gelling agent that exhibit at least equivalent average powder retention characteristics compared to HPMC capsules containing a gelling agent. Furthermore, the mechanical properties needed to be acceptable for the manufacture and use of the capsules.

[0021] Furthermore, parameters crucial to the capsule's function in its intended use, namely parameters within the DPI device, must be met, such as the need for capsule puncture and release to function as required. Therefore, for example, the puncture force must provide efficient release of the capsule, either completely unbroken or at least minimally broken.

[0022] Surprisingly, the problem was solved by adding a specific amount of CaCl2 to the shell material of the HPMC capsule in the absence of a gelling agent. The average powder retention characteristics shown in Example 4 and Figure 3 are better than those of pure HPMC capsules, and are at least equivalent to, and in some cases even better than, HPMC capsules containing a gelling agent. The mechanical properties in the impact test shown in Example 3 are equal to those of pure HPMC capsules. The puncture test shown in Example 5 shows even better performance than HPMC capsules containing a gelling agent.

[0023] Abbreviations and definitions used herein API Active Pharmaceutical Ingredients cP centipoise is 1 / 100th of a poise, or 1 millipascal-second (mPa·s) in SI units (1 cP = 10⁻¹⁰ -3 Pa·s = 1 mPa·s) DPI dry powder inhaler HPMC hypromellose, cellulose, 2-hydroxypropyl methyl ether; cellulose hydroxypropyl methyl ether, also known as [9004-65-3], hydroxypropyl methylcellulose. The definition of hypromellose used in this invention is: US Pharmacopeia Document Type: USP & NF DocId:1_GUID-6A0B0F3C-FA70-433C-AD55-2020BBC64718_4_en-US Print from: https: / / online.uspnf.com / uspnf / document / 1_GUID-6A0B0F3C-FA70-433C-AD55-2020BBC64718_4_en-US c 2020 USPC Page Information: USP43-NF38-2279 USP42-NF37-2229 It can be found in USP41-NF36-2105. RH Relative Humidity: The term "relative humidity" is used herein to mean the ratio of the actual water vapor pressure at a given temperature to the vapor pressure that would occur if the air were saturated with water at the same temperature. Many techniques for humidity measuring devices known to those skilled in the art exist, and all of these will give substantially the same RH value. Weight % Weight percent or percent by weight

Summary of the Invention

[0024] The subject of the present invention is a capsule shell CAPSSHELL containing HPMC and CaCl2, The amount of CaCl2 contained in CAPSSHELL is 3,000 to 9,000 ppm based on the weight of HPMC contained in CAPSSHELL, CAPSSHELL does not contain a gelling agent, CAPSSHELL does not contain a combination of a gelling agent and a gelling aid.

[0025] The present invention will be described again with reference to the accompanying drawings.

Brief Description of the Drawings

[0026] [Figure 1]The SEM image shows the residual powder on the inner surface of the capsule after the powder has been emptied from the capsule by the operation of the DUSA instrument. This indicates that the film-building polymer of the capsule shell was HPMC, and the capsule shell contained CaCl2. [Figure 2] The image shows an SEM photograph of the residual powder on the inner surface of the capsule after the powder has been emptied from the capsule by the operation of the DUSA instrument. The film-building polymer of the capsule shell was HPMC, and the capsule shell did not contain CaCl2. [Figure 3] Table 3 shows a graph of PR values ​​relative to LOD based on the data. [Modes for carrying out the invention]

[0027] CAPSSHELL is a capsule shell for filling powders containing substances selected from the group consisting of active pharmaceutical ingredients, drugs, and mixtures thereof. CAPSSHELL is a type of capsule used in pharmaceutical or healthcare applications.

[0028] HPMC and CaCl2 are contained in the capsule shell itself, i.e., the wall that actually constructs the capsule shell. Another word for "construct" could be "constitute" or "form". HPMC is the film-forming material that actually constructs the wall, i.e., the capsule shell itself, and CaCl2 is contained in HPMC, i.e., CaCl2 is contained in the wall.

[0029] The HPMC and CaCl2 as defined by this invention do not mean that they are contained in the capsule shell, i.e., in the powder that is filled into the capsule shell, such as a drug in powder form.

[0030] Suitable HPMCs are commercially available.

[0031] HPMC may have a methoxy content of 27.0-30.0% (w / w).

[0032] HPMC may have a hydroxypropoxy content of 4.0-12.0% (w / w).

[0033] Preferably, the HPMC may have a methoxy content of 27.0-30.0% (w / w) and a hydroxypropoxy content of 4.0-12.0% (w / w).

[0034] In the present invention, the HPMC methoxy and hydroxypropoxy content is expressed in accordance with the United States Pharmacopeia, and references to the United States Pharmacopeia are cited herein.

[0035] There are different types of HPMC. HPMC is, for example, HPMC2910 contains approximately 7.0-12.0% hydroxypropoxy groups and approximately 28.0-30.0% methoxy groups. HPMC2906 contains approximately 4.0-7.5% hydroxypropoxy groups and approximately 27.0-30.0% methoxy groups. HPMC2208 contains approximately 4.0-12.0% hydroxypropoxy groups and approximately 19.0-24.0% methoxy groups. The group can be selected from HPMC1828, which contains approximately 23.0-32.0% hydroxypropoxy groups and approximately 16.5-20.0% methoxy groups.

[0036] The HPMC in CAPSSHELL may be one type of HPMC or a mixture of different types of HPMC.

[0037] In one embodiment, HPMC may be HPMC2906, HPMC2910, or a mixture thereof.

[0038] CAPSSHELL may contain 3,500 to 9,000 ppm of CaCl2, preferably 4,000 to 9,000 ppm, more preferably 4,500 to 9,000 ppm, even more preferably 4,750 to 9,000 ppm, specifically 5,000 to 9,000 ppm, more specifically 6,000 to 9,000 ppm, more specifically 6,000 to 8,000 ppm, particularly 6,000 to 7,000 ppm, and more particularly 6,000 to 6,500 ppm, where ppm is based on the weight of HPMC contained in CAPSSHELL.

[0039] CAPSSHELL may contain 3,500 to 7,000 ppm of CaCl2, preferably 4,000 to 7,000 ppm, more preferably 4,500 to 7,000 ppm, even more preferably 4,750 to 7,000 ppm, specifically 5,000 to 7,000 ppm, more specifically 6,000 to 7,000 ppm, and even more specifically 6,000 to 6,500 ppm, where ppm is based on the weight of HPMC contained in CAPSSHELL.

[0040] In another embodiment, CAPSSHELL may contain 3,500 to 6,500 ppm of CaCl2, preferably 4,000 to 6,500 ppm, more preferably 4,500 to 6,500 ppm, even more preferably 4,750 to 6,500 ppm, specifically 5,000 to 6,500 ppm, and more specifically 6,000 to 6,500 ppm, where ppm is based on the weight of HPMC contained in CAPSSHELL.

[0041] CAPSSHELL may contain 70% by weight or more, preferably 80% by weight or more, more preferably 90% by weight or more, even more preferably 95% by weight or more, specifically 97.5% by weight or more, more specifically 99% by weight or more, even more specifically 99.3% by weight or more, and particularly 99.35% by weight or more of HPMC, where the weight percentage is based on the weight of dry CAPSSHELL.

[0042] The upper limit for HPMC is 99.65% by weight, where the weight percentage is based on the weight of dry CAPSSHELL.

[0043] In one embodiment, the dried CAPSSHELL consists of HPMC and CaCl2.

[0044] In one embodiment, the CAPSSHELL consists of HPMC, CaCl2, and residual water, where the possible amount of CaCl2 is preferably based on the weight of HPMC contained in the CAPSSHELL disclosed herein, including all embodiments herein.

[0045] In one embodiment, the dry CAPSSHELL consists of 99.4 to 99.35% by weight of HPMC and 0.6 to 0.66% by weight of CaCl2, with the total amount of HPMC and CaCl2 being 100% by weight, and the weight percentage is based on the weight of the dry CAPSSHELL.

[0046] In one embodiment, the CAPSSHELL is a rigid capsule shell.

[0047] The wall thickness of a CAPSSHELL is known to those skilled in the art, and a typical value may be about 100 micrometers, with a typical range of 60 to 150 micrometers.

[0048] Typical sizes of CAPSSHELLs are known to those skilled in the art and may be represented, for example, by sizes 00, 0, 1, 2, or 3.

[0049] CAPSSHELL contains residual water. Since the residual water may originate from the manufacturing process using an aqueous mixture for preparing CAPSSHELL, the water in CAPSSHELL is typically residual water remaining in CAPSSHELL after drying, and may also originate from the humidity of the air surrounding CAPSSHELL. The typical residual water content in CAPSSHELL is 14% by weight or less, preferably 10% by weight or less, more preferably 9% by weight or less, and even more preferably 7% by weight or less, where the weight percentage is based on the weight of CAPSSHELL.

[0050] The typical range of residual water content in CAPSSHELL is 0 to 14% by weight, preferably 1 to 14% by weight, more preferably 2 to 14% by weight, specifically 2 to 10% by weight, more specifically 2 to 9% by weight, and even more specifically 2 to 7% by weight, where the weight percentage is based on the weight of CAPSSHELL.

[0051] In one embodiment, CAPSSHELL does not contain the gelling agent GELAGE, or a combination of the gelling agent GELAGE and the gelling aid GELAID.

[0052] The gelling agent GELAGE used in the manufacture of capsules, and the combination of the gelling agent GELAGE and the gelling aid GELAID are known to those skilled in the art.

[0053] Typical gelling agents such as agar gum, guar gum, locust bean gum (carob), carrageenan, pectin, xanthan gum, gellan gum, konjac mannan, or gelatin are known to those skilled in the art.

[0054] Typical gelling aids GELAID that can be used in combination with the gelling agent GELAGE are known to those skilled in the art, K + na + Li + NH4 + Ca 2+ , or Mg 2+ These could be cations.

[0055] CAPSSHELL may contain one or more additives ADD in addition to HPMC and CaCl2, and therefore ADD may be a viscosity modifier, defoaming aid, plasticizer, lubricant, colorant, solvent, solvent aid, surfactant, dispersant, solubilizer, stabilizer, corrector, sweetener, absorbent, adsorbent, adhesive, antioxidant, disinfectant, preservative, desiccant, flavoring agent, fragrance, pH adjuster, binder, humectant, disintegrant, release control agent, acid, salt, or mixture.

[0056] Therefore, typical ADDs may be viscosity modifiers, defoaming agents, plasticizers, colorants, surfactants, dispersants, antioxidants, pH adjusters, humectants, acids, salts, or mixtures.

[0057] Therefore, preferred ADDs may be viscosity modifiers, defoaming aids, plasticizers, colorants, surfactants, dispersants, antioxidants, pH adjusters, humectants, salts, or mixtures thereof.

[0058] The plasticizer may be glycerol, propylene glycol, sorbitol, or lecithin. To avoid excessive softness, the plasticizer content should not be too high, such as a maximum of 2% by weight, preferably a maximum of 1% by weight, and the percentage by weight is based on the weight of the dry CAPSSHELL.

[0059] The coloring agent may be a pigment such as TiO2, or a dye.

[0060] The typical amount of pigment or dye may be 0.01 to 10% by weight, preferably 0.01 to 5% by weight, more preferably 0.01 to 2.5% by weight, and even more preferably 0.01 to 1% by weight, where the weight percentage is based on the weight of the dry CAPSSHELL.

[0061] The dispersant may be sodium lauryl sulfate, sorbitan, or lecithin.

[0062] The antioxidant could be ascorbic acid.

[0063] The acid could be acetic acid.

[0064] The typical amount of acid can be 0.025–0.75% by weight, preferably 0.04–0.6% by weight, where the weight percentage is based on the weight of HPMC.

[0065] The possible content of any ADD in CAPSSHELL may be 0.025 to 29.65% by weight, preferably 0.04 to 22% by weight, where the weight percentage is based on the total weight of the dry CAPSSHELL.

[0066] In one embodiment, the dried CAPSSHELL consists of HPMC, CaCl2, and a coloring agent.

[0067] In one embodiment, the dried CAPSSHELL consists of HPMC, CaCl2, and a pigment.

[0068] In one embodiment, CAPSSHELL comprises HPMC, CaCl2, residual water, and optionally a pigment, wherein the possible amount of CaCl2 is based on the weight of HPMC contained in the CAPSSHELL disclosed herein, including all embodiments herein. If the pigment is contained in the CAPSSHELL, the possible amount of HPMC is preferably based on the weight of the CAPSSHELL disclosed herein, including all embodiments herein.

[0069] A further subject of the present invention is a method for preparing CAPSSHELL, The CAPSSHELL is formed by the PROCFORMCAPS process for forming a capsule shell from the mixture DIPMIX, where DIPMIX is water containing CaCl2 and HPMC. CAPSSHELL is as defined herein, including in all embodiments thereof.

[0070] Preferably, CaCl2 is present in DIPMIX in the form of an aqueous solution.

[0071] Preferably, HPMC is present in DIPMIX in the form of an aqueous solution.

[0072] DIPMIX is also called a dissolve by those skilled in the art.

[0073] PROCFORMCAPS can be any conventional process known to those skilled in the art for forming capsule shells, such as extrusion molding, injection molding, casting, or dip molding, preferably dip molding.

[0074] Dip molding can also be called dip coating.

[0075] A CAPSSHELL produced by dip molding consists of two parts, the cap and the body. These two parts are often also called two halves, but they do not necessarily have to be the same size, nor do each of them necessarily have to be exactly half the size of the CAPSSHELL. The cap and the body are two separate parts. When joined together, they form a capsule or capsule shell, which may be empty or filled. The words “capsule” and “capsule shell” are usually used synonymously. The term shell usually refers to the capsule-shaped polymer that forms the film that again forms the walls of the shell, and therefore the capsule-shaped polymer is also called the shell. The cap can be obtained from molding pins having respective geometric shapes complementary to the desired shape of the cap. The body can be formed from molding pins having respective geometric shapes complementary to the desired shape of the body. Either the cap or the body can be obtained by using the respective molding pins in dip molding.

[0076] Therefore, a CAPSSHELL may consist of two parts: a cap and a body. The cap and body are retractably engageable to provide the CAPSSHELL. Typically, the cap and body each have two regions: a dome-shaped region which is the closed end of the cap or body, and an essentially cylindrical region which extends from the dome-shaped region and ends at the open end of the cap or body, respectively.

[0077] An essentially cylindrical region of the cap, or at least a portion thereof, is expandable and retractable with an essentially cylindrical region of the body, or at least a portion thereof. This is essentially inserting the body into the cap, or vice versa. This insertion is typically sliding the cap over the body, or vice versa. Typically, the cap slides over the body. Thereafter, an essentially cylindrical region of the body, or at least a portion thereof, lies inside the essentially cylindrical region of the cap, or at least a portion thereof. Thus, the essentially cylindrical regions of the cap and body slide, in some cases, over other regions. Therefore, typically, the body is inserted into the cap, i.e., the body slides into the cap. The expandable and retractable engagement occurs coaxially with respect to the longitudinal axis of the cap and body.

[0078] Therefore, the retractable and retractable cap and body constitute the capsule.

[0079] DPIMIX needs to be provided for dip molding.

[0080] Dip molding is, (1) The first half of the molding pin of the CAPSSHELL is dipped into the DIPMIX, (2) The step of withdrawing the molding pin from DIPMIX while forming a film on the molding pin, (3) The step of drying the film on a molding pin that provides the first half of the CPASSHELL, (4) The step of removing half of the CAPSSHELL from the molding pin, CAPSSHELL and DIPMIX are as defined herein, including in all embodiments herein.

[0081] CAPSSHELL consists of two parts, which are called the CAPSSHELL cap and the CAPSSHELL body.

[0082] Steps (1) to (4) are performed on both the pin molded to provide the cap and the pin molded to provide the body.

[0083] Steps (1) through (4) must be carried out in the order presented.

[0084] After preparing both parts of the CAPSSHELL, the two parts are joined together to form the capsule.

[0085] Half of the capsule shell removed from the molding pin may still be longer than half of the desired target length of the capsule shell. In this case, the halves of the capsule shell on and after removal from the molding pin constitute mismatched portions, which can be cut to the desired size to provide the desired half of a capsule shell of the desired length.

[0086] The molding pin may have a high temperature pintemp for dip molding. In one embodiment, the molding pin is dipped in DIPMIX and has a high temperature while the film dries on the molding pin after dipping.

[0087] PINTEMP can exceed the gelation temperature of DIPMIX by 1.0°C or more, preferably 5°C or more, and more preferably 10°C or more. The upper limit of PINTEMP may be 95°C.

[0088] PINTEMP can be selected according to the desired capsule size.

[0089] A typical range for PINTEM may be 45 to 95°C, preferably 45 to 80°C, more preferably 45 to 70°C, even more preferably 50 to 70°C, and specifically 50 to 65°C.

[0090] Therefore, before step (1), the molding pin can be preheated to the desired PINTEMP.

[0091] The temperature of DIPMIX during dipping of the molded pin into DIPMIX, DIPMIXTEMP, can be up to 1.0°C, preferably 10 to 1.0°C, more preferably 6 to 1.0°C, and even more preferably 6 to 2°C below the gelation temperature of DIPMIX.

[0092] As an example of HPMC grade 2906, the DIPMIXTEMP may be 10-29°C, preferably 15-29°C, and more preferably 20-29°C.

[0093] The film on the molded pins may be dried by air drying. Drying may be carried out at a high temperature that exceeds the gelation temperature of DIPMIX.

[0094] Therefore, the temperature of the air used for drying may exceed the gelation temperature of DIPMIX.

[0095] The temperature of the air used to dry the film on the molding pins may be 45-90°C, preferably 45-80°C.

[0096] Generally, the duration of step (3) is 5 to 60 minutes.

[0097] Generally, step (3) is carried out at RH of 20-90%, preferably 20-70%, and more preferably 20-60%.

[0098] In a preferred embodiment, drying is carried out as disclosed in WO2008 / 050205A1.

[0099] DIPMIX contains HPMC and CaCl2 in amounts based on the weight of dry DIPMIX that are equal to the amounts of HPMC and CaCl2 in CAPSSHELL based on the weight of dry CAPSSHELL as defined herein.

[0100] DIPMIX may contain 15-25% by weight, preferably 17-23% by weight, and more preferably 17.5-22.5% by weight of HPMC, where the weight percentage is based on the weight of DIPMIX.

[0101] The HPMC concentration in DIPMIX can be measured at a temperature 10 to 1.0°C below the gelation temperature of DIPMIX and selected to obtain a viscosity of DIPMIX of 1,000 to 3,000 mPa*s, preferably 1,200 to 2,500 mPa*s, and more preferably 1,600 to 2,000 mPa*s.

[0102] The amount of CaCl2 in DIPMIX, based on the weight of HPMC in DIPMIX, corresponds to the CaCl2 content in dry CAPSSHELL.

[0103] DIPMIX can be prepared by mixing the mixture CCMIX, where CCMIX is a mixture of CaCl2 and water, and the mixture HPMCMIX, where HPMCMIX is a mixture of HMPC in water.

[0104] CCMIX may contain 15-25% by weight, preferably 17.5-22.5% by weight of CaCl2, where the weight percentage is based on the weight of CCMIX.

[0105] HPMCMIX may contain 15-25% by weight, preferably 17.5-22.5% by weight of HPMC, where the weight percentage is based on the weight of HPMCMIX.

[0106] The amounts of HPMCMIX and CCMIX, as well as their concentrations, and the amounts of HPMC and CaCl2, are calculated and selected in such a manner that they provide the desired amounts of CaCl2 and HPMC in DIPMIX in order to provide the desired amounts of CaCl2 and HPMC in CAPSSHELL.

[0107] The amounts of CaCl2 and HPMC in dried DIPMIX are equal to the amounts of each in dried CAPSSHELL.

[0108] CCMIX can be prepared by mixing MIXCC, which is a mixture of CaCl2 and water.

[0109] HPMCMIX can be prepared by mixing HPMC with water.

[0110] The water may be at a temperature above room temperature, preferably above 60°C, and more preferably above 70°C. The optimal temperature can be determined by those skilled in the art. Dispersion of HPMC in water is provided by mixing HPMC with water at a temperature above 60°C. To achieve dissolution of HPMC, the dispersion may be cooled to a temperature of 10-20°C.

[0111] The gelation temperature of any solution of HPMC in water, such as HPMCMIX or DIPMIX, can be determined by measuring the viscosity by gradually heating the solution. The temperature at which the viscosity begins to increase rapidly is considered the gelation temperature. As an example, at a concentration of about 19 wt% in water, any HPMC of the present invention that satisfies the USP definition of HPMC type 2906 has a gelation temperature of about 30–40°C. As an additional example, at a concentration of 15–25 wt% in water, an HPMC of the present invention that satisfies the USP definition of HPMC with a hydroxypropoxy content of about 6% has a gelation temperature of about 30–40°C.

[0112] A further subject of the present invention is a CAPSSHELL filled with a formulation FILLFORM containing the active ingredient ACTINGR, wherein ACTINGR may be selected from the group consisting of active pharmaceutical ingredients, drugs, and mixtures thereof. CAPSSHELL is as defined herein, including in all embodiments thereof.

[0113] FILLFORM may be in powder form.

[0114] A further subject of the present invention is the use of CAPSSHELL for filling FILLFORM, where CAPSSHELL and FILLFORM are as defined herein, including in all embodiments herein.

[0115] FILLFORM may contain ACTINGR in an amount of 0.05 to 100% by weight, preferably 0.5 to 90% by weight, more preferably 1 to 50% by weight, and even more preferably 5 to 30% by weight, where the weight percentage is based on the weight of the dry FILLFORM.

[0116] Examples of candidate drugs or APIs for ACTINGR to be filled into CASPSSHELL are typically those known to those skilled in the art, used in DPI applications, including mucolytics, bronchodilators, corticosteroids, xanthine derivatives, leukotriene antagonists, proteins or peptides, and mixtures thereof.

[0117] A further subject of the present invention is the use of CAPSSHELL in a dry powder inhaler, where CAPSSHELL is as defined herein, including in all embodiments herein.

[0118] In this use of CAPSSHELL in a dry powder inhaler, CAPSSHELL, in the form of a capsule filled with FILLFORM, is used in the dry powder inhaler to distribute FILLFORM during operation of the dry powder inhaler. FILLFORM is released from CAPSSHELL upon operation of the dry powder inhaler. The release of FILLFORM provides the patient with the opportunity to inhale FILLFORM.

[0119] A further subject of the present invention is a dry powder inhaler in which a CAPSSHELL is inserted, preferably the CAPSSHELL is filled with FILLFORM, and the CAPSSHELL and FILLFORM are as defined herein, including all embodiments herein. [Examples]

[0120] Materials, apparatus, methods, and further abbreviations used herein CC Calcium chloride as calcium chloride dihydrate, CaCl2.2H2O, CAS 10035-04-8, Product 22317.297, Potency 99.8%, VWR International bvba, 3001 Leuven, Belgium HPMC, also known as hypromellose, hydroxypropyl methylcellulose, grade 2906, METHOCEU "FS Premium LV Hydroxypropyl Methylcellulose," The Dow Chemical Company, SWITZERLAND, 29.5% methoxyl, 6.2% hydroxypropoxyl Lactose Blend DFE Pharma, 47568 Goch, Germany, offers inhalable lactose of the quality available as Respitose ML001, d10 or 4 micrometers, d50 of 49 micrometers, and d90 of 169 micrometers. Murphy, Seamus. (2014). UNERSTANDING 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. LOD (Limited Occupation) loss during drying Device • One Mettler Toledo type AB204 electronic balance • One drying oven type Memmert U40 • One aluminum container

[0121] procedure To measure the Level of Disability (LOD), proceed as follows: • Capsule material weighing 1 + / - 0.001 g in a pre-weighed aluminum container. Place the container in a drying oven set to 100-105°C and cover the container with a mesh wire rack. Store and dry at 100-105°C for 18 hours. The capsules are cooled in a desiccator equipped with a desiccant, and then weighed after a maximum of 30 minutes. • Calculate the loss during drying as a percentage of the original weight. • Reproduce the process three times as needed to evaluate the accuracy of the LOD determination. PR powder residue SD standard deviation SML Sorbitan Monolaurate, Glycomul L KFG (Non-GMO) / SCHL-470LB, Acid Value 6, Color-Gardner 1963 is 16, Hydroxyl Value 358, Saponification Value 165, KF 1.3, Water content according to Lonza, 3930 Visp, Switzerland. RF10 SOLEC(TM) RF-10 Standard rapeseed oil lectin fluid, acid value 28.60, acetone insoluble 62.80%, Solae Europe, SA, 2, 1218 Le Grand Saconnex, Switzerland Capsugel, a tube testing machine, developed in-house. method: The capsule's fracture and elastic behavior are measured by its resistance to impact tests using a tube.

[0122] procedure 1. Store the capsules for 5 days, then test them in a dryer. Available storage conditions are 10%, 23%, 33%, and 45% RH. Store 50 capsules for each condition in the opened box. Then, close the box to prevent moisture exchange with the surrounding atmosphere. 2. Place the capsule horizontally on a flat surface. Place a 3,100g weight into the tube. 4. Place the tube on top of the capsule and press the latch to release the weight. Test 5.50 capsules.

[0123] After equilibrating with the selected RH, use a sealed storage box and do not remove 50 capsules at a time (to avoid reabsorption of humidity).

[0124] Record the number of times the main body, cap, or capsule (main body and cap) has been damaged.

[0125] The tube testing machine 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 Plus registered trademark, Quali-V registered trademark and gelatin capsules," International Journal of Pharmaceutics, Volume 386, Issues 1-2, 15 February 2010, Pages 30-41, Chapter 2.5. Mechanical strength evaluation Electronic balance XPE205DR, Mettler-Toledo AG Friability / Abrasion Tester TAR, ERWEKA GmbH, 63225 Langen, Germany A DUSA (Dose Delivery Unit Sampling) device, also known as the DDU (Dose Delivery Uniformity) device for dry powder inhalers, equipped with a critical flow controller (product model name TPK2000), an HCP5 vacuum pump, a PALLFLEX 47mm filter, and a DFM2000 flow meter (Copley Scientific), for testing inhalation products. SEM Scanning Electron Microscope FlexSEM1000

[0126] Example 1: Preparation of CC solution Step 1: Preparation of HPMC solution (HPMCMIX) List of compounds for preparing HPMC solutions: HPMC: 20.55% by weight Water 79.45% by weight

[0127] The HPMC solution was prepared by filling a container with water at 80-85°C that had been filled with and mixed with HPMC. The container was then cooled to 10-20°C to solubilize the HPMC. After 1 hour at 10-20°C, the HPMC solution was heated to 29°C and maintained at that temperature for further use.

[0128] Step 2: Preparation of CaCl2.2H2O solution (CCMIX) CaCl2.2H2O was added to 80°C water under stirring at 200 rpm.

[0129] Step 3: Preparation of CC solution (DIPMIX) The CC solution is a mixture of the HPMC solution prepared according to Step 1 and the CaCl2.2H2O solution prepared according to Step 2.

[0130] A solution of CaCl2.2H2O was mixed with the HPMC solution prepared according to Step 1, thereby providing a CC solution.

[0131] Three CC solutions, CC-A* solution, CC-A**, and CC-B solution were prepared using this method, and a fourth solution, CC-A solution, was prepared using the same method. The quantities of these CC solutions are shown in Table 1. [Table 1] The mass of CaCl2 is 110.98 g / mol. The molecular weight (MW) of CaCl2.2H2O is 147.01 g / mol. Weight of CaCl2: CC-A:503.41g*(110.98 / 147.01)=380.03g CC-A*:503.41g*(110.98 / 147.01)=380.03g CC-A**:497.05g*(110.98 / 147.01)=375.23g CC-B:59.59g 20wt%=11.918g CaCl2.2H2O 11.918g * (110.98 / 147.01) = 9.0g HPMC + CaCl2 based on weight: CaCl2 ppm: CC-A:380.03g / (57'540g+380.03g)*1'000'000=6'561ppm CC-A*:380.03g / (59'820g+380.03g)*1'000'000'=6'313ppm CC-A**:375.23g / (49'530g+375.23g)*1'000'000'=7'519ppm CC-B:4'500g 20.55wt%=924.75g HPMC 9.0g / (924.75g+9.0g)*1'000'000'=9'639ppm ppm of CaCl2 based on HPMC weight: CC-A:380.03g / 57'540g*1'000'000=6'605ppm CC-A*:380.03g / 59'820g*1'000'000=6'353ppm CC-A**:375.23g / 49'530g*1'000'000=7'576ppm CC-B:9.0g / 924.75g*1'000'000=9'732ppm

[0132] Example 2: Preparation of CC shells and CC capsules, and HPMC shells and HPMC capsules Using the respective CC solutions CC-A* and CC-B prepared according to Example 1, and the HPMC solution prepared according to Step 1 of Example 1, CC shells and HPMC shells in the form of half capsules (body and cap) with capsule size 3 and standard target weight (capsule weight 47+ / -3mg) were manufactured by conventional molding dips, which involved dipping a stainless steel molding pin at a temperature of 55°C into the respective CC solution or HPMC solution at a temperature of 29°C. A film was formed on the molding pin. After a first drying of the film on the molding pin at 50-60°C and 30-40% RH for 15-20 minutes, and a second drying at 50-60°C and 25-30% RH for 30 minutes, half CC capsules and half HPMC capsules were obtained, respectively.

[0133] The capsules were always assembled by joining one cap to one body.

[0134] Example 3: Capsule Testing - Mechanical Performance The fracture behavior of capsules prepared according to Example 2 was measured by their resistance to impact tests using a tube testing machine. For test preparation, capsules were stored in a dryer under four storage conditions: 10%, 23%, 33%, and 45% RH for 5 days to obtain capsules with different LODs. Fifty capsules were tested at each RH value, and the number of broken capsules or broken caps was recorded. The percentage of broken capsules is shown in Table 2. [Table 2]

[0135] If the amount of CaCl2 is too high, the mechanical performance will deteriorate.

[0136] Example 4: Test on capsules - PR of powder retention inside capsules A DUSA instrument from Copley Scientific was used to determine the residual powder inside the capsules. The capsules were equilibrated to different LODs by storing them in a dryer at 23, 33, 45, and 50% RH. Ten capsules prepared according to Example 2 were filled with 25 + / - 1 mg of lactose blend. These ten lactose-filled capsules were placed in a 25 ml capacity plastic bottle with a lid and tumbled 100 times in a brittleness tester (TAR). The capsules were emptied using a DUSA instrument. The settings were adjusted according to Apparatus B of USP Pharmacopeia guideline paragraph 601 heading, “Sampling the Delivered Dose from Dry Powered Inhalers”: As required by the cited USP Pharmacopeia guideline paragraph 601, the fluid was drawn from the inhaler using two pumps with a flow rate parameter of 100 L / min and an inhalation time of 2.4 seconds to match a volume of 4 L of air. The weights of these 10 capsules were determined before filling with powder (Wempty) and after emptying with the DUSA device (Wemptied). The total amount of powder filled into these 10 capsules was also recorded (Wpowder). PR is the percentage of residual powder and was determined from equation EQ1: EQ1: PR%=100*[(Wemptied-Wempty) / Wpowder]

[0137] The results, representing the mean and standard deviation (SD) of the three samples, are shown in Table 3, with each of the 10 capsules tested being evaluated. [Table 3]

[0138] Figure 3 shows a graph of PR values ​​against LOD from the data in Table 3. Individual values ​​are shown in black, and the average value is shown in gray. ▲ Triangle: Capsules made from CC-A* dissolved material are represented by a triangle. ● Black circle: Capsules made from CC-A** dissolved material are represented by a black circle. ■ Square: Capsules made from CC-B dissolved material are represented by a square. ◆ Rhombus: The capsule used in Example 17 of US5,626,871 (a medical rigid capsule essentially composed of hydroxypropyl methylcellulose [composition: 93 parts by weight of hydroxypropyl methylcellulose, "TC-5R" manufactured by Shinetsu Kagaku, 1 part by weight of carrageenan, 1 part by weight of potassium chloride, 5 parts by weight of water]) is represented by a square. ○ White circle: HPMC capsules are represented by triangles.

[0139] result: HPMC capsules exhibit the highest average PR value compared to capsules made from CC-A* and CC-A** lysates. Capsules prepared from CC-A* and CC-A** solutions exhibit either equivalent or better PR values ​​compared to capsules containing the gelling agent used in Example 17 of US5,626,871. Capsules prepared from CC-A* and CC-A** lysates consistently show lower average PR values ​​than capsules prepared from HPMC lysates.

[0140] Example 5: Testing of capsules - SEM imaging of the inner surface of the capsule after DUSA testing. CC-A* capsules and HPMC capsules having a LOD of 4.5–5.0, prepared according to Example 2 and stored in a dryer at 50% RH as described in Example 4, were also tested using powder obtained by purchasing commercially available drugs in the form of powder-filled capsules from a pharmacy, extracting the powder, and filling the capsules with it. The capsules were then emptied using a DUSA machine as described in Example 4, and the residual powder was determined by visual inspection. Visual inspection showed that the CC-A* capsules contained significantly less powder compared to the HPMC capsules.

[0141] PR was 0.6% for HPMC capsules and 0.11% for CC-A* capsules.

[0142] Figure 1 shows an SEM image of the residual powder on the inner surface of one such CCA* capsule after the powder has been emptied from the capsule by the operation of a DUSA instrument, so the film-building polymer of the capsule shell was HPMC and the capsule shell contained CaCl2.

[0143] Figure 2 shows an SEM image of the residual powder on the inner surface of the capsule after the powder has been emptied from the capsule by the operation of the DUSA instrument. This indicates that the film-building polymer of the capsule shell was HPMC, and the capsule shell did not contain CaCl2.

[0144] Clearly, Figure 1 shows a much smaller number of powder particles than Figure 2.

[0145] Example 6: Capsule Testing - Puncture Test Puncture tests were performed using capsules prepared from CC-A* dissolved solution and capsules used in Example 17 of US5,626,871 (medical hard capsules essentially composed of hydroxypropyl methylcellulose [composition: 93 parts by weight of hydroxypropyl methylcellulose, "TC-5R" manufactured by Shinetsu Kagaku, 1 part by weight of carrageenan, 1 part by weight of potassium chloride, 5 parts by weight of water]).

[0146] Puncture test protocol: • Capsules (N=15) were equilibrated in a dryer under 23% and 45% RH storage conditions for 5 days. • For the puncture test, the Plastiape RS01 dry powder inhaler (Plastiape Spa con socio unico, Osnago, Italy) was used. The capsule was placed inside the inhaler chamber and punctured by simultaneously pressing it against the two lateral needles of the inhaler. Upon puncture, each capsule was visually inspected to identify unsuitable capsules that either had their lids not punctured or had their lids or parts of them detached, posing a risk of some capsule particles accumulating in the patient along with the powder upon inhalation. The selected capsules were counted and presented as a percentage of the total number of capsules analyzed. The results are shown in Table 6. [Table 4]

[0147] Capsules prepared from CC-A* and CC-A** dissolved materials performed significantly better in puncture tests compared to capsules containing the gelling agent used in Example 17 of US5,626,871, and no unsuitable capsules were observed.

[0148] Comparative example including additives Preparation of additive solutions and their capsules Instead of CaCl2.2H2O, two other additives were tested.

[0149] The additives were as follows: Sorbitan monolaurate SML Rapeseed lecithin RF10 The additive content in each solution was 5000 ppm relative to the weight of HPMC, with Step 2 differing in the amounts shown in Table 4, and in Step 3, a dispersion of each additive was used instead of CaCl2.2H2O. Each solution was prepared according to the procedure of Example 1.

[0150] Step 2: Preparation of the additive dispersion The additive was added to water and homogenized using an Ultra-Turrax, IKA T25 at a speed of 8000-9000 rpm for 5 minutes.

[0151] The SML dispersion was allowed to stand until the bubbles disappeared before adding it to the HPMC solution. Since no bubbles formed in the RF10 dispersion, it was used directly without needing to stand. [Table 5]

[0152] For the preparation of the additive solutions, two solutions were provided: an RF10 solution and an SML solution. Then, using these two additive solutions, additive capsule shells were prepared according to the dip molding method described in Example 2.

[0153] Testing of additive capsules prepared from additive solutions - PR of powder retention within capsules The PR (Patent Reduction) using additive capsules with an LOD (Level of Discharge) of 5.0–5.5% was tested according to the method described in Example 4. As noted in the remarks (*) below, an LOD of 5.0–5.5% was obtained. Table 5 shows the PR values. [Table 6]

Claims

1. HPMC and CaCl for use in a dry powder inhaler (DPI) 2 A capsule shell containing, CaCl contained in CAPSSHELL 2 The amount is 3,000 to 9,000 ppm, based on the weight of HPMC contained in CAPSSHELL. The CAPSSHELL does not contain a gelling agent, or a combination of a gelling agent and a gelling aid. The gelling agent is selected from the group consisting of agar gum, guar gum, locust bean gum (carob), carrageenan, pectin, xanthan gum, gellan gum, konjac mannan, and gelatin. and the gelling aid is K + , Na + , Li + , NH 4 + , Ca 2+ , and Mg 2+ and the capsule shell CAPSSHELL is selected from the group consisting of cations such as these.

2. The aforementioned HPMC, HPMC2910 contains approximately 7.0-12.0% hydroxypropoxy groups and approximately 28.0-30.0% methoxy groups. HPMC2906 contains approximately 4.0-7.5% hydroxypropoxy groups and approximately 27.0-30.0% methoxy groups. HPMC2208 contains approximately 4.0-12.0% hydroxypropoxy groups and approximately 19.0-24.0% methoxy groups. The CAPSSHELL according to claim 1, selected from the group consisting of HPMC1828 containing approximately 23.0 to 32.0% hydroxypropoxy groups and approximately 16.5 to 20.0% methoxy groups.

3. The CAPSSHELL according to claim 1, wherein the HPMC has a methoxy 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 any one of claims 1 to 4, wherein the HPMC is HPMC2906, HPMC2910, or a mixture thereof.

6. Capsshell is 3,500 to 9,000 ppm CaCl 2 A CAPSSHELL according to any one of claims 1 to 5, wherein the ppm is based on the weight of HPMC contained in the CAPSSHELL.

7. Capsshell is 4,000 to 9,000 ppm CaCl 2 A CAPSSHELL according to any one of claims 1 to 6, wherein the ppm is based on the weight of HPMC contained in the CAPSSHELL.

8. A capsshell according to any one of claims 1 to 7, wherein the capsshell contains 70% by weight or more of HPMC, and the weight percentage is based on the weight of the dry capsshell.

9. The CAPSSHELL according to any one of claims 1 to 8, wherein the CAPSSHELL comprises one or more additives ADD, and ADD is a viscosity modifier, defoaming aid, plasticizer, lubricant, colorant, solvent, solvent aid, surfactant, dispersant, solubilizer, stabilizer, corrector, sweetener, absorbent, adsorbent, adhesive, antioxidant, disinfectant, preservative, desiccant, flavoring agent, fragrance, pH adjuster, binder, humectant, disintegrant, release control agent, acid, salt, or mixture.

10. Dried capsshell contains HPMC and CaCl 2 A CAPSSHELL according to any one of claims 1 to 8, comprising:

11. The dry capsshell contains 99.4 to 99.35% by weight of HPMC and 0.6 to 0.66% by weight of CaCl 2 It consists of HPMC and CaCl 2 The amount of the material totals 100% by weight, and the weight percentage is based on the weight of the dry capsshell, according to any one of claims 1 to 8.

12. Dried capsshell contains HPMC, CaCl 2 A capsshell according to any one of claims 1 to 9, comprising a coloring agent.

13. A method for preparing a capsshell, The CAPSSHELL is formed by the PROCFORMCAPS process for forming a capsule shell from the mixture DIPMIX, where DIPMIX is CaCl 2 and water containing HPMC, A method wherein the CAPSSHELL is as defined in claim 1.

14. A method for preparing a capsshell according to claim 13, wherein the procformacps are extrusion, injection molding, casting, or dip molding.

15. A method for preparing a capsshell according to claim 13 or 14, wherein the procformacps are dip-molded.

16. The aforementioned dip molding, (1) The step of dipping the first half of the molding pin of the CAPSSHELL into the DIPMIX, (2) The step of pulling out the molding pin from the DIPMIX while forming a film on the molding pin, (3) The film on the molding pin that provides the first half of the CPASHELL The drying step, (4) The step of removing half of the capsshell from the molding pin, CAPSSHELL is as defined in claim 1, and DIPMIX is as defined in claim 13. The capsshell is composed of two parts, which are referred to as the cap and body of the capsshell. A method for preparing a capsshell according to claim 15, wherein steps (1) to (4) are performed on both a pin molded to provide the cap and a pin molded to provide the body.

17. A capsshell filled with a formulation fillform containing the active ingredient ACTINGR, wherein ACTINGR may be selected from the group consisting of active pharmaceutical ingredients, drugs, and mixtures thereof. A capsshell as defined in any one of claims 1 to 12.

18. Use of a capsshell for filling a fillform, wherein the capsshell is as defined in claim 1 and the fillform is as defined in claim 17.

19. A dry powder inhaler in which a CAPSSHELL is inserted, wherein the CAPSSHELL is as defined in any one of claims 1 to 12 and 17.

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