Patent Application
20230165802
The invention discloses hydroxypropyl methylcellulose (HPMC) capsules containing a small amount of CaCl2, which show reduced powder retention when used in Dry Powder Inhalers (DPI), and a method for making them.
Capsules are used in the pharmaceutical industry to allow oral administration of drugs or to administer powder for inhalation. In the latter case, the capsule is pierced using an adequate inhalation device and the powder is inhaled via the mouth or sometimes via the nose.
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 to said capsule. [0011] mentions that some amount of drug will be still present in the capsule after inhalation.
U.S. Pat. No. 5,626,871 discloses capsules for use in intratracheobronchial administration of powder contain 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.
HPMC is a polymer that gels vice versa compared to a conventional film forming polymer such as gelatin: It can be completely dissolved at ambient like temperatures and gels only at elevated temperatures, whereas gelatin gels at ambient like temperatures and is dissolved at elevated temperatures. HPMC capsules, which are produced using the conventional gelling technique, that is at ambient like temperatures, require a gelling agent in order to gel at such ambient like temperatures.
Typical gelling agents are known to the skilled person and may be gellan gum, carrageenan, konjac gum, xanthan gum, and guar gum and the like.
Gelling agents are often used in combination with a gelling aid, which is usually a cation such as potassium or calcium. The gelling aid enhances the gelling ability of the gelling agent.
CN 189 846 851 A discloses such HPMC capsules which are prepared with the help of a gelling agent using the conventional gelling technique. The gelling agent is gellan gum in Examples 1, 2 and 3 and konjac gum in Example 4, 5 and 6. Further gelling agents are mentioned in the description in [0012].
The cations in form of their salts, which are disclosed in the examples, such as potassium and specifically calcium salts, serve as gelling aids.
CN 106 166 143 B discloses such IPMC capsules which are prepared with the help of a gelling agent using the conventional gelling technique. Gelling agents mentioned in the examples are gellan gum, carrageenan and pectin.
The cations in form of their salts, which are disclosed in the examples, such as potassium and specifically calcium salts, serve as coagulant, that is as gelling aids.
U.S. Pat. No. 5,626,871 A discloses in Examples 17-21 such IPMC capsules which have been prepared with the help of a gelling agent using the conventional gelling technique. The gelling agent mentioned is carrageenan.
The potassium in form of its salt potassium chloride, which is disclosed in the examples 17-21, serves as gelling aid.
None of D1, D2 or D3, whether alone or in combination, gives any motivation to change for DPI applications from IPMC capsules containing a gelling agent to gelling agent free IPMC capsule, even less they give a motivation to use small amounts of CaCl2) in gelling agent free IPMC capsules.
A gelling agent may have a detrimental effect on the performance of the capsule, for example the presence of a gelling agent in the IPMC capsules may interfere with components in the dissolution media such as ions, specifically cations, or else, leading to changed and to different dissolution profiles. This is not desired.
There is a second method to gel IPMC, which is thermal gelation method, the IPMC is gelled at elevated temperature above the gelling point of IPMC. In the thermal gelation method no gelling agent is required.
It was found that pure IPMC capsules show less favorable powder retention properties compared with IPMC capsules containing a gelling agent.
There was a need for 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, in order to exclude any differences in the dissolution properties caused by the interaction of any ions or else in the dissolution media with a gelling agent. Furthermore the mechanical properties need to be acceptable for the production of capsules and for their use.
Also parameters which are important for the functioning of the capsules in the intended use, that is in a DPI apparatus, should be met, such as the puncturing and opening of the capsules should function according to the needs. So for example the puncturing force needs to provide for an efficient opening of the capsules without or at least with minimum fragmenting.
Surprisingly the problem was solved by adding a certain amount of CaCl2 into the shell material of the HPMC capsule in the absence of a gelling agent. The average powder retention properties as shown in Example 4 and displayed in
Subject of the invention is a capsule shell CAPSSHELL comprising HPMC and CaCl2; the amount of CaCl2 comprised in CAPSSHELL is from 3,000 to 9,000 ppm based on the weight of HPMC comprised in CAPSSHELL;
CAPSSHELL does not contain a gelling agent;
CAPSSHELL does not contain a combination of the gelling agent with a gelling aid.
The present invention will be described again with reference to the enclosed drawings, wherein:
Further subject of the invention is a method for preparation of CAPSSHELL, wherein CAPSSHELL is formed by a process PROCFORMCAPS for forming a capsule shell from a mixture DIPMIX, DIPMIX is water containing CaCl2 and HPMC;
with CAPSSHELL as defined herein, also with all its embodiments.
Preferably, CaCl2 is present in DIPMIX in form of its solution in the water.
Preferably, HPMC is present in DIPMIX in form of its solution in the water DIPMIX is also called a melt by the skilled person.
PROCFORMCAPS may be any conventional process for forming capsule shells known to the skilled person, such as extrusion molding, injection molding, casting or dip molding, preferably dip molding.
Dip molding can also be called dip coating.
CAPSSHELL made by dip molding comprises two parts of a capsule shell, the two parts are the called the cap and the body. These two parts are often also called two halves, but they do not necessarily need to have the same size and each of them does not necessarily need to have exactly half of the size of CAPSSHELL. Cap and body are two separate parts. When joined together they form the capsule, or the capsule shell, which can be empty or filled. The words “capsule” and capsule shell” are usually used interchangeably. The term shell refers usually to the capsule shaped polymer which forms the film which again forms the wall of the shell, that again is the shell, so the capsule shaped polymer is also called the shell. The cap may be obtained from by a mold pin having the respective geometric shape complementary to the desired shape of the cap. The body may be formed by a mold pin having the respective geometric shape complementary to the desired shape of the body. By using the respective mold pin in the dip molding either the cap or the body is obtained.
CAPSSHELL may therefore comprise two parts, the cap and the body. Said cap and body are telescopically engageable to provide CAPSSHELL. Typically, the cap and the body have each two regions, a dome shaped region, which is the closed end of the cap or of the body respectively, and an essentially cylindrically shaped region, which extends from the dome shaped region and which ends with the open end of the cap or of the body respectively.
The essentially cylindrically shaped region of the cap, or at least part of it, is telescopically engageable with the essentially cylindrically shaped region of the body, or at least with part of it. It is essentially an inserting of the body into the cap or vice versa. This inserting is typically a sliding of the cap over the body or vice versa. Typically the cap slides over the body. Thereby the essentially cylindrically shaped region of the body, or at least part of this region of the body, is inside the essentially cylindrically shaped region of the cap, or at least inside part of this region of the cap. So the essentially cylindrically regions of cap and body slide over the other one, as the case may be. So typically the body is inserted into the cap, i.e. the body slides into the cap. The telescopical engagement happens co-axial with respect to the longitudinal axis of the cap and the body.
So the telescopically engaged cap and body is the capsule.
DPIMIX needs to be provided for dip molding.
The dip molding comprises the steps of:
with CAPSSHELL and DIPMIX as defined herein, also with all its embodiments.
CAPSSHELL comprises two parts, the two parts are called the cap and the body of CAPSSHELL.
Steps (1) to (4) are done both with a pin which is shaped to provide for the cap, and with a pin which is shaped to provide the body.
Steps (1) to (4) need to be performed in the order they are presented.
After the preparation of both parts of CAPSSHELL, both parts are joined with each other to form the capsule.
The half of a capsule shell which is removed from the mold pin may have a length which is still longer than the target length of the desired half of a capsule shell, in this case the half of the capsule shell on the mold pin and after removal from the mold pin represents an unmachined part, and is cut to the desired size to provide the desired half of a capsule shell in the desired length.
The mold pin may have an elevated temperature PINTEMP for the dip molding. In one embodiment it has an elevated temperature when it is dipped into DIPMIX and while the film is dried on the mold pin after the dipping.
PINTEMP may be 1.0° C. or more, preferably 5° C. or more, more preferably 10° C. or more, above the gelling temperature of DIPMIX. An upper limit of PINTEMP may be 95° C.
PINTEMP may be chosen according to the desired capsule size.
Typical ranges for PINTEMP may be from 45 to 95° C., preferably from 45 to 80° C., more preferably from 45 to 70° C., even more preferably from 50 to 70° C., especially from 50 to 65° C.
Therefore before step (1), the mold pin may be pre-heated to the desired PINTEMP.
The temperature DIPMIXTEMP of DIPMIX during the dipping of the mold pins into DIPMIX may be up to 1.0° C., preferably from 10 to 1.0° C., more preferably from 6 to 1.0° C., even more preferably from 6 to 2° C., below the gelling temperature of DIPMIX.
As an example for IPMC grade 2906, DIPMIXTEMP may be from 10 to 29° C., preferably from 15 to 29° C., more preferably from 20 to 29° C.
Drying of the film on the mold pin may be done by air drying. Drying may be done at elevated temperature with the temperature being above the gelling temperature of DIPMIX.
So the temperature of the air that is used for drying may be above the gelling temperature of DIPMIX.
The temperature of the air for drying of the film on the mold pin may be from 45 to 90° C., preferably from 45 to 80° C.
In general the duration of step (3) is 5 to 60 min.
In general step (3) is done at a RH of from 20 to 90%, preferably, from 20 to 70%, more preferably from 20 to 60%.
In a preferred embodiment, drying is performed as disclosed in WO 2008/050205 A1.
DIPMIX comprises HPMC and CaCl2 in amounts based on the weight of dry DIPMIX which are equivalent to the amounts of HPMC and CaCl2 in CAPSSHELL based on the weight of dry CAPSSHELL as defined herein.
DIPMIX may comprise from 15 to 25 wt %, preferably from 17 to 23 wt %, more preferably from 17.5 to 22.5 wt %, of HPMC, the wt % being based on the weight of DIPMIX.
The concentration of IPMC in DIPMIX may be chosen to obtain a viscosity of DIPMIX of from 1,000 to 3,000 mPa*s, preferably of from 1,200 to 2,500 mPa*s, more preferably of from 1,600 to 2,000 mPa*s, measured at a temperature of 10 to 1.0° C. below gelling temperature of DIPMIX.
The amount of CaCl2 in DIPMIX based on the weight of IPMC in DIPMIX corresponds to the content of CaCl2 in dry CAPSSHELL.
DIPMIX may be prepared by a mixing MIX of a mixture CCMIX, CCMIX being a mixture of CaCl2 with water, with a mixture HPMCMIX, HPMCMIX being a mixture of HMPC in water.
CCMIX may comprise from 15 to 25 wt %, preferably from 17.5 to 22.5 wt %, of CaCl2, the wt % being based on the weight of CCMIX.
HPMCMIX may comprise from 15 to 25 wt %, preferably from 17.5 to 22.5 wt %, of HPMC, the wt % being based on the weight of HPMCMIX.
The amounts of HPMCMIX and CCMIX and their concentrations and the amounts of HPMC and of CaCl2 are calculated and chosen in such a way that the desired amounts of CaCl2 and of IPMC in DIPMIX is provided in order to provide for the desired amounts of CaCl2 and of HPMC in CAPSSHELL.
The amounts of CaCl2 and of HPMC in dry DIPMIX are equivalent to the respective amounts in dry CAPSSHELL.
CCMIX may be prepared by a mixing MIXCC of CaCl2 with water.
HPMCMIX may be prepared by a mixing MIXHPMC of HPMC with water.
The water may be at a temperature above room temperature, preferably above 60° C., more preferably above 70° C. Optimal temperatures can be determined by the skilled person. The mixing of HPMC with water at a temperature above 60° C. provides a dispersion of HPMC in water. The dispersion may be cooled to a temperature of from 10 to 20° C. to achieve the dissolution of the HPMC.
The gelling temperature of any solution of HPMC in water, such as HPMCMIX or DIPMIX, may be determined by a measurement of the viscosity by progressively heating the solution. The temperature at which the viscosity starts to sharply increase is considered as the gelling temperature. As an example, for a concentration of about 19 wt % in water, any HPMC of the invention fulfilling the USP definition of HPMC type 2906 has a gelling temperature of about between 30 and 40° C. As an additional example, for concentrations between 15 and 25 wt % in water, an HPMC of the invention fulfilling the USP definition of HPMC with a hydroxypropoxy content of about 6%, has a gelling temperature between about 30 and 40° C.
Further subject of the invention is CAPSSHELL filled with a formulation FILLFORM comprising an active ingredient ACTINGR, ACTINGR may be selected from the group consisting of active pharmaceutical ingredient, medicament, and a mixture thereof, with CAPSSHELL as defined herein, also with all its embodiments.
FILLFORM may have the form of a powder.
Further subject of the invention is the use of CAPSSHELL for filling with FILLFORM, with CAPSSHELL and FILLFORM as defined herein, also with all its embodiments.
FILLFORM may comprise ACTINGR in an amount from 0.05 to 100 wt %, preferably from 0.5 to 90 wt %, more preferably from 1 to 50 wt %, even more preferably from 5 to 30 wt %, the wt % being based on the weight of dry FILLFORM.
Examples for medicaments or for API which are candidates for ACTINGR to be filled in CASPSSHELL are those which are typically used in DPI applications and are known to the skilled person, such as from the class of mucolytics, bronchodilators, corticosteroids, xanthine derivatives, leukotriene antagonists, proteins or peptides, and mixtures thereof.
Further subject of the invention is the use of CAPSSHELL in dry powder inhalers, with CAPSSHELL as defined herein, also with all its embodiments.
For this use of CAPSSHELL in dry powder inhalers, CAPSSHELL in form of a capsule filled with FILLFORM is used in dry powder inhalers for dispensing the FILLFORM during the action of the dry powder inhaler. FILLFORM is released from CAPSSHELL by action of the dry powder inhaler upon CAPSSHELL. The release of FILLFORM provides for inhalation of FILLFORM by the patient
Further subject of the invention is a dry powder inhaler with CAPSSHELL inserted in the dry powder inhaler, preferably with CAPSSHELL filled with FILLFORM, with CAPSSHELL and FILLFORM as defined herein, also with all their embodiments.
Materials, Apparatus, Methods and Further Abbreviations Used in this Specification
Method:
Procedure
List of compounds to prepare HPMC melt:
HPMC: 20.55 wt %
Water 79.45 wt %
Preparation of HPMC melt was done by filling the vessel with water of 80 to 85° C. into which HPMC is charged and mixed. Then the vessel was cooled to 10 to 20° C. solubilize the HPMC. After one hour at 10 to 20° C. the HPMC melt is heated to and maintained at 29° C. for further use.
Step 2: Preparation of Solution of CaCl2.2H2O (CCMIX) CaCl2.2H2O was added into the water of 80° C. under stirring of 200 rpm.
The CC melt is a mixture of the HPMC melt, prepared according to Step 1, and the solution of CaCl2.2H2O, prepared according to Step 2.
The solution of CaCl2.2H2O was mixed with the HPMC melt prepared according to Step 1, thereby providing a CC melt.
Three CC melts, CC-A* melt, CC-A** and CC-B melt, were prepared in this way, a fourth melt, CC-A melt, is prepared in this way, the amounts for these CC melts are given in Table 1.
MW of CaCl2=110.98 g/mol
MW of CaCl2.2H2O=147.01 g/mol
Weight of CaCl2):
ppm of CaCl2 based on weight of HPMC+CaCl2:
ppm of CaCl2 based on weight of HPMC:
The respective CC melts CC-A* and CC-B, prepared according to example 1, and the HPMC melt, prepared according to examples 1 step 1, were used to produce CC shells and HPMC shells in form of capsule halves (bodies and caps) with capsule size 3 and standard target weights (capsule weight 47+/−3 mg) through conventional mold dipping by dipping stainless steel mold pins with a temperature of 55° C. into the respective CC melt or HPMC melt respectively with a temperature of 29° C. A film was formed on the mold pins. After first drying of the film on the mold pins at 50 to 60° C. and 30 to 40% RH for 15 to 20 min, and a second drying at 50 to 60° C. and 25 to 30% RH for 30 min, CC capsule halves and HPMC capsule halves respectively were obtained.
Capsules were assembled by joining always one cap with one body.
The fracture behavior of the capsules prepared according to Example 2, was measured by its resistance to an impact test with a tube tester. In preparation of the test the capsules were stored for equilibration for five days under four storage conditions in desiccators: 10, 23, 33 and 45% RH in order to obtain capsules with different LOD. Number of capsules tested was 50 per each RH value and the number of broken body or broken cap was recorded. Percentage of broken capsules is presented in Table 2.
When the amount of CaCl2 is too high the mechanical performance deteriorates.
To determine residual powder in capsules DUSA equipment from Copley Scientific was used. Capsules were equilibrated to different LOD by storage in desiccators 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 capsules filled with lactose blend were placed in a plastic bottle with a volume of 25 ml with a lid and tumbled in a friabilator TAR for 100 times. DUSA device was used to empty the capsules. Its set up was adjusted according to USP Pharmacopea guidelines section 601, heading “Sampling the Delivered Dose from Dry Powered Inhalers” Apparatus B; two pumps were used with the flow parameters of 100 L/min and time of aspiration of 2.4 s in order to match the volume of air of 4 L as required by the cited USP Pharmacopeia guideline section 601, to be withdrawn from the inhaler. Of this total of ten capsules the weight before filling with powder (Wempty) and after emptying (Wemptied) by the DUSA device was determined. The total amount of powder that was filled into these ten capsules was also recorded (Wpowder). PR is the percentage of residual powder and was determined from the equation EQ1:
% PR=100*[(Wemptied−Wempty)/Wpowder] EQ1:
Results represent mean and standard deviation SD of 3 samples, each of a total 10 capsules tested and are given in the Table 3:
Individual values are shown in black and mean values in grey.
Results:
CC-A* capsules and HPMC capsules with LOD from 4.5 to 5.0, prepared according to Example 2 and storage in desiccator at 50% RH as described in Example 4, were also tested using powder that was obtained by purchasing a publicly available medicament in form of a capsule filled with powder in a pharmacy and extracting this powder and filling it into the capsules. Then the capsules were emptied by action of 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 compared to HPMC capsules.
The PR was 0.6% for the HPMC capsules and 0.11% for the CC-A* capsules.
Obviously
A puncture test was done with the capsules made from CC-A* melt and the capsules which were used in U.S. Pat. No. 5,626,871 Example 17 (medical hard capsules composed essentially of hydroxypropyl methyl cellulose [composition: 93 parts by weight of hydroxypropyl methyl cellulose, “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]).
Protocol of the puncture test:
Once punctured, capsules are one by one checked visually and capsules not qualifying were identified which were capsules whose operculum was not pierced or operculum of the capsule or some of its parts are detached risking to deposit some capsules particles together with powder in the patient by the inhalation.
Sorted capsules are counted and presented as a percentage of total capsules analysed, results are given in Table 6.
Capsules made from CC-A* melt and from CC-A** melt show significantly better performance in the puncture test compared to the capsules with a gelling agent used in U.S. Pat. No. 5,626,871 Example 17, no not qualifying capsules were observed.
Two other additives were tested instead to CaCl2.2H2O.
The additives were:
The content of the additive in the respective melt was 5000 ppm on weight of HPMC and the respective melts were prepared according to the procedure of example 1 with the difference in step 2 and with the amounts given in Table 4, and in step 3 the respective dispersion of additive was used. instead of the solution of CaCl2.2H2O
The additive was added into the water and subjected to homogenization by an Ultra-Turrax, IKA T25 with 8000 to 9000 rpm speed for 5 min.
The SMVL dispersion was left to stand until the foam had vanished prior to the addition into HPMC melt, while the dispersion of RF10 was used directly without the need of letting it stand since no foam had formed.
The preparation of additive melts provided two melts: RF10 melt and SMVL melt. With these two additive melts then additive capsules shells were prepared according to the method of dip molding as described in example 2.
Testing on Additive Capsules Prepared from Additives Melts—Powder Retention PR in Capsules
PR by the additive capsules with an LOD (0%) of 5.0 to 5.5 was tested according to the method described in Example 4. The LOD of 5.0 to 5.5 0% was obtained as described under remark (*). Table 5 shows the PR values.
| Number | Date | Country | Kind |
|---|---|---|---|
| 20172719.5 | May 2020 | EP | regional |
| 21155241.9 | Feb 2021 | EP | regional |
| 21159324.9 | Feb 2021 | EP | regional |
| 21159631.7 | Feb 2021 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2021/060220 | 4/20/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63013917 | Apr 2020 | US |
