Patent Application
20220347106
The invention discloses opaque capsule shells made from gelatin with ground CaCO3 as opacifier; and a method for making them.
Certain medicaments or other active ingredients such as nutraceutical are not light stable but are sensitive to degradation by light and need to be stored in a light-shielded manner. Within capsules, the opacity of the capsule shell hence regulates the light-shielding. Typically in the prior art, titanium dioxide is used for creating opacity in the capsule shells.
There are certain concerns about and restrictive regulations of the use of titanium dioxide as opacifier in capsule shells which necessitate the search for a replacement.
U.S. Pat. No. 6,790,495 B1 discloses the use of calcium carbonate in capsule shells based in starch. The type of calcium carbonate which use is not mentioned.
CN 105 796 803 A (embodiment 15) discloses a soft capsule shell comprising gelatin (39 wt %), ground CaCO3 (GCC) (3 wt %), methylparahydroxybenzoate (0.08 wt %), propyl parahydroxybenzoate (0.02 wt %), greyish purple (0.2 wt %) and the water of surplus.
CN 105 796 803 A is silent about capsule shells whose main component with 70 wt % or more is gelatin.
There was a need for finding a suitable replacement of titanium dioxide as opacifier in capsule shells based mainly on gelatin as wall forming polymer.
Surprisingly it was found that ground calcium carbonate GCC shows better behavior with respect to crosslinking, tensile strength and light transmittance in gelatin capsule shells than precipitated calcium carbonate PCC and encapsulated calcium carbonate ECC: GCC shows a better dissolution behavior, higher tensile strength and lower light transmittance than PCC or ECC when used as opacifier in capsule shells.
Subject of the invention is a capsule shell CAPSSHELL comprising gelatin and GCC, GCC is ground CaCO3, wherein CAPSSHELL comprises from 70 to 97 wt % of gelatin, with the wt % being based on the total weight of dry CAPSSHELL
CAPSSHELL is a capsule shell for filling with an active pharmaceutical ingredient, medicament, nutritional supplement, nutraceutical, vitamin, mineral, cosmetic, health food or a mixture thereof.
The gelatin and the GCC are contained in the capsule shell itself, that is in the wall that actually builds the capsule shell. Another word for “build” may be “constitute” or “form”. The gelatin is the film forming substance that actually builds the wall, that is that builds the capsule shell itself; the GCC is contained in the gelatin, that is the GCC is contained in the wall.
The gelatin and the GCC meant by the invention are not meant to be contained in the content which is filled into the capsule shell, such as a medicament etc.
CAPSSHELL may comprise from 3 to 12 wt %, preferably from 3.5 to 11.5 wt %, more preferably from 4 to 11 wt %, even more preferably from 4.5 to 10.5 wt %, of GCC, with the wt % being based on the total weight of dry CAPSSHELL.
In one embodiment, CAPSSHELL may comprise from 3 to 7 wt %, preferably from 3.5 to 6 wt %, more preferably from 4 to 6 wt %, even more preferably from 4.5 to 5.5 wt %, of GCC, with the wt % being based on the total weight of dry CAPSSHELL
In another embodiment, CAPSSHELL may comprise from 8 to 12 wt %, preferably from 6 to 11.5 wt %, more preferably from 9 to 11 wt %, even more preferably from 9.5 to 10.5 wt %, of GCC, with the wt % being based on the total weight of dry CAPSSHELL.
CAPSSHELL may comprise preferably from 75 to 96.5 wt %, more preferably from 75 to 96 wt %, even more preferably from 80 to 96 wt %, especially from 80 to 95.5 wt %, in another embodiment from 85 to 96 wt %, more especially from 87.5 to 96 wt %, in another embodiment from 85 to 95.5 wt %, even more especially from 87.5 to 95.5 wt %, of gelatin, with the wt % being based on the total weight of dry CAPSSHELL.
In one embodiment, CAPSSHELL may comprise from 75 to 97 wt %, preferably from 80 to 96 wt %, more preferably from 85 to 95.5 wt %, even more preferably 90 to 95.5 wt %, of gelatin, with the wt % being based on the total weight of dry CAPSSHELL.
In another embodiment, CAPSSHELL may comprise from 70 to 92 wt %, preferably from 75 to 91 wt %, more preferably from 80 to 90.5 wt %, even more preferably 85 to 90.5 wt %, of gelatin, with the wt % being based on the total weight of dry CAPSSHELL.
The GCC may have a median particle size or a D50 of from 0.2 to 5 micrometer, preferably from 0.5 to 5 micrometer, more preferably from 1 to 5 micrometer, even more preferably from 1 to 4 micrometer.
The term “D50”, indicates that in the particle mixture, the diameter of 50% (on the total mass) of the particles is smaller than, and the diameter of the other 50% (on the total mass) of the particles is larger than the indicated D50 value. Typical measurement techniques are sieve analysis, direct imaging, for examples with electron microscopy, and laser diffraction and are known in the art and are chosen by the skilled person according to the D50 which the powder which is examined is expected to have.
Preferably, GCC particles have a substantially round or prismatic particle shape. In a particular embodiment, GCC particles are uniform round or prismatic particles.
In one embodiment CAPSSHELL may have a light transmittance at 650 nm of 45% or lower, preferably of 43% or lower more preferably 42% or lower.
In one embodiment CAPSSHELL may have a light transmittance at 650 nm of 22% or lower, preferably of 21% or lower, more preferably 20% or lower.
CAPSSHELL may be a hard or soft capsule shell, preferably a hard capsule shell.
The wall thickness of CAPSSHELL is known to the skilled person, a typical value may be 100 micrometer, a typical range may be from 90 to 110 micrometer.
Typical sizes of CAPSSHELL are known to the skilled person and may be for examples expressed in the sizes 000, 00, 0, 1, 2 or 3.
CAPSSHELL may comprise water. The water stems from the production process which is using a aqueous mixture for preparing CAPSSHELL, so the water in CAPSSHELL is typically residual water remaining in CAPSSHELL after drying. Typical content of water in CAPSSHELL is 25 wt % or less, preferably 20 wt % less than, more preferably from 0 to 14 wt %, even more preferably from 1 to 14 wt %, especially from 2 to 14 wt %, more preferably from 3 to 14 wt %, of water, the wt % being based on the weight of the CAPSSHELL.
CAPSSHELL may, additionally to the gelatin and the GCC, comprise one or more additives ADD, ADD is a viscosity modifier, defoaming aid, plasticizer, lubricant, colorant, solvent, solvent aid, surfactant, dispersant, solubilizer, stabilizer, corrective, sweetener, absorbent, adsorbent, adherent's, antioxidant, antiseptic, preservative, desiccant, flavor, perfume, pH adjuster, binder, humectant, disintegrating agent, release-controlling agent, acid, salt, or a mixture therefore.
CAPSSHELL may, additionally to the gelatin and the GCC, comprise one or more additives ADD, ADD is a viscosity modifier, defoaming aid, plasticizer, colorant, surfactant, dispersant, antioxidant, pH adjuster, acid, salt, or a mixture therefore.
Colorant may be a pigment or a dye.
Plastiziser may be glycerol, sorbitol or lecithin.
Dispersant may be (iota-)carrageenan, sodium lauryl sulfate, sorbitan, or lecithin.
Antioxidant may be ascorbic acid.
pH adjuster may be a salt such as Na2HPO4 or K2HPO4.
Acid may be acetic acid or ascorbic acid.
Typical amount of acid may be from 0.025 to 0.75 wt %, preferably from 0.04 to 0.6 wt %, the wt % being based on the total weight of dry CAPSSHELL
Possible content of ADD may be from 0.025 to 25 wt %, preferably from 0.04 to 22 wt %, the wt % being based on the total weight of dry CAPSSHELL
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 dispersion DIPDISP, DIPDISP is a dispersion of GCC in water comprising dissolved gelatin; with CAPSSHELL as defined herein, also with all its embodiments.
PROCFORMCAPS may be any conventional process for forming capsule shells known to the skilled person, such as extrusion moulding, injection moulding, casting or dip molding.
Dip molding can also be called dip coating.
CAPSSHELL made by dip molding comprises two halves of a capsule shell, the two halves are the called the cap and the body. 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 cap is form by a mold pin having the respective geometric shape complementary to the desired shape of the cap. The body is form by a mold pin having the respective geometric shape complementary to the desired shape of the body. By using the respective mold pin 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.
Dip molding comprises the steps of:
with DIPDISP as defined herein, also with all its embodiments.
After the preparation of both halves of CAPSSHELL, both halves 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 size which is still longer then 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 a green body or can also be called 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 the elevated temperature when it is dipped into DIPDISP and while the film is dried on the mold pin after the dipping.
PINTEMP may be from ambient temperature to 40° C., preferably from ambient temperature to 30° C.
The temperature of DIPDISP during the dipping of the mold pins into DIPDISP may be from ambient temperature to 75° C., preferably from 25 to 70° C., more preferably from 30 to 75° C., even more preferably from 35 to 70° C., especially from 35 to 65° C.
Drying of the film on the mold pin may be done by air drying. Drying may be done at elevated temperature
The temperature for drying of the film on the mold pin may be from ambient temperature to 40° C., preferably from 20 to 35° C., more preferably from 20 to 30° C.
After the joining of both halves to form the capsule, CAPSSHELL may be further dried; this drying may be done at a temperature of from ambient temperature to 40° C., preferably from 20 to 35° C., more preferably from 20 to 30° C.
DIPDISP comprises GCC and gelatin in an amount based on the dry weight of DIPDISP which are equal to the amount of GCC and gelatin in CAPSSHELL based on the dry weight of CAPSSHELL as defined herein.
DIPDISP may be prepared by a mixing MIX of a dispersion GCCDISP of GCC in water with a solution GELSOL of gelatin in water.
GCCDISP may comprise from 20 to 35 wt %, preferably from 25 to 30 wt %, of GCC, the wt % being based on the total weight of GCCDISP.
GELSOL may comprise from 20 to 40 wt %, preferably from 25 to 35 wt %, of gelatin, the wt % being based on the total weight of GELSOL.
MIX may be done in one or more steps.
In one embodiment MIX is done in two mixing steps MIX1 and MIX2;
MIXTUREGCCDISPGELSOL may comprise from 10 to 30 wt %, preferably from 15 to 25 wt %, of gelatin, the wt % being based on the total weight of MIXTUREGCCDISPGELSOL.
MIXTUREGCCDISPGELSOL may comprise from 2 to 10 wt %, preferably from 3 to 9 wt %, more preferably from 4 to 8 wt %, of GCC, the wt % being based on the total weight of MIXTUREGCCDISPGELSOL.
The amounts of GELSOL, GCCDISP and MIXTUREGCCDISPGELSOL and their concentration and amounts of gelatin and of GCC are calculated and chosen in such a way that the desired amounts of GCC and of gelatin in DIPDISP is provided in order to provide for the desired amounts of GCC and of gelatin in CAPSSHELL.
The amounts of GCC, of gelatin and of any ADD in dry DIPDIPS is equal to the respective amounts in dry CAPSSHELL.
DIPDISP may comprise, additionally to GCC and gelatin, ADD;
with ADD as defined herein, also with all its embodiments.
DIPDISP may comprise ADD in an amount based on the dry weight of DIPDISP which are equal to the amount of any ADD in CAPSSHELL based on the dry weight of CAPSSHELL as defined herein.
GCCDISP may be prepared by a mixing MIXGCC of GCC with water.
Any mixing such as MIXGCC, MIX, MIX1 and MIX2 is preferably done under conditions of eleveated shear.
Any such mixing may be done with an Ultra Turrax from IKA-Werke GmbH & CO. KG, 79219 Staufen, Germany, or a similar instrument.
Mixing speeds may be from 5′000 to 25′000 rpm, preferably 6′000 to 23′000 rpm.
Mixing times may be from 1 to 30 min, preferably from 2 to 20 min, even more preferably from 2 to 10 min.
Conditions of elevated shear may also be referred to as high shear conditions.
MIXGCC may be done with mixing speeds of from 15′000 to 25′000 rpm, preferably 17′000 to 23′000 rpm.
Mixing times for MIXGCC may be from 4 to 30 min, preferably from 4 to 20 min, even more preferably from 4 to 10 min.
DIPDISP, GCCDISP and MIXTUREGCCDISPGELSOL have the form of a dispersion or slurry. The dispersion or the slurry is a dispersion of GCC in aqueous medium.
GELSOL may be prepared by dissolving DISSGEL of gelatin in water. DISSGEL may be done at elevated temperature, the temperature for DISSGEL may be from 35 to 100° C., preferably from 40 to 95° C.
GELSOL may be stored and used for MIX at elevated temperatures, such as from 35 to 60° C., preferably from 40 to 55° C.
Further subject of the invention is CAPSSHELL filled with a formulation FILLFORM comprising an active ingredient ACTINGR, ACTINGR may be an active pharmaceutical ingredient (API), medicament, nutritional supplement, nutraceutical, vitamin, mineral, cosmetic, health food or a mixture thereof;
with CAPSSHELL as defined herein, also with all its embodiments.
ACTINGR may be an active ingredient which is not stable in or sensible to visible or UV light, preferably visible light.
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 total dry weight of FILLFORM.
The GCC of CAPSSHELL provides for a shielding of the ACTINGR against light.
Examples for medicaments or for API which are candidate for ACTINGR to be filled in CASPSSHELL to obtain effective light shielding are dihydropyridine derivatives (e.g., nifedipine), antiviral HIV protease inhibitors (e.g., Ritonavir, Saquinavir), therapeutic agents for hyperlipidemia (e.g., clofibrate), iodine compounds (e.g., sodium iopodate, sodium iodide), polyunsaturated fatty acid derivatives (e.g., ethyl eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)), carotenoids (e.g., lycopene, bixin, β-carotene, xanthophyll, lutein), ubiquinones (coenzyme Q) (e.g., ubidecarenone used as a metabolizable cardiac stimulant), various vitamin derivatives, as well as indomethacin, colchicine, diazepam, syrosingopine, norethisterone, piretanide, propericyazine, perphenazine, mequitazine, medazepam, menatetrenone, indenolol hydrochloride, reserpine, sofalcone, bromocriptine mesilate, bufetolol hydrochloride and oxprenolol hydrochloride when they are filled into the capsule formulation of the present invention. Among vitamin derivatives, fatsoluble ones are preferred for use. Examples include vitamin A derivatives (e.g., tretinoin, liver oil, retinol palmitate), vitamin A analogs (e.g., etretinate), vitamin D derivatives, vitamin E derivatives (e.g., tocopherol nicotinate, tocopherol acetate, tocopherol calcium succinate), or vitamin K derivatives (e.g., phytonadione (vitamin K1), menaquinone (vitamin K2), menadione (vitamin K3), menatetrenone, phytonadione).
A medicament or an API as ACTINGR can be filled into CAPSSHELL either alone or in combination with any base or carrier, additive, or excipient. Any type of base or carrier, either fat-soluble or water-soluble, can be used as long as it does not impair the medicament's or API's activity and does not affect various physical properties of CAPSSHELL, such as strength, gas permeability, and disintegration or dissolution profiles. Likewise, the base per se may be in a liquid or solid state at normal temperature as long as it can be filled into CAPSSHELL with the help of heating or dilution with other solvents, etc. Examples of such a base include vegetable oils (e.g., soybean oil, sesame oil, cottonseed oil, olive oil), fatty acid glycerides (e.g., medium chain triglycerides), propylene glycol, propylene glycol fatty acid esters, polyethylene glycol, polyvinylpyrrolidone, triacetin, liquid paraffin, polyoxyethylene sorbitan fatty acid esters, sucrose fatty acid esters, ethanol and purified water, which may be used alone or in combination. Bases preferred for dissolving fat-soluble medicaments or APIs such as vitamins A, D, E and K are vegetable oils or fatty acid glycerides, with medium chain triglycerides being particularly preferred. In the case of using a water-soluble base, it is preferable to provide a protection layer between the capsule shell layer and the medicament or API layer or a crystallization inhibitor in consideration of influences on CAPSSHELL.
A medicament or API to be filled into CAPSSHELL of the present invention is preferably exemplified by, but not limited to, those in a liquid form or those dissolved, suspended or emulsified in such a base as listed above. The medicament or API may also be in a solid form (e.g., powders, granules) or in a semi-solid form (e.g., creams or gels).
SML is mixed with hot water and dry gelatin is then added. The mixture is heated to 90° C. in 90 min. Cold water and acetic acid are then added to the mixture. Then SLS is added. The temperature of the mixture is maintained at 53° C. under stirring and vacuum 0.6 mbar for 80 min. Stirring is then stopped and the obtained aqueous solution of gelatin is kept without stirring for 80 min at 53° C. Then the gelatin aqueous solution is kept at and used with 45° C.
Water was added to CaCO3 and the mixture was homogenized with high shear mixing at 21000 rpm with an Ultra Turrax (3 times 2 minutes with 30 sec pause between each mixing) to provide a dispersion of CaCO3 in water.
Then aqueous gelatin solution is added and mixed into the dispersion of CaCO3 under stirring with Ultra Turrax at 7′000 rpm during 3 min, thereby forming a slurry.
Step 4: Preparation of the HGC melt (DIPDIPS by MIX2) with desired concentration of CaCO3:
The slurry is then mixed with aqueous gelatin solution, thereby providing a HGC melt with the desired content of CaCO3 and of gelatin by manual mixing with a respective spatula.
This procedure is used for GCC, PCC and ECC.
Table 1 shows the amounts used in each step.
Films were formed as follows:
Glass plates were kept at 60° C., the HGC melt with the desired content of CaCO3 was kept at 55° C. and films were casted using a plate coater (CAMAG, 4132 Muttenz, Switzerland). The films were then left to dry overnight at 22° C. at a RH of 50%. Thickness of the films was between 85 and 100 micrometer.
Transmittance at 650 nm were tested and the results are given in Table 3.
The measurement was done with a UV spectrophotometer.
The lower the transmittance the better, obviously GCC shows lower transmittance than PCC and than ECC
Tensile tests have been performed on the films. For each sample, 20 film strips (dimensions: width 12.7 mm, length 80 mm) per CaCO3 grade and percentage were cut and stored for 5 days at two different RH (23% RH and 50% RH).
Then they were tested and average values of the 20 films were calculated.
Test conditions: initial length 25 mm, speed rate 50 mm per min
Tables 4 and 5 show the results.
26 ± 7.2
The higher the deformation the better; GCC shows highest deformation compared to PCC and to ECC.
The films were cut to pieces of ca. 2.5 times 3.0 cm while the weight was adjusted to a weight of 75 mg+/−1 mg.
With these film pieces first dissolution tests were performed (T=0).
Other film pieces stored in accelerated conditions (climatic chamber at 50° C.+/−2° C. and with a RH of 80+/−5% for 4 weeks) and tested after the first (T=1W), the second (T=2W) and the fourth (T=4W) week.
For testing the film pieces were placed in cage shaped sinker in a stirred dissolution media, the dissolution media used was demineralized water at 36.5 to 37.5° C.
Measurements of Optical Density (OD) were performed with UV-visible spectrophotometer at the wavelength of 218 nm. Measurements were done at the times t=0, 3, 6, 9, 12, 15 min. After these 15 min, stirring was applied to facilitate complete dissolution and then after another 15 min complete dissolution of the gelatin was obtained and measured, providing the infinity dissolution value DO100%.
Calculation was done by comparison with infinity dissolution value:
with
DO optical density
t time in min
Results are shown in Table 6.
In order to meet specification and thereby to qualify, the % dissolved need to be greater than 50% after 9 min of testing.
The use of PCC causes gelatin crosslinking in accelerated conditions which diminishes the dissolution ability whereas the use of ground CaCO3 shows improved behavior, that is less crosslinking.
The HGC melts prepared according to example 1 were used to produce HGC shells with capsule size 0 and standard target weights (Body 60+/−2 mg, Cap 36+/−1.2 mg) through conventional mold dipping by dipping stainless steel mold pins at room temperature (22° C.) into a the HCG melt with 45° C. A film was formed on the mold pins. After first drying of the film on the mold pins at 25 to 29° C. and 40% RH for 30 to 40 min, and a second drying at 20 to 22° C. and 50% RH for 10 min, HGC shells in form of its halves (bodies and caps) were obtained with shell wall thickness of:
| Number | Date | Country | Kind |
|---|---|---|---|
| 19202478.4 | Oct 2019 | EP | regional |
| 19206112.5 | Oct 2019 | EP | regional |
| 19209355.7 | Nov 2019 | EP | regional |
| 20173739.2 | May 2020 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2020/078280 | 10/8/2020 | WO |
