(19)

*EP004215187A1*
(11) EP 4 215 187 A1
(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) International Patent Classification (IPC):

26.07.2023 Bulletin 2023/30 A61K 9/50 (2006.01) A61K 9/16 (2006.01)
A61K 9/20 (2006.01) A61K 31/80 (2006.01)
(21) Application number: 23160382.0 A61K 9/00 (2006.01)

(22) Date of filing: 14.09.2018 (52) Cooperative Patent Classification (CPC):

A61K 9/5057; A61K 9/0056; A61K 9/1658;
A61K 9/2081; A61K 9/501; A61K 9/5042;
A61K 9/5089; A61K 31/80

(84) Designated Contracting States: (72) Inventors:

AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • MCNALLY, Gerard P.
GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Fort Washington, 19034 (US)
PL PT RO RS SE SI SK SM TR • SZYMCZAK, Christopher
Fort Washington, 19034 (US)
(30) Priority: 29.09.2017 US 201762565850 P
(74) Representative: Carpmaels & Ransford LLP
(62) Document number(s) of the earlier application(s) in One Southampton Row
accordance with Art. 76 EPC: London WC1B 5HA (GB)
18779802.0 / 3 687 502
Remarks:
(71) Applicant: Johnson & Johnson Consumer Inc. This application was filed on 07-03-2023 as a
Skillman, NJ 08558 (US) divisional application to the application mentioned
under INID code 62.

(54) SOLID SIMETHICONE PARTICLES AND DOSAGE FORM THEREOF

(57) The present invention is directed to microencapsulated simethicone particles containing simethicone and a
water soluble coating, wherein the simethicone is about 50% by weight of the particle.
EP 4 215 187 A1

Processed by Luminess, 75001 PARIS (FR)

 EP 4 215 187 A1

Description

BACKGROUND OF THE INVENTION

5 Field of the Invention

[0001] The present invention relates to novel solid simethicone particles and methods for making such particles.
[0002] Simethicone has been used to treat intestinal discomfort, pressure, fullness, and bloating. It is typically admin-
istered in a liquid or solid form either alone or in combination with antacids or anti-diarrheals, such as loperamide.
10 [0003] Typically, to incorporate simethicone into a solid formulation, it must first be adsorbed onto a suitable carrier
or substrate. There have been several inventions related to this problem, substrate materials vary from polysaccharides
to inorganic materials such as calcium phosphates or metalo-silicates. A limitation of the polysaccharide approach is
that the limited loading capacity i.e. a stable concentration of simethicone adsorbed onto the substrate resides in the
range of 20-25% which implies a simethicone/adsorbate dose of 500-625mg for a 125 mg dose of simethicone. A
15 drawback of the inorganic substrates is their insolubility and gritty mouthfeel. Thus these approaches to generating solid
phase simethicone powder or granules are not suitable for certain delivery formats such as orally disintegrating tablets
(ODTs) or orally dispersible granules (ODGs). A microencapsulated simethicone particle with a water soluble coating
would address the limitations of the existing approaches to producing free flowing simethicone powders.
[0004] The primary benefit of the novel microencapsulated simethicone particle with a water soluble coating are that
20 it addresses the limitations of the existing approaches to producing free flowing simethicone powders. Additional benefits
of the coating includes adding a separating layer between simethicone and other materials, such as active ingredients.
However it may not survive a typical tablet compression process as it is likely that the microencapsulated oil particles
would be ruptured. Certain ODT manufacturing processes such as sintering, freeze drying and 3D printing do not expose
the ODT ingredients to excessive pressures so could enable a novel solution to making a fast dissolving simethicone
25 containing ODT. Similarly ODG formulations would be enabled by this approach.

SUMMARY OF THE INVENTION

[0005] The present invention is directed to microencapsulated simethicone particles comprising:

30 simethicone and a water soluble coating, wherein the simethicone is about 50% by weight of the particle.
[0006] In one embodiment, the present invention is directed to a method of preparing microencapsulated simethicone
particles comprising the steps of (a) forming a water coating solution, (b) combining simethicone and the water soluble
coating solution and forming an emulsion, and (c) spray drying the emulsion.
[0007] The present invention also includes a method of preparing microencapsulated simethicone particles comprising
35 the steps of (a) preparing simethicone granules; (b) preparing a coating solution; and (c) coating the simethicone granules
with the coating solution.
[0008] The present invention also includes a method of preparing microencapsulated simethicone particles comprising
the steps of (a) forming a complex coacervate of simethicone particles and hydrocolloids; (b) cooling the complex
coacervate to a gel temperature at a pH of about 5 to deposit a protein shell around each of the simethicone particles;
40 (c) further cooling the complex coacervate to a cross-linking temperature below the gel temperature at a pH of about 7
to stabilize the protein shell; and (d) adding an enzyme to the water for enzymatically cross-linking the stabilized protein
shell at about pH 7 to form microencapsulated simethicone particles.

DETAILED DESCRIPTION OF THE INVENTION

45
[0009] The present invention is directed to a microencapsulated simethicone particle containing simethicone and a
water soluble coating, wherein the simethicone is about 50% by weight of the particle.
[0010] Simethicone may be orally ingested and is typically used to relieve symptoms of excess gas such as belching,
bloating and pressure in the stomach and/or intestines. It works by breaking up gas bubbles.
50 [0011] The simethicone particle is at least about 50% by weight simethicone. In one embodiment, the simethicone
particle is from about 50% to about 99% by weight simethicone. In another embodiment, the simethicone particle is from
about 60% to about 97% by weight simethicone. In still another embodiment, from about 70% to about 95% by weight
of the particle.
[0012] Another essential component is a water soluble coating. Suitable water soluble coatings include, for example,
55 gelatin, pectin, water soluble materials, combinations of water soluble materials with water insoluble materials, whey
protein isolate, or mixtures thereof.
[0013] Suitable gelatins include but are not limited to Croda SPA® (45-85 Bloom), derived from specially tanned cow
hides, or Type A or Type B derived from bovine skin, bovine bone, pork skin, fish. The gelatins are present at levels of

2
 EP 4 215 187 A1

10 to 60%, more preferably 20 to 50%, most preferably 20 to 35% by weight.

[0014] In certain embodiments the coating may be partially water soluble or pH sensitive, such that it does not dissolve
in the oral cavity but is immediately released in the stomach or intestine. For example, the coating may incorporate a
portion of water insoluble material such as a water insoluble polymer. Suitable water insoluble polymers include but are
5 not limited to ethylcellulose, cellulose acetate, and polymethacrylates. Suitable pH dependent polymers include cellulose
acetate phthalate, hydrocypropylcellulose phthalate, shellac, hydroxypropylcellulose succinate, anionic copolymers
based on methacrylic acic and methyl methacrylate such as those sold under the tradename of Eudragit L100.
[0015] In one embodiment, non-hydrolyzed gelatins are preferred.
[0016] In another embodiment, whey protein isolate containing about 98% protein is utilized as the water soluble coating.
10 [0017] Alternatively, the simethicone is adsorbed on anhydrous dibasic calcium phosphate and further coated with a
water soluble coating.
[0018] In another embodiment, the water soluble coating may comprise a swellable erodible hydrophilic material, and
a pH dependent polymer.
[0019] Examples of swellable, erodible hydrophilic materials for use in the coating include water swellable cellulose
15 derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays, and gelling
starches. Examples of water swellable cellulose derivatives include sodium carboxymethylcellulose, cross-linked hy-
droxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,
hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropyl-
ethylcellulose, hydroxypropylbutylcellulose, and hydroxypropylethylcellulose. Examples of polyalkylene glycols include
20 polyethylene glycol. Examples of water soluble vinyl based polymers include polyvinyl alcohol, polyvinyl alcohol poly-
ethylene glycol copolymers and mixtures thereof. Examples of suitable thermoplastic polyalkylene oxides include poly
(ethylene oxide). Examples of acrylic polymers include potassium methacrylatedivinylbenzene copolymer, polymethyl-
methacrylate, and high-molecular weight cross-linked acrylic acid homopolymers and copolymers.
[0020] Suitable pH-dependent polymers for use as for use in the coating include: enteric cellulose derivatives such
25 as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and cellulose acetate
phthalate; natural resins such as shellac and zein; enteric acetate derivatives such as polyvinylacetate phthalate, cellulose
acetate phthalate, and acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example
polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1:2 (available from Rohm Pharma
GmbH under the tradename EUDRAGIT S) and poly(methacrylic acid, methyl methacrylate) 1:1 (available from Rohm
30 Pharma GmbH under the tradename EUDRAGIT L).
[0021] In another embodiment, the coating may include a plasticizer or a surfactant. Suitable plasticizers include for
example, glycerin, polyethylene glycol, propylene glycol, dibutyl sebecate, triethyl citrate, vegetable oils such as castor
oil. Suitable surfactants include Polysorbate-80, sodium lauryl sulfate and dioctyl-sodium sulfosuccinate. The plasticizer
may comprise from 1 percent to 30 percent by weight of the coating. The surfactant may comprise from 1 to 20 percent
35 of the coating.
[0022] The inventive simethicone particles may be prepared using various known processing methods. For example,
spray drying, fluid bed coating, or coacervation processing techniques may be utilized to form the simethicone particles.
[0023] The microencapsulated simethicone particles may be used in various applications. For example, the inventive
particles may be included in an oral dosage form, such as an orally disintegrating tablet, a capsule, a compressed tablet
40 such as a chewable tablet a lozenge, a chewing gum or a gummy form. Alternatively, the particles may be included in
orally dissolving granules.
[0024] In one embodiment, the tablet is containing the encapsulated simethicone is prepared such that the tablet is
relatively soft (e.g., capable of disintegrating in the mouth or being chewed). In one embodiment, the hardness of the
tablet is preferably less than about 3 kiloponds per square centimeter (kp/cm2) (e.g., less than about 2 kp/cm2, such as
45 less than about 1 kp/cm 2). Hardness is a term used in the art to describe the diametral breaking strength as measured
by conventional pharmaceutical hardness testing equipment, such as a Schleuniger Hardness Tester. In order to compare
values across different size tablets, the breaking strength must be normalized for the area of the break. This normalized
value, expressed in kp/cm2, is sometimes referred in the art as tablet tensile strength. A general discussion of tablet
hardness testing is found in Leiberman et al., Pharmaceutical Dosage Forms--Tablets, Volume 2, 2.sup.nd ed., Marcel
50 Dekker Inc., 1990, pp. 213-217, 327-329.
[0025] A more preferred test for hardness of the tablet of the present invention relies upon a Texture Analyzer TA-
XT2i that is fitted with a 7 millimeter diameter flat faced probe and setup to measure and report compression force in
grams. The probe moves at 0.05millimeters per second to a depth of penetration of 2 millimeters. The maximum com-
pression force is recorded. In one embodiment, the measured forces recorded for tablets made in accordance with the
55 present invention are less than 10,000 grams (e.g., less than about 1000 grams, such s led than about 700 grams. In
one embodiment, the measured forces recorded for tablets made in accordance with the present invention ranges from
about 100 grams to about 6000 grams, such as from about 100 grams to about 1000 grams, such as from about 75
grams to about 700 grams) with a deviation of 650 grams. In another embodiment the measured forces recorded for

3
 EP 4 215 187 A1

tablets is less than 700 grams.

[0026] Optionally, other ingredients may be included in the composition or dosage form of the present invention.
[0027] The microencapsulated simethicone particles may be combined with any active pharmaceutical ingredient
("API").
5 [0028] For example, the API may be for, analgesics, anti-inflammatories, antipyretics, antihistamines, decongestants,
cough suppressants and expectorants, muscle relaxants, stimulants, sedatives, appetite suppressants, anesthetics,
statins, antidiarrheal agents, H2 antagonists, proton pump inhibitors, antacids and the like. More specifically, the API
may include famotidine, calcium carbonate, aluminum hydroxide, magnesium hydroxide, magnesium oxide, loperamide,
and/or racecadotril.
10 [0029] For example, a glidant may also be included in the core composition to assist in the flow properties of the
composition. Suitable glidants include, for example, silicon dioxide such as colloidal silica, fumed silica, mixtures thereof,
and the like.
[0030] In one embodiment, the core may include from about 0.01 to about 3 wt.% of the glidant. In another embodiment,
the core includes from about 0.05 to about 2 wt.% of the glidant. In yet another embodiment, the core includes from
15 about 0.1 to about 1 wt.% of the glidant.
[0031] Other ingredients or components that may be added to the composition include, but are not limited to, super-
disintegrants, lubricants, aromas; sweeteners such as, sorbitol, sugar, and high intensity sweeteners such as sucralose,
aspartame and saccharine and the like may be included.
[0032] Any coloring agent suitable for use in a food or pharmaceutical product may be used in the present inventive
20 composition. Typical coloring agents include, for example, azo dyes, quinopthalone dyes, triphenylmethane dyes, xan-
thene dyes, indigoid dyes, iron oxides, iron hydroxides, titanium dioxide, natural dyes, and mixtures thereof. More
specifically, suitable colorants include, but are not limited to patent blue V, acid brilliant green BS, red 2G, azorubine,
ponceau 4R, amaranth, D&C red 33, D&C red 22, D&C red 26, D&C red 28, D&C yellow 10, FD&C yellow 5, FD&C
yellow 6, FD&C red 3, FD&C red 40, FD&C blue 1, FD&C blue 2, FD&C green 3, brilliant black BN, carbon black, iron
25 oxide black, iron oxide red, iron oxide yellow, titanium dioxide, riboflavin, carotenes, antyhocyanines, turmeric, cochineal
extract, clorophyllin, canthaxanthin, caramel, betanin, and mixtures thereof.
[0033] Similarly, a flavor may be included in the composition or solid dosage form. The amount of flavor added to the
composition will be dependent upon the desired taste characteristics.
[0034] The microencapsulated simethicone particles are from about and average of 20 microns to about 400 microns
30 in size. Preferably, from about 50 microns to about 200 microns in size.
[0035] The microencapsulated simethicone particles are useful in various applications, particularly in pharmaceutical
and over the counter medicine products. In the present invention, the simethicone may be present in various forms prior
to or upon microencapsulation or coating. The simethicone may be present as a pure oil, as an emulsion mixed with
various emulsification materials, or adsorbed onto a solid substrate. Suitable emulsification materials may include but
35 are not limited to emulsifiers such as fats, lipids; monoglycerides, diglycerides and triglycerides and mixtures thereof.
[0036] In one embodiment, the microencapsulated simethicone particles of the present invention may be compressed
with other components to form a tablet or as at least one layer of a multilayer tablet. In another embodiment the micro-
encapsulated simethicone particles may be deposited into a capsule form. In another embodiment, the microencapsulated
simethicone particles may be used for direct administration from a sachet.
40 [0037] The microencapsulated simethicone particles may be prepared by any suitable process.
[0038] In one embodiment, the microencapsulated simethicone particles are prepared by spray drying. The process
comprises the steps of (a) forming a water coating solution, (b) combining simethicone and the water soluble coating
solution and forming an emulsion, and (c) spray drying the emulsion. Optionally, silicon dioxide may be added during
spray drying as a flow agent. In various embodiments, the process may include the step of adjusting the pH of the water
45 soluble coating solution to a pH of 7. Optionally, an organic solvent may also be added to the spray drying solution.
Suitable organic solvents may include ethanol, isopropanol, or acetone.
[0039] In another embodiment, the microencapsulated simethicone particles are prepared by spray congealing. The
process comprises the steps of (a) melting a suitable wax, lipid or combination of waxes; (b) combining the simethicone
and mixing; and (c) spraying the particulates at a temperature which will solidify the particles and (d) collecting the
50 microencapsulated particles.
[0040] The microencapsulated simethicone particles may also be made using a fluidized bed. The process comprises
the steps of (a) preparing simethicone granules; (b) preparing a coating solution; and coating the simethicone granules
with the coating solution.
[0041] Alternatively, the microencapsulated simethicone particles may be prepared by coacervation. In one embodi-
55 ment, the complex coacervation process comprises the steps of (a) forming a complex coacervate of simethicone particles
and hydrocolloids; (b) cooling the complex coacervate to a gel temperature at a pH of about 5 to deposit a protein shell
around each of the simethicone particles; (c) further cooling the complex coacervate to a cross-linking temperature below
the gel temperature at a pH of about 7 to stabilize the protein shell; and (d) adding an enzyme to the water for enzymatically

4
 EP 4 215 187 A1

cross-linking the stabilized protein shell at about pH 7 to form stable protein-encapsulated simethicone particles. In
another embodiment, a simple or phase separation coacervation process is utilized. The simple coacervation process
involves adding a first polymer (coating agent) to an organic solvent. The simethicone is then dispersed in a second
organic solvent which is then added to the first organic solvent containing the polymer. The precipitate is then filtered,
5 collected and dried as a coated particle.
[0042] The following examples are provided to further illustrate the compositions and methods of the present invention.
It should be understood that the present invention is not limited to the example described.

EXAMPLE 1
10
Example 1: Preparation of Encapsulated Simethicone utilizing a Spray Drying Process and Gelatin

[0043]

15 Table 1
Component Batch w/w (g)
Simethicone 3000
Non-Hydrolyzed Gelatin 1500
20
Water (removed upon drying) 6000
Syloid 742 31.5
Total 10531.5 (4531.5 g as solids)
25 2 Commercially available from W.R. Grace and Company

Part A: Procedure

30
[0044]

1. Add water to a suitable sized (2L) vessel and heat to 60°C.

2. Disperse gelatin into hot water while mixing, continue until dissolved.
3. Add simethicone to the solution and emulsify.
35
4. Spray dry solution in a Niro Utility Spray Drier.
5. Add Syloid (silicon dioxide) to the spray chamber.
6. Collect the encapsulated simethicone particles.

Example 2: Manufacture of Orally Disintegrating Tablet Containing Encapsulated Simethicone

40
[0045] The following tablet is prepared using the encapsulated simethicone granlues from Example 1. The dose of
simethicone is equivalent to 125mg of simethicone.
[0046] Table 2 lists the components in a powder blend needed to manufacture an orally disintegrating tablet.
[0047] Sucralose, flavor, polyethylene glycol and maltodextrin from Table 2 are passed through a 20 mesh screen.
45
The sieved materials are placed into a 500cc plastic bottle and blended end over end with the remaining materials in
Table 2.

Description of the tablet activation process

50
[0048] A portion of the powder blend from Table 2 is placed into an electrically insulative Teflon, or ceramic die platen
having a forming cavity that is approximately 1.1 inches in diameter and 0.175 inches thick. The powder blend is then
tamped between upper and lower metal forming tools, into a shape conformal to the surface of the forming tools. The
tamping pressure is typically between 10 and approximately 100 psi of pressure. The forming tools, die platen and tablet
shape are then placed between the upper RF electrode and lower RF electrode of an RF heating unit using a COSMOS
55
Model C10X16G4 (Cosmos Electronic Machine Corporation, Farmingdale, NY) RF generator having an output of 4 KW
of power and a frequency of 27 MHz). The upper RF electrode is brought into contact with the upper forming tool and
the lower RF electrode is brought into contact with the lower forming tool. The RF heating unit is energized for 5 seconds.
After cooling, the resulting tablet is then ejected from the die platen using the lower forming tool.

5
 EP 4 215 187 A1

Table 2: Powder Blend Formulation Containing Simethicone

Ingredient G/Batch Mg/Tablet

5 Dextrose Monohydrate 246.81 246.81

Encapsulated Simethicone (66% Potency) 189.39 189.39
Polyethylene Glycol 80001 51.43 51.43
Maltodextrin2 105.00 105.00
10
Orange Flavor 1.71 1.71
Sucralose USP 1.37 1.37
Citric Acid USP Anhydrous 4.29 4.29

15 Total 600.00 600.00

1 Commercially available from Clariant PF in Rothausstr, Switzerland
2 Commercially available from National Starch in Bridgewater, NJ

20 Example 3: Encapsulation of Simethicone Granules by Fluid Bed Coating

Part A: Adsorbed Simethicone Granules using Anhydrous Dibasic Calcium Phosphate

[0049]
25
1) Add 700 g of granular anhydrous dibasic calcium phosphate, (Emcompress. RTM. Anhydrous, Mendell, Paterson,
N.J.) to the mixing bowl of a Kitchen Aid mixer.
2) While mixing at low speed, add 200 gm of simethicone USP over a period of 5 minutes.
3) Continue mixing at low speed for an additional 5 minutes.
30 4) Add 7.5 gm of silicon dioxide and mix an additional 5 minutes.

[0050] This intermediate is a free flowing granulation with no large agglomerates.

Part B: Preparation of Coating Solution and Polymer Coating of Simethicone Granules:

35
[0051]

1) Add 1572g of Acteone to a suitable mixing vessel (5L stainless steel vessel)
2) While mixing slowly, add 203.6 g of Cellulose Acetate (CA298-10, 38% acetyl content) and 10.7 g of Eudragit®
40 E-100 over 5 minutes, and mix until dissolved. The ratio of Cellulose acetate to Eudragit® E100 is 95:5. The final
solution solids percentage is 12%.
3) Add 500g of the simethicone granules from Part A to a Glatt GPGC 1/3. Coat the granules with the coating solution
from Step 2, at a rate of approx. 5-8 g/minute until coated drug particles containing 10% by weight of the polymer
coating are obtained.
45
Example 4: Manufacture of Orally Disintegrating Tablet Containing Encapsulated Simethicone (by Fluid Bed
Drying)

[0052] The following tablet is prepared using the coated simethicone granlues in Example 3. The dose is equivalent
50 to 62.5mg of simethicone.
[0053] The powder blend for an orally disintegrating tablet, containing the ingredients of Table 3, is manufactured as
follows. The sucralose, flavor, polyethylene glycol and maltodextrin from the formula in Table 3 are passed through a
20 mesh screen. The sieved materials are placed into a 500cc plastic bottle and blended end over end with the remaining
materials in Table 3. The powder blend is placed into an upper and lower set of © inch flat faced forming tools, tamped,
55 and activated with RF energy as described in Example 2 for approximately 2 minutes to form an orally disintegrating
tablet. The resulting tablet is then removed from the die.

6
 EP 4 215 187 A1

Table 3: Powder Blend Formulation Containing Simethicone

Ingredient G/Batch Ma/Tablet

5 Dextrose Monohydrate 193.25 193.25

Encapsulated Simethicone (19.8% Potency) 315.65 315.65
Polyethylene Glycol 80001 60.00 60.00
Maltodextrin2 122.5 122.5
10
Orange Flavor 2.00 2.00
Sucralose USP 1.60 1.60
Citric Acid USP Anhydrous 5.00 5.00

15 Total 700.00 700.00

1 Commercially available from Clariant PF in Rothausstr, Switzerland
2 Commercially available from National Starch in Bridgewater, NJ

20 Example 5: Spray Drying Preparation of Simethicone Granules using Whey Protein Isolate

[0054]

Table 4: Materials for Simethicone Granules using Whey Protein Isolate

25 Batch # Batch w/w (g)
Simethicone 2750
Whey Protein Isolate1 (98% protein) 100
Water (removed upon drying) 10000
30
Syloid 742 32.0
TOTAL 12882.0 (2882.0g as solids upon drying)
1 Commercially available from Bipro Davisco Foods International
2 Commercially available from W.R. Grace and Company
35

Part A: Procedure for preparing the Encapsulated Simethicone (Using the formula in Table 4)

Simethicone Oil Emulsion and Particulate preparation using Spray Drying

40

[0055]

1. Add water to a suitable sized (20L) vessel at 20°C.

2. Disperse whey protein isolate into hot water while mixing until dissolved. Adjust pH to 7.0 using 0.1m NaOH/HCl.
45
3. Slowly add simethicone to the solution (over 5 minute time period) while mixing and emulsifying.
4. Homogenize the emulsion using a 2 stage homogenizer.
5. Pass the whey protein-simethicone emulsion through a plate heat exchanger held at 82°C to facilitate cross linking.
6. Spray dry the solution in a Niro Utility Spray Drier.
7. Add the Syloid (silicon dioxide) to the spray chamber.
50
8. Collect the encapsulated simethicone particles.

Example 6: Manufacture of Orally Disintegrating Tablet Containing Simethicone Granules (using Whey Protein
Isolate)
55
[0056] The following tablet is prepared using the coated simethicone granules in Example 5. The dose is equivalent
to 125mg of simethicone.
[0057] The powder blend for an orally disintegrating tablet, containing the ingredients of Table 5, is manufactured as

7
 EP 4 215 187 A1

follows. The sucralose, flavor, polyethylene glycol and maltodextrin from the formula in Table 5 are passed through a
20 mesh screen. The sieved materials are placed into a 500cc plastic bottle and blended end over end with the remaining
materials in Table 5. The powder blend is placed into an upper and lower set of © inch flat faced forming tools, tamped,
and activated with RF energy as described in Example 2 for approximately 2 minutes to form the orally disintegrating
5 tablet and subsequently removed from the die.

Table 5: Powder Blend Formulation Containing Simethicone

Ingredient G/Batch Mg/Tablet

10 Dextrose Monohydrate 229.48 229.48

Encapsulated Simethicone (∼ 95% Potency) 131.57 131.57
Polyethylene Glycol 80001 42.85 42.85
Maltodextrin2 87.50 87.50
15
Orange Flavor 2.00 2.00
Sucralose USP 1.60 1.60
Citric Acid USP Anhydrous 5.00 5.00

20 Total 500.00 500.00

1 Commercially available from Clariant PF in Rothausstr, Switzerland
2 Commercially available from National Starch in Bridgewater, NJ

25 Example 7: Preparation of Simethicone Microcapsules by Coacervation

Part A: Procedure for preparing the Simethicone Microcapsules by Coacervation

[0058]
30
1. Add deionized water to a suitable sized (20L) vessel and heated to 50°C.
2. Add 18.70g of carboxymethylcellulose and 1.86g of Gum Arabic powder while mixing until dissolved.
3. Cool the mixture from Step 2 to 35-40°C.
4. Mix 1863.1g of Gelatin 250 bloom type A with 1678g of deionized water until completely dissolved.
35 5. Cool the gelatin solution from Step 4 to 35-40°C and add to the Gum Arabic mixture from Step 3.
6. Prepare a solution of 50 w/w sodium hydroxide in 5500g of deionized water and heat in a suitable vessel to 35-40°C.
7. Prepare a solution of 50 w/w citric acid in 5500g of deionized water and heat in a suitable vessel to 35-40°C.
8. Add 1491g of simethicone to the combined Gelatin and Gum Arabic solution from Step 5 and mix until the droplets
are between about 100-300 microns.
40 9. Adjust the pH of the solution to between 5.0 and 5.6.
10. Cool the combined solution to 25°C, at a rate of 1°C per 5 minutes, and then cool to 10°C and adjust to pH of
7.0 utilizing sodium hydroxide.
11. Slowly add 2.33g of Transglutamase and agitate for 16 hours at 10°C.
12. Adjust the batch to a pH of 2.75 utilizing 50% citric acid and mix for 30 minutes.
45 13. Filter, remove, and try dry the capsules at 60°C in an oven for 10 hours.

Example 8: Manufacture of Orally Disintegrating Tablet Containing Simethicone Microcapsules (by Coacerva-
tion)

50 [0059] The following tablet is prepared using the coated simethicone microcapsules in Example 7. The dose is equiv-
alent to 62.5mg of simethicone.
[0060] The powder blend for an orally disintegrating tablet, containing the ingredients of Table 6, is manufactured as
follows. The sucralose, yellow colorant, flavors, polyethylene glycol and maltodextrin from the formula in Table 6 are
passed through a 20 mesh screen. The sieved materials are placed into a 500cc plastic bottle and blended end over
55 end with the remaining materials in Table 6. The powder blend is placed into an upper and lower set of © inch flat faced
forming tools, tamped, and activated with RF energy as described in Example 2 for approximately 2 minutes to form the
orally disintegrating tablet and subsequently removed from the die.

8
 EP 4 215 187 A1

Table 6: Powder Blend Formulation Containing Simethicone

Ingredient G/Batch Mg/Tablet

5 Dextrose Monohydrate 294.15 294.15

Encapsulated Simethicone (∼ 44% Potency) 142.05 142.05
Polyethylene Glycol 80001 51.43 51.43
Maltodextrin2 105.00 105.00
10
Orange Flavor 1.71 1.71
Sucralose USP 1.37 1.37
Citric Acid USP Anhydrous 4.29 4.29

15 Total 600.00 600.00

1 Commercially available from Clariant PF in Rothausstr, Switzerland
2 Commercially available from National Starch in Bridgewater, NJ

20 Example 9: Manufacture of Orally Disintegrating Tablet Containing Encapsulated Simethicone and Loperamide

[0061] The following tablet is also prepared using the encapsulated simethicone granlues in Example 1. The dose of
simethicone is equivalent to 125mg of simethicone. The tablet also contains loperamide HCl with a dose of 2 mg.
[0062] The powder blend for an orally disintegrating tablet, containing the ingredients of Table 2, is manufactured as
25 follows. The sucralose, flavor, polyethylene glycol, loperamide HCl and maltodextrin from the formula in Table 7 are
passed through a 20 mesh screen. The sieved materials are placed into a 500cc plastic bottle and blended end over
end with the remaining materials in Table 7. The powder blend is placed into an upper and lower set of © inch flat faced
forming tools, tamped, and activated with RF energy as described in Example 2 for approximately 2 minutes to form the
orally disintegrating tablet and subsequently removed from the die.
30
Table 7: Powder Blend Formulation Containing Simethicone
Ingredient G/Batch Mg/Tablet
Dextrose Monohydrate 244.81 244.81
35 Encapsulated Simethicone (66% Potency) 189.39 189.39
Polyethylene Glycol 80001 51.43 51.43
Loperamide HCl 2.00 2.00
Maltodextrin2 105.00 105.00
40
Orange Flavor 1.71 1.71
Sucralose USP 1.37 1.37
Citric Acid USP Anhydrous 4.29 4.29
45 Total 600.00 600.00
1 Commercially available from Clariant PF in Rothausstr, Switzerland
2 Commercially available from National Starch in Bridgewater, NJ

50 Example 10: Preparation of Simethicone Encapsulated in Isomalt

Part A: Procedure for preparing the Simethicone Encapsulated granules

[0063] 200g of isomalt is heated in a stainless steel vessel to approximately 166oC to 170oC. While mixing, approx-
55 imately 400g of simethicone is dispersed into the isomalt. The molten mixture is then passed (extruded) through a 40
mesh screen and manually chopped into individual granules using a metal spatula. The resulting granules contain
approximately 66.7% simethicone.

9
 EP 4 215 187 A1

Example 11: Preparation of Encapsulated Simethicone utilizing a Spray Drying Process and Polymer (Ethylcel-
lulose)

[0064]
5
Table 8: Encapsulation Procedure using Ethylcellulose
Batch # Batch w/w (g)
Simethicone 3000
10 Ethylcellulosea 1157
Tri ethyl citrate 129
Ethanol 17000
Syloid 742 31.5
15
Total 21317.5 (4317.5 g as solids)
2 Commercially available as Ethocel from Dow Corporation

20 Part A: Procedure for preparing the Encapsulated Simethicone (using formula from table 8)

[0065]

1. Add ethanol to a suitable sized (2L) vessel.

25 2. Add ethylcellulose and triethylcitrate into the ethanol while mixing until completely dissolved.
3. Add simethicone to the solution and emulsified.
4. Spray dry the solution in a Niro Utility Spray Drier.
5. Add the Syloid (silicon dioxide) to the spray chamber.
6. Collect the encapsulated simethicone particles.
30
Example 12: Manufacture of Orally Disintegrating Tablet Containing Encapsulated Simethicone

[0066] The following tablet is prepared using the encapsulated simethicone granules in Example 11, utilizing the tablet
process in Example 2. The dose of simethicone is equivalent to 125mg of simethicone
35 [0067] The powder blend for an orally disintegrating tablet, containing the ingredients of Table 9, is manufactured as
follows. The sucralose, flavor, polyethylene glycol and maltodextrin from the formula in Table 2 are passed through a
20 mesh screen. The sieved materials are placed into a 500cc plastic bottle and blended end over end with the remaining
materials in Table 9. The powder blend is placed into an upper and lower set of © inch flat faced forming tools, tamped,
and activated with radiofrequency (RF) energy using the activation process described in Example 2 for approximately
40 2 minutes to form the orally disintegrating tablet and subsequently removed from the die.

Table 9: Powder Blend Formulation Containing Simethicone

Ingredient G/Batch Mg/Tablet

45 Dextrose Monohydrate 255.94 255.94

Encapsulated Simethicone (69.5% Potency) 179.86 179.86
Polyethylene Glycol 80001 51.43 51.43
Maltodextrin2 105.00 105.00
50
Orange Flavor 1.71 1.71
Sucralose USP 1.37 1.37
Citric Acid USP Anhydrous 4.29 4.29

55 Total 600.00 600.00

1 Commercially available from Clariant PF in Rothausstr, Switzerland
2 Commercially available from National Starch in Bridgewater, NJ

10
 EP 4 215 187 A1

Example 13: Wettability Method for Simethicone Powders

Formula:

5 [0068]

SIMETHICONE LV 150.0g
NEUSILIN US2 175.0g
STEARIC ACID 6.75g
10
[0069] Neusilin powder was placed in a planetary mixer on low speed and simethicone liquid was gradually added
until uniform. One gram of material was compressed on Natoli hand press to average hardness of 3.6kp (11/16 inch
round flat faced tooling) for each "slug" or tablet. Approximately 100 tablets were compressed and remaining powder
blend set aside (uncoated powder for analysis). Tablets were ground into granules using a glass mortar and pestle and
15 coated using a VFC micro fluid bed with aqueous solution containing hydroxyethyl cellulose, glycerin and sodium citrate
using target parameters for inlet temperature of 70-80C, air flow of 50-110 LPM, 12 psi spray atomization and approx-
imately 1g/min. Coating level was 1% by weight of each component of the coating solution.

1. A small plastic lid was inverted and used as a sample holder and overfilled with test powder and then carefully
20 leveled to provide a continuous flat powder bed.
2. A plastic USP dropper was filled with purified water and placed vertically above surface using a clamp and ring stand.
3. A camera (Samsung SPH-L710 (S3)) with macro feature was placed level directly horizontal to the leveled surface.
4. The dropper was squeezed allowing a single drop of fixed volume (USP droplet) onto the test surface and a photo
was taken.
25 5. The photo was analyzed using by photoshop carefully counting the pixels in the horizontal and vertical of the drop
on the surface. (The height over the horizontal leg was used to calculate contact angle.)

30
[0070] The slugged/coated material has increased wetting over the uncoated (38.6 vs 42.8), therefore indicating that
the hydrophobic simethicone is less available for contact with water when coated.
[0071] While the invention has been described above with reference to specific embodiments thereof, it is apparent
that many changes, modifications, and variations can be made without departing from the inventive concept disclosed
35 herein. Accordingly, it is intended to embrace all such changes, modifications, and variations that fall within the spirit
and broad scope of the appended claims. All patent applications, patents, and other publications cited herein are incor-
porated by reference in their entirety.

EMBODIMENTS:
40
[0072]

1. Microencapsulated simethicone particles comprising:

45 simethicone and a water soluble coating,

wherein the simethicone is at least about 50% by weight of the particle.

2. The particles of embodiment 1, wherein the water soluble coating is gelatin, anhydrous dibasic calcium phosphate,
whey protein isolate, or mixtures thereof.
50
3. The particles of embodiment 2, wherein the gelatin is non-hydrolyzed gelatin.

4. The particles of embodiment 1, wherein the particle is prepared by spray drying, fluid bed coating, or coacervation.

55 5. The particles of embodiment 1, wherein the particle is from about 60% to about 97% by weight simethicone.

6. The particles of embodiment 1, wherein the particles are from about 50 microns to about 200 microns.

11
 EP 4 215 187 A1

7. An orally disintegrating tablet comprising the particles of embodiment 1.

8. Orally dissolving granules comprising the particles of embodiment 1.

5 9. A method for making a microencapsulated simethicone particles comprising the steps of:

(a) forming a water coating solution,

(b) combining simethicone and the water soluble coating solution and forming an emulsion, and
(c) spray drying the emulsion.
10
10. The method of embodiment 9, wherein the water soluble coating is gelatin or whey protein isolate.

11. The method according to embodiment 10, wherein said gelatin is unhydrolyzed.

15 12. The method according to embodiment 10, wherein said gelatin content is 20-35%.

13. The method of embodiment 9, further comprising the step of adjusting the pH of the water soluble coating solution
to a pH of 7.

20 14. The method of embodiment 9, wherein silicon dioxide is added during spray drying.

15. An oral dosage form comprising the particles of embodiment 9.

16. A method of making microencapsulated simethicone particles comprising the steps of:
25
(a) preparing simethicone granules;
(b) preparing a coating solution; and
(c) coating the simethicone granules with the coating solution.

30 17. The method of embodiment 16, wherein the simethicone granules preparation comprises simethicone, anhydrous
dibasic calcium phosphate, and silicon dioxide.

18. The method of embodiment 16, wherein the coating solution comprises acetone and cellulose acetate.

35 19. An oral dosage form comprising the particles of embodiment 16.

20. A method of preparing microencapsulated simethicone particles comprising:

(a) forming a complex coacervate of simethicone particles and hydrocolloids;

40 (b) cooling the complex coacervate to a gel temperature at a pH of about 5 to deposit a protein shell around
each of the simethicone particles;
(c) further cooling the complex coacervate to a cross-linking temperature below the gel temperature at a pH of
about 7 to stabilize the protein shell; and
(d) adding an enzyme to the water for enzymatically cross-linking the stabilized protein shell at about pH 7 to
45 form microencapsulated simethicone particles.

21. The method of embodiment 20, wherein the microencapsulated simethicone particles are from about 50 microns
to about 200 microns.

50 22. The method of embodiment 20 wherein the complex coacervate is formed from an emulsion of two oppositely
charged colloids.

23. An oral dosage form comprising the particles of embodiment 20.

55
Claims

1. Microencapsulated simethicone particles comprising:

12
 EP 4 215 187 A1

simethicone and a water soluble coating,

wherein the simethicone is at least about 50% by weight of the particle, and
wherein the water soluble coating is gelatin, whey protein isolate, or mixtures thereof.

5 2. The particles of claim 1, wherein the gelatin is non-hydrolyzed gelatin.

3. The particles of claim 1, wherein the particle is prepared by spray drying, fluid bed coating, or coacervation.

4. The particles of claim 1, wherein the particle is from about 60% to about 97% by weight simethicone.
10
5. An orally disintegrating tablet or orally dissolving granules comprising the particles of claim 1.

6. A method for making the microencapsulated simethicone particles of claim 1 comprising the steps of:

15 (a) forming a water soluble coating solution, wherein the water soluble coating is gelatin or whey protein isolate,
(b) combining simethicone and the water soluble coating solution and forming an emulsion, and
(c) spray drying the emulsion.

7. The method according to claim 6, wherein said gelatin is unhydrolyzed and/or wherein said gelatin content is 20-35%
20 by weight.

8. The method of claim 6, further comprising the step of adjusting the pH of the water soluble coating solution to a pH of 7.

9. The method of claim 6, wherein silicon dioxide is added during spray drying.
25
10. A method of making the microencapsulated simethicone particles of claim 1 comprising the steps of:

(a) preparing simethicone granules;

(b) preparing a coating solution; and
30 (c) coating the simethicone granules with the coating solution.

11. The method of claim 10, wherein the coating solution comprises acetone and cellulose acetate.

12. A method of preparing the microencapsulated simethicone particles of claim 1 comprising:

35
(a) forming a complex coacervate of simethicone particles and hydrocolloids;
(b) cooling the complex coacervate to a gel temperature at a pH of about 5 to deposit a protein shell around
each of the simethicone particles;
(c) further cooling the complex coacervate to a cross-linking temperature below the gel temperature at a pH of
40 about 7 to stabilize the protein shell; and
(d) adding an enzyme to the water for enzymatically cross-linking the stabilized protein shell at about pH 7 to
form microencapsulated simethicone particles.

13. The particles of claim 1 or the method of claim 12, wherein the microencapsulated simethicone particles are from
45 about 50 microns to about 200 microns.

14. The method of claim 12 wherein the complex coacervate is formed from an emulsion of two oppositely charged
colloids.

50 15. An oral dosage form comprising the particles of any one of claims 7, 10 or 12.

55

13
 EP 4 215 187 A1

10

15

20

25

30

35

40

45

50

55

14
 EP 4 215 187 A1

10

15

20

25

30

35

40

45

50

55

15
 EP 4 215 187 A1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European
patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be
excluded and the EPO disclaims all liability in this regard.

Non-patent literature cited in the description

• LEIBERMAN et al. Pharmaceutical Dosage

Forms--Tablets. Marcel Dekker Inc, 1990, vol. 2,
213-217, 327-329 [0024]

16