U.S. patent application number 14/357202 was filed with the patent office on 2014-12-11 for acid resistant banding solution for acid resistant two piece hard capsules.
This patent application is currently assigned to CAPSUGEL BELGIUM NV. The applicant listed for this patent is Capsugel Belgium NV. Invention is credited to Dominique Nicolas Cade, Xiongwei He.
Application Number | 20140360404 14/357202 |
Document ID | / |
Family ID | 48916112 |
Filed Date | 2014-12-11 |
United States Patent
Application |
20140360404 |
Kind Code |
A1 |
He; Xiongwei ; et
al. |
December 11, 2014 |
ACID RESISTANT BANDING SOLUTION FOR ACID RESISTANT TWO PIECE HARD
CAPSULES
Abstract
The present disclosure relates to acid resistant banding
solutions for two piece hard capsules endowed with acid resistant
properties, and methods of making and using acid resistant banding
solutions. The present disclosure also relates, in part, to methods
for banding such acid resistant capsules which provides an acid
resistant seal between the capsules parts and achieves increased
acid resistance in vitro.
Inventors: |
He; Xiongwei; (Andolsheim,
FR) ; Cade; Dominique Nicolas; (Colmar, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Capsugel Belgium NV |
Bomem |
|
BE |
|
|
Assignee: |
CAPSUGEL BELGIUM NV
Bornem
BE
|
Family ID: |
48916112 |
Appl. No.: |
14/357202 |
Filed: |
November 8, 2012 |
PCT Filed: |
November 8, 2012 |
PCT NO: |
PCT/IB2012/003133 |
371 Date: |
May 8, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61557623 |
Nov 9, 2011 |
|
|
|
61577127 |
Dec 19, 2011 |
|
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Current U.S.
Class: |
106/168.01 ;
106/172.1 |
Current CPC
Class: |
A61K 9/4891 20130101;
A23V 2002/00 20130101; A61K 9/4808 20130101; A61K 9/4816 20130101;
A23P 10/30 20160801; A61K 31/167 20130101; A61K 9/4883
20130101 |
Class at
Publication: |
106/168.01 ;
106/172.1 |
International
Class: |
A61K 9/48 20060101
A61K009/48 |
Claims
1. An acid resistant banding composition for acid resistant two
piece hard capsules, comprising at least one acid resistant
polymer, at least one alkaline compound, and water.
2. The composition according to claim 1, wherein the acid resistant
polymer is selected from the group consisting of methacrylic acid
copolymers, cellulose acetate phthalate (CAP), cellulose acetate
trimellitate (CAT), hydroxypropyl methylcellulose acetate succinate
(HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), carboxy
methyl ethyl cellulose (CMEC), polyvinyl derivatives, and mixtures
thereof.
3. The composition according to claim 1, wherein the at least one
alkaline compound is selected from the group consisting of sodium
bicarbonate, sodium carbonate, potassium carbonate, potassium
bicarbonate, sodium hydroxide, tri sodium phosphate, sodium
perborate, potassium hydroxide, lithium hydroxide, lithium
carbonate, lithium bicarbonate, ammonium carbonate, ammonium
bicarbonate, ammonium hydroxide, ammonia, and mixtures thereof.
4. The composition according to any one of claims 1 to 3, further
comprising at least one pharmaceutically acceptable or food
acceptable plasticizer and/or coloring agent.
5. The composition according to any one of claims 1 to 3, wherein
the composition has a viscosity from about 50 cP to about 10,000 cP
at room temperature.
6. The composition according to claim 5, wherein the viscosity is
from about 100 cP to about 5000 cP.
7. The composition according to claim 6, wherein the viscosity is
from about 1500 cP to about 3100 cP.
8. The composition according to claim 1, wherein the at least one
acid resistant polymer is hydroxypropyl methylcellulose phthalate
(HPMCP), and the at least one alkaline compound is ammonia.
9. The composition according to claim 8, further comprising at
least one pharmaceutically acceptable or food acceptable
plasticizer and/or coloring agent.
10. The composition according to claim 1, wherein the at least one
acid resistant polymer is cellulose acetate phthalate (CAP), and
the at least one alkaline compound is ammonia.
11. The composition according to claim 10, further comprising at
least one pharmaceutically acceptable or food acceptable
plasticizer and/or coloring agent.
12. The composition according to claim 1, wherein the at least one
acid resistant polymer is hydroxypropyl methylcellulose acetate
succinate (HPMCAS), and the at least one alkaline compound is
ammonia.
13. The composition according to claim 12, further comprising at
least one pharmaceutically acceptable or food acceptable
plasticizer and/or coloring agent.
14. An acid resistant banding composition for acid resistant two
piece hard capsules, comprising: at least one acid resistant
polymer selected from the group consisting of hydroxypropyl
methylcellulose phthalate (HPMCP), cellulose acetate phthalate
(CAP), and hydroxypropyl methylcellulose acetate succinate
(HPMCAS); ammonia; and water.
15. A method for the preparation of an acid resistant banding
solution, comprising: dispersing at least one acid resistant
polymer in water under mixing; and adding at least one alkaline
compound progressively under gentle stirring until the at least one
acid resistant polymer is dissolved.
16. The method according to claim 15, wherein the preparation of
the banding solution is carried out at room temperature.
17. The method according to claim 15 or 16, further comprising the
step of adjusting viscosity of the banding solution by adjusting
the polymer concentration of the solution.
18. The method according to claim 17, wherein the viscosity is from
about 50 cP to about 10,000 cP at room temperature.
19. The method according to claim 18, wherein the viscosity is from
about 100 cP to about 5000 cP.
20. The method according to claim 19, wherein the viscosity is from
about 1500 cP to about 3100 cP.
21. The method according to any one of claims 16 to 20, further
comprising adding to the banding solution at least one
pharmaceutically acceptable or food acceptable plasticizer and/or
coloring agent.
22. An acid resistant hard capsule comprising an acid resistant
banding composition according to any one of claims 1 to 14 for use
for oral administration of at least one of pharmaceuticals,
veterinary products, foods, and dietary supplements to humans or
animals.
23. The capsule according to claim 22, wherein the capsule
comprises a dip molded or injection molded
hydroxypropylmethylcellulose (HPMC) acid resistant hard
capsule.
24. A method for banding an acid resistant hard capsule with an
acid resistant banding composition comprising at least one acid
resistant polymer, at least one alkaline compound, and water
comprising: determining the desired banding composition amount;
measuring the banding composition required; and applying the
banding composition to the acid resistant capsule.
25. The method according to claim 24, wherein the capsule comprises
a dip molded or injection molded hydroxypropylmethylcellulose
(HPMC) acid resistant hard capsule.
26. The method according to claim 24, wherein the acid resistant
polymer is selected from the group consisting of methacrylic acid
copolymers; cellulose acetate phthalate (CAP), cellulose acetate
trimellitate (CAT), hydroxypropylmethylcellulose acetate succinate
(HPMCAS), hydroxypropylmethylcellulose phthalate (HPMCP), carboxy
methyl ethyl cellulose (CMEC), polyvinyl derivatives, and mixtures
thereof.
27. The method according to claim 24, wherein the at least one
alkaline compound is selected from the group consisting of sodium
bicarbonate, sodium carbonate, potassium carbonate, potassium
bicarbonate, sodium hydroxide, tri sodium phosphate, sodium
perborate, potassium hydroxide, lithium hydroxide, lithium
carbonate, lithium bicarbonate, ammonium carbonate, ammonium
bicarbonate, ammonium hydroxide, ammonia, and mixtures thereof.
28. The method according to claim 24, wherein the at least one acid
resistant polymer is hydroxypropylmethylcellulose phthalate
(HPMCP), and the at least one alkaline compound is ammonia.
29. The method according to claim 28, further comprising at least
one pharmaceutically acceptable or food acceptable plasticizer
and/or coloring agent.
30. The method according to claim 24, wherein the at least one acid
resistant polymer is cellulose acetate phthalate (CAP), and the at
least one alkaline compound is ammonia.
31. The method according to claim 30, further comprising at least
one pharmaceutically acceptable or food acceptable plasticizer
and/or coloring agent.
32. The method according to claim 24, wherein the at least one acid
resistant polymer is hydroxypropylmethylcellulose acetate succinate
(HPMCAS), and the at least one alkaline compound is ammonia.
33. The method according to claim 32, further comprising at least
one pharmaceutically acceptable or food acceptable plasticizer
and/or coloring agent.
34. The method according to claim 24, wherein the banding
composition is applied to the capsule at room temperature.
Description
[0001] This application claims priority to U.S. Provisional
Application 61/557,623, filed Nov. 9, 2011, and to U.S. Provisional
Application No. 61/577,127, filed Dec. 19, 2011.
[0002] The present disclosure relates to acid resistant banding
solutions for banding acid resistant two piece hard capsules, and
use of such capsules for example for oral administration of at
least one of pharmaceuticals, veterinary products, foods and
dietary supplements to humans or animals.
[0003] Two piece hard capsules are the oral dosage form preferred
by patients, and have traditionally been made from gelatin for more
than a century. Over the past twenty years, new types of hard
capsules have been developed with alternative raw materials, mainly
with hypromellose and pullulan. All these capsules are of immediate
release or designed for releasing their content in the stomach
rapidly after administration.
[0004] Efforts were made to impart a specific functionality to the
hard capsules. The most successful example is the gastric resistant
hard capsules which can protect the content from the acid
conditions, with a delayed release or an intestinal release.
Generally, such capsules are utilized in the pharmaceutical and
food industries to hold pharmaceutically active materials such as
medicines, vitamin preparations and other edibles both solid and
liquid and protect them from the acid conditions in the
stomach.
[0005] Delayed release capsules resistant to the acid conditions of
the stomach were developed early on using gelatin insolubilization
by treatment with formaldehyde. See, e.g., Ridgway et al., Hard
Capsule Development & Technology, The Pharmaceutical Press,
1978, p. 11.
[0006] With the development of capsule coating technology the
enteric hard capsules ("enteric coated capsules") became more
popular on the pharmaceutical market. See, e.g., Ridgway et al.,
Hard Capsule Development & Technology, The Pharmaceutical
Press, 1978, pp. 229 to 232.
[0007] In both above cases, the capsule itself is of immediate
release, and its acid resistance is achieved by a
post-manufacturing treatment of the capsule, generally after the
filling of the capsule in the pharmaceutical company site.
[0008] More recently, an intrinsically acid resistant HPMC hard
capsule was developed and marketed under the name of DRCAPS.TM.
capsules by CAPSUGEL.RTM.. This capsule is made with an acid
resistant I-IPMC formula. Consequently, the capsule shell itself is
acid resistant and does not need a post-fill treatment to attain
acid resistance.
[0009] Further evaluation of DRCAPS.TM. capsules has revealed that
there remains a risk under some conditions for the two parts of the
capsule, body and cap, to become separated; for example, under the
mechanical stress of in vitro dissolution testing, notably during
the in vitro disintegration test under acid conditions. Similarly,
diffusion of dissolution medium into the closed capsule and/or
diffusion of content from the capsule through the gap between body
and cap remain a risk.
[0010] Consequently, there is a need to develop a way to
effectively prevent the body-cap separation and the diffusion
through the gap during the in vitro dissolution tests, and thus to
improve the in vivo acid resistance performance of the final dosage
form.
[0011] A number of solutions to decrease the leakage through the
body-cap gap have been developed. For example, hard gelatin capsule
banding with a gelatin banding solution is commonly used to prevent
the content leakage during storage.
[0012] Another method to decrease leakage is to seal the cap and
the body of the capsule directly to each other by means of a
"sealing fluid." See, e.g., U.S. Pat. No. 3,071,513; U.S. Pat. No.
2,924,920; FR 2,118,883, EP 0152517; U.S. Pat. No. 4,756,902; FR 2
118883; EP 0152517; and U.S. Pat. No. 4,756,902. Methods of banding
two piece hard capsules, as well as apparatuses for banding are
disclosed, for example, in U.S. Pat. Nos. 8,181,425; 7,229,639;
7,094,425; 5,054,208; 4,940,499; 4,922,682; 4,761,932 and
4,734,149, all of which are incorporated by reference herein.
[0013] Furthermore, the development of acid resistant capsules, and
hypromellose capsules such as, for example,
hydroxypropylmethylcellulose (HPMC) DRCAPS.TM.(CAPSUGEL.RTM.)
capsules, created a need to adapt the composition of the banding
solution to the polymer properties in order to assure acid
resistance of the banded capsule. See, e.g., WO2007/020529;
WO2011/036601.
[0014] All the previously known ways of banding did not exhibit
appropriate acid resistance, and therefore dissolved in acid media
during in vitro testing, and also in the acid conditions of the
stomach. Thus, there existed a need to develop a safe and effective
method for use in acid resistant capsules to prevent body-cap
separation and the diffusion through the gap.
Definitions
[0015] As used herein, the following words, phrases, and symbols
are generally intended to have the meanings as set forth below,
except to the extent that the context in which they are used
indicates otherwise.
[0016] The terms "optional" or "optionally" means that the
subsequently described event, component, or circumstance may or may
not occur, and that the description includes instances where the
event, component, or circumstance occurs, and instances in which it
does not.
[0017] The term "about" is intended to mean approximately, in the
region of, roughly, or around. When the term "about" is used in
conjunction with a numerical range, it modifies that range by
extending the boundaries above and below the numerical values set
forth. Unless otherwise indicated, it should be understood that the
numerical parameters set forth in the following specification and
attached claims are approximations. At the very least, and not as
an attempt to limit the application of the doctrine of equivalents
to the scope of the claims, numerical parameters should be read in
light of the number of reported significant digits and the
application of ordinary rounding techniques.
[0018] Unless otherwise indicated, "cellulose acetate phthalate" is
also referred to as CAP, and is commonly known in the field of
polymers with the following alternative nomenclature: CAS registry
number 9004-38-0; chemical common synonyms, such as: acetyl
phthalyl cellulose, cellulose acetate hydrogen
1,2-benzenedicarboxylate, cellulose acetate hydrogen phthalate,
cellulose acetate monophthalate, cellulose acetophthalate, and
cellulose acetyl phthalate; and non proprietary names, such as:
cellacephate (British Pharmacopeia), cellulose acetate phthalate
(Japanese Pharmacopeia), cellulosi acetas phthalas (PhEur), and
cellacefate (U.S. Pharmacopeia).
[0019] Unless otherwise indicated, "cellulose acetate trimellitate"
is also referred to as CAT.
[0020] Unless otherwise indicated, "hydroxypropylmethylcellulose
acetate succinate" is also referred to as HPMCAS.
[0021] Unless otherwise indicated, "hydroxypropyl methylcellulose
phthalate" is also referred to as HPMCP.
[0022] Unless otherwise indicated, "carboxy methyl ethyl cellulose"
is also referred to as CMEC.
[0023] Unless otherwise indicated, "polyvinyl derivatives" includes
but is not limited to polyvinyl acetate phthalate which is also
referred to as PVAP.
[0024] Unless otherwise indicated, the term "room temperature"
means about 18.degree. C. to about 28.degree. C., and more
particularly from about 20.degree. C. to about 24.degree. C.
(22.degree. C. +/-2.degree. C.).
[0025] Unless otherwise indicated, the term "acid resistant two
piece hard capsules" refers to two piece hard capsules described as
acid resistant, or manufactured from acid resistant formulas or
obtained by appropriate treatment post the capsule manufacturing,
and includes but is not limited to capsules as described in WO
2011/030952, EP22236851, and/or U.S. 2010/113620 A1.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] The accompanying drawings, which are incorporated in and
constitute a part of the specification, illustrate presently
embodiments of the present disclosure, and together with the
general description given above and the detailed description of the
embodiments given below, serve to explain the principles of the
present disclosure.
[0027] FIG. 1 is a disintegration test at pH 1.2; and FIG. 2 is a
dissolution test as a function of time.
DETAILED DESCRIPTION
[0028] Accordingly, one aspect of the present disclosure provides
acid resistant banding solutions for banding acid resistant two
piece hard capsules, wherein said capsules comprise telescopically
engaged capsule parts and are endowed with improved acid resistance
properties compared to such capsules closed but without
banding.
[0029] In another aspect, the present disclosure provides an
acid-resistant banding composition comprising an acid resistant
polymer, at least one neutralizing compound such as an alkaline
compound, and water as solvent.
[0030] In another aspect, the present disclosure provides a method
for banding two piece capsules which provides an acid resistant
seal between the capsule parts and achieves an increased acid
resistance in vitro.
[0031] In a further aspect, the present disclosure relates to
banding solutions for acid resistant capsules, and methods of
banding acid resistant capsules with an acid resistant banding
solution, which can be achieved without the use of organic
solvents, and taking advantage of conventional banding techniques
and equipment. See, e.g., F. Podczeck and B. Jones, Pharmaceutical
Capsules, 2.sup.nd Ed., Pharmaceutical Press (2004),
pp.182-183.
[0032] In one embodiment, a banding composition and method for
banding acid resistant hard capsules is provided comprising at
least one acid resistant polymer, at least one alkaline compound,
and water.
[0033] In another embodiment, the at least one acid resistant
polymer in the banding composition for hard capsules is selected
from the group consisting of methacrylic acid copolymers
(copolymers of methacrylic acid and either methyl methacrylate or
ethyl acrylate such as poly(methacrylic acid-co-ethyl acrylate)
1:1); cellulose acetate phthalate (CAP); cellulose acetate
trimellitate (CAT); hydroxypropyl methylcellulose acetate succinate
(HPMCAS); hydroxypropyl methylcellulose phthalate (HPMCP); carboxy
methyl ethyl cellulose (CMEC); polyvinyl derivatives (e.g.,
polyvinyl acetate phthalate), and mixtures thereof.
[0034] In another embodiment, the at least one alkaline compound of
the banding composition is at least one compound selected from the
group consisting of sodium bicarbonate, sodium carbonate, potassium
carbonate, potassium bicarbonate, sodium hydroxide, tri sodium
phosphate, sodium perborate, potassium hydroxide, lithium
hydroxide, lithium carbonate, lithium bicarbonate, ammonium
carbonate, ammonium bicarbonate, ammonium hydroxide, ammonia, and
mixtures thereof.
[0035] In one embodiment, the acid resistant banding composition is
applied to, and therefore further comprises, an acid resistant
capsule, and in another embodiment, the acid resistant banding
composition is applied to and therefore further comprises a dip
molded or injection molded hydroxypropylmethylcellulose (HPMC) acid
resistant capsule. In other embodiments, the acid resistant banding
composition is applied to, and therefore comprises, an enteric
capsule such as a dip molded HPMCAS or CAP capsule.
[0036] In one embodiment, the banding composition optionally
further comprises at least one pharmaceutically acceptable or food
acceptable plasticizer.
[0037] In a further embodiment, the banding composition according
to the present disclosure may further comprise at least one
pharmaceutically acceptable or food acceptable coloring agent.
[0038] The present disclosure also provides a method for the
preparation of an acid resistant banding solution comprising:
dispersing at least one acid resistant polymer in water under
mixing; and adding at least one alkaline compound progressively
under gentle stirring until the at least one acid resistant polymer
is dissolved.
[0039] In another embodiment, the method according to the present
disclosure provides for the preparation of the banding solution
carried out at room temperature. In another embodiment, the method
according to the present disclosure provides for the use of the
banding solution by banding hard capsules carried out at room
temperature. Banding methods include automated and hand applied
banding methods. See, e.g., Capsule Filling by D. K. Lightfoot,
Tablets and Capsules Magazine, CSC Publishing (January 2007).
[0040] In a further embodiment, the method for the preparation of
an acid resistant banding solution further comprises adjusting the
viscosity to a level appropriate for the hard capsule banding
method. Non-limiting examples of appropriate viscosity for an acid
resistant hard capsule banding solution and method are, for
example, viscosities from about 50 cP to about 10,000 cP at room
temperature; from about 100 cP to about 5000 cP; and from about
1500 cP to about 3100 cP. Desired viscosity is obtained by
adjusting the concentration of the solution (i.e., by varying the
amount of water and/or the amount of polymer).
[0041] In other embodiments, the method for the preparation of an
acid resistant banding solution further comprises adding to the
solution at least one pharmaceutically acceptable or food
acceptable plasticizer and/or at least one pharmaceutically
acceptable or food acceptable coloring agent.
[0042] Examples of pharmaceutically acceptable or food acceptable
coloring agents include but are not limited to soluble dyes,
including Tartrazine E102, FD&C Yellow 5D&C Yellow 10;
Sunset Yellow E110, FD&C Yellow 6; D&C Red No. 22; D&C
Red No. 28; D&C Red No. 33 (Acid Fushine); Allura Red E129,
FD&C Red 40; Indigo carmine E132, FD&C Blue 2; Brilliant
Blue FCF E133, FD&C Blue 1; Caramel, USP E150c; FD&C Green
3; FD&C red 3/Erythrosine; Azorubine; Brilliant Black;
Chlorophyllin Copper Complex or sodium copper chlorophyllin;
Ponceau 4R; Patent Blue V; Quinolone yellow; Curcumin, Red cabbage;
and mixtures thereof. Other examples of pharmaceutically acceptable
or food acceptable coloring agents include but are not limited to
pigments, including Titanium Dioxide, Yellow Iron Oxide, Red Iron
Oxide, Black Iron Oxide, Candurin silver fine, and mixtures
thereof.
[0043] The present disclosure also provides a method for banding an
acid resistant hard capsule as described herein with an acid
resistant banding composition comprising at least one acid
resistant polymer, at least one alkaline compound, and water. The
method includes determining the desired banding composition amount,
measuring the banding composition required, and applying the
banding composition to the acid resistant capsule.
[0044] The present disclosure also provides an effective acid
resistant banding of acid resistant hard capsules even with low
band thickness or weight, such as lower than 10 mg, or even lower
than 5 mg. These values are calculated based on the quantity,
deposit, and concentration of the banding solution and results
obtained for the dry band weight for size 0 capsules, and will be
proportional for smaller capsules. The band weight is adapted as a
function of the capsule size.
[0045] The following non-limiting examples are offered to clarify
the disclosure and are not intended to limit the scope of the
present claims. The acid resistant capsules used in the banding
examples are DRcaps.TM. capsules (HPMC) of size 0, natural
transparent (N.T.) from CAPSUGEL.RTM., but any acid resistant
capsule may be used. The banding solutions and methods according to
the present disclosure can be applied to any size of DRcaps.TM.
capsules or to any size of other acid resistant two piece capsules.
The banding solution of the present disclosure can be applied to
any two piece hard capsules with acid resistance performance, for
example but without limitation, enteric capsules fabricated from
hydroxypropylmethylcellulose acetate succinate (HPMCAS) or from
cellulose acetate phthlalate CAP) may be banded using the banding
solutions and methods according to the present disclosure.
EXAMPLES
[0046] Three samples of banding solution were prepared using the
HPMCP (HP-55), CAP, or HPMCAS respectively as acid resistant
polymers. The alkaline compound used was an aqueous ammonia
solution with a 35% NH.sub.3 concentration (ammonia solution 0.88
S.G. (35% NH.sub.3) from Fisher Scientific). The appropriate
quantity by weight of polymer powder was first dispersed in the
water at room temperature under stirring to obtain the desired
weight ratio (see Table 1). Then the indicated amount of ammonia
solution was added to the dispersion progressively under gentle
stirring until the polymer particles were totally dissolved. A 0.1%
solution of Patent Blue V--C.I. Food Blue 5 E131 (based on the
polymer weight) was added to aid in the visualization of the
banding. Table 1 presents the compositions and characteristics of
the obtained banding solutions.
TABLE-US-00001 TABLE 1 NH.sub.3 Viscosity Chemical Quantity Water
Concentration (35%) (cPs) name Supplier Grade (g) (g) (%, w/w) (ml)
at 22.degree. C. pH HPMCP Shin-Etsu HP-55 100 400 20.0 17.5 1570
4.9 CAP Eastman CAP, 82.5 417.5 16.5 19.8 1959 7.4 NF HPMCAS
Shin-Etsu Aquot 85 415 17.0 6.7 3012 5.5 AS-LG
[0047] DRcaps.TM. capsules, size 0 were used for these banding
tests. Capsules were first filled with a blend of lactose and
FD&C Blue 2 or Acetyl paraminophenol (APAP) for visual
disintegration testing or dissolution dosage testing,
respectively.
[0048] The band thickness or amount needed to provide an effective
acid resistant banding was determined by the screening of the
banding solution quantity applied on the capsule. The quantity of
the banding solution applied on the capsules was determined by
weighing the capsule before and immediately after the banding
procedure and comparing the weights obtained. Banding was performed
on a lab scale banding equipment from MG2 (Model SL/M) with drying
under room temperature conditions.
[0049] The banded capsules were tested using the United States
Pharmacopeia ("USP") disintegration method (Chapter 701) in pH 1.2
media and evaluated by the visual approach. Accordingly, the sample
capsules were filled with a blend of lactose and FD&C Blue 2.
Table 2 summarizes the visual results of the test for the size 0
capsules.
TABLE-US-00002 TABLE 2 Disintegration with disc at pH 1.2
USP/37.degree. C. Sample size n = 6 capsules Approx. State at 30
min State at 1 hour banding # # Banding solution Shell # Shell
Polymer weight (mg) # Leaked # Emptied disintegration # Leaked
Emptied disintegration HP-55 25 0 0 0 0 0 0 20 0 0 0 0 0 0 15 0 0 0
1 0 0 10 0 0 0 1 0 0 CAP 25 0 0 0 0 0 0 20 0 0 0 0 0 0 15 0 0 0 0 0
0 10 0 0 0 0 0 0 HPMCAS 25 0 0 0 0 0 0 20 0 0 0 0 0 0 15 0 0 0 0 0
0 10 0 0 0 4 1 0
[0050] The HP-55 banding solution was effective at about 20 mg or
greater banding solution weight for size 0 capsules. The CAP
banding solution was effective at all weights tested for size 0
capsules, i.e., about 10 mg or greater banding solution weight. The
HPMCAS polymer banding solution was effective at about 15 mg or
greater banding solution weight. Because the banding solution
weight is proportional to the capsule size (i.e., diameter), these
results for size 0 capsules (with a diameter of about 0.3 inches)
may be extrapolated to smaller capsules, since smaller capsules
would require less banding solution by weight.
[0051] The banded capsules filled with APAP were tested using the
USP disintegration method in pH 1.2 media and evaluated by the
dosage approach, which measures the % of APAP dissolved after an
hour disintegration test at pH 1.2. Table 3 and FIG. 1 summarize
the results of the test.
TABLE-US-00003 TABLE 3 DRCAPS .TM. Capsules, #0 1 hour
disintegration test at pH1.2/37.degree. C. USP Banding type Closed
HP-55 banding Banding 0 25 mg 20 mg 15 mg 10 mg quantity Tested N N
= 3 N = 3 N = 3 N = 3 N = 3 N = 3 N = 3 N = 3 N = 3 N = 3
Observation Opened Opened Resistant 4/6 cap moved % APAP 97.7 92.6
6.2 8.4 8.0 7.4 8.4 6.9 6.3 7.7 dissolved AVG % APAP 95.2 7.3 7.7
7.7 7.0 Dissolved Banding type / CAP banding Banding 25 mg 20 mg 15
mg 10 mg quantity Tested N N = 3 N = 3 N = 3 N = 3 N = 3 N = 3 N =
3 N = 3 Observation Resistant % APAP 6.7 6.7 5.8 5.7 4.4 4.5 6.7
4.1 dissolved AVG % APAP 6.7 5.8 4.5 5.4 Dissolved Banding type /
HPMCAS banding Banding 25 mg 20 mg 15 mg 10 mg quantity Tested N N
= 3 N = 3 N = 3 N = 3 N = 3 N = 3 N = 3 N = 3 Observation Resistant
5/6 opened 1/6 cap moved % APAP 8.6 8.5 7.2 7.5 8.8 7.6 94.0 70.5
dissolved AVG % APAP 8.5 7.4 8.2 82.3 Dissolved
[0052] Table 4 and FIG. 2 present the results obtained with the
banded capsules filled with APAP by the dosage method assay (the
APAP (acetaminophen) concentration in the dissolution media was
measured with a UV spectrophotometer at a wavelength of 300 nm and
compared to known concentration standards) in order to determine
the % of APAP dissolved over a period of up to 240 minutes by the
USP dissolution test (Chapter 711) and the Japanese Pharmacopoeia
dissolution test (Chapter 9.41) methods. Six capsules were tested
for each data point.
TABLE-US-00004 TABLE 4 DRCAPS .TM. Capsules, #0 Banded with Banded
with Banded with Time Closed HP-55 CAP HPMCAS Medium (min) % APAP
dissolved pH 1.2/ 0 0.0 0.0 0.0 0.0 37.degree. C. 15 0.7 0.4 0.7
0.4 USP 30 2.1 0.9 1.0 1.1 45 4.1 1.5 1.2 1.8 60 6.1 2.4 1.6 2.7 75
8.1 3.3 2.0 3.8 90 10.0 4.3 2.5 4.8 105 12.1 5.5 3.0 5.9 120 14.8
6.7 3.4 7.1 (max: 18.2) (max: 8.1) (max: 8.1) (max: 8.1) pH 6.8/
135 33.7 45.8 35.7 41.7 37.degree. C. 150 76.5 68.7 59.4 67.0 JP2
165 90.7 80.7 74.7 81.1 (min: 86.0) (min: 72.5) (min: 72.1) (min:
72.8) 180 95.7 88.2 85.0 89.3 195 97.4 94.1 90.4 95.1 210 97.9 97.5
95.0 98.1 225 98.1 99.4 97.0 98.8
[0053] All of the banding solutions tested were effective at
retaining the acid resistance of a two piece HPMC hard capsule, and
capsules with the banding solutions tested had greater acid
resistance in in vitro testing compared with closed capsules
without banding.
[0054] In addition to DRCAP.TM. capsules, enteric capsules such as
those fabricated from HPMCAS or from CAP can also be used with the
methods according to the Examples and in banding tests such as the
USP disintegration method described herein.
[0055] Additional advantages and modifications will readily occur
to those skilled in the art. Therefore, the present disclosure in
its broader aspects is not limited to the specific details and
representative embodiments shown and described herein. Accordingly,
various modifications may be made without departing from the spirit
or scope of the general inventive concept as defined by the
appended claims and their equivalents.
* * * * *