U.S. patent application number 14/074255 was filed with the patent office on 2014-03-06 for controlled release pharmaceutical compositions for acid-labile drugs.
The applicant listed for this patent is Abbott Products GmbH. Invention is credited to Claus-Juergen Koelln, Andreas Koerner, Jens Onken, Frithjof Sczesny, George Shlieout.
Application Number | 20140065232 14/074255 |
Document ID | / |
Family ID | 38194041 |
Filed Date | 2014-03-06 |
United States Patent
Application |
20140065232 |
Kind Code |
A1 |
Shlieout; George ; et
al. |
March 6, 2014 |
CONTROLLED RELEASE PHARMACEUTICAL COMPOSITIONS FOR ACID-LABILE
DRUGS
Abstract
An enteric-coated oral dosage form comprising an acid labile
active pharmaceutical ingredient where the composition is
substantially free of monomeric phthalic acid esters and synthetic
oils is described herein. Also provided are methods for making and
using the enteric-coated oral dosage form. The disclosed
pharmaceutical compositions comprise an enteric coating which
includes at least one plasticizer, at least one film-forming agent
and optionally at least one anti-sticking agent.
Inventors: |
Shlieout; George; (Sehnde,
DE) ; Koelln; Claus-Juergen; (Neustadt, DE) ;
Sczesny; Frithjof; (Hannover, DE) ; Onken; Jens;
(Barsinghausen, DE) ; Koerner; Andreas; (Springe,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abbott Products GmbH |
Hannover |
|
DE |
|
|
Family ID: |
38194041 |
Appl. No.: |
14/074255 |
Filed: |
November 7, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11464754 |
Aug 15, 2006 |
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14074255 |
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60708526 |
Aug 15, 2005 |
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60708692 |
Aug 15, 2005 |
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Current U.S.
Class: |
424/494 ;
424/94.21; 427/2.21 |
Current CPC
Class: |
A61K 9/50 20130101; C12Y
301/01 20130101; A61K 38/48 20130101; A61K 38/465 20130101; A61K
38/465 20130101; A61K 9/5015 20130101; A61K 9/5031 20130101; A61K
38/47 20130101; A61K 9/5036 20130101; C12Y 302/01 20130101; A61K
38/47 20130101; A61K 9/5047 20130101; C12Y 304/21004 20130101; A61K
9/5042 20130101; A61K 38/4826 20130101; C12Y 304/00 20130101; A61K
38/48 20130101; A61K 9/1635 20130101; A61K 9/5089 20130101; A61K
38/54 20130101; A61K 2300/00 20130101; A61K 9/0053 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/494 ;
424/94.21; 427/2.21 |
International
Class: |
A61K 9/50 20060101
A61K009/50; A61K 38/54 20060101 A61K038/54 |
Claims
1.-12. (canceled)
13. A method of treating a medical condition in a mammalian
subject, comprising the steps of: a. providing pancreatin
micropellets manufactured according to the process of claim 1 in a
dosage form suitable for oral administration; and b. orally
administering the dosage form to the subject to provide pancreatin
in an amount sufficient to treat the medical condition; wherein the
medical condition is selected from the group consisting of:
pancreatic exocrine insufficiency, pancreatitis, cystic fibrosis,
diabetes type I and diabetes type II.
14. (canceled)
15. A pharmaceutical composition, prepared by a process comprising
the steps of: a. preparing an extrudable mixture comprising: i.
about 10% to about 95% pancreatin; ii. about 5% to about 90% of at
least one pharmaceutically acceptable binding agent; iii. 0% to
about 1 0% of at least one pharmaceutically acceptable excipient;
and iv. one or more enzyme-friendly organic solvents in an amount
sufficient to form an extrudable mixture; wherein the percentages
of components are weight to weight of the extrudable mixture; b.
creating pancreatin micropellet cores from the extrudable mixture;
c. forming the pancreatin micropellet cores into approximately
spherical or approximately ellipsoidal shape in the presence of
additional enzymefriendly organic solvent; d. removing the one or
more enzyme-friendly organic solvents from the pancreatin
micropellet cores such that the pancreatin micropellet cores are
substantially free of the one or more enzyme-friendly organic
solvents; wherein the pancreatin micropellet cores are
substantially free of synthetic oils; e. coating the pancreatin
micropellet cores with an enteric-coating solution wherein the
temperature of the pancreatin micropellet cores during coating is
kept at a temperature suitable to apply the enteric-coating
solution and wherein the enteric-coating solution is substantially
free of monomeric phthalic acid esters; f. drying the coated
pancreatin micropellet cores; and g. placing the coated pancreatin
micropellet cores in a dosage form suitable for oral
administration.
16. The process of claim 15 wherein the pancreatin is present
between about 70% and about 90% weight to weight of the pancreatin
micropellet cores.
17. The process of claim 15 wherein the binding agent is present
between about 10% and about 30% weight to weight of the pancreatin
micropellet cores.
18. The process of claim 15 wherein the binding agent is selected
from the group consisting of: polyethylene glycol 1500,
polyethylene glycol 2000, polyethylene glycol 3000, polyethylene
glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000,
polyethylene glycol 10000, hydroxypropyl methylcellulose,
polyoxyethylen, copolymers of polyoxyethylen-polyoxypropylen and
mixtures of said organic polymers.
19. The process of claim 15 wherein the binding agent is
polyethylene glycol 4000.
20. The process of claim 15 wherein the at least one
pharmaceutically acceptable excipient is selected from the group
consisting of: magnesium stearate, calcium stearate, stearic acid,
talcum, starch, calcium phosphate, corn starch, dextrans, dextrin,
hydrated silicon dioxide, microcrystalline cellulose, kaolin,
lactose, mannitol, polyvinyl pyrrolidone, precipitated calcium
carbonate, sorbitol, silicic acid, alginic acid, amylose, calcium
alginate, calcium carbonate, formaldehyde gelatin, pectic
carbonate, sago starch, sodium bicarbonate and glycerol.
21. The process of claim 15 wherein the one or more enzyme-friendly
organic solvents are present between about 15% and about 35% by
weight relative to the amount of pancreatin.
22. The process of claim 15 wherein the one or more enzyme-friendly
organic solvents is selected from the group consisting of: acetone,
chloroform, dichloro-methane, methanol, ethanol, 1-propanol,
2-propanol, 2-butanol, tert-butanol and mixtures of said
solvents.
23. The process of claim 15 wherein the one or more enzyme-friendly
organic solvents is 2-propanol.
24. The process of claim 15 wherein removing the one or more
enzyme-friendly organic solvents from the pancreatin micropellet
cores is by drying at a temperature between about 30.degree. C. and
about 75.degree. C.
25. A pharmaceutical composition, prepared by a process comprising
the steps of: a. providing pancreatin micropellet cores wherein the
pancreatin micropellet cores are substantially free of synthetic
oils; b. providing an enteric-coating solution comprising i. at
least one film-forming agent ii. a plasticizer in an amount of
greater than about 1.5% by weight relative to the one or more
film-forming agents film-forming agents wherein the plasticizer is
substantially free of monomeric phthalic acid esters; and iii.
optionally at least one anti-sticking agent in one or more
enzyme-friendly organic solvent; c. coating the pancreatin
micropellet cores with the enteric-coating solution wherein the
temperature of the pancreatin micropellet cores during coating is
kept at a temperature suitable to apply the enteric-coating
solution ; and d. drying the coated pancreatin micropellet cores;
and e. placing the coated pancreatin micropellet cores in a dosage
form suitable for oral administration.
26. The composition of claim 25 wherein the enteric coating is
between about 20% and about 30% by weight of the pancreatin
micropellets.
27. The composition of claim 25 wherein the one or more
film-forming agents is selected from the group consisting of: agar,
carbomer polymers, carboxymethyl cellulose, carboxymethylethyl
cellulose, carrageen, cellulose acetate phthalate, cellu-lose
acetate succinate, cellulose acetate trimelliate, chitin, corn
protein extract, ethyl cellulose, gum arabic, hydroxypropyl
cellulose, hydroxypropylmethyl acetate succinate, hydroxypropyl
methylcellulose acetate succinate, hydroxypropyl methyl-cellulose
phthalate, methacrylic acid-ethyl methacrylate-copolymer, methyl
cellulose, pectin, polyvinyl acetate phthalate, polivinyl alcohol,
shellac, sodium alginate, starch acetate phthalate, styrene/maleic
acid copolymer and mixtures of said film-forming polymers.
28. The composition of claim 25 wherein the plasticizer is selected
from the group consisting of: saturated linear monohydric alcohols
having 12 to 30 carbon atoms, lauryl alcohol, tridecyl alcohol,
myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl
alcohol, stearyl alcohol, nonadecyl alcohol, arachic alcohol,
behenyl alcohol, carnaubyl alcohol, ceryl alcohol, corianyl
alcohol, melissyl alcohol, acetyl tributyl citrate, dibutyl
sebacate, fatty acid esters of glycerol, glycerol, polyethylene
glycol, propyleneglycol, sorbitan fatty acids, triacetin, triethyl
citrate and mixtures of any of said plasticizers.
29. The composition of claim 25 wherein the plasticizer is cetyl
alcohol.
30. The composition of claim 25 wherein the plasticizer is triethyl
citrate present in an amount of between about 5% and about 20% by
weight relative to the film-forming agent.
31. The composition of claim 25 wherein the plasticizer is a
mixture of cetyl alcohol and triethyl citrate which are
collectively present in an amount of greater than about 3% by
weight relative to the film-forming agent.
32. The composition of claim 31 wherein the ratio of cetyl alcohol
to triethyl citrate is between about 0.05:1 and about 1:1 by
weight.
33. The composition of claim 25 wherein the anti-sticking agent is
selected from the group consisting of: dimethicone and castor
oil.
34. The composition of claim 25 wherein the anti-sticking agent is
present in an amount between about 1.5% and about 3% by weight
relative to the film-forming agent.
35. The composition of claim 25 wherein the one or more
enzyme-friendly organic solvents is selected from the group
consisting of: acetone, chloroform, dichloro-methane, methanol,
ethanol, 1-propanol, 2-propanol, 2-butanol, tert-butanol and
mixtures of said solvents.
36.-43. (canceled)
44. A pharmaceutical composition, prepared by a process comprising
the steps of: a. preparing an extrudable mixture comprising: i.
about 1 0% to about 95% of an acid labile active pharmaceutical
ingredient; ii. about 5% to about 90% of at least one
pharmaceutically acceptable binding agent; iii. 0% to about 1 0% of
at least one pharmaceutically acceptable excipient; and iv. one or
more enzyme-friendly organic solvents in an amount sufficient to
form an extrudable mixture; wherein the percentages of components
are weight to weight of the extrudable mixture; b. creating
micropellet cores from the extrudable mixture; c. forming the
micropellet cores into approximately spherical or approximately
ellipsoidal shape in the presence of additional enzyme-friendly
organic solvent; d. removing the one or more enzyme-friendly
organic solvents from the micropellet cores such that the
micropellet cores are substantially free of the one or more
enzyme-friendly organic solvents; wherein the micropellet cores are
substantially free of synthetic oils; e. coating the micropellet
cores with an enteric-coating solution wherein the temperature of
the micropellet cores during coating is kept at a temperature
suitable to apply the enteric-coating solution and wherein the
enteric-coating solution is substantially free of monomeric
phthalic acid esters; f. drying the coated micropellet cores; and
g. placing the coated micropellet cores in a dosage form suitable
for oral administration.
45.-46. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Nos. 60/708,526 and 60/708,692 which were both filed
Aug. 15, 2005 and are both hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] Described herein is a pharmaceutical composition in an oral
dosage form and methods for making and using the same. More
specifically, described herein are pharmaceutical compositions for
acid-labile active pharmaceutical ingredients in an enteric-coated
oral dosage form where the dosage form is substantially free of
both monomeric phthalic acid ester plasticizers and synthetic
oils.
BACKGROUND
[0003] Numerous active pharmaceutical ingredients (API) are know to
be incompatible with the acidic environment present in mammalian,
such as human, stomachs. Due to this incompatibility, it can be
advantageous to protect these acid-labile compounds until such time
as they reach a point in the GI tract having a pH which is more
compatible with the particular API. Controlled or delayed release
pharmaceutical compositions for acid-labile drugs, in particular
for acid-labile drugs that need to be delivered to the upper
intestine of a mammal and where exposure of the acid-labile API to
the acidic gastric environment is to be avoided, is often
desirable.
[0004] One such acid-labile API which is advantageously delivered
to the human duodenum is pancreatin. Pancreatin is a substance
which is derived from mammalian pancreas glands and comprises
different digestive enzymes such as lipases, amylases and
proteases. Pancreatin has been used to treat pancreatic exocrine
insufficiency (PEI) which is often associated with cystic fibrosis,
chronic pancreatitis, post-pancreatectomy, post-gastrointestinal
bypass surgery (e.g. Billroth II gastroenterostomy) and ductal
obstruction from neoplasm (e.g. of the pancreas or common bile
duct). Pancreatin microspheres are the treatment of choice for
diseases or disorders caused by digestive enzyme deficiency in
mammals such as humans. This is due to the fact that
high-performance pancreatin microsphere products like Creon.TM.
provide a therapeutically effective load of active enzymes while at
the same time providing properly sized microspheres capable of
targeting the optimal location in the digestive tract where
digestive enzyme activity will be needed, in particular the upper
intestine such as the duodenum.
[0005] Recently, governmental health authorities have initiated a
reassessment of the compatibility of certain pharmaceutical
excipients which had previously been used in the formulation of
pancreatin-containing products and have provided advice concerning
the use of specific pharmaceutical excipients such as mineral oil
(see e.g. US Code of Federal Regulations, 21 CFR .sctn.201.302) and
dibutyl phthalate (see e.g. directive 2003/36/EC of the European
Parliament and the Council of 26 May 2003 amending for the
25.sup.th time Council Directive 76/769/EEC). As a result, it is
now recommended that mineral oil not be provided indiscriminately
to either pregnant women or infants. Similarly, health authorities
today recommend restricting the use of dibutyl phthalate.
Therefore, a need exists to provide patients with formulations of
pharmaceutical products which would be responsive to the current
advice of health authorities.
[0006] Some controlled release pharmaceutical preparations and/or
methods for preparing them are disclosed in EP 0063014 or U.S. Pat.
No. 5,725,880.
[0007] Pharmaceutical preparations which may comprise pancreatin
and an enteric coating are disclosed in DE 19907764; EP 0021129
(U.S. Pat. No. 4,280,971); EP 0035780; EP 0583726 (U.S. Pat. No.
5,378,462); U.S. Pat. No. 5,225,202; U.S. Pat. No. 5,750,148; U.S.
Pat. No. 6,224,910; US 2002/0146451 and WO 02/40045.
[0008] U.S. Pat. No. 4,786,505 discloses pharmaceutical
preparations for oral use.
[0009] Published patent application US 2004/0213847 discloses
delayed release pharmaceutical compositions containing proton pump
inhibitors.
[0010] Published patent application US 2002/061302 discloses the
use of physiologically acceptable enzyme mixtures for the treatment
of diabetes.
SUMMARY
[0011] Accordingly, one embodiment disclosed herein is an
enteric-coated oral dosage form containing an acid-labile API where
the dosage form is substantially free of monomeric phthalic acid
ester plasticizers and synthetic oils.
[0012] Other objects, features and advantages will be set forth in
the Detailed Description that follows, and in part will be apparent
from the description or may be learned by practice of the claimed
invention. These objects and advantages will be realized and
attained by the processes and compositions particularly pointed out
in the written description and claims hereof.
DETAILED DESCRIPTION
[0013] While the present invention is capable of being embodied in
various forms, the description below of several embodiments is made
with the understanding that the present disclosure is to be
considered as an exemplification of the invention, and is not
intended to limit the disclosure to the specific embodiments and
examples illustrated. The headings used throughout this disclosure
are provided for convenience only and are not to be construed to
limit the disclosure in any way. Embodiments illustrated under any
heading may be combined with embodiments illustrated under the same
or any other heading.
[0014] It has now been surprisingly discovered that a controlled
release pharmaceutical composition comprising acid-labile drugs,
such as pancreatin, in the upper intestine can be achieved by
providing an enteric-coated oral dosage form wherein the
enteric-coating comprises at least one plasticizer and at least one
film-forming agent as described in more detail below. The new
enteric coating as disclosed herein is substantially free of both,
monomeric phthalic acid ester plasticizers, such as dibutyl
phthalate, and synthetic oils, such as paraffins or mineral oils,
while at the same time providing the desired targeted release and
storage stability. The enteric coating as disclosed herein further
provides beneficial properties which are comparable to the
respective properties of pharmaceutical compositions which contains
dibutyl phthalate and synthetic oil in the formulation.
[0015] It is therefore provided herein an enteric coating
comprising [0016] a) one or more film-forming agents; [0017] b) at
least one plasticizer in an amount of greater than about 1.5% by
weight relative to the one or more film-forming agents wherein the
plasticizer is substantially free of monomeric phthalic acid
esters; and [0018] c) optionally at least one anti-sticking
agent.
[0019] The enteric coating can be applied to oral dosage forms of
acid-labile drugs, such as pancreatin, which need to be delivered
to the the GI tract at a location having a pH higher than the
stomach. By applying the enteric coating as disclosed herein to
oral dosage forms of acid-labile drugs, controlled release
pharmaceutical compositions (CRPC) of the acid-labile drugs can be
achieved.
[0020] Film-forming agent(s), plasticizer(s) and anti-sticking
agent(s) (when present) as used for preparing the enteric coating
are hereinafter commonly referred to as "non-solvent coating
constituents".
[0021] Suitable film-forming agents include agar, Carbopol.TM.
(carbomer) polymers (i.e. high molecular weight, crosslinked,
acrylic acid-based polymers), carboxymethyl cellulose,
carboxymethylethyl cellulose, carrageen, cellulose acetate
phthalate, cellulose acetate succinate, cellulose acetate
trimelliate, chitin, corn protein extract, ethyl cellulose, gum
arabic, hydroxypropyl cellulose, hydroxypropylmethyl acetate
succinate, hydroxypropyl methylcellulose acetate succinate,
hydroxypropyl methylcellulose phthalate, methacrylic acid-ethyl
methacrylate-copolymer, methyl cellulose, pectin, polyvinyl acetate
phthalate, polivinyl alcohol, shellac, sodium alginate, starch
acetate phthalate and/or styrene/maleic acid copolymer or mixtures
of said film-forming polymers. Cellulose acetate phthalate,
hydroxypropyl methylcellulose acetate succinate and/or methacrylic
acid-ethyl methacrylate-copolymer are the preferred film-forming
agents. Most preferred is hydroxypropyl methylcellulose phthalate,
e.g. HP 55 or HPMCP HP-50. Synthetic oils are not to be regarded as
preferred film-forming agents. The foregoing list of film-forming
agents is not meant to be exhaustive but merely illustrative, as a
person or ordinary skill in the art would understand that many
other film-forming agents or combination of film-forming agents
could also be used.
[0022] The plasticizer(s) may generally be present in an amount
greater than about 1.5%, and typically in an amount between about
2% and about 20% by weight, relative to the film-forming agent. The
plasticizer may contain saturated linear monohydric alcohols having
12 to 30 carbon atoms. More specifically, acceptable plasticizers
include lauryl alcohol, tridecyl alcohol, myristyl alcohol,
pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl
alcohol, nonadecyl alcohol, arachic alcohol, behenyl alcohol,
carnaubyl alcohol, ceryl alcohol, corianyl alcohol, melissyl
alcohol, acetyl tributyl citrate, dibutyl sebacate, fatty acid
esters of glycerol, glycerol, polyethylene glycol, propyleneglycol,
sorbitan fatty acids, triacetin, triethyl citrate and mixtures of
said plasticizers. Preferred plasticizers are cetyl alcohol,
stearyl alcohol, triethyl citrate and mixtures thereof. When cetyl
alcohol is used as a single plasticizer, it may be present in an
amount of greater than about 1.5%, typically in an amount of about
2% to about 15%, preferably about 2% to about 10%, by weight
relative to the film-forming agent. When triethyl citrate is used
as a single plasticizer, it may be present in an amount between
about 5% and about 20%, preferably between about 12% and about 15%,
by weight relative to the film-forming agent. Synthetic oils and
monomeric phthalic acid esters are not to be regarded as suitable
plasticizers. The foregoing list of plasticizers is not meant to be
exhaustive but merely illustrative, as a person or ordinary skill
in the art would understand that many other plasticizers or
combination of plasticizers could also be used so long as they are
substantially free of both synthetic oils and monomeric phthalic
acid esters.
[0023] In one embodiment the plasticizer is comprised of cetyl
alcohol and triethyl citrate which are collectively present in an
amount of greater than about 3%, typically in an amount of about 4%
to about 20%, in particular between about 6% and about 15%, more
particularly between about 7% and about 10%, by weight in relation
to the film-forming agent. The weight to weight ratio of cetyl
alcohol to triethyl citrate when both are present may be from about
0.05:1 to about 1:1, for example 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1,
0.6:1, 0,7:1, 0.8:1 or 0.9:1. In particular, the ratio of cetyl
alcohol to triethyl citrate may be from about 0.25:1 to about
0.5:1, preferably from about 0.3:1 to about 0.45:1, more preferably
from about 0.35:1 to about 0.4:1, and even more preferably from
about 0.38:1 to about 0.4:1 (w/w).
[0024] The enteric coating optionally comprises an anti-sticking
agent. Suitable anti-sticking agents include dimethicone and castor
oil. Dimethicone, in particular dimethicone 1000, is the preferred
anti-sticking agent. The amount of anti-sticking agent (if present)
in the enteric coating is between about 1.5% and about 3% by weight
relative to the film-forming agent. Synthetic oils are not to be
regarded as preferred anti-sticking agents. The foregoing list of
anti-sticking agents is not meant to be exhaustive but merely
illustrative, as a person or ordinary skill in the art would
understand that many other anti-sticking agents or combination of
anti-sticking agents could also be used.
[0025] Additional embodiments are also located in U.S. patent
application Ser. No. ______ filed on Aug. 15, 2006 and claiming the
benefit of U.S. Provisional Application Nos. 60/708,526 and
60/708,692 which were both filed on Aug. 15, 2005. U.S. patent
application Ser. No. ______ is hereby incorporated by
reference.
[0026] The term "synthetic oils" means unsaponifiable hydrocarbons
or mixtures of hydrocarbons and comprises e.g. liquid and solid
paraffins, in particular liquid paraffins (mineral oils), more
particularly highly liquid paraffin (light mineral oil).
[0027] The phrase "substantially free of synthetic oils" means that
the manufacturing processes described herein and used to make the
enteric coating or the enteric coated oral dosage forms of
acid-labile drugs where applicable do not utilize one or more
synthetic oils as an excipient although synthetic oils may be
present as pharmaceutically acceptable trace contaminants in the
API, binding agent(s), enteric coating constituents, organic
solvents and/or excipients which are used to manufacture the
enteric coating and/or the enteric coated oral dosage forms of
acid-labile drugs described herein.
[0028] The phrase "substantially free of monomeric phthalic acid
esters" means that the manufacturing processes described herein and
used to make the enteric coating or the enteric coated oral dosage
forms of acid-labile drugs where applicable do not utilize one or
more monomeric phthalic acid esters (e.g. dibutyl phthalate) as an
excipient although monomeric phthalic acid esters may be present as
pharmaceutically acceptable trace contaminants in the API, binding
agent(s), enteric coating constituents, organic solvents and/or
excipients which are used to manufacture the enteric coating and/or
the enteric coated oral dosage forms of acid-labile drugs described
herein.
[0029] Examples of acid-labile drugs which may be coated with the
eneric coating as disclosed herein are e.g.
(+)-N-{3-[3-(4-fluorophenoxy)
phenyl]-2-cyclopenten-1-yl)-N-hydroxyurea, amylase, aureomycin,
bacitracin, beta carotene, cephalosporins, chloromycetin,
cimetidine, cisapride, cladribine, clorazepate, deramciclane,
didanosine, digitalis glycosides, dihydrostreptomycin,
erythromycin, etoposide, famotidine, hormones (in particular
estrogens, insulin, adrenalin and heparin), lipase, milameline,
novobiocin, pancreatin, penicillin salts, polymyxin, pravastatin,
progabide, protease, quinapril, quinoxaline-2-carboxylic acid,
[4-(R)-carbamoyl-1-(S-3-fluorobenzyl-2-(S),7-dihydroxy-7-methyl-oct-
yl]amide, quinoxaline-2-carboxylic
acid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxyca-
rbamoyl-butyl]-amide, ranitidine, streptomycin, subtilin,
sulphanilamide and acid-labile proton pump inhibitors like
esomeprazole, lansoprazole, minoprazole, omeprazole, pantoprazole
or rabeprazole. Amylase, lipase and protease may be coated together
or separately. Amylases, lipases and proteases which are suitable
as digestive enzyme supplement or digestive enzyme substitute in
mammals, particularly humans, are preferred. Amylase, lipase and/or
protease may be derived from microbial or animal, in particular
mammalian, sources. Pancreatin is the preferred acid-labile drug.
The foregoing list of acid-labile drugs is not meant to be
exhaustive, but merely illustrative as a person of ordinary skill
in the art would understand that many other acid-labile drugs or
combination of acid-labile drugs could also be used.
[0030] Pancreatin is a mixture of different physiologically active
endogenous ingredients which is derived from mammalian pancreas
glands and comprises as its main constituents different digestive
enzymes like lipases, amylases and proteases. Mammalian pancreatic
lipase is typically used as a digestive enzyme supplement or
substitute for the treatment of PEI but pancreatic proteases and
amylases also contribute to the therapeutic value of pancreatin.
Pancreatin for pharmaceutical use is typically of bovine or porcine
origin. Porcine pancreatin is preferred.
[0031] The oral dosage form containing the acid-labile drugs may be
in the form of, for example, capsules, granules, granulates,
micropellets, microspheres, microtablets, pellets, pills, powders
and/or tablets. For the purposes of this invention, the prefix
"micro" is used to describe an oral dosage form if the diameter of
the oral dosage form or all of its dimensions (length, height,
width) is equal to or below about 5 mm.
[0032] In one embodiment the enteric coating comprises between
about 20% and about 30% by weight, more preferably between about
22% and about 26% by weight, yet more preferably between about
22.5% and about 25% by weight of the total composition of the
enteric coated oral dosage form or CRPC.
[0033] In one embodiment, the oral dosage form is a pancreatin
micropellet or pancreatin microsphere which comprise between about
10% and about 95% by weight of pancreatin, between about 5% and
about 90% by weight of at least one pharmaceutically acceptable
binding agent and between 0% and about 10% by weight of at least
one pharmaceutically acceptable excipient. More specifically,
pancreatin micropellet cores can be produced by the process
described herein which comprise between about 70% and about 90% by
weight of pancreatin, between about 10% and about 30% by weight of
at least one pharmaceutically acceptable binding agent and between
0% and about 5% by weight of at least one pharmaceutically
acceptable excipient. In one embodiment, pancreatin micropellet
cores can be produced which comprise between about 70% and about
90% by weight pancreatin, and between about 10% and about 30% by
weight of at least one pharmaceutically acceptable binding agent.
In one embodiment the pancreatin micropellet or pancreatin
microsphere is approximately spherical and has a diameter between
about 0.5 mm and about 2.0 mm.
[0034] Examples of pharmaceutically acceptable binding agents
include polyethylene glycol 1500, polyethylene glycol 2000,
polyethylene glycol 3000, polyethylene glycol 4000, polyethylene
glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000,
hydroxypropyl methylcellulose, polyoxyethylen, copolymers of
polyoxyethylen-polyoxypropylen and mixtures of said organic
polymers. The foregoing list of pharmaceutically acceptable binding
agents is not meant to be exhaustive, but merely illustrative as a
person of ordinary skill in the art would understand that many
other pharmaceutically acceptable binding agents or combination of
binding agents could also be used. Polyethylene glycol 4000 is the
preferred pharmaceutically acceptable binding agent.
[0035] Examples of suitable pharmaceutically acceptable excipients
include gliding agents like magnesium stearate or calcium stearate,
stearic acid, talcum and/or starch; fillers like calcium phosphate,
corn starch, dextrans, dextrin, hydrated silicon dioxide,
microcrystalline cellulose, kaolin, lactose, mannitol, polyvinyl
pyrrolidone, precipitated calcium carbonate, sorbitol and/or
talcum; disintegrating agents like Aerosil.TM. (silicic acid),
alginic acid, amylose, calcium alginate, calcium carbonate,
formaldehyde gelatin, pectic carbonate, sago starch, sodium
bicarbonate and/or starch; and/or moisturizers like glycerol and/or
starch. The foregoing list of pharmaceutically acceptable
excipients is not meant to be exhaustive, but merely illustrative
as a person or ordinary skill in the art would understand that many
other pharmaceutically acceptable excipients or combination of
excipients could also be used. For the purposes of the present
disclosure, synthetic oils and monomeric phthalic acid esters are
not to be regarded as suitable pharmaceutically acceptable
excipients. In one embodiment, the pancreatin micropellets or
pancreatrin microspheres contain no pharmaceutically acceptable
excipients, but can optionally contain a greater amount of
pancreatin.
[0036] In one embodiment, pancreatin micropellets can be prepared
by a manufacturing process comprising the steps of: [0037] a)
preparing an extrudable mixture comprising: [0038] i. about 10% to
about 95% pancreatin; [0039] ii. about 5% to about 90% of at least
one pharmaceutically acceptable binding agent; [0040] iii. 0% to
about 10% of at least one pharmaceutically acceptable excipient;
and [0041] iv. one or more enzyme-friendly organic solvents in an
amount sufficient to form an extrudable mixture; wherein the
percentages of components are weight to weight of the pancreatin
micropellets; [0042] b) creating pancreatin micropellets from the
extrudable mixture; [0043] c) forming the pancreatin micropellets
into approximately spherical or approximately ellipsoidal shape in
the presence of additional enzyme-friendly organic solvent; and
[0044] d) removing the one or more enzyme-friendly organic solvents
from the pancreatin micropellets such that the pancreatin
micropellets are substantially free of the one or more
enzyme-friendly organic solvents.
[0045] Process variations wherein the pancreatin micropellets are
substantially free of synthetic oils are preferred.
[0046] Further, process variations wherein the pharmaceutically
acceptable excipients are present in an amount of 0% are
preferred.
[0047] The amounts of pancreatin, pharmaceutically acceptable
binding agent(s), pharmaceutically acceptable excipient(s) and/or
enzyme-friendly organic solvent may be varied by those skilled in
the art to arrive at the pancreatin micropellets having the
preferred composition and characteristics as indicated herein.
[0048] Enzyme-friendly organic solvents facilitate mixing and other
processing procedures and may afterwards be removed, for example,
by drying. Typically, after removal of the enzyme-friendly organic
solvents, a certain amount of solvent remains in the pancreatin
micropellet cores. The remaining solvent in the micropellet cores
can comprise enzyme-friendly organic solvents, water, or a mixture
of enzyme-friendly organic solvents with water. If water is present
as a solvent, this will typically have been present in the
pancreatin which was used as the starting material. The amount of
solvent present in the pancreatin micropellet cores after removal
of the enzyme-friendly organic solvents is typically less than
about 5% and normally less than about 3% by weight of the
pancreatin micropellet core.
[0049] Examples of suitable enzyme-friendly organic solvents are
acetone, chloroform, dichloromethane or straight-chained or
branched C.sub.1-4-alcohols, particularly methanol, ethanol,
1-propanol, 2-propanol, 2-butanol, tert-butanol or mixtures of said
solvents. 2-propanol is the preferred enzyme-friendly organic
solvent. For the purposes of the present disclosure, synthetic oils
are not to be regarded as suitable enzyme-friendly organic
solvents. The enzyme-friendly organic solvent is typically used in
an amount of about 15% to about 35% by weight, preferably of about
20% to about 30% by weight, relative to the amount of pancreatin
used. The foregoing list of suitable enzyme-friendly organic
solvents is not meant to be exhaustive, but merely illustrative as
a person or ordinary skill in the art would understand that many
other enzyme-friendly organic solvents or combination of solvents
could also be used.The amounts of pancreatin, pharmaceutically
acceptable binding agent(s), pharmaceutically acceptable
excipient(s) and/or enzyme-friendly organic solvent may be varied
by those skilled in the art to arrive at the pancreatin
micro-pellets having the preferred composition as indicated
herein.
[0050] The term "substantially free of enzyme-friendly organic
solvents" means that the quantity of enzyme-friendly organic
solvents present in the oral dosage form would be less than about
5% by weight.
[0051] Removal of the one or more enzyme-friendly organic solvents
from the oral dosage form means that the oral dosage form is
subject to conditions whereby it becomes substantially free from
enzyme-friendly organic solvents. Removal of the enzyme-friendly
organic solvents can be by methods known to those of ordinary skill
in the art. The preferred method is by drying. Additionally,
removal of the one or more enzyme-friendly organic solvents would
also typically result in the oral dosage form containing an amount
of water which is less than about 5% and typically less than about
3% by weight.
[0052] In one embodiment the pancreatin micropellets are created in
process step b) by extrusion. Remarkably, an extrudable mixture is
obtained even when the mixture is substantially free of synthetic
oils. In process step b), if the creating of the micropellets from
the extrudable mixture is accomplished by means of extrusion, then
the temperature preferably does not exceed about 70.degree. C.
during extrusion, more preferably the temperature does not exceed
about 50.degree. C. Also, in the event of extrusion, piercing dies
are preferably used which have a hole diameter of about 0.5 to
about 2.0 mm, preferably of about 0.7 to about 1.5 mm, and more
preferably about 0.8 mm. Preferably, the pancreatin micropellet or
pancreatin microsphere has a diameter of about 0.5 to about 2.0 mm,
in particular of about 0.7 to about 1.5 mm, 0.8 mm. If the
extrudable mixture is extruded, then the extrudate fragments are
brought to a suitable length for the forming step. This can be done
e.g. by means of a cutting device arranged downstream to the
extruding press in a manner known to the a person of ordinary skill
in the art. The forming in process step c) can be carried out e.g.
in a customary rounding apparatus. In the rounding apparatus, the
extrudate fragments are then formed into an approximately spherical
or approximately ellipsoidal shape in the presence of additional
enzyme-friendly organic solvent which may be the same or different
than the enzyme-friendly organic solvent used in process step
a).
[0053] When prepared substantially free of synthetic oils,
processing of the extrudate fragments in the rounding apparatus is
improved relative to other known processes which use synthetic
oils. For example, a lower amount of enzyme-friendly organic
solvent needs to be added when forming the pancreatin micropellets
into an approximately spherical or approximately ellipsoidal shape
and fewer of the extrudate fragments stick to parts of the rounding
apparatus when the process is practiced with an extruder and
rounding apparatus.
[0054] The invention further provides a process for producing a
CRPC which is an enteric coated oral dosage form of an acid-labile
drug comprising the steps of: [0055] a. providing an oral dosage
form of an acid-labile drug; [0056] b. providing an enteric-coating
solution comprising [0057] i. one or more film-forming agents;
[0058] ii. at least one plasticizer in an amount of greater than
about 1.5% by weight relative to the one or more film-forming
agents wherein the plasticizer is substantially free of monomeric
phthalic acid esters; [0059] iii. optionally, at least one
anti-sticking agent; and [0060] iv. one or more volatile organic
solvents; [0061] c. coating the oral dosage form with the
enteric-coating solution wherein the product temperature of the
pancreatin micropellet cores during coating is kept at a
temperature suitable to apply the enteric-coating solution; [0062]
d. drying the coated oral dosage form.
[0063] In the foregoing process for producing an enteric-coated
oral dosage form of an acid-labile drug, the oral dosage form(s),
the film-forming agent(s), the plasticizer(s), the anti-sticking
agent(s) and the enzyme-friendly organic solvents generally have
the meanings as set forth above.
[0064] Process step b) may be performed at a temperature between
about 15.degree. C. and about 60.degree. C. Performing process step
b) at ambient temperature (i.e. room temperature, approximately
between about 20.degree. C. and about 30.degree. C.), is preferred.
Examples of suitable enzyme-friendly organic solvents include
acetone, 2-butanol, tert.-butanol, chloroform, dichloromethane,
ethanol, methanol, 1-propanol, 2-propanol and mixtures of said
solvents. Acetone, ethanol and 2-propanol or their mixtures are
preferred as enzyme-friendly organic solvents. Acetone is most
preferred. The foregoing list of enzyme-friendly organic solvents
in process step b) is not meant to be exhaustive but merely
illustrative, as a person or ordinary skill in the art would
understand that many other enzyme-friendly organic solvents or
combination of solvents could also be used.
[0065] The enzyme-friendly organic solvent is typically used in an
amount between about 6 and about 10 times, preferably between about
7 and about 8 times, the weight of the non-solvent coating
constituents used to prepare the pancreatin micropellets. For
example, if the non-solvent coating constituents make up to a total
weight of about 1.5 g, then about 9 g to about 15 g of
enzyme-friendly organic solvent may be used in process step a).
[0066] The enteric coating optionally comprises an anti-sticking
agent. Suitable anti-sticking agents include dimethicone and castor
oil. Dimethicone, in particular dimethicone 1000, is the preferred
anti-sticking agent. The anti-sticking agent is usually present in
the enteric coating in an amount of between about 1.5% and about 3%
by weight relative to the film-forming agent. Synthetic oils are
not to be regarded as preferred anti-sticking agents. The foregoing
list of anti-sticking agents is not meant to be exhaustive but
merely illustrative, as a person or ordinary skill in the art would
understand that many other anti-sticking agents or combination of
anti-sticking agents could also be used.
[0067] Due to the process for producing CRPCs, viz the coating
process as described herein, pharmaceutically acceptable residual
amounts of the enzyme-friendly organic solvent(s) present in the
enteric-coating solution may still be present in the final enteric
coated oral dosage form. It is understood that CRPCs comprising
pharmaceutically acceptable residual amounts of enzyme-friendly
organic solvent(s) are within the scope of the present
invention.
[0068] In process step c) the product temperature of the oral
dosage form, in one embodiment, is usually maintained between about
30.degree. C. and about 60.degree. C. while coating, preferably
between about 32.degree. C. and about 55.degree. C., more preferred
between about 35.degree. C. and about 50.degree. C., most
preferably between about 37.degree. C. and about 49.degree. C. In
process step c), when cetyl alcohol or both cetyl alcohol and
triethyl citrate are used the product temperature of the oral
dosage form is maintained between about 40.degree. C. and about
46.degree. C. Maintaining the product temperature of the oral
dosage form within the preferred temperature ranges while coating
results in improved gastric-acid resistant properties of the CPRC,
in particular when the enteric coating comprise cetyl alcohol and
triethyl citrate as plasticizers. The coating in process step c)
can be accomplished by any process or method known to a person of
ordinary skill in the art. Spray coating is preferred. If the
coating in process step c) is performed by spray coating, the spray
rate can be between about 97 kg/h and about 115 kg/h. Usually,
process step c) is performed in a way that the enteric coating
comprises between about 20% and about 30% by weight, preferably
between about 22% and about 26% by weight and more preferably
between about 22.5% and about 25% by weight of the total
composition of the enteric coated oral dosage form or CRPC. The
exact parameters to be applied in process step c) to achieve the
desired enteric coating will depend on the coating technique used.
The person skilled in the art understands how to achieve coating
films of a desired thickness when using different coating
techniques.
[0069] Drying of the enteric-coated oral dosage form of the
acid-labile drug in process step dd.) is preferably performed
between about 30.degree. C. and about 90.degree. C., preferably
between about 30.degree. C. and about 55.degree. C., and preferably
between about 35.degree. C. and about 50.degree. C. for a period of
between about 1 hour and about 60 hours, between about 6 hours and
about 60 hours, preferably for a period of between about 6 hours
and about 36 hours.
[0070] In one embodiment of the process for producing an enteric
coated oral dosage form of an acid-labile drug, the acid-labile
drug is pancreatin. Disclosed herein is a process for the
manufacture of pancreatin micropellets, comprising the steps of:
[0071] aa. providing pancreatin micropellet cores wherein the
pancreatin micropellet cores are substantially free of synthetic
oils; [0072] bb. providing an enteric-coating solution comprising
[0073] i. one or more film-forming agents; [0074] ii. a plasticizer
in an amount greater than about 1.5% by weight relative to the one
or more film-forming agents film-forming agents wherein the
plasticizer is substantially free of monomeric phthalic acid
esters; and [0075] iii. optionally, at least one anti-sticking
agent, and [0076] iv. one or more enzyme-friendly organic
solvent(s); [0077] cc. coating the pancreatin micropellet cores
with the enteric-coating solution wherein the temperature of the
pancreatin micropellet cores during coating is kept at a
temperature suitable for applying the enteric-coating solution; and
[0078] dd. drying the coated pancreatin micropellet cores.
[0079] In the foregoing process for producing pancreatin
micropellets, the film-forming agent(s), the plasticizer(s), the
anti-sticking agent(s) and the enzyme-friendly organic solvents
generally have the meanings as previously set forth.
[0080] Due to the process for producing pancreatin micropellets,
viz. the coating process as described herein, pharmaceutically
acceptable residual amounts of the enzyme-friendly organic
solvent(s) present in the enteric-coating solution may still be
present in the pancreatin micropellet after drying. It is
understood that pancreatin micropellets comprising pharmaceutically
acceptable residual amounts of enzyme-friendly organic solvent(s)
are within the scope of the present invention.
[0081] Process step bb) may be performed at a temperature between
about 15.degree. C. and about 60.degree. C. Performing process step
bb) at ambient temperature (i.e. room temperature, approximately
between about 20.degree. C. and about 30.degree. C.), is preferred.
Examples of suitable enzyme-friendly organic solvents include
acetone, 2-butanol, tert.-butanol, chloroform, dichloromethane,
ethanol, methanol, 1-propanol, 2-propanol and mixtures of said
solvents. Acetone, ethanol and 2-propanol or their mixtures are
preferred as enzyme-friendly organic solvents. Acetone is most
preferred. The foregoing list of enzyme-friendly organic solvents
in process step bb.) is not meant to be exhaustive but merely
illustrative, as a person or ordinary skill in the art would
understand that many other enzyme-friendly organic solvents or
combination of solvents could also be used.
[0082] The enzyme-friendly organic solvent is typically used in an
amount between about 6 and about 10 times, preferably between about
7 and about 8 times, the weight of the non-solvent coating
constituents used to prepare the pancreatin micropellets. For
example, if the non-solvent coating constituents make up to a total
weight of about 1.5 g, then about 9 g to about 15 g of
enzyme-friendly organic solvent may be used in process step
aa).
[0083] In process step cc.) the temperature of the pancreatin
micropellet core, in one embodiment, is usually maintained between
about 30.degree. C. and about 60.degree. C. while coating,
preferably between about 32.degree. C. and about 55.degree. C.,
more preferred between about 35.degree. C. and about 50.degree. C.,
most preferably between about 37.degree. C. and about 49.degree. C.
In process step cc.), when cetyl alcohol or both cetyl alcohol and
triethyl citrate are used the temperature of the pancreatin
micropellet core is maintained between about 40.degree. C. and
about 46.degree. C. Maintaining the temperature of the pancreatin
micropellet cores within the preferred temperature ranges while
coating results in improved gastric-acid resistant properties of
the pancreatin micropellets, in particular when the enteric coating
comprise cetyl alcohol and triethyl citrate as plasticizers. The
coating in process step cc.) can be accomplished by any process or
method known to a person of ordinary skill in the art. Spray
coating is preferred. Usually, process step cc.) is performed in a
way that the enteric coating comprises between about 20% and about
30% by weight, preferably between about 22% and about 26% by weight
and more preferably between about 22.5% and about 25% by weight of
the total composition of the pancreatin micropellet. The exact
parameters to be applied in process step cc.) to achieve the
desired enteric coating will depend on the coating technique used.
The person skilled in the art understands how to achieve coating
films of a desired thickness when using different coating
techniques.
[0084] Drying of the enteric-coated pancreatin micropellet cores in
process step dd) is performed between about 30.degree. C. and about
90.degree. C. preferably between about 30.degree. C. and about
55.degree. C., preferably between about 35.degree. C. and about
50.degree. C., and for a period of between about 1 hour and about
60 hours, between about 6 hours and about 60 hours, preferably for
a period of between about 6 hours and about 36 hours.
[0085] The invention further provides a CRPC which is an enteric
coated oral dosage form of an acid-labile drug, in particular of
pancreatin, which is obtainable by the process or its variants
described herein. If the CRPC is a pancreatin micropellet or
pancreatin microsphere, the preferred a diameter is about 0.6 to
about 2.1 mm and preferrably between about 0.7 mm and 1.6 mm.
[0086] In one embodiment, oral CRPCs are described wherein
pancreatin is the acid-labile drug for delivery to an area of the
GI tract having a pH greater than the pH of the stomach,
specifically to the small intestine, usually to the duodenum, of
mammals such as humans. The oral CRPCs comprising pancreatin are
particularly suited for the prophylaxis and/or treatment of
digestive disorders of different origins like maldigestion and/or
for the prophylaxis and/or treatment of pancreatitis, cystic
fibrosis, diabetes type I, diabetes type II and/or other conditions
resulting from pancreatine exocrine insufficiency in mammals and
humans.
[0087] Maldigestion in mammals such as humans is usually based on a
deficiency of digestive enzymes, in particular on a deficiency of
endogenous lipase, but also of protease and/or amylase. The cause
of such a deficiency of digestive enzymes is frequently a
hypofunction of the pancreas (e.g. pancreatic insufficiency,
usually known as pancreatic exocrine insufficiency), the organ
which produces the largest quantity of, and the most important,
endogenous digestive enzymes. If the pancreatic insufficiency is
pathological, it may be congenital or acquired. Acquired chronic
pancreatic insufficiency may, for example, result from alcoholism.
Congenital pancreatic insufficiency may, for example, result from
disease such as cystic fibrosis. The consequences of the deficiency
of digestive enzymes may be severe symptoms of under-nutrition and
malnutrition, which may be accompanied by increased susceptibility
to secondary illnesses. In one specific embodiment, pancreatin
micropellets according to the invention are therefore particularly
suited for treating pancreatic exocrine insufficiency of any
origin.
[0088] In another embodiment, an enteric coated oral dosage form of
pancreatin is provided as previously described, for the manufacture
of a medicament for the treatment of medical conditions such as
digestive disorders, pancreatic exocrine insufficiency,
pancreatitis, cystic fibrosis, diabetes type I and/or diabetes type
II.
[0089] In yet another embodiment, a method is provided for the
treatment of a medical condition such as digestive disorders,
pancreatic exocrine insufficiency, pancreatitis, cystic fibrosis,
diabetes type I and/or diabetes type II by administering a
therapeutically effective amount of an enteric coated oral dosage
form of pancreatin to a person in need of such treatment.
[0090] The CRPCs described herein comprise enteric coated capsules,
granules, granulates, micropellets, microspheres, microtablets,
pellets, pills, powders and/or tablets. Enteric coated granules,
granulates, micropellets, microspheres, pellets, pills or powders,
if desired may be filled into capsules or sachets or may be
compressed to form microtablets or tablets. Equally, uncoated
granules, granulates, micropellets, microspheres, pellets, pills or
powders may be first compressed to form microtablets or tablets
which may then be coated with the enteric coating as provided
according to the invention. Microtablets or tablets may likewise be
filled into capsules. Capsules or sachets maybe opened to permit
mixing of the contents with compatible foods or liquids to
facilitate administration of the contents of the capsule or
sachet.
[0091] Granules are asymmetric agglomerates of powder particles
cemented together and having no regular geometric form. The surface
of the granule may be spherical, rod-shaped or cylindrical and is
usually uneven and ridged. Granules are preferably produced by melt
or wet granulation. Granulates are usually defined to be sedimented
agglomerates of granules. Tablets are usually made from the powder
or the granules. Pellets and micropellets can be produced either by
exploiting the thermoplastic properties of the excipients in a high
share mixer (melt pelletisation) or by other methods such as
extrusion (e.g. melt extrusion or wet extrusion) and
spheronisation. Pharmaceutical pellets are usually of a defined
geometrical form and have a generally smooth surface. Specific
methods of producing micropellets or microspheres are described
herein. Microspheres and micropellets are the preferred oral dosage
forms described herein.
[0092] The enteric coating as disclosed herein will usually be
applied to oral dosage forms selected from granules, granulates,
micropellets, microspheres, microtablets, pellets, pills, powders
and/or tablets and the coated oral dosage forms may then be
incorporated into uncoated capsules. However, in an alternative
embodiment, the invention also comprises enteric coated capsules
which contain coated or, more commonly, uncoated oral dosage forms
selected from granules, granulates, micropellets, microspheres,
microtablets, pellets, pills, powders and/or tablets. The coated
oral dosage forms of the acid-labile drug selected from granules,
granulates, micropellets, microspheres, microtablets, pellets,
pills, powders and/or tablets or the capsules may further be
incorporated into at least one outer package e.g. selected from
blisters or bottles. In embodiments of the invention, a
pharmaceutical pack or kit is provided comprising one or more
containers filled with the ingredients of a pharmaceutical
composition of the invention. Associated with such container(s) can
be various written materials such as instructions for use, or a
notice in the form prescribed by a governmental agency regulating
the manufacture, use or sale of pharmaceuticals products, which
notice reflects approval by the agency of manufacture, use, or sale
for human or veterinary administration.
[0093] The CRPCs as disclosed herein are substantially free of both
monomeric phthalic acid ester plasticizers, such as dibutyl
phthalate, and synthetic oils, such as paraffins or mineral oils,
while providing the desired performance in terms of targeted
release and storage stability. Further, the CRPCs presently
disclosed, in particular in their preferred embodiments, possess
superior gastric acid resistance and protective properties, e.g.
superior resistance and protective properties in an acidic
environment, specifically at pH 1 and/or pH 5. The enteric coating
as proposed for the presently disclosed CPRCs have additional
desirable properties such as dissolution profiles. In prefered
CRPCs disclosed herein, the plasticizer is comprised of cetyl
alcohol and triethyl citrate (CA/TEC-Compositions).
CA/TEC-Compositions in general preserve a higher lipase content
when pancreatin is the acid-labile drug and usually possess a lower
water content compared to CRPCs when other plasticizers are
used.
EXAMPLES
[0094] The following examples are meant to be illustrative and not
to limit the present disclosure. Other suitable modifications and
adaptations are of the variety normally encountered by those
skilled in the art and are fully within the spirit and scope of the
present disclosure.
A. Preparation of an Enteric Coated Oral Dosage Form of an
Acid-Labile Drug
1. Preparation of Uncoated Pancreatin Micropellets
[0095] 15.9 kg of pancreatin was mixed with 3.975 kg of
polyethylene glycol 4000 in a commercially available high shear
mixer and thoroughly moistened with 3.975 kg of 2-propanol. The
resulting mixture was extruded by means of a commercially available
extruding press which was equipped with a piercing die having 0.8
mm internal diameter bores and a cutting device arranged
downstream. The temperature was less than 50.degree. C. while
pressing. The extruded mass was cut into extrudate fragments of
approximately 5 mm length by means of the cutting device.
[0096] The resulting 14.64 kg of the extrudate fragments were
transferred in four portions of roughly equal size to a
commercially available rounding apparatus and rounded to give
approximately elliptically or approximately spherically shaped
micropellet cores. An additional 135 g of 2-propanol was added
while rounding.
[0097] After drying in a commercially available continuous vacuum
dryer (Votsch type) at a temperature in a range from between
35.degree. C. and 50.degree. C. for 12 hours, the pancreatin
micropellets were graded, first with a 3.15 mm sieve (sieving of
oversize grain>3.15 mm) and then with a 0.7 mm sieve (sieving of
undersize grain<0.7 mm) and afterwards with a 1.25 mm sieve
(sieving of oversize grain>1.25 mm) to yield 11.98 kg of
pancreatin micropellet cores having a pancreatin content of 80% and
a bulk density of 0.67 g/ml.
2. Enteric Coating of Pancreatin Micropellet Cores
[0098] A coating solution was prepared by adding 1623.2 g of
hydroxypropyl methylcellulose phthalate (HP 55), 90.2 g of triethyl
citrate, 34.3 g of cetyl alcohol and 38.9 g of dimethicone 1000 to
14030 g of acetone at room temperature while stirring.
[0099] 5025 g of pancreatin micropellet cores (prepared analogously
to the process as described herein) were fed into a commercially
available fluid bed coater and were spray-coated at a spray rate of
97-101 kg/h and an air pressure of 1.7 bar with the coating
solution as prepared above until the desired film-thickness of the
coating had been reached. The product temperature of the pancreatin
micropellet cores was monitored and maintained in the range between
about 37.degree. C. and about 43.degree. C. during coating. The
resulting pancreatin micropellets were then dried in a commercially
available vacuum dryer (Votsch type) at a temperature in a range
between 35.degree. C. and 50.degree. C. for 12 hours. The dried
pancreatin micropellets were then graded, first with a 0.7 mm sieve
(sieving of undersize grain<0.7 mm) and then with a 1.6 mm sieve
(sieving of oversize grain>1.6 mm) to yield 6532 g of pancreatin
micropellets having a pancreatin content of about 60% relative to
the enteric-coated pancreatin micropellets. The bulk density of the
pancreatin micropellets was about 0.69 g/ml.
[0100] Further pancreatin micropellets were prepared according to
the procedure described above and different coatings were applied
in a manner similar to the coating process set forth above to yield
further CRPCs. The compositions of the further CRPCs and other
compositions are set forth in Table 1 along with certain process
parameters from their respective coating processes. Composition G
can be produced according to processes as described in U.S. Pat.
No. 5,378,462. Comparative composition H was prepared according to
a process which includes dibutylphthalate used as a plasticizer in
the coating. All batches have been produced in laboratory scale
unless otherwise noted.
TABLE-US-00001 TABLE 1 Pancreatin containing compositions
Composition Ingredients mg/capsule A B C D 1 2 Micropellet
Pancreatin 150.00 150.00 150.00 150.00 150.00 150.00 Cores PEG 4000
37.50 37.50 37.50 37.50 37.50 37.50 Enteric HP 55 48.60 48.60 48.60
48.60 48.60 48.60 Coating Dimethicone 1.25 1.25 1.25 1.25 1.25 1.25
(film) TEC 0 0 3.0 4.10 5.00 0 CA 0 0.40 0 0 0 1.00 Sum 237.40
237.75 240.35 241.45 242.4 238.35 Process Pellet temp. 40.degree.
C. 40.degree. C. 40.degree. C. 40.degree. C. 40.degree. C.
40.degree. C. parameters while coating Composition Ingredients
mg/capsule 3 4 5 6* 7 8 Micropellet Pancreatin 150.00 150.00 150.00
150.00 150.00 150.00 Cores PEG 4000 37.50 37.50 37.50 37.50 37.50
37.50 Enteric HP 55 52.60 48.60 48.60 52.25 52.25 52.25 Coating
Dimethicone 1.25 1.25 1.25 1.25 1.25 1.25 (film) TEC 0 3.60 3.00
2.90 2.90 2.90 CA 1.15 0.40 1.00 1.10 1.10 1.10 Sum 242.50 241.35
241.35 245.00 245.00 245.00 Process Pellet temp. 40.degree. C.
40.degree. C. 40.degree. C. 40.degree. C. 30.degree. C. 35.degree.
C. parameters while coating Composition Ingredients mg/capsule 9 10
11 12 13 14 Micropellet Pancreatin 150.00 150.00 150.00 150.00
150.00 150.00 PEG 4000 37.50 37.50 37.50 37.50 37.50 37.50 Enteric
HP 55 56.34 56.34 56.34 52.25 52.25 56.34 Dimethicone 1.35 1.35
1.35 1.25 1.25 1.35 Coating TEC 3.13 3.13 3.13 2.90 2.90 3.13
(film) CA 1.19 1.19 1.19 1.10 1.10 1.19 Sum 249.51 249.51 249.51
245.00 245.00 249.51 Process Pellet temp. 37.degree. C. 40.degree.
C. 43.degree. C. 49.degree. C. 40.degree. C. 46.degree. C.
parameters while coating Composition Ingredients mg/capsule 15 E F
G H Micropellet Pancreatin 128.06 150.00 150.00 150.00 150.00 Cores
PEG 4000 32.01 37.50 37.50 37.50 37.50 Light mineral 0 0 0 3.75 0
oil Enteric HP 55 48.10 48.60 48.60 48.60 48.60 Coating Dimethicone
1.15 1.25 1.25 1.25 1.25 (film) TEC 2.67 1.00 2.00 0 0 CA 1.01 0 0
0 0 DBP 0 0 0 4.10 4.10 Light mineral 0 0 0 3.30 0 oil Sum 213.00
238.35 239.35 248.50 241.50 Process Pellet temp. n.a. 40.degree. C.
40.degree. C. 40.degree. C. 40.degree. C. parameters while coating
PEG = polyethylene glycol; TEC = triethyl citrate; CA = cetyl
alcohol; HP 55 = hydroxypropyl methylcellulose phthalate; temp. =
temperature; DBP = dibutyl phthalate; *= production scale; n.a:
data not available. Compositions A, B, C, D, E, F, G and H are
comparative compositions. Composition G is a currently available
high-quality pharmaceutical composition comprising pancreatin and
light mineral oil. Compositions No. 6, 10, 13, 14 and 15 are
examples of compositions containing CA/TEC as the plasticizer.
Composition No. 3 is an example of a composition comprising cetyl
alcohol as the plasticizer.
B. Determination of the Gastric Acid Resistance of Enteric Coated
Pancreatin Micropellets at pH 1 and pH 5
[0101] The resistance to gastric acid of the pancreatin
micropellets of Table 1.
[0102] Resistance to gastric juice (pH 1) of the different
pancreatin micropellets from Table 1 was determined by immersing
the micropellets for 2 hours in 0.1 mol/l hydrochloric acid in a
disintegration tester according to the European Pharmacopoeia (Ph.
Eur.). Then the un-dissolved portion of the pellets was separated
from the solution and their residual lipase activity was determined
according to the lipase assay of Ph. Eur./The International
Pharmaceutical Federation" (FIP), PO Box 84200; 2508 AE The Hague;
The Netherlands. The results of these tests for gastric resistance
of the enteric coating are presented in Table 2 ("stability at pH
1").
[0103] Further, a similar test at pH 5 was performed using the same
conditions as outlined above, with the exception that a phosphate
buffer pH 5.0 (2.0 g sodium chloride and 9.2 g sodium di-hydrogen
phosphate monohydrate per liter adjusted to pH 5.0) was used as a
solvent instead of 0.1 mol/l hydrochloric acid. The results of
these tests for gastric resistance are also presented below in
Table 2 ("stability at pH 5").
[0104] The gastric acid resistances of the compositions from Table
1 (see above) are each given in Table 2 as percentages of the
residual lipolytic activity after the incubation in relation to the
actual lipolytic activity of the samples tested prior to the
incubation (relative gastric acid resistance). The lipolytic
activity is determined according to the lipase assay described in
the USP monograph "pancrelipase delayed-release capsules". In
principle, any standardized and characterized pancreatin sample may
be used as the lipase reference standard. For example, a
predetermined lipolytic activity standard may be obtained from the
"International Pharmaceutical Federation" (FIP), PO Box 84200; 2508
AE The Hague; The Netherlands. For the purposes of the present
invention, an internal pancreatin standard was used which is
available on request from Solvay Pharmaceuticals GmbH,
Hans-Boeckler-Allee 20, 30173 Hannover, Germany.
TABLE-US-00002 TABLE 2 Relative gastric acid resistances
(stabilities) of compositions in Table 1 at pH 1 and pH 5 Stability
at pH 5 Stability at pH 1 Composition [%] [%] A 15.3 15.9 B 63.2
53.8 C 71.6 84.2 D 52.0 93.6 1 87.0 96.0 2 76.4 92.6 3 92.1 94.5 4
85.3 93.7 5 92.0 93.0 6 94.9 99.4 7 67.4 89.8 8 80.5 95.2 9 83.8
90.8 10 97.9 99.6 11 89.0 93.5 12 83.7 94.8 13 100.2 102.7 14 93.6
98.7 E 48.6 65.0 F 36.5 75.0 G 98.6 100.6
[0105] Preferred CRPCs have a gastric acid resistance (stability)
at pH 1 of at least 75%, in particular of at least 85%, preferably
of at least 90%, more preferred of at least 95%, relative to a
predetermined pancreatin lipolytic activity standard.
[0106] Other preferred CRPCs as disclosed herein have a gastric
acid resistance at pH 5 of at least 75%, in particular of at least
85%, preferably of at least 90%, more preferred of at least 95%,
relative to a predetermined pancreatin lipolytic activity
standard.
[0107] CRPCs which are most preferred have a gastric acid
resistance at pH 1 of at least 90% and an additional gastric acid
resistance at pH 5 of at least 90%, relative to a predetermined
pancreatin lipolytic activity standard.
C. Determination of the Dissolution Profile of Enteric Coated
Pancreatin Micropellets
[0108] The dissolution profile of different compositions from Table
1 (see above) was determined according to a test procedure as
described in the United States Pharmacopoeia (USP) monograph
"pancrelipase delayed-release capsules" with increased gastric
resistance phase which is hereby incorporated by reference.
[0109] The determination of the resistance to gastric fluid was
performed using gastric juice without enzymes according to USP
under standardized conditions (37.degree. C., 100 rpm) for 2 hours
in the dissolution apparatus (basket apparatus USP). Then the
un-dissolved portion of the enteric coated pancreatin micropellets
was separated from the solution and transferred into the paddle
apparatus according to USP, filled with phosphate buffer solution
at pH 6.0 to determine the dissolution of enzymes. The enteric
coated pancreatin micropellets were agitated in a dissolution
tester under standardized conditions for usually 90 minutes (see
exact timepoints in Table 3 below) at 37.degree. C. and 50 rpm.
[0110] The lipase activity was determined after selected time
points (see Table 3) according to the lipase assay described in the
USP monograph "pancrelipase delayed-release capsules".
[0111] Further, a test similar to that described above was
performed with a "Mcllvain buffer" (pH 6.0; for preparation mix
solution A: 7.098 g Na.sub.2HPO.sub.4 anhydrous and 4 g of bile
salts in 1000 ml water with solution B: 5.25 g
C.sub.6H.sub.8O.sub.7.H.sub.2O and 4 g of bile salts in 100 ml
water) instead of a USP-compliant phosphate buffer. All other
conditions remained as described above for the USP-compliant
phosphate buffer.
[0112] The results of the dissolution profile tests are presented
below as "% residual lipase activity of actual lipase activity" for
the test series performed with USP-compliant phosphate buffer (see
Table 3a) and for the test series performed with Mcllvain buffer
(see Table 3b).
TABLE-US-00003 TABLE 3a Dissolution profiles of the enteric coated
pancreatin micropellets in phosphate buffer Time % lipase activity
of initial actual activity points for each composition No. [min.] G
2 3 4 5 13 14 5 0.0 -- 3.0 -- 0.0 4.6 NA 10 0.0 -- 4.9 -- 6.2 4.6
15.37 15 11.9 -- 16.4 -- 37.8 17.6 34.38 20 48.0 -- 39.3 -- 63.5
40.8 NA 25 62.3 -- 59.0 -- 72.4 59.8 NA 30 73.5 -- 67.8 -- 80.0
66.2 73.86 45 77.1 -- 80.5 -- 84.0 76.6 84.45 60 79.9 -- 77.8 --
84.2 81.9 81.25 75 78.4 -- 77.1 -- 78.9 79.8 80.40 90 78.2 -- 72.3
-- 77.2 77.4 NA
TABLE-US-00004 TABLE 3B Dissolution profiles of the enteric coated
pancreatin micropellet in Mcllvain buffer Time % lipase activity of
initial actual activity points for each composition No. [min.] G 2
3 4 5 13 5 0.0 1.0 0.5 0.4 0.0 0.7 10 0.5 8.8 1.7 7.7 4.5 1.2 15
6.3 39.6 9.8 39.1 30.2 8.1 20 23.6 60.5 24.3 62.7 65.6 24.6 25 47.2
68.7 40.6 79.6 79.3 43.1 30 66.3 75.2 58.3 84.7 85.2 58.9 45 88.1
76.9 75.4 86.3 87.5 83.7 60 91.0 74.0 80.9 84.5 85.4 87.1 75 88.4
73.9 81.4 80.2 -- 87.1 90 -- 71.2 80.6 -- -- 85.4 105 -- -- 77.7 --
-- --
[0113] For the dissolution profile test results as provided in
Tables 3a and 3b, a comparison of the compositions nos. 2, 3, 4, 5
and 13 was performed in each case with the reference composition
"G". The comparison was based on the "Guidance for Industry",
SU-PAC-MR, Modified Release Solid Oral Dosage Forms (September
1997), which is hereby incorporated by reference, by calculating
the similarity factor (f2). The two acceptance limits for
determining similarity of two compared curves were (i) a factor
(f2) >50 and (ii) the average deviation at any dissolution
sampling point should not be greater than 15%.
[0114] In vitro dissolution profile comparisons can be made using a
model independent approach using similarity factor. Dissolution
profiles may be compared using the following equation that defines
a similarity factor (f.sub.2):
f.sub.2=50log{[1+1/n.SIGMA..sub.t=1.sup.n=(R.sub.t-T.sub.t).sup.2].sup.--
0.5*100}
where log=logarithm to base 10, n=number of sampling time points,
.SIGMA.=summation over all time points, R.sub.t=dissolution at time
point t of the reference (unchanged drug product, i.e. prechange
batch), T.sub.t=dissolution at time point t of the test (changed
drug product, i.e., post-change batch).
[0115] For comparison of multipoint dissolutionprofiles obtained in
multiple media, similarity testing should be preformed using
pairwise dissolution profiles (i.e., for the changed and unchanged
product) obtained in each individual medium. An f.sub.2 value
between 50 and 100 suggests the dissolution profiles are
similar.
[0116] When applying the above-stated acceptance limits for
determining similarity it was found that the dissolution profiles
of pancreatin micropellet CRPCs no. 2, 4 and 5 (see Table 1) could
not be considered to be similar to the dissolution profile of the
reference pancreatin micropellet "G" (see Table 1). However, when
applying the above-stated acceptance limits for determining
similarity it was found that the dissolution profiles of pancreatin
micropellet CRPCs no. 3 and 13 (see Table 1) could be considered to
be similar to the dissolution profile of the reference pancreatin
micropellet "G" (see Table 1). Thus, pharmaceutical compositions
containing pancreatin and their methods of manufacturing which are
similar to composition G in Table 1 are specifically described
herein.
D. Storage Stability Studies for Enteric Coated Pancreatin
Micropellet CPRCs
[0117] For determining storage stability of different pancreatin
micropellets from Table 1 (see above), hard gelatin capsules of
size 0 were filled with approximately 497 mg of pancreatin
micropellets (see Table 1) and packed into 30 ml HDPE bottles for
performing the following tests.
[0118] The packed pancreatin micropellets were stored for 5 months
under normal or two different aggravated storage conditions (see
below for details) and the residual lipase activity was determined
in each case analogously to the instructions of Ph. Eur. The
results of these storage stability tests of the CPRCs after 5
months' storage periods are presented below in Tables 4a and 4b,
respectively ("Lipase").
[0119] Resistance to gastric juice (pH 1) of the different
pancreatin micropellets from Table 1 was also determined after a
total storage period of 5 months by immersing pancrelipase
delayed-release pellets for 2 hours in 0.1 mol/I hydrochloric acid
in a disintegration tester according to the Ph. Eur. (Section
2.9.1. "disintegration"). The un-dissolved portion of the pellets
was then separated from the solution and their residual lipase
activity was determined according to the lipase assay of Ph. Eur.
(monograph "pancreas powder"). The results of these tests for
gastric resistance of the enteric coating after 5 months' storage
periods under normal or two different aggravated storage conditions
are presented in Tables 4a and 4b, respectively ("gastric
resistance at pH 1").
[0120] Further, a similar test at pH 5 was done using the same
conditions as outlined in the previous paragraph, with the
exception that a phosphate buffer pH 5.0 (2.0 g sodium chloride and
9.2 g sodium di-hydrogen phosphate monohydrate per liter adjusted
to pH 5.0) was used as a solvent instead of 0.1 mol/l hydrochloric
acid. The results of these tests for gastric resistance of the
enteric coating after 5 months' storage periods are presented below
in Tables 4a and 4b, respectively ("gastric resistance at pH
5").
TABLE-US-00005 TABLE 4a Stability results for select compositions
from Table 1 at 30.degree. C. and 65% rel. humidity (slightly
aggravated storage conditions) % lipase activity of initial
activity CPRC Months Conditions No. 0 5 Lipase (initial activity) G
100 92 3 100 88 13 100 94 Gastric resistance at pH 1 G 101 91
(actual activity) 3 95 95 13 103 99 Gastric resistance at pH 5 G 99
92 (actual activity) 3 92 86 13 100 95
TABLE-US-00006 TABLE 4b Stability results for select compositions
from Table 1 at 40.degree. C. and 75% rel. humidity (aggravated
storage conditions) % lipase activity of initial activity CPRC
Months Conditions No. 0 1 2 3 4 5 Lipase (initial activity) G 100
90 80 77 69 64 3 100 87 79 69 64 61 13 100 97 87 81 73 67 Gastric
resistance at G 101 96 101 94 96 96 pH 1 (actual activity) 3 95 94
94 96 87 86 13 103 95 97 97 96 89 Gastric resistance at G 99 92 95
76 87 40 pH 5 (actual activity) 3 92 86 78 63 51 22 13 100 90 83 73
43 15
[0121] The data presented in Tables 4a and 4b illustrate that the
tested composition Nos. G, 3 and 13 (see Table 1) are of
satisfactory storage stability under normal and slightly aggravated
storage conditions over a 5 months storage period. The lipase
content of composition No. 13, although similar to the two
comparative compositions, was best preserved over the observed 5
months' periods under slightly aggravated and aggravated storage
conditions.
[0122] Under slightly aggravated storage conditions, which are most
relevant in practice, composition No. 13 performed best in terms of
gastric resistance at pH 1 and pH 5 over the observed 5 months'
periods.
[0123] All references, including publications, patent applications,
and patents, cited herein are hereby incorporated by reference to
the same extent as if each reference there individually and
specifically indicated to be incorporated by reference were set
forth in its entirety herein.
[0124] In the present disclosure, where numeric values are given as
ranges, the respective range limits are generally meant to be
included in and being part of the given ranges unless expressly
stated otherwise.
[0125] The use of the terms "a" and "an" and "the" and similar
references in the context of this disclosure (especially in the
context of the following claims) are to be construed to cover both
the singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. All methods described herein can
be performed in any suitable order unless otherwise indicated
herein or otherwise clearly contradicted by context. The use of any
and all examples, or exemplary language (e.g., such as, preferred,
preferably) provided herein, is intended merely to further
illustrate the content of the disclosure and does not pose a
limitation on the scope of the claims. No language in the
specification should be construed as indicating any non-claimed
element as essential to the practice of the invention.
[0126] Alternative embodiments of the claimed invention are
described herein, including the best mode known to the inventors
for carrying out the claimed invention. Of these, variations of the
disclosed embodiments will become apparent to those of ordinary
skill in the art upon reading the foregoing disclosure. The
inventors expect skilled artisans to employ such variations as
appropriate, and the inventors intend for the invention to be
practiced otherwise than as specifically described herein.
[0127] Accordingly, this invention includes all modifications and
equivalents of the subject matter recited in the claims appended
hereto as permitted by applicable law. Moreover, any combination of
the above described elements in all possible variations thereof is
encompassed by the invention unless otherwise indicated herein or
otherwise clearly contradicted by context.
[0128] The use of individual numerical values are stated as
approximations as though the values were preceded by the word
"about" or "approximately" unless clearly indicated by context
otherwise. Similarly, the numerical values in the various ranges
specified in this application, unless expressly indicated
otherwise, are stated as approximations as though the minimum and
maximum values within the stated ranges were both preceded by the
word "about" or "approximately." In this manner, variations above
and below the stated ranges can be used to achieve substantially
the same results as values within the ranges. As used herein, the
terms "about" and "approximately" when referring to a numerical
value shall have their plain and ordinary meanings to a person of
ordinary skill in the art to which the claimed subject matter is
most closely related or the art relevant to the range or element at
issue. The amount of broadening from the strict numerical boundary
depends upon many factors. For example, some of the factors which
may be considered include the criticality of the element and/or the
effect a given amount of variation will have on the performance of
the claimed subject matter, as well as other considerations known
to those of skill in the art. As used herein, the use of differing
amounts of significant digits for different numerical values is not
meant to limit how the use of the words "about" or "approximately"
will serve to broaden a particular numerical value. Thus, as a
general matter, "about" or "approximately" broaden the numerical
value. Also, the disclosure of ranges is intended as a continuous
range including every value between the minimum and maximum values
plus the broadening of the range afforded by the use of the term
"about" or "approximately". Thus, recitation of ranges of values
herein are merely intended to serve as a shorthand method of
referring individually to each and every separate rate value
falling within the range, unless otherwise indicated herein, and
each separate value is incorporated into the specification as if it
were individually recited herein.
* * * * *