U.S. patent application number 17/478051 was filed with the patent office on 2022-01-06 for active ingredient containing stabilised solid medicinal forms and methods for the production thereof.
This patent application is currently assigned to Losan Pharma GmbH. The applicant listed for this patent is Losan Pharma GmbH. Invention is credited to Peter GRUBER, Dirk Spickermann.
Application Number | 20220000785 17/478051 |
Document ID | / |
Family ID | |
Filed Date | 2022-01-06 |
United States Patent
Application |
20220000785 |
Kind Code |
A1 |
GRUBER; Peter ; et
al. |
January 6, 2022 |
ACTIVE INGREDIENT CONTAINING STABILISED SOLID MEDICINAL FORMS AND
METHODS FOR THE PRODUCTION THEREOF
Abstract
The invention relates to solid medicinal forms containing at
least one active ingredient and at least one pharmaceutically
compatible, water soluble drying agent which is selected from the
group consisting of trimagnesium dicitrate and/or calcium chloride,
the solid medicinal form having a drying loss of at most 6% and a
relative equilibrium moisture content of 25% or less. The invention
also relates to solid medicinal forms containing a
moisture-sensitive active ingredient and trimagnesium
dicitrate.
Inventors: |
GRUBER; Peter; (Merzhausen,
DE) ; Spickermann; Dirk; (Staufen, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Losan Pharma GmbH |
Neuenburg |
|
DE |
|
|
Assignee: |
Losan Pharma GmbH
Neuenburg
DE
|
Appl. No.: |
17/478051 |
Filed: |
September 17, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16795900 |
Feb 20, 2020 |
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17478051 |
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16213655 |
Dec 7, 2018 |
10603280 |
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16795900 |
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15705599 |
Sep 15, 2017 |
10206879 |
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16213655 |
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12441629 |
Mar 17, 2009 |
9775807 |
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PCT/EP2007/008006 |
Sep 14, 2007 |
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15705599 |
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International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 9/16 20060101 A61K009/16 |
Claims
1. A non-effervescent solid medicinal form comprising: (i) 5 to 50%
by weight of a moisture-sensitive active ingredient, wherein said
moisture-sensitive active ingredient is not trimagnesium dicitrate;
and (ii) 20-50% by weight of trimagnesium dicitrate acting as a
drying agent that stabilizes the moisture-sensitive active
ingredient against hydrolysis during storage; wherein said solid
medicinal form comprises a tablet or granule, further wherein said
solid medicinal form exhibits a relative equilibrium moisture,
measured at 25.degree. C., of at most 20%.
2. The non-effervescent solid medicinal form of claim 1, wherein
said solid medicinal form further comprises 5 to 30% of weight of a
microcrystalline cellulose.
3. The non-effervescent solid medicinal form of claim 1, wherein
said solid medicinal form exhibits a relative equilibrium moisture,
measured at 25.degree. C., of at most 15%.
4. The non-effervescent solid medicinal form of claim 1, wherein
said solid medicinal form exhibits a drying loss, measured at
120.degree. C./30 min, of at most 6%.
5. The non-effervescent solid medicinal form of claim 1, wherein
said solid medicinal form is a tablet.
6. The non-effervescent solid medicinal form of claim 5, wherein
said tablet comprises at least one further excipient selected from
the group consisting of lactose, mannitol, xylitol, lubricants,
disintegrants, silica, and combinations thereof.
7. The non-effervescent solid medicinal form of claim 6, wherein
said lubricant is selected from magnesium stearate, stearic acid
and combinations thereof
8. The non-effervescent solid medicinal form of claim 6, wherein
said disintegrant is selected from the group consisting of such as
cross-linked povidone, cross-linked carboxymethyl-cellulose, and
combinations thereof
9. The non-effervescent solid medicinal form of claim 5, wherein
said tablet is a film tablet.
10. The non-effervescent solid medicinal form of claim 1, wherein
said solid medicinal form is a granule.
11. The non-effervescent solid medicinal form of claim 1, wherein
said solid medicinal form is packaged together with an external
drying agent in a tight packaging that is substantially impermeable
to water.
Description
PRIORITY
[0001] This application is a continuation of U.S. Ser. No.
16/795,900 filed Feb. 20, 2020, which, in turn, is a continuation
of U.S. Ser. No. 16/213,655 filed Dec. 7, 2018, now U.S. Pat. No.
10,603,280 issued Mar. 31, 2020, which, in turn, is a continuation
of U.S. Ser. No. 15/705,599 filed Sep. 15, 2017, now U.S. Pat. No.
10,206,879 issued Feb. 19, 2019, which, in turn is a continuation
of U.S. Ser. No. 12/441,629 filed Mar. 17, 2009, now U.S. Pat. No.
9,775,807 issued Oct. 3, 2017, which, in turn, corresponds to the
national phase of International Application No. PCT/EP2007/008006
filed Sep. 14, 2007 which, in turn, claims priority to European
Patent Application No. 06.020008.6 filed Sep. 25, 2006, the
contents of which are incorporated by reference herein in their
entirety.
FIELD OF THE PRESENT INVENTION
[0002] The present invention relates to solid medicinal forms
containing at least one active ingredient and at least one
pharmaceutically compatible, water soluble drying agent which is
selected from the group consisting of trimagnesium dicitrate and/or
calcium chloride, the solid medicinal form having a drying loss of
at most 6% and a relative equilibrium moisture content of 25% or
less. The invention also relates to solid medicinal forms
containing a moisture-sensitive active ingredient and trimagnesium
dicitrate.
BACKGROUND OF THE PRESENT INVENTION
[0003] The stability of solid medicinal forms or solid food
supplement forms must be ensured during the entire life thereof.
The term stability comprises the chemical stability of the active
ingredient and also the physico-technical properties, such as
flowability, freedom from agglomerates, splittability of tablets,
and very important aspects, such as appearance, avoidance of change
in color of the product and in particular taste which is very
important for e.g. lozenges, chewable tablets or forms, such as
effervescent tablets or drinking granules, which are to be
dissolved before being applied. In the pharmaceutical field, the
chemical stability over the entire life of the preparation is
extremely important since the active ingredient content shall not
be reduced, if possible, and also the formation of disintegration
products which may be quite toxic shall be avoided to the greatest
possible extent.
[0004] Along with oxygen, in particular water which every active
ingredient and every excipient contain in different amounts, is
responsible for all kinds of stability, such as chemical stability,
stability towards change in color, stability of flavor.
[0005] The person skilled in the art is familiar with a plurality
of possibilities of how to ensure, or at least improve, the
stability within said wide scope. Thus, it is quite common to store
certain, highly sensitive medicinal products in a deep-freezer,
e.g. at -15 to -25.degree. C., or at least in a refrigerator prior
to the application thereof. This measure extremely limits the
applicability and markedly raises the cost for the medicinal
product.
[0006] The measure of drying the active ingredients and, where
appropriate, also all excipients linked with the active ingredients
prior to the production of the solid forms is wide-spread. However,
partially tremendous problems occur in this connection. Dried
powders or granules, for example, show extreme electrostatic
charges. They thus lose their flowability and, on production
machines, cannot be filled into capsules or sachets, for example.
The bond resulting when tablets are compressed is impossible
without the involvement of water. Therefore, no tablets which have
sufficient mechanical stability can be produced from overdried
granules. Every thermal drying process implies the danger of an
already starting disintegration of the sensitive active
ingredient.
[0007] Finally, the person skilled in the art has the possibility
of drying said solid forms after the production. However, this also
creates problems since e.g. dried capsules and tablets can be
electrostatically charged and can no longer be filled in
trouble-free manner into the containers by high-speed packaging
machines. Hard gelatin capsules, for example, lose their
flexibility and are also electrostatically charged after drying and
cannot be filled under the aspects of an efficient pharmaceutical
production.
[0008] However, here, too, the person skilled in the art ultimately
has the possibility of filling the solid forms into containers such
as tightly sealed glass vials or bottles, polyethylene (PE) cans or
aluminum tubes and provide them with a dry plug containing a
suitable drying agent, such as silica gel or molecular sieve.
However, this ultimate possibility of stabilizing
moisture-sensitive solid forms also has numerous drawbacks. Such
vials are usually refused by patients since their handling is much
more impractical than that of blister strips. The dry plug in
itself is an expensive component of packaging means and the drying
agent in the plug only has a limited intake capacity. For example,
when 50 or 100 tablets having an individual weight of 500 mg are
filled, the dry plug cannot extract the amount of water necessary
to stabilize the product from the tablets and absorb it. In
particular in the case of very sensitive active ingredients, the
greatest drawback is, however, that the drying of the solid form in
the sealed packaging means usually takes weeks and the
moisture-sensitive active ingredient is already excessively
disintegrated during this period. In addition, as shown in the
course of the invention, there is an extreme gradient of the drying
of the solid forms as a function of the distance of the solid form
from the dry plug. Thus, tablets or capsules are usually overdried
in the vicinity of the dry plug and solid forms which are disposed
farther away are insufficiently stabilized by an inadequate
extraction of water. This problem cannot be solved even if instead
of a dry plug a dry capsule is added to the product as such between
the filled tablets, e.g. in a vial or bottle.
[0009] A last possibility--in particular for active ingredients
highly sensitive with respect to moisture--would consist of drying
said solid forms and, where appropriate, manually filling them into
sealed packaging means (on account of electrostatic charges) in
rooms having a relative humidity <10%, preferably <5%, so
that the product highly hygroscopic due to drying has no
possibility of absorbing greater amounts of moisture endangering
the stability of the product. Such a production can only be carried
out in individual cases, e.g. in the production of freeze-dried
products which are very expensive. It is very expensive to ensure
said climatic conditions in production rooms, and it is not
acceptable to burden the staff for hours, even under these
extremely dry conditions.
[0010] Said problems can be overcome in individual cases by mixing
the solid form with the drying agent silica (e.g. Syloid AL 1,
trade name). Syloid is generally known as a drying agent and can
firmly bond some percents of water under the condition of
25.degree. C./10% relative humidity. In other words this means that
the mixed-in silica extracts water e.g. from the granule
constituents or tablet constituents (including the active
ingredient), and directly absorbs it.
[0011] However, silica has the major drawback of being an extremely
fine, dusty product usually having a particle size of some few
micrometers so that it is known to be used as a flow regulator. It
is insoluble in water and, when several percents are admixed to the
solid form, the mixture is not compressible. The bond strength of
water is already strongly reduced at 40.degree. C. so that only
disappointing results are obtained when the world-wide applicable
guidelines for the stress stability tests in the pharmaceutical
field (40.degree. C., 75% relative humidity) are applied.
[0012] Classical drying agents, such as phosphorus pentoxide,
calcium oxide, calcium sulfate, silica gel, are excluded for
various reasons. Phosphorus pentoxide and calcium oxide are much
too aggressive and together with numerous active ingredients and
excipients result in incompatibilities. Calcium sulfate and silica
gel are insoluble and is disappointing in particular with respect
to the strength of the water bond at 40.degree. C. Molecular sieve
would be an internal drying agent suitable to only a limited
extent; however, it is not permitted for oral purposes and would
also have no sufficient compression properties and is
insoluble.
SUMMARY OF THE PRESENT INVENTION
[0013] Therefore, it is one object of the present invention to
provide a solid medicinal form which is storage-stable and suitable
for active ingredients that are very sensitive to moisture.
[0014] This object is achieved by the subject matter of the
claims.
[0015] It has surprisingly been found that by using certain water
soluble drying agents that do not only have a high drying capacity
but can also firmly bond water, it is possible to produce solid
medicinal forms having excellent storage stability. In particular,
moisture-sensitive active ingredients show a very good stability in
the medicinal forms according to the invention.
[0016] For example, the results of the test with amoxicilline
trihydrate (see Example 2) which prove that dried trimagnesium
dicitrate has a bonding tendency for water higher than that of the
known drying agent silica gel, are fully surprising to the person
skilled in the art. Contrary to silica gel, dried trimagnesium
dicitrate can bond the entire water of crystallization of
amoxicilline trihydrate. Due to this test, it has been proved
specifically that dried trimagnesium dicitrate mixed into a solid
form can bond relatively great amounts of water and dry the
constituents of this mixture, in particular a moisture-sensitive
active ingredient so as to largely avoid a disintegration caused by
water of the active ingredient. It was also possible to obtain very
favorable results with calcium chloride.
[0017] Therefore, the invention relates to a solid composition,
preferably a solid medicinal form, containing at least one active
ingredient and at least one pharmaceutically compatible, water
soluble drying agent, which is selected from trimagnesium
dicitrate, calcium chloride and combinations thereof, characterized
in that the solid composition has a drying loss, measured at
120.degree. C./30 min, of at most 6% and a relative equilibrium
moisture content, measured at 25.degree. C., of 25% or less.
[0018] The preferred drying agents according to the present
invention have the following properties:
[0019] They are [0020] physiologically harmless, cost-effective and
world-wide accepted in the pharmaceutical and foodstuff fields;
[0021] water soluble, have no bad taste in the amounts used; [0022]
available and well processable with respect to production
technology within a mean grain size range of 0.02 to 2.5 mm; [0023]
compressible without any problems, compactable; [0024] chemically
compatible with a plurality of active ingredients, in particular
with moisture-sensitive active ingredients, such as acetylsalicylic
acid (ASS), clavulanic acid, proton pump inhibitors, such as
omeprazole, lansoprazole, pantoprazole and numerous
moisture-sensitive prodrugs.
[0025] They have [0026] virtually no negative influence on the
release rate of active ingredients from said solid forms; [0027]
the highest and firmest possible adsorbability of water in the
range of up to 25% relative humidity and a temperature of at most
40.degree. C.; [0028] a pH of 5 to 8, preferably 5.5 to 7.5, as the
0.1 molar solution.
[0029] Suitable drying agents are calcium chloride, magnesium
sulfate, tricalcium citrate, carnitine. However, to the skilled
person's surprise, trimagnesium dicitrate is the best to comply
with the above mentioned preferred properties of an internal drying
agent. It is an inexpensive, physiologically fully harmless, water
soluble salt having sufficiently good compression and compacting
properties. Both the 12-hydrate and the 9-hydrate and a dried form
are known. The salt is available in both micronized form having a
mean grain size of 25 .mu.m and a mean grain size of 1 to 2 mm.
[0030] The medicinal form according to the invention has a drying
loss of at most 6%, preferably of at most 4.5%, more preferably at
most 3.5%, even more preferably at most 3.0%, most preferably 2.5%
or less, e.g. 0.1% to 2.5% or 0.5% to 2.5%.
[0031] The drying loss is a measure of the amount of water in a
solid form:
drying .times. .times. loss .times. .times. in .times. .times. % =
mass .times. .times. of .times. .times. the .times. .times. water
.times. .times. in .times. .times. the .times. .times. sample total
.times. .times. mass .times. .times. of .times. .times. the .times.
.times. sample .times. 100 ##EQU00001##
[0032] In order to determine the drying loss of a sample (e.g. a
solid medicinal form), the sample is spread over a so-called drying
balance and (e.g. by an accurately working infrared radiator)
adjusted to the desired temperature, e.g. of 105.degree. C. After a
certain time (e.g. after 20 or 30 minutes), the drying loss due to
the evaporation of water is directly read off the balance in
percent. Unless otherwise specified in this application, the
expression "drying loss" refers to the drying loss determined under
the conditions of 105.degree. C./30 min. A suitable device for
measuring of the drying loss is the Moisture Analyzer HR83 of
Mettler-Toledo company (CH-8606 Greifensee, Switzerland). The
device or the drying balance is preferably used in a closed
interior having an ambient temperature of 20.degree. C. and 20%
relative humidity.
[0033] The drying loss is silent on the strength of the water bond
and does not permit a statement on how strongly and in what form
the water is bonded. Theoretically there is retained water,
capillary water, swelling water, absorbed water and water of
crystallization. The former is not bonded and readily evaporates,
the water of crystallization can be bonded very firmly and requires
a high temperature and a long drying time for the determination of
the drying loss.
[0034] In connection with the present invention it is, however,
very important to have a method furnishing information on the
bonding mechanism of water and the strength of the water bond. For
this purpose, the so-called "relative equilibrium moisture content"
(hereinafter also abbreviated as "equilibrium moisture content") is
measured which forms on the sample in a fully sealed measuring cell
at a certain temperature. It is also referred to as equilibrium
activity or water activity. The water activity describes the bond
strength of water to the active ingredient and/or the individual
components of the active ingredient mixture. The measured value for
the water activity and/or for the equilibrium moisture (Equilibrium
Relative Humidity) has a decisive influence on the chemical
stability of a moisture-sensitive active ingredient which is
embedded in a solid form, such as granules, a capsule or
tablet.
[0035] The equilibrium moisture content is the value of the
relative humidity in which a hygroscopic product can be stored
without a net moisture exchange taking place between the product
and its environment. Thus, if a solid form has an equilibrium
moisture content of 10% and is stored at a relative humidity of
15%, it absorbs water from its environment, if the relative
moisture of the environment is below 10%, the solid form releases
water to its environment and becomes even drier.
[0036] The correlation between the equilibrium moisture content and
the moisture content of a solid form (drying loss) can be shown by
means of the known sorption isotherm, the equilibrium moisture
and/or the water activity being given on the abscissa and the water
content in percent on the ordinate.
[0037] Unless otherwise specified, the equilibrium moisture content
is determined as follows in a thermostatted small, tightly sealed
measuring cell having a volume of about 50 ml. In the upper part of
this measuring cell there is a sensor which can measure the
relative moisture content resulting from the evaporation of water
from the sample to be measured (the device HygroLab having the AWVC
measuring cell of Rotronic company, CH 8303 Bassersdorf,
Switzerland, is used). The device is officially calibrated and the
measuring inaccuracy is no more than +1% relative humidity or
+0.3.degree. C. The measuring accuracy can be repeated at any time
with standardized salt solutions as known to the person skilled in
the art. The measurement takes place at 25.degree. C.
[0038] If crystalline citric acid, for example, is measured with a
drying loss of 0.2% (measured at 70.degree. C./30 min), the
measurement of the measuring cell thermostatted to 25.degree. C.
yields an equilibrium moisture content of 63%. However, if corn
starch having a drying loss of 8.5% is measured (also determined at
70.degree. C./measuring time 30 min), an equilibrium moisture
content of only 22% can be measured. A comparison of both measuring
values clearly shows that in the case of citric acid the water is
only bonded very loosely in contrast to corn starch and thus is
readily available for the disintegration of a moisture-sensitive
active ingredient, for example.
[0039] The drying agents according to the invention which are not
only strongly hygroscopic but also firmly bond the absorbed water,
can suppress almost fully a disintegration caused by water or a
change in color, etc., in combination with moisture-sensitive
active ingredients.
[0040] The equilibrium moisture content in the solid form can be
lowered by the kind and amount of the employed drying agents which
is incorporated with the moisture-sensitive active ingredient into
the solid form such that almost no free water is available for the
disintegration of the active ingredient.
[0041] The medicinal form according to the invention has an
equilibrium moisture content, measured at 25.degree. C., of at most
25%, preferably at most 20%, more preferably at most 15%, even more
preferably at most 10%, most preferably at most 6%, e.g. 1% to 6%,
or 1.5% to 4% or even 1.5% to 2.5%.
[0042] The concentration of the drying agent in the medicinal form
is 10 to 99.0%, preferably 15 to 75%, more preferably 20 to 50%,
most preferably 30 to 40%. Unless otherwise specified, the %
indications in this application referring to the concentration of
substances in the solid medicinal form, are % by weight.
[0043] The concentration of the active ingredient in the medicinal
form is usually 1% to 75%, more preferably 5% to 50%, even more
preferably 10% to 45%, most preferably 20% to 40%, e.g. 30% to
40%.
[0044] The active ingredient can be any substance which can cause a
therapeutic and/or preventive effect. The active ingredient is
preferably an organic compound, i.e. a molecule containing carbon.
The medicinal forms of the present invention are particularly
suited for active ingredients which are sensitive to moisture
(referred to as moisture-sensitive active ingredients in the
present application). In the sense of the present application, an
active ingredient is regarded as moisture-sensitive if a pattern of
a pure active ingredient adjusted to an equilibrium moisture
content of 25% at 20.degree. C., has a disintegration of over 1% in
a sealed packaging means at 40.degree. C. within 6 months. As a
function of the toxicity of the resulting disintegration product or
products, the disintegration can also be up to 3%, in very rare
cases up to 5%. 40.degree. C. is the maximum stress temperature
matched and harmonized world-wide in the pharmaceutical field for
active ingredients and medicinal forms.
[0045] Examples of moisture-sensitive active ingredients are ASS,
clavulanic acid, omeprazole and lansoprazole. The expression
"active ingredient" in the sense of the present invention includes
so-called prodrugs, i.e. precursors of the actually
pharmacologically active substances which are not converted into
one or more active metabolites in the organism until the
administration thereof. Reasons for the development of a prodrug
can be poor resorbability (enalaprile enalaprilate), poor
solubility, a high first pass effect or high toxicity of the active
substance. Prodrugs are often sensitive to moisture. They include
in particular ester and amide compounds which in the presence of
water tend to hydrolyze.
[0046] Therefore, the invention also relates to a solid medicinal
form containing 1 to 75% by weight of moisture-sensitive active
ingredient, 10 to 95% by weight of trimagnesium dicitrate and,
where appropriate, further excipients. The preferred embodiments of
this aspect of the invention correspond to the preferred
embodiments which have been described in connection with other
aspects of the invention.
[0047] The active ingredient differs from the drying agent which is
also present in the medicinal form. For example, the medicinal form
which includes trimagnesium dicitrate as a drying agent contains an
active ingredient other than trimagnesium dicitrate and Mg2+.
[0048] The medicinal form of the present invention is not
particularly limited. It can be e.g. powder, granules, tablets,
capsules or other solid forms. As to the intended use, the
medicinal forms can be prepared for peroral, oral, parenteral or
external application. So-called standard tablets, mini-tablets
(diameter <4 mm), dragee cores, chewing tablets, orodispersible
tablets, coating tablet, multi-layer tablets, retard tablets
according to the coating or embedding principle, structural
tablets, matrix tablets, floating tablets, bioadhesive tablets,
film tablets, gastric juice resistant tablets, tablets soluble in
the large intestine, effervescent tablets. These and further tablet
kinds are described in "Die Tablette", W. A. Ritschel, A.
Bauer-Brandl, Editio Cantor Verlag Aulendorf, 2002, whose content
is herewith inserted in this application.
[0049] The medicinal form can also contain further conventional
excipients, as described in "Die Tablette" W. A. Ritschel, A.
Bauer-Brandl, Editio Cantor Verlag Aulendorf, 2002, whose content
is herewith inserted in this application. The medicinal form can
contain microcrystalline cellulose, lactose, mannitol, xylitol and
disintegrants, such as cross-linked povidone or cross-linked sodium
carboxymethyl cellulose. For example, silica (with the trade name
of Syloid AL 1) is particularly suited as a flow regulator. Typical
lubricants for the production of tablets, such as magnesium
stearate and stearic acid, may also be contained. The medicinal
form preferably contains microcrystalline cellulose, lactose,
mannitol, xylitol, tricalciumphosphate, lubricant, flow regulator
and/or sliding agents. The concentration of microcrystalline
cellulose is preferably 5 to 30%, more preferably 10 to 20%, that
of the lubricant is 0.3 to 2%, that of the flow regulator is 0.2 to
2.0% and that of the sliding agent is 1.0 to 5%. Finally,
conventional fillers may also be contained.
[0050] Another aspect of the invention is a sealed package
containing a solid medicinal form as described herein. The
expression "sealed" means that the package is substantially
impermeable to water. The package may have various forms. Suitable
packages are e.g. the standard known packaging means, such as
sachet and stick pack, produced from aluminum-coated foils, glass
vials, PE or PP tubes having reliably sealing plugs or screw caps
with sealing inserts. As to extremely moisture-sensitive active
ingredients, an aluminum tube having a tight PE plug is
particularly suited. Glass vials or bottles closed with a
pilferproof closure known to the person skilled in the art have
also excellently proved of value. Blister strips made of aluminum
foil are possible as well.
[0051] A further aspect of the invention is a solid medicinal form
according to the invention, packed in a sealed packaging means, as
described above.
[0052] The solid form preferably has an equilibrium moisture
content of at most 25%, preferably at most 20%, more preferably at
most 15%, even more preferably at most 10%, most preferably at most
6%, e.g. 1% to 6%, or 1.5% to 4% or even 1.5% to 2.5%, each
measured at 25.degree. C., for at least 3 months, preferably for at
least 6 months, preferably for at least 1 year, most preferably for
the entire life of the product in the packaging means.
[0053] Along with tablets, capsules are approved embodiments of
this invention. Unfortunately, hard gelatin capsules are only
suited to a limited extent since the gelatine contains too much
water.
[0054] When the gelatine capsules are dried, they strongly
embrittle, are electrostatically charged and lose their
flexibility. Therefore, hydroxypropylmethyl cellulose (HPMC)
capsules are preferred which basically contain markedly less water.
Although the disintegration time of these capsules is somewhat
prolonged, they have the advantage that even strongly dried
capsules retain their flexibility.
[0055] A preferred embodiment of the present invention is thus e.g.
a HPMC capsule which was filled into a glass vial having a tightly
fitted plug. The filling material of the capsule consists of 30 to
40% highly moisture-sensitive active ingredient, 30 to 40%
trimagnesium dicitrate, 10 to 20% dried microcrystalline cellulose,
1 to 2% lubricant and 1 to 3% sliding agent such as talcum or
preferably silica. Under the severe drying condition of 120.degree.
C./30 min, the drying loss of the capsule content is 0.5 to 3.5%,
preferably 1.5-3.0%, the equilibrium moisture of the content is
less than 10%, preferably less than 6%. The drying loss of the HPMC
capsule is 1.5 to 2.5%. However, the equilibrium moisture which has
to be observed within said limits on all accounts, is very
decisive.
[0056] The capsule disintegrates in water in the disintegration
test, which is specified in European Pharmacopoe EP 5.0, between 6
and 12 minutes, in artificial gastric juice within 5 to 10
minutes.
[0057] If in place of the preferred drying agent trimagnesium
dicitrate, calcium chloride or mixtures of both are used, the
preferred weight ratios as indicated above do not change. The
drying loss of the capsule content is 2 to 6 percent, the drying
loss of the capsule is unchanged, each measured under equal drying
conditions. The equilibrium moisture content of the capsule content
is also preferably below 6%.
[0058] In the case of particularly moisture-sensitive active
ingredients or in the case that relatively large amounts of
moisture-sensitive active ingredient must be processed at the
expense of a sufficient amount of drying agent or in the case of
particularly long exposition times of the solid forms during the
production and filling, the product filled in a tube or vial can
also be closed with a drying agent plug in the individual case.
Here, in particular dry plugs filled with the particularly active
drying agent, i.e. molecular sieve, prove of value.
[0059] Another aspect of the present invention is a process for the
production of a solid medicinal form. In one embodiment, the
process comprises the steps of: [0060] a) mixing at least one
active ingredient having a drying agent which is selected from the
group consisting of trimagnesium dicitrate, calcium chloride and
combinations thereof, [0061] b) where appropriate, dry granulating
the composition obtained in step a) to obtain granules, [0062] c)
compressing or encapsulating the composition obtained in step a) or
the granules obtained in step b) to obtain the solid medicinal
form, and [0063] d) where appropriate, packing the solid medicinal
form into a sealed packaging agent.
[0064] In this connection, the ratio of drying agent to active
ingredient in step a) should be chosen and the process be carried
out under conditions such that the solid medicinal form obtained in
step c) or the solid, packed medicinal form obtained in step d) has
a drying loss, measured at 120.degree. C./30 min, of at most 6% and
a relative equilibrium moisture content, measured at 25.degree. C.,
of 25% or less.
[0065] The preferred drying agent in the method of the invention is
dried trimagnesium dicitrate. The drying agent can be dried with
the active ingredient before mixing, e.g. at 100 to 150.degree. C.,
preferably 110 to 140.degree. C., most preferably 120 to
135.degree. C. The drying time can be at least 0.5 h, preferably at
least 1 h, more preferably at least 2 h, most preferably at least 3
h, e.g. 1 to 6 h, 2 to 5 h or 3 to 4 h. Alternatively, a
substantially anhydrous drying agent can be used which does not
have to be predried if the drying loss is at most 3.0% or less
(measured at 150.degree. C./30 min).
[0066] The maximum drying loss for calcium chloride may be at most
5.0% (measured at 150.degree. C./30 min).
[0067] The drying agent to be used should have a drying loss of
less than 3%, preferably less than 2%, most preferably less than
1%, directly before being mixed with the active ingredient. The
equilibrium moisture content of the drying agent should be less
than 5%, preferably less than 3%, most preferably less than 1%,
directly before being mixed with the active ingredient.
[0068] The ratio of the mass of the drying agent to the mass of the
active ingredient in step a) can be 0.5 to 2, preferably it is 0.75
to 1.5, most preferably 1 to 1.3.
[0069] As known to the person skilled in the art and also mentioned
at the beginning, it is virtually impossible to fill or compress
powder mixtures or granules having an excessively low equilibrium
moisture on account of electrostatic charges or lack of
compressibility (see "Die Tablette", W. A. Ritschel, A.
Bauer-Brandl, Editio Cantor Verlag Aulendorf, 2002, page 286).
[0070] By suitable drying agents, such as calcium chloride and
preferably dried trimagnesium dicitrate, it is, however, possible,
e.g. in powder mixtures, granules, tablets, etc., to realize with a
moisture-sensitive active ingredient a low equilibrium moisture
content such that the sensitive active ingredient is stabilized or
can be inserted in solid forms at all.
[0071] This addition can be made directly before the filling of
granules, for example. As a result of the avoidance of drying for
the purpose of removal, electrostatic charges are avoided and the
filling step in a dense packaging means, such as a stick pack or a
sachet, consisting of aluminum-coated foil, is carried out. The
amount of the preferred homogeneously distributed drying agent
trimagnesium dicitrate is determined by the person skilled in the
art such that it firmly bonds both the water absorbed during the
filling step and the water present in the entire mixture such that
it is no longer available for the disintegration of the active
ingredient. As shown in Example 3, the ASS granule mixture in the
sealed packaging means is dried by the addition of the
physiologically fully harmless trimagnesium dicitrate unproblematic
as regards taste such that the disintegration of the active
ingredient ASS is markedly minimized. The flavors are also
stabilized by the reduction of the equilibrium moisture so that
along with the chemical stability of the active ingredient the
sensory stability of the flavor is also markedly improved during
the entire life of the preparation.
[0072] Of course, it is an advantage if in the case of highly
sensitive active ingredients the production of the solid form and
the filling take place under climatic control. Here, conditions of
20 to 25% relative humidity at about 20.degree. C. (or 15 to 25 or
18 to 22.degree. C.) have proved of value world-wide in the
pharmaceutical production field. As a result of the reduced
moisture in the rooms, the absorption of moisture during the
working operations such as screening, mixing, tabletting and
filling, is thus lowered. If the drying agents according to the
invention are ignored for the work, said climatic conditions of 20%
are by far not sufficient with moisture-sensitive active
ingredients to guarantee a product stable for years since for
reasons of stability the equilibrium moisture of the product must
often be markedly below 10%. Such a product would not absorb any
moisture only if in the production room the relative humidity was
also below 10%.
[0073] As shown in Example 4, the highly moisture-sensitive active
ingredient clavulanic acid can be excellently stabilized by the
approach according to the invention. The example proves that by the
addition of dried trimagnesium dicitrate the equilibrium moisture
content of the mixture to be filled is only 5% (25.degree. C.).
Irrespective of this extremely low equilibrium moisture, the
product can still be filled without hesitation in production rooms
at 25%/20.degree. C. The moisture inevitably absorbed during the
filling step is firmly bonded by the preferred trimagnesium
dicitrate and to the skilled person's surprise does not change the
equilibrium moisture content of the powder mixture filled into a
sealed vial. In the case of an equilibrium moisture of only 5% ,
the clavulanic acid is only in contact in a very small water amount
so that the stability of the active ingredient can markedly be
improved by the inventive measures. If as a result of complex and
prolonged unavoidable production processes, the exposition times of
the inventive powder mixture, granules, tablets, capsules, film
tablets are extended, it is advisable to use the inventive drying
agent in a coarser particle size. As a result, the water absorption
of the hygroscopic drying agent is reduced due to a smaller
particle surface during the exposition time. Here, particle sizes
between 0.2 and 2 mm have proved of value in the case of
trimagnesium dicitrate and calcium chloride, the preferred mean
particle size being about 0.8 mm. However, if the active ingredient
is particularly moisture-sensitive and the water inevitably
introduced into the mixture by the use of excipients must be
rapidly removed, the use of e.g. micronized trimagnesium dicitrate
is recommended. This material has a preferred mean grain size of
0.025 mm.
[0074] In the production of solid forms having moisture-sensitive
active ingredients corresponding to the invention, it is of course
preferably tried to use dried excipients or excipients having a low
drying loss or excipients having very firmly bonded water. Powders,
granules, capsules, tablets are usually produced without moisture
granulation. For this purpose, the components are mixed with the
moisture-sensitive active ingredient and then filled into e.g.
sealed sachets, hard gelatin capsules or are compressed into
tablets. The active ingredients and the necessary excipients having
a low water content are often not well flowable so that the person
skilled in the art carries out dry granulation by tabletting or
compacting the mixture followed by screening such that well
flowable dry granules form. Basically, all excipients common in the
production of granules, capsules or tablets can be used if they
have a low drying loss or were predried. Predried microcrystalline
cellulose, spray-dried, well tabletted lactose, mannitol, xylitol
and disintegrants, such as cross-linked povidone or cross-linked
sodiumcarboxymethyl cellulose are particularly suited. For example,
silica (with the trade name of Syloid AL 1) is particularly suited
as a flow regulator. Typical lubricants for the production of
tablets, such as magnesium stearate and stearic acid, can be used
without any problems since they only contain small amounts of
moisture and are usually only used in an amount of 0.5%.
[0075] Another object for the person skilled in the development
field is to chose along with the selection of suitable excipients
the amounts of moisture-sensitive active ingredients, excipients
necessary for the production process and the preferred drying
agents such that powders and granules can be filled into sachets or
capsules and sufficiently hard and mechanically stable tablets form
which in the individual case can even be transferred into film
tablets, preferably with an alcoholic coating solution. Of course,
the person skilled in the art must keep an eye on the aspects, such
as disintegration time of the tablets and capsules and the release
rate of the active ingredient from these solid forms, for the
qualitative and quantitative selection of the excipients and the
preferred drying agents.
[0076] The amount to preferred drying agent must be chosen by the
person skilled in the art such that [0077] a) after filling, an
equilibrium moisture corresponding to the moisture sensitivity of
the active ingredient adjusts in the solid form which has proved of
value on the basis of stability investigations [0078] b) the
moisture absorption inevitable during the production and filling
operations is compensated and the stability-required equilibrium
moisture content adjusts in the sealed packaging means.
[0079] Fortunately, calcium chloride and in particular trimagnesium
dicitrate show a favorable processing behavior so that e.g. in the
dry granulation of even maximum amounts of drying agent create no
difficulties. Since both preferred excipients are also soluble in
water, no problems occur with respect to the active ingredient
release. As a function of the amount of moisture-sensitive active
ingredient to be processed and in particular the degree of its
moisture sensitivity, the solid forms consist of 10 to 99.5,
preferably 15 to 75 and most preferably 20 to 50% of said drying
agents.
[0080] A further aspect of the invention is the use of trimagnesium
dicitrate to stabilize moisture-sensitive active ingredients or to
increase the stability of moisture-sensitive active ingredients.
The chemical stability of the active ingredients is preferably
increased. In a particular embodiment, trimagnesium dicitrate is
used to protect the active ingredient from hydrolysis.
[0081] Still another aspect of the invention is the use of
trimagnesium dicitrate as a drying agent in solid medicinal
forms.
[0082] Finally, the invention relates to a method for increasing
the stability of moisture-sensitive active ingredients,
characterized in that the active ingredient is mixed with
trimagnesium dicitrate.
[0083] The latter aspects of the invention can, of course, be
combined with the above described embodiments of other aspects.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0084] The invention is specified by the below examples without
being limited thereto.
EXAMPLE 1
[0085] If the preferred drying agent trimagnesium dicitrate is
dried at 130.degree. C. for several hours, a product is obtained
which to the skilled person's surprise has an equilibrium moisture
content having a hardly measurable value of 0.6% at 25.degree.
C.
[0086] Sodium sulfate which has a drying loss at 130.degree. C.
(testing period 30 min) of 0.06%, still yields a value of 32.7%
when the equilibrium moisture content is determined. This value
proves that sodium sulfate cannot adsorb either a water amount
worth mentioning or firmly bonds these adsorbed amounts. This
substance is fully unsuited to stabilize moisture-sensitive active
ingredients.
TABLE-US-00001 TABLE 1 weight increase (%) drying loss at
equilibrium with storage at 15% 130.degree. C./30 min moisture
relative humidity/25.degree. C. microcrystalline 0.5 <1.0 2.2
cellulose trimagnesium 0.2 <1.0 8.6 dicitrate calcium chloride
0.02 <1.0 45.9 sorbitol 0.1 9.0 0.1 silica 0.5 <1.0 6.4
[0087] The substances were dried at 130.degree. C. for 5 hours
(sorbitol: 70.degree. C.) and the drying loss was determined. Then,
the weight increase of the individual substances was determined at
25.degree. C./15% relative humidity over 27 days.
[0088] The table proves that even with a very low humidity of 15%
calcium chloride can absorb major amounts of water and that to the
skilled person's surprise the preferred trimagnesium dicitrate
bonds more water than the generally known drying agent silica
(silica gel).
EXAMPLE 2
[0089] In a tightly sealing glass vessel, two Arcellas having 3.5 g
trimagnesium dicitrate, dried at 130.degree. C., or having 1.264 g
amoxicilline trihydrate (water content 13.1%) are placed side by
side and stored at 25.degree. C. After 14 days, the weight of
amoxicilline is only 1,105 g whereas the weight of trimagnesium
dicitrate is 3.66 g. The amoxicilline released 12.6% water of
crystallization which was absorbed by the drying agent. The new
drying agent is active such that it virtually split off the entire
water of crystallization of amoxicilline (theoretical value:
12.9%).
[0090] If this experiment is repeated with the known drying agent
silica gel, the antibiotic only loses 0.1% weight after 25 days.
This means that the dried trimagnesium dicitrate according to the
invention represents an extremely potent drying agent.
[0091] Under precisely equal test conditions, the amoxicilline only
loses 9.0% with calcium chloride dried at 130.degree. C. after 26
days/25.degree. C.
EXAMPLE 3
[0092] Two dry mixtures having the following composition were
produced:
TABLE-US-00002 TABLE 2 a) b) acetylsalicylic acid 500 mg 500 mg
sorbitol 950 mg 950 mg citric acid 59 mg 59 mg magnesium oxide 25
mg 25 mg aspartame 10 mg 10 mg lemon flavor 25 mg 25 mg
trimagnesium dicitrate -- 125 mg (TOTAL 1694)
[0093] The components were mixed, filled into aluminum-coated bags
and stored at 40.degree. C. for three months.
[0094] In case a), a disintegration caused by water of
acetylsalicylic acid occurred while 3.2% salicylic acid and glacial
acetic acid were formed. The pattern was uneatable.
[0095] Pattern b) showed a disintegration of 0.6% and virtually no
odor of glacial acetic acid. The pattern was still o.k. as regards
taste.
[0096] The equilibrium moisture of pattern a) was 34% (25.degree.
C.) and that of pattern b) 8.4% due to the addition of trimagnesium
dicitrate. The low equilibrium moisture according to the invention
markedly stabilizes the active ingredient due to its water
bond.
EXAMPLE 4
[0097] Trimagnesium dicitrate, calcium chloride.times.2H2O are
dried at 130.degree. C. for several hours. The drying loss,
measured at 150.degree. C./30 min, is:
TABLE-US-00003 Trimagnesium dicitrate: 1.6%; equilibrium moisture
content <0.5% Calcium chloride: 3.4%; equilibrium moisture
content <0.5% clavulanic acid 3.0 kg trimagnesium dicitrate 4.0
kg (mean particle size 0.25 mm) microcrystalline cellulose 1.5 kg
mannitol 1.0 kg silica (Syloid AL 1) 0.2 kg povidone K25 0.2 kg
magnesium stearate 0.1 kg
[0098] The components were sieved in a room at 22.degree. C., 19%
relative humidity and then compacted to a slug in a roll compactor.
The slug was dry granulated over 2.5 mm and 1.0 mm. The granules
were kept in a sealingly closing container prior to the
encapsulation.
[0099] The drying loss of the granules, measured at 105.degree.
C./30 min, was 2.4%, the equilibrium moisture content was 4.6%
(25.degree. C.). Under exactly the same conditions, the test was
repeated with 3.0 kg dried calcium chloride as described above. The
calcium chloride was similarly well processed into granules.
[0100] Drying loss: 1.7% (105/30 min)
[0101] Equilibrium moisture: 5.4% (25.degree. C.)
[0102] Both granules were filled at 21.degree. C./22% relative
humidity in undried HPMC capsules (filling weight 417 mg per
capsule size 1) and under the same room conditions into glass vials
(20 items) and closed with sealingly closing PE plugs. Some plugs
contained 2.0 g molecular sieve.
[0103] The patterns were subjected to a stress test at 40.degree.
C./75% relative humidity for 6 months.
TABLE-US-00004 TABLE 3 3 6 6 Test parameters Start months months
months* appearance capsule content white white almost almost white
white disintegration time capsule in 8.5 min 9.2 min 9.1 min 8.8
min water, 37.degree. C. drying loss 2.8% 2.6% 2.9% 2.5% capsule
content equilibrium moisture content 5.2% 4.8% 5.5% 4.2% capsule
content drying loss 2.7% 2.3% 2.2% 2.1% HPMC capsule drying loss
1.2% -- -- 1.6% drying agent/plug content clavulanic acid 101.4%
99.8% 96.1% 96.7% *pattern with dry plug All drying losses measured
at 105.degree. C./30 min, Drying loss drying agent/plug at
200.degree. C./30 min
[0104] Results (clavulanic acid capsules with calcium
chloride):
TABLE-US-00005 TABLE 4 3 6 6 Test parameters start months months
months* appearance capsule content white almost yellow white/yellow
white disintegration time capsule in 7.9 min 8.2 min 8.6 min 8.4
min water, 37.degree. C. drying loss 2.1% 2.3% 2.2% 1.7% capsule
content equilibrium moisture content 5.9 % 6.9% 7.2% 5.2% capsule
content drying loss 3.1% 3.2% 2.9% 2.5% HPMC capsule drying loss
1.2% -- -- 6.4% drying agent/plug content clavulanic acid 100.7%
98.7% 93.1% 94.6% *pattern with dry plug All drying losses at
105.degree. C./30 min Drying loss drying agent/plug at 200.degree.
C./30 min
[0105] Although the drying losses of the capsule content increase
in both test examples due to the exposition time during the capsule
filling and the water content of the undried capsule, the
equilibrium moisture content of the capsule content does virtually
not change in both test examples. This proves that the water
absorbed during filling and extracted from the capsule is absorbed
by the drying agent without the equilibrium moisture content
decisive for the stability of the moisture-sensitive clavulanic
acid changing. Due to the dense packaging agent, the drying losses
of the capsule content and the accompanying equilibrium moisture
contents hardly change during stress storage for 3 and 6 months.
This is an essential precondition for the stabilization of the
active ingredient. The results on the drying loss of the drying
agent in the plugs are very interesting. Although the person
skilled in the art knows that molecular sieve is an extremely
severe drying agent, it hardly removed water from the capsules with
content to the skilled person's surprise in the case of the drying
agent trimagnesium dicitrate and the drying loss only increased
from 1.2 to 1.6%. This is a clear evidence for the strong bond of
the water to trimagnesium dicitrate. Again to the skilled person's
surprise, the water absorption of the molecular sieve markedly
increased from 1.2% to 6.4% in the case of the clavulane capsules
with the drying agent calcium chloride. Although calcium chloride
is considered a strong drying agent, the molecular sieve absorbed
over 5% water from the capsules. This in turn proves that although
to the skilled person's surprise trimagnesium dicitrate can bind
less water than calcium chloride, the strength of the water bond is
markedly higher. This makes trimagnesium dicitrate the preferred
drying agent for active ingredients highly sensitive to water since
the new drying agent can so to speak irreversibly bond the water up
to the conditions of about 40.degree. C. and largely dry the
sensitive active ingredient by ensuring in the solid form
equilibrium moisture contents around 5% up to temperatures of
40.degree. C.
[0106] If the clavulanic acid granules are produced without one of
both drying agents, they have an equilibrium moisture content of
28.9% after the production, which is an equilibrium moisture
content very low for capsule granules. The active ingredient in
this mixture loses, when stored at 40.degree. C. in a sealed vial,
over 25% content within one week and changes its color to light
brown. Normal capsule mixtures have an equilibrium moisture content
of 35 to 55%. Thus, clavulanic acid is indeed an extremely
moisture-sensitive active ingredient which even in the presence of
small amounts of water rapidly loses activity.
* * * * *