U.S. patent application number 12/135580 was filed with the patent office on 2008-10-02 for process for producing solid oral dosage forms with sustained release of active ingredient.
Invention is credited to Hermann Ascherl, Dieter Flick, Karl KOLTER.
Application Number | 20080241261 12/135580 |
Document ID | / |
Family ID | 7645638 |
Filed Date | 2008-10-02 |
United States Patent
Application |
20080241261 |
Kind Code |
A1 |
KOLTER; Karl ; et
al. |
October 2, 2008 |
PROCESS FOR PRODUCING SOLID ORAL DOSAGE FORMS WITH SUSTAINED
RELEASE OF ACTIVE INGREDIENT
Abstract
The present invention relates to a process for producing solid
oral dosage forms with sustained release of active ingredient,
comprising at least one active ingredient, a preformulated mixture
of polyvinyl acetate and polyvinylpyrrolidone, where appropriate,
water-soluble polymers or lipophilic additives and, where
appropriate, other conventional excipients, wherein this mixture or
parts of this mixture are granulated by heating to from 40.degree.
C. to 130.degree. C., and the granules are, after admixture with
conventional excipients, subsequently tabletted.
Inventors: |
KOLTER; Karl; (Limburgerhof,
DE) ; Flick; Dieter; (Boehl-Iggelheim, DE) ;
Ascherl; Hermann; (Dirmstein, DE) |
Correspondence
Address: |
NOVAK DRUCE DELUCA + QUIGG LLP
1300 EYE STREET NW, SUITE 1000 WEST TOWER
WASHINGTON
DC
20005
US
|
Family ID: |
7645638 |
Appl. No.: |
12/135580 |
Filed: |
June 9, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09873431 |
Jun 5, 2001 |
7413750 |
|
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12135580 |
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Current U.S.
Class: |
424/489 |
Current CPC
Class: |
A61K 9/1635 20130101;
A61P 3/02 20180101; A61K 9/1652 20130101; A61K 9/2095 20130101;
A61K 9/2027 20130101; A61P 9/12 20180101 |
Class at
Publication: |
424/489 |
International
Class: |
A61K 9/14 20060101
A61K009/14 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 19, 2000 |
DE |
10029201.1 |
Claims
1.-16. (canceled)
17. An oral dosage form comprising a) a formulated mixture of
polyvinyl acetate and polyvinylpyrrolidone, wherein the
polyvinylpyrrolidone is finely dispersed in the polyvinyl acetate,
b) at least one active ingredients c) optionally where appropriate
water-soluble polymers or low or high molecular weight lipophilic
additives, and d) optionally excipients, wherein the mixture of a)
to d) or a) to c) or a) and b) and d) or a) and b) is granulated by
heating to from 40.degree. C. to 130.degree. C.
18. An oral dosage form as claimed in claim 17, which comprises as
active ingredients food supplements or additives, vitamins,
minerals or trace elements or active pharmaceutical
ingredients.
19. An oral dosage form as claimed in claim 17, which comprises
active pharmaceutical ingredients as active ingredients.
20. An oral dosage form as claimed in claim 19, wherein the active
pharmaceutical ingredient is selected from the group of
benzodiazepines, antihypertensives, vitamins, cytostatics,
anesthetics, neuroleptics, antidepressants, antibiotics,
antimycotics, fungicides, chemotherapeutics, urologicals, platelet
aggregation inhibitors, sulfonamides, spasmolytics, hormones,
immunoglobulins, sera, thyroid therapeutics, psychopharmaceuticals,
antiparkinson agents and other antihyperkinetics,
ophthalmologicals, neuropathy products, calcium metabolism
regulators, muscle relaxants, lipid-lowering agents, liver
therapeutics, coronary agents, cardiac agents, immunotherapeutics,
regulatory peptides and their inhibitors, hypnotics, sedatives,
gynecologicals, antigout agents, fibrinolytics, enzyme products and
transport proteins, enzyme inhibitors, emetics, perfusion
promoters, diuretics, diagnostics, corticoids, cholinergics,
biliary therapeutics, antiasthmatics, bronchospasmolytics,
beta-receptor blockers, calcium channel blockers, ACE inhibitors,
arteriosclerosis remedies, antiinflammatory agents, anticoagulants,
antihypotensives, antihypoglycemics, antifibrinolytics,
antiepileptics, antiemetics, antidotes, antidiabetics,
antiarrhythmics, antianemics, antiallergics, anthelmintics,
analgesics, analeptics, aldosterone antagonists, weight-reducing
agents.
21. An oral dosage form as claimed in claim 17, which is used to
produce compressed tablets.
22. A drug product with delayed release of active ingredient, which
is an oral dosage form as claimed in claim 17.
23. A drug product for delayed release of active ingredient, which
is an oral dosage form as claimed in claim 17 which has been
produced by compression.
24.-25. (canceled)
26. An oral dosage form as claimed in claim 17 which comprises
water or solvent in amounts of less than 5% to increase surface
moisture.
27. An oral dosage form as claimed in claim 17, wherein the
polyvinyl acetate to polyvinylpyrrolidone ratio is from 6:4 to
9:1.
28. An oral dosage form as claimed in claim 17, wherein the active
ingredient to component (c) ratio employed in the combination is
from 5:95 to 85:15.
29. A method of delaying the release of at least one active
ingredient which comprises producing the oral dosage form of claim
17 wherein the at least one active ingrdient comprises food
supplements or additives, vitamins, minerals or trace elements.
30. An oral dosage form comprising a) a formulated mixture of
polyvinyl acetate and polyvinylpyrrolidone which acts as a binder
and a matrix former, and wherein the polyvinylpyrrolidone has a
molecular weight of from 20,000 to 1,000,000, and the
polyvinylpyrrolidone is finely dispersed in the polyvinyl acetate,
b) at least one active ingredient, c) optionally water-soluble
polymers or low or high molecular weight lipophilic additives, and
d) optionally excipients, which is obtained by a process which
comprises granulating a mixture of a) to d) or a) to c) or a) and
b) and d) or a) and b) by heating to a temperature of from
40.degree. C. to 130.degree. C. in the absence of solvents.
31. An oral dosage form as claimed in claim 30, which comprises as
active ingredients food supplements or additives, vitamins,
minerals or trace elements or active pharmaceutical
ingredients.
32. An oral dosage form as claimed in claim 30, which comprises
active pharmaceutical ingredients as active ingredients.
33. An oral dosage form as claimed in claim 32, wherein the active
pharmaceutical ingredient is selected from the group of
benzodiazepines, antihypertensives, vitamins, cytostatics,
anesthetics, neuroleptics, antidepressants, antibiotics,
antimycotics, fungicides, chemotherapeutics, urologicals, platelet
aggregation inhibitors, sulfonamides, spasmolytics, hormones,
immunoglobulins, sera, thyroid therapeutics, psychopharmaceuticals,
antiparkinson agents and other antihyperkinetics,
ophthalmologicals, neuropathy products, calcium metabolism
regulators, muscle relaxants, lipid-lowering agents, liver
therapeutics, coronary agents, cardiac agents, immunotherapeutics,
regulatory peptides and their inhibitors, hypnotics, sedatives,
gynecologicals, antigout agents, fibrinolytics, enzyme products and
transport proteins, enzyme inhibitors, emetics, perfusion
promoters, diuretics, diagnostics, corticoids, cholinergics,
biliary therapeutics, antiasthmatics, bronchospasmolytics,
beta-receptor blockers, calcium channel blockers, ACE inhibitors,
arteriosclerosis remedies, antiinflammatory agents, anticoagulants,
antihypotensives, antihypoglycemics, antifibrinolytics,
antiepileptics, antiemetics, antidotes, antidiabetics,
antiarrhythmics, antianemics, antiallergics, anthelmintics,
analgesics, analeptics, aldosterone antagonists, weight-reducing
agents.
34. An oral dosage form as claimed in claim 30 which comprises
water or solvent in amounts of less than 5% to increase surface
moisture.
35. An oral dosage form as claimed in claim 30, wherein the
polyvinyl acetate to polyvinylpyrrolidone ratio is from 6:4 to
9:1.
36. An oral dosage form as claimed in claim 30, wherein the active
ingredient to component (c) ratio employed in the combination is
from 5:95 to 85:15.
37. An oral dosage form as claimed in claim 30, wherein polyvinyl
acetate and polyvinylpyrrolidone each have a molecular weight of
from 20,000 to 1,000,000.
38. A method of delaying the release of at least one active
ingredient which comprises producing the oral dosage form of claim
30 wherein the at least one active ingrdient comprises food
supplements or additives, vitamins, minerals or trace elements.
Description
[0001] A process for producing solid oral dosage forms with
sustained release of active ingredient
[0002] The present invention relates to a process for producing
solid oral dosage forms with sustained release of active
ingredient, comprising at least one active ingredient, a
preformulated mixture of polyvinyl acetate and
polyvinylpyrrolidone, where appropriate water-soluble polymers or
lipophilic additives and, where appropriate, other conventional
excipients, wherein this mixture or parts of this mixture are
granulated by heating to from 40.degree. C. to 130.degree. C., and
the granules are, after admixture with conventional excipients,
subsequently tabletted.
[0003] So-called depot or sustained release dosage forms are
becoming increasingly important especially in pharmaceutical
technology. Because it is possible, through the choice of suitable
excipients, to control the release of active ingredient, the
intention is to improve the therapeutic effect of the dosage form.
The release principles in this connection extend from delayed
dissolution of active ingredient, the setting up of diffusion
barriers or the swelling-based release to chemically controlled
release of bioerosion. In practice, the principle of matrix tablets
is frequently used.
[0004] The production of these sustained release dosage forms,
matrix tablets, frequently takes place by granulation and
subsequent tabletting. A particular form of agglomeration is
represented by melt granulation. In contrast to conventional wet
granulation, in which a mixture is moistened with solvent or a
binder solution, there is not addition in this process of
additional solvent. On the contrary, in this type of agglomeration
there is use of binders which are solid at room temperature and
melt at temperatures above about 50.degree. C. The omission of
additional solvent is particularly interesting since, because there
are no drying periods, the process times are distinctly shorter
and, in the specific case of water-sensitive active ingredients, it
is unnecessary to use organic solvents.
[0005] The matrix formers frequently employed are substances from
the group of cellulose derivatives, but also substances from the
group of fats and waxes. However, since these substances, as well
as the active ingredients, can frequently be processed in tablet
presses only with difficulty or not at all, because of their
physical properties, granulation is often unavoidable.
[0006] Many of the matrix formers employed additionally lack a
sufficient ability to act also as binders, allowing tablets with
adequate mechanical stability to be produced. This therefore
frequently makes it necessary to use other excipients which lead
not only to stable granules but also to tablets with optimal
properties.
[0007] In DE 19729487 or DE2357503 there is use of binders which
are already molten or are converted into the molten state of
aggregation during the process (for example cetyl alcohol, stearyl
alcohol or polyethylene glycol). Besides the disadvantage of the
change in the state of aggregation, this has the additional
disadvantage that the tablet properties are not satisfactory
either.
[0008] DE 4408326 describes the production of a sustained release
tablet with a content of diclofenac-Na. The matrix is formed by
using the frequently employed methylhydroxypropylcellulose, which
is a associated with the crucial disadvantage that the production
of the granules by wet granulation takes place in a fluidized bed,
and thus a drying step is made necessary. It is particularly
complicated in this case to adjust the release of active
ingredient, because this takes place via a two-layer tablet.
[0009] DE 3829398 describes a fixed pharmaceutical combination in
which, although it is possible to dispense with the use of fillers,
there is also a use as matrix farmers of stearyl alcohol alone
and/or acrylic resins, which must be processed in a melt.
[0010] EP 097 523 describes the production of sustained release
drugs where the active ingredients represent a combination of salt
and the free base. This elaborate process requires several process
steps in order to obtain the finished granules. Thus, the actual
granules are produced by conventional wet granulation and dried and
only then coated with a molten hydrophobic component, or a mixture
of such constituents, these usually being fatty alcohols.
[0011] U.S. Pat. No. 5,403,593 describes the production of a
sustained release dosage form in which a combination of hydrophilic
cellulose polymers and a granulating medium with a melting point
above 30.degree. C. are employed. It is clear in this case too that
a large number of excipients is necessary in order on the one hand
to achieve the desired granulation effect, and on the other hand to
adjust the release of active ingredient. Although this process can
be carried out in one apparatus, in this case cooling of granules
to room temperature is necessary before further processing.
[0012] Although DE 4 031 881 describes the production of granules
which contain, inter alia, polyvinyl acetate as thermoplastic, on
the one hand the granules are produced from a melt, and on the
other hand the molten active ingredient acts in this process as
solvent for the excipient(s) bringing about the sustained
release.
[0013] U.S. Pat. No. 5,169,645 describes inter alia the production
of granules with waxes whose properties can be influenced by the
addition of other substances such as, for example, polyvinyl
acetate. In this case it is necessary on the one hand for the wax
to be molten, and on the other hand for the properties such as, for
example, that of release to be adjusted by adding other substances.
The situation is similar in the U.S. Pat. No. 5,000,965, where the
polyvinyl acetate is melted and additionally mixed with emulsion
excipients.
[0014] DE 19729487 describes a process for producing active
ingredient preparations with controlled release from a matrix. In
this case, the release characteristics are adjusted by means of a
thermal after-treatment in a fluidized bed. This form of production
is very inconvenient because a second step is necessary after the
granulation, including changing the operating equipment, in which
the granules must be heated again until the melting point of the
binder is reached.
[0015] EP 0204596 describes the production of microparticles by
extrusion. In this process it is necessary to add nonhydrophilic
polymers and a mixture of at least two lipid binders, which again
makes the overall process very complicated.
[0016] DE 3612212 describes the production of pharmaceutical forms
by extrusion or injection molding, in which the fusible
N-vinylpyrrolidone polymer is employed and, where appropriate,
additional nitrogen- and/or oxygen-containing comonomers are
included in the polymer. However, in this case, the process
requires complete melting of the mixture.
[0017] The preparations and processes described above frequently
involve the use of very lipophilic, completely melting excipients.
In the liquid state of aggregation, these very lipophilic
excipients, such as, for example, waxes, dissolve active
ingredients and/or completely entrap them. During release therefore
the lipophilic drugs which have high affinity for these very
lipophilic excipients are not completely released.
[0018] The general disadvantage is always that very lipophilic
regions exist which are not rendered hydrophilic by hydrophilic
polymers. It is therefore impossible for water to penetrate into
such regions.
[0019] An additional factor is that the compressibility of these
lipophilic excipients is very poor. The hardnesses achieved are
only low, the friability is high, and adhesion occurs during
production, which can be eliminated--if at all--only with very
large amounts of release agents.
[0020] If the melt granulation aids are added to the powder mixture
in the molten state, a problem which often arises is that of
uniform distribution of the melt in the powder. An irregular
particle structure, poor filling of the die and non-uniform release
are the consequence.
[0021] Although a number of possibilities for producing sustained
release drug forms are now known, there is still a need for simple,
rapid and thus cost-effective processes which allow both
water-soluble and water-insoluble active ingredients to be used
without complications.
[0022] It is an object of the present invention to produce active
ingredient-containing granules with good physical properties, which
can be converted by tabletting into high-dose pharmaceutical dosage
forms with sustained release of active ingredient and good
mechanical properties. It was intended secondly that the process
have short processing times allowing the granules to be produced
with relatively little technical complexity and being suitable both
for water-sensitive and for water-insensitive active ingredients,
with which it is also possible to dispense very substantially with
additional excipients.
[0023] We have found that this object is achieved by a process for
producing an oral dosage form with sustained release of active
ingredient, comprising [0024] a) a formulated mixture of polyvinyl
acetate and polyvinylpyrrolidone [0025] b) at least one active
ingredient [0026] c) where appropriate water-soluble polymers or
low or high molecular weight lipophilic additives [0027] d) and,
where appropriate, other conventional excipients, wherein the
mixture of a) to d) or a) to c) or a) and b) and d) or a) and b) is
granulated by heating to from 40.degree. C. to 130.degree. C., and
the granules are then tabletted after admixture of conventional
excipients.
[0028] The process of the invention applies the principle of melt
granulation, and a formulated mixture of polyvinyl acetate and
polyvinylpyrrolidone acts both as binder and as matrix former, the
matrix which is responsible for the sustained release being formed
only after the tabletting. The special feature of this process is
that no melt is present in the granulation; on the contrary, merely
because of the low glass transition temperature (T.sub.g) of
polyvinyl acetate the surface of the polyvinyl acetate starts to
become tacky at temperatures above about 35.degree. C., and thus a
granulation effect occurs. The process is in principle independent
of the physicochemical properties of the active ingredient. The
latter may be water-soluble, water-insoluble, acidic or basic or
low-melting.
[0029] The invention also relates to the oral dosage forms produced
by the process of the invention.
[0030] The dosage forms are preferably employed for active
pharmaceutical ingredients. However, they can also be employed for
any other active ingredient for which delayed release is
desired.
[0031] The active ingredient or a combination of different active
ingredients is premixed alone or with water-soluble or low or high
molecular weight lipophilic additives and/or with conventional
excipients and the formulated mixture of polyvinyl acetate and
polyvinylpyrrolidone, preferably in a mixer, granulated in the same
apparatus, continuously or batchwise, by heating to temperatures
between 40 and 130.degree. C., preferably in a range from 45 to
100.degree. C. It is possible according to the invention for the
granules also to be produced by extrusion or in a fluidized bed. A
possible option is to force the granules while still warm or after
cooling through a screen with mesh widths between 0.2 mm and 3.0
mm, and then compress them to tablets by adding conventional
tabletting excipients such as, for example, fillers or lubricants.
The properties of the granules can be adjusted by the skilled
worker inter alia via the parameters of temperature and residence
time. Higher temperatures and longer residence times usually mean a
greater granulation effect and thus coarser particles.
[0032] The surface moisture can be increased by adding small
amounts of water or solvent (<5%) to the dosage form.
[0033] It is surprisingly possible in the process of the invention
to employ as mixer both the double cone, ploughshare or V mixers
mainly employed for blending, and the sigma kneaders, planetary
mixing kneaders, intensive mixers or extruders normally employed in
pharmaceutical technology for granulation. It is possible for the
energy required for the superficial melting in the mixers to be
supplied optionally by means of the heat of friction or
conventional heating methods such as, for example, jacket heating
or microwaves. A particular advantage which has unexpectedly
emerged in this connection is that an apparatus for cooling is not
absolutely necessary as in processes employed to date, because this
process does not involve a melt in the conventional sense. Adhesion
effects and accretions on mixer implements or mixer walls therefore
do not occur.
[0034] It is possible by adding highly swelling water-soluble
polymers or lipophilic additives to vary the release within almost
any limits while, at the same time, the flowability of the
tabletting mixture is good, and the tablets have great hardness and
low friability. It is possible to increase the rate of active
ingredient release by adding low-viscosity, nonswelling
water-soluble polymers such as polyvinyl alcohols, polyethylene
glycols, polyoxyethylene/polyoxypropylene block copolymers,
polyvinylpyrrolidones and derivatives, vinyl
acetate/vinylpyrrolidone copolymers, preferably polyethylene
glycols, polyvinylpyrrolidones, vinyl acetate/vinylpyrrolidone
copolymers or maltodextrins.
[0035] These additives are employed in concentrations of from 1 to
40%, preferably from 2 to 30%, based on the total weight of the
tablets. This is necessary with very low-dose active ingredients,
where the amount of formulated mixture of polyvinyl acetate and
polyvinylpyrrolidone required to build up the structure entails the
release being slowed too much. This also applies to active
ingredients of low solubility, where although small amounts of
release-slowing agent lead to delayed release, the structure is not
completely built up and is subject to wide variations, and the
mechanical stability of the tablets is inadequate. This is
especially the case when the compressibility of the active
ingredient is poor.
[0036] The poor flowability of the active ingredient then cannot be
decisively improved by small amounts of formulated mixture of
polyvinyl acetate and polyvinylpyrrolidone. Increasing the content
of release-slowing agent improves these properties, but then leads
to release being too slow. The water-soluble nonswelling polymer
increases the rate of release and stabilizes the latter to all
external effects. The reproducibility is also very much better.
Conventional tabletting excipients such as lactose, calcium
phosphates, sorbitol, mannitol, microcrystalline cellulose or
starch are able to do this insufficiently or not at all. It is
probable that an interaction of the water-soluble polymer with a
formulated mixture of the polymers polyvinyl acetate and
polyvinylpyrrolidone leads to the very stable and reproducible
release which is independent of the compressive force. The hardness
of the tablets and the friability also show excellent values, and
are often in fact better than without admixture of water-soluble
polymers.
[0037] Water-soluble but swelling, high-viscosity polymers
surprisingly lead to slower release. It would have been expected
that the inert structure would be destroyed by the swelling
polymer, and the active ingredient would be released more rapidly.
The fact that this does not occur probably derives from the great
elasticity of the formulated mixture of polyvinyl acetate and
polyvinylpyrrolidone. The highly viscous solution formed from the
water-soluble, swelling polymer in the pores of the structure
blocks them and thus slows down diffusion of the active ingredient
to the outside. The release is frequently slowed down more than by
the two components on their own. A synergistic effect is present.
An additional factor is that the initial release is also reduced by
gel formation on the surface, and the release profile is thus
"linearized". The mechanical properties of the tablets remain at a
very high level.
[0038] Water-soluble swelling polymers which can be employed are:
alginates, pectins, galactomannans, carrageenans, dextran, curdlan,
pullulan, gellan, chitin, gelatin, xanthans, hemicelluloses,
cellulose derivatives such as methylcellulose,
hydroxypropylmethylcellulose, hydroxypropylcellulose,
hydroxyethylcellulose, carboxymethylcellulose, starch derivatives
such as carboxymethylstarch, degraded starch, maltodextrins,
polyacrylic acid, polymethacrylic acid, acrylic acid/methacrylic
acid copolymers, polyvinyl alcohols, high molecular weight
polyethylene glycols, polyoxyethylene/polyoxypropylene block
copolymers, high molecular weight polyvinylpyrrolidones and
derivatives thereof.
[0039] The ratio of active ingredient to release-slowing agent is
between 5:95 and 85:15.
[0040] The release-slowing effect can also be intensified by
fine-particle lipophilic additives. This entails these additives
being trapped in the pores and channels of the structure of
polyvinyl acetate and polyvinylpyrrolidone and blocking them. It is
important that these substances are employed in small particle
size, because they have only a slight effect or no effect in coarse
form. Lipophilic additives which can be used are both polymers and
low molecular weight compounds. The polymers are, however,
preferred.
[0041] These additives include: cellulose derivatives such as
ethylcellulose, cellulose acetate, cellulose acetate phthalate,
cellulose acetate succinate, hydroxypropylmethylcellulose acetate
phthalate, hydroxypropylmethylcellulose acetate succinate, acrylic
ester/methacrylic ester copolymers, especially methyl
methacrylate/ethyl acrylate copolymers, ammoniomethacrylate
copolymer type A and type B, methacrylic acid/acrylic ester
copolymers, especially methacrylic acid/ethyl acrylate copolymers,
fatty alcohols such as stearyl alcohol, fatty acids such as stearic
acid, fatty acid esters and fatty alcohol esters, glycerides,
waxes, lecithin.
[0042] Water-soluble additives which can be employed are the
following:
[0043] Polyvinyl alcohols, polyethylene glycols,
polyoxyethylene/polyoxypropylene block copolymers,
polyvinylpyrrolidone and derivatives, vinyl
acetate/vinylpyrrolidone copolymers, preferably polyethylene
glycols, polyvinylpyrrolidones, vinyl acetate/vinylpyrrolidone
copolymers or maltodextrins, and salts thereof.
[0044] These additives are employed in concentrations of from 1 to
40%, preferably from 2 to 30%, based on the total weight of the
tablets.
[0045] The formulated mixture of polyvinyl acetate and
polyvinylpyrrolidone is present in the preparations of the
invention in concentrations of from 10 to 80%, preferably from 20
to 60%. The molecular weights of polyvinyl acetate and
polyvinylpyrrolidone are in each case between 20 000 and 1 000
000.
[0046] The ratio of polyvinyl acetate and polyvinylpyrrolidone in
the formulated mixture is between 6:4 and 9:1, preferably 8:2. This
formulation is designed so that the polyvinylpyrrolidone is
extremely finely dispersed in the polyvinyl acetate.
[0047] The dosage forms of the invention comprise oral dosage forms
such as tablets, extrudates, pellets or granules.
[0048] Smaller shaped articles such as, for example, pellets or
microtablets can also be introduced into capsules.
[0049] Dosage forms of this invention are distinguished by the fact
that additional excipients are not absolutely necessary and
accordingly solid drug forms with a high active ingredient content
can be produced. If, nevertheless, excipients are used in order to
adjust particular properties, they are substances from the class of
fillers such as, for example, lactose, cellulose powder, mannitol,
calcium diphosphate or various starches, silicates, and
disintegrants and adsorbents, lubricants, flowability agents, dyes,
stabilizers such as antioxidants, wetting agents, preservatives,
release agents, flavorings or sweeteners, preferably fillers.
[0050] Lubricants which can be used are stearates of aluminum,
calcium, magnesium and tin, and magnesium silicate, silicones and
the like.
[0051] Flowability agents can be, for example, talc or colloidal
silica.
[0052] An example of a binder is microcrystalline cellulose.
[0053] Disintegrants can be crosslinked polyvinylpyrrolidone or
crosslinked sodium carboxymethylstarch. Stabilizers can be ascorbic
acid or tocopherol.
[0054] Examples of fillers which can be added are inorganic fillers
such as oxides of magnesium, aluminum, silicon, titanium carbonate
or calcium carbonate, calcium phosphates or magnesium phosphates or
organic fillers such as lactose, sucrose, sorbitol, mannitol.
[0055] Examples of dyes are iron oxides, titanium dioxide,
triphenylmethane dyes, azo dyes, quinoline dyes, indigotine dyes,
carotenoids, for coloring the dosage forms, opacifying agents such
as titanium dioxide or talc in order to reduce the transparency to
light and to save on dyes.
[0056] The dosage forms of the invention may contain any active
ingredient for which delayed release is desired.
[0057] The active ingredients preferably employed are food
supplements or additives, vitamins, minerals or trace elements, but
particularly preferably active pharmaceutical ingredients.
[0058] Pharmaceutical formulations of the abovementioned type can
be obtained by processing the claimed compounds with active
pharmaceutical ingredients by conventional methods and with use of
known and novel active ingredients. The active ingredients may
moreover come from any area of indications.
[0059] Examples which may be mentioned here are the following:
[0060] Benzodiazepines, antihypertensives, vitamins, cytostatics,
anesthetics, neuroleptics, antidepressants, antibiotics,
antimycotics, fungicides, chemotherapeutics, urologicals, platelet
aggregation inhibitors, sulfonamides, spasmolytics, hormones,
immunoglobulins, sera, thyroid therapeutics, psychopharmaceuticals,
antiparkinson agents and other antihyperkinetics,
ophthalmologicals, neuropathy products, calcium metabolism
regulators, muscle relaxants, lipid-lowering agents, liver
therapeutics, coronary agents, cardiac agents, immunotherapeutics,
regulatory peptides and their inhibitors, hypnotics, sedatives,
gynecologicals, antigout agents, fibrinolytics, enzyme products and
transport proteins, enzyme inhibitors, emetics, perfusion
promoters, diuretics, diagnostics, corticoids, cholinergics,
biliary therapeutics, antiasthmatics, bronchospasmolytics,
beta-receptor blockers, calcium channel blockers, ACE inhibitors,
arteriosclerosis remedies, antiinflammatory agents, anticoagulants,
antihypotensives, antihypoglycemics, antifibrinolytics,
antiepileptics, antiemetics, antidotes, antidiabetics,
antiarrhythmics, antianemics, antiallergics, anthelmintics,
analgesics, analeptics, aldosterone antagonists, weight-reducing
agents.
[0061] Surprisingly, any active ingredient which does not decompose
at the stated temperatures and whose average particle size is in a
range between 20 and 700 .mu.m, but preferably in a range between
30 and 500 .mu.m, is suitable.
[0062] The shape of the tablet can be varied within wide limits.
Thus, biconvex, biplanar, round or polygonal tablets can be
produced, as well as oblong or football shapes. The upper limit on
size is determined by the swallowability, while the lower limit is
determined by machine design limits. Conventional tablet sizes are
between 1 and 16 mm, preferably between 2 and 13 mm, in
diameter.
[0063] It is also possible to produce two-layer or multilayer
tables in which one layer contains the complete dose of active
ingredient or at least has a very large active ingredient content,
whereas the other layer has a very large content of the polyvinyl
acetate/polyvinylpyrrolidone combination. It is possible in this
way specifically to influence active ingredient release
additionally. It is even possible on use of two or more active
ingredients to release these at different rates by incorporating
them entirely or for the most part separately in individual
layers.
[0064] Besides the formulated mixture of polyvinyl acetate and
polyvinylpyrrolidone, it is additionally possible to add
release-sustaining excipients. The addition can optionally take
place both before and after the granulation.
[0065] The combination of the two polymers polyvinyl acetate and
polyvinylpyrrolidone makes it possible by means of the chosen
process to produce granules in a "one-pot system", it being
possible to dispense with the addition of any solvents, and it
being unnecessary either for an additional thermal after-treatment
to be carried out or for the tablets to be coated. Another
advantage is that active ingredients whose tablettability is known
to be poor can be processed in a simple manner.
[0066] The particular advantages of the produced granules are
immediately evident in the properties of the granules of
paracetamol (fine crystals type) which is known to be difficult to
process. On the basis of the distinctly better flow
characteristics, the first advantage of the granules produced by
elt granulation from polyvinyl acetate and polyvinylpyrrolidone in
the ratio 8:2 (Kollidon SR) is evident compared with other atrix
formers frequently used.
TABLE-US-00001 TABLE 1 Flow properties of paracetamol granules
Granule composition Angle of repose Flow time Paracetamol/Kollidon
SR (1:1).sup.1 32.9.degree. 7.84 s Paracetamol/Methocel K 15M
(1:1).sup.1 48.2.degree. flow stops Paracetamol/stearyl alcohol
(1:1).sup.2 45.6.degree. flow stops Paracetamol/Kollidon SR
(1:1).sup.3 34.2.degree. flow stops .sup.1Granulation in a type
UMC5 electronic Stephan mixer (from A. Stephan u. Sohne)
Parameters: 85.degree. C. (jacket heating), 12.5 min, 650 rpm
.sup.2Granulation in an intensive mixer (Diosna V20) Parameter:
12.5 min .sup.3Physical mixture
[0067] The angle of repose was determined by the Pfrengle method
specified in DIN 53916.
[0068] The dosage forms of the invention show good hardnesses and
uniformities of weight for the tablets produced from the granules.
The paracetamol/Methocel K 15M combination granule properties are
distinctly worse, resulting in the relative standard deviation for
the tablet masses being twice as large, and the poor hardnesses. In
order to improve the tablet properties it was therefore frequently
necessary for additional binders and satisfactorily compressible
fillers to be added.
TABLE-US-00002 TABLE 2 Properties of paracetamol tablets Tablet
composition Hardness Weight srel Paracetamol/Kollidon SR
(1:1).sup.1 175N 319.0 mg 0.4% Paracetamol/Methocel K 15M
(1:1).sup.1,2 112N 320.5 mg 0.8% Paracetamol/stearyl alcohol
(1:1).sup.1,2 53N 311.8 mg 0.6% .sup.1Tabletting in a Korsch (type
Ek0) eccentric press Excipient: 0.5% magnesium stearate Punch: 10
mm, beveled; compressive force: 18 kN .sup.2Additional excipient:
1.0% Aerosil 200
[0069] The tablet properties (hardness and tablet weight) were
measured using an automatic tablet tester from Kraemer (type
HT-TMB).
[0070] On use of a formulated mixture of polyvinyl acetate and
polyvinylpyrrolidone the tablet properties achieved without the
addition of other fillers are excellent, even with products whose
tablettability is poor.
[0071] In contrast to conventional methods, it is possible with the
method of the invention by simple manipulation to produce sustained
release tablets which are distinguished by good mechanical
properties and easily adjustable release characteristics.
EXAMPLE 1
[0072] 400 g of a Kollidon SR/paracetamol mixture composed of 50%
Kollidon SR and 50% paracetamol were premixed in a Stephan mixer
with jacket heating and granulated at various temperatures (70 to
85.degree. C.) and at 650 rpm for various times. The still hot
granules were then passed through a 1 mm screen, leading to very
homogeneous granules. After admixture of 0.5% magnesium stearate,
10 mm beveled tablets were produced in a Korsch Ek0 eccentric
press.
[0073] Table 3 shows the dependence of the granule particle size on
the granulation temperature and the residence time, the granulation
effects achieved being, as expected, better with a longer
granulation time and higher granulation temperature.
TABLE-US-00003 TABLE 3 Dependence of the average particle size on
the granulation temperature and the granulation time Granulation
Granulation temperature [.degree. C.] time [min] 75 80 85 7.5 147.4
.mu.m 146.2 .mu.m 279.2 .mu.m 12.5 157.6 .mu.m 164.6 .mu.m 391.8
.mu.m 17.5 179.7 .mu.m 296.8 .mu.m 416.6 .mu.m
[0074] The average particle size was measured by laser diffraction.
The D[4,3] value is stated.
EXAMPLE 2
[0075] 400 g of a Kollidon SR/paracetamol mixture composed of 50%
Kollidon SR and 50% paracetamol were premixed in a Stephan mixer
with jacket heating and granulated at about 80.degree. C. and at
650 rpm for 12.5 min. The paracetamol employed had previously been
fractionated in order to establish the effect of the active
ingredient particle size on the granulation. The still hot granules
were passed through a 1 mm screen, leading to very homogeneous
granules. After admixture of 0.5% magnesium stearate, 10 mm beveled
tablets were produced in a Korsch Ek0 eccentric press.
[0076] Table 4 shows that even small active ingredient particles
can be granulated without problems, and that there is no dusting,
as might be suspected, of the polymer particles, thus preventing
granulation.
TABLE-US-00004 TABLE 4 Dependence of the average particle size of
the granules on the average particle size of the active ingredient
Average particle Average particle size of active ingredient size of
granules [.mu.m] [.mu.m] 58.0 182.6 63.1 178.3 92.8 287.9 116.8
502.2 179.4 590.2 412.2 640.1 557.6 655.3 685.2 672.7 930.9
707.1
[0077] The average particle size was measured by laser diffraction.
The D[4,3] value is stated.
[0078] Table 5 shows that there are only slight effects on the
hardness despite distinct differences in the starting material.
TABLE-US-00005 TABLE 5 Dependence of the hardness on the average
particle size of the active ingredient Average particle size of
active ingredient Hardness [.mu.m] [N] 58.0 157 63.1 148 92.8 148
116.8 170 179.4 183 412.2 161 557.6 167 685.2 159 930.9 156
[0079] The hardness was measured using an automatic tablet tester
from Kraemer (type HT-TMB).
[0080] Table 6 shows the active ingredient release from tablets by
the paddle method in deionized water at 37.degree. C. over 16
h.
TABLE-US-00006 TABLE 6 Dependence of the active ingredient release
on the average particle size Active ingredient released [%] Average
particle size of Average particle size of Time granules = 178 .mu.m
granules = 590 .mu.m [h] (active ingredient = 63 .mu.m) (active
ingredient = 179 .mu.m) 0.5 12.5 13.4 1.0 17.8 18.8 1.5 21.5 23.0
2.0 25.1 26.4 3.0 31.2 30.0 4.0 35.0 33.6 6.0 40.4 40.3 8.0 44.2
44.7 12.0 50.7 52.2 16.0 58.1 57.9
EXAMPLE 3
[0081] 400 g of a Kollidon SR/theophylline mixture composed of
[0082] a) 50% Kollidon SR and 50% theophylline [0083] b) 43.75%
Kollidon SR and 56.25% theophylline [0084] c) 37.5% Kollidon SR and
62.5% theophylline [0085] d) 25% Kollidon SR and 75% theophylline
were premixed in a Stephan mixer with jacket heating and granulated
at about 85.degree. C. and at 650 rpm for 12.5 min. The still hot
granules were then passed through a 1 mm screen, leading to
homogeneous granules each time. After admixture of 0.5% magnesium
stearate and 1% Aerosil 200, 10 mm beveled tablets were produced in
a rotary press (Korsch PH 106). Release took place in analogy to
example 2.
[0086] Table 7 shows clearly the effect of the amount of Kollidon
SR on the active ingredient release and on the hardness.
TABLE-US-00007 TABLE 7 Properties of theophylline tablets Tablet
composition Hardness t.sub.50 a.sup.1 220N >16 h b.sup.1 202N
15.2 h c.sup.1 186N 12.3 h d.sup.1 153N 11.6 h .sup.1Tabletting in
a Korsch rotary press (Korsch PH 106) Excipients: 1.0% Aerosil 200;
0.5% magnesium stearate Punch: 10 mm, beveled; compressive force:
18 kN
[0087] The hardness was measured in an automatic tablet tester from
Kraemer (type HT-TMB). The release time for determining the
t.sub.50 of the tablets was 16 h (paddle method; test medium: 0 to
2 h: 0.1 N HCl, 2 to 16 h: phosphate buffer pH 6.8; test
temperature: 37.degree. C.).
EXAMPLE 4
[0088] 400 g of a Kollidon SR/caffeine/alginate mixture composed of
47.5% Kollidon SR, 47.5% paracetamol and 5% alginate were premixed
in a high-speed mixer with jacket heating (Gral Collette type) and
granulated at a temperature of about 85.degree. C. The still hot
granules were then passed through a 1 mm screen, leading to
homogeneous granules each time. After a granulation time of about
10 min, the granules were passed through a 1 mm screen and, after
admixture of 0.5% magnesium stearate, 10 mm beveled tablets were
produced in an eccentric press (Korsch Ek0).
[0089] The tablets have a hardness of about 160 N even with a
compressive force of 10 kN.
EXAMPLE 5
[0090] The fact that a release-slowing effect is achieved only
after tabletting was demonstrated on the basis of the following
experiment (Kollidon SR/paracetamol 1:1) through the release from
[0091] a) the physical mixture [0092] b) the granules (Stephan
mixer: 650 rpm, 85.degree. C., 12.5 min) [0093] c) tablets produced
from the physical mixture (10 mm, beveled; compressive force: 18
kN) [0094] d) tablets produced from the granules (10 mm, beveled;
compressive force: 18 kN)
[0095] Table 8 shows that there is no release-slowing effect either
with the physical mixture or with the melt granules. An effect is
evident only after tabletting, the release being delayed even more
from the tablet produced from the melt granules. This result shows
that the process of melt granulation of the invention distinctly
enhances the release-slowing effect in the tablet with the
formulated mixture of polyvinylacetate and polyvinylpyrrolidone,
preferably in the ratio 8:2.
TABLE-US-00008 TABLE 8 Dependence of active ingredient release on
the dosage form Active ingredient released [%] Granules (650 rpm,
Tablet from Time Physical 85.degree. C., Tablet from physical [h]
mixture 12.5 min) granules.sup.1 mixture.sup.1,2 0.5 99.8 100.1
10.6 11.5 1.0 15.4 18.0 1.5 18.4 20.9 2.0 21.4 25.0 3.0 24.0 29.9
4.0 27.5 31.8 6.0 32.9 28.4 8.0 33.5 44.4 12.0 41.6 52.7 16.0 47.7
58.3 .sup.1Tabletting in a Korsch eccentric press (type Ek0)
Excipient: 0.5% magnesium stearate Punch: 10 mm, beveled;
compressive force: 18 kN .sup.2Additional excipient: 1.0% Aerosil
200
[0096] Active ingredient release from the tablets was carried out
by the paddle method in deionized water at 37.degree. C. over 16
h.
EXAMPLE 6
[0097] A Kollidon SR/caffeine mixture composed of 50% Kollidon SR
and 50% caffeine was mixed in a drum mixer (from Turbula, type T
10B). The mixture was kneaded in a single screw extruder (from
Haake, type Rheocord 90) at a temperature of 50.degree. C. to give
a homogeneous composition. The strands were cut by a cutting device
to give granules which were again passed through a 1 mm screen and,
after admixture of 0.5% magnesium stearate, compressed to 10 mm
beveled tablets in an eccentric press (Korsch Ek0).
TABLE-US-00009 TABLE 9 Comparison of the average particle size of
the physical mixture with the granules Caffeine/Kollidon SR (1:1)
Average particle size 80.23 .mu.m of physical mixture Average
particle size 553.88 .mu.m of granules
[0098] The average particle size was measured by laser diffraction.
The D[4,3] value is stated.
[0099] Comparative Example hydroxypropylmethylcellulose
[0100] 400 g of a Methocel K15M/paracetamol mixture composed of 50%
Methocel K15M and 50% paracetamol were premixed in a Stephan mixer
with jacket heating and granulated at about 85.degree. C. and at
650 rpm for 12.5 min. The still hot mixture was passed through a 1
mm screen. After admixture of 0.5% magnesium stearate and 1%
Aerosil 200, 10 mm beveled tablets were produced in a Korsch Ek0
eccentric press.
[0101] In addition to the absence of a granulation effect, the flow
properties are distinctly worse and the tablet properties are
worse. The brittle paracetamol in fact results in particle
comminution, as a result of fracture of crystals, in place of
granulation.
TABLE-US-00010 TABLE 10 Comparison of granule and tablet properties
Paracetamol/ Paracetamol/Kollidon SR Methocel K 15M (1:1).sup.1,2
(1:1).sup.1,2,3 Particle size D[4, 3] 115.91 154.97 [.mu.m]
(physic. mixture) Particle size D[4, 3] 539.17 139.34 [.mu.m]
granules) Angle of repose [.degree.] 32.90 48.20 Flow time [s] 7.84
flow stops Hardness [N] 175.00 112.00 Weight [mg] (srel [%]) 319
(0.4) 320.5 (0.8) t.sub.50 [h] >16 12.9 .sup.1Granulation in a
Stephan type UMC5 electronic mixer (from A. Stephan u. Sohne)
Parameters: 85.degree. C. (jacket heating), 12.5 min, 650 rpm
.sup.2Tabletting in a Korsch eccentric press (type Ek0) Excipient:
0.5% magnesium stearate Punch: 10 mm, beveled; compressive force:
18 kN .sup.3Additional excipient: 1.0% Aerosil 200
[0102] The average particle size was measured by laser diffraction.
The D[4,3] value is stated. The angle of repose was determined by
the Pfrengle method as described in DIN 53916. The tablet
properties were determined using an automatic tablet tester from
Kraemer (type HT-TMB). The release time for determining the
t.sub.50 of the tablets was 16 h at 37.degree. C. in deionized
water (paddle method).
Comparative Example Stearyl Alcohol
[0103] The molten stearyl alcohol is added to the paracetamol in an
intensive mixer and granulated for 12.5 min. The cooled granules
are passed through a 1 mm screen. After admixture of 0.5% magnesium
stearate and 1% Aerosil 200, 10 mm beveled tablets were produced in
a Korsch Ek0 eccentric press.
[0104] In addition to the poor flow characteristics, the tablet
properties are distinctly worse. Tabletting with a compressive
force of 18 kN was possible under the same conditions as in Example
1 only with provisos because every second tablet was capped on
ejection from the die. The intact tablets have low hardness and a
friability of 100%.
TABLE-US-00011 TABLE 11 Comparison of the granule and tablet
properties Paracetamol/ Paracetamol/Kollidon SR stearyl alcohol
(1:1).sup.1,3 (1:1).sup.2,3,4 Angle of repose [.degree.] 32.9 45.57
Flow time [s] 7.84 flow stops Hardness [N] 175 53 Weight [mg] (srel
[%]) 319 (0.4) 311.8 (0.6) t.sub.50 [h] >16 4.8
.sup.1Granulation in the Stephan type UMC5 electronic mixer (from
A. Stephan u. Sohne) Parameters: 85.degree. C., 12.5 min, 650 rpm
.sup.2Granulation in an intensive mixer (Diosna V20), 12.5 min
.sup.3Tabletting in a Korsch eccentric press (type Ek0) Excipient:
0.5% magnesium stearate Punch: 10 mm, beveled; compressive force:
18 kN .sup.4Additional excipient: 1.0% Aerosil 200
[0105] The angle of repose was determined by the Pfrengle method
specified in DIN 53916. The tablet properties were measured using
an automatic tablet tester from Kraemer (type HT-TMB). The release
time for determining the t.sub.50 of the tablets was 16 h at
37.degree. C. in deionized water (paddle method).
* * * * *