Note: Descriptions are shown in the official language in which they were submitted.
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SOLID PHARMACEUTICAL FORMULATIONS OF
ACID-SENSITIVE PROTON-PUMP BLOCKERS
The present invention relates to solid preparations of an
acid-labile proton pump inhibitor as active substance, in which
the active substance is present in X-ray amorphous form as a
solid solution. The invention further relates to a process for
producing such preparations.
Acid-labile proton pump inhibitors for the purpose of this
invention are, in particular, acid-labile benzimidazoles such as,
for example, pantoprazole, lansoprazole, pariprazole,
lemnoprazole and, in particular, omeprazole.
Omeprazole is a substance belonging to the class of proton pump
inhibitors. It has a direct and dose-dependent inhibitory effect
on the enzyme H+/K+-ATPase ("proton pump"), which is responsible
for the secretion of gastric acid in the border cell in the
stomach. Omeprazole is of proven use for the therapy of duodenal
ulcer, gastric ulcer, reflux esophagitis and Zollinger-Ellision
syndrome. Parenteral and solid oral drug products are used for
this purpose.
Omeprazole is absorbed in the upper duodenum, and the maximum
plasma concentrations are reached 1 to 3 hours after
administration.
Omeprazole decomposes very quickly under acidic conditions and on
exposure to heat to give inactive compounds. This process is
associated with the white omeprazole powder becoming brownish
violet. To prevent the unwanted acid-induced degradation
reactions, oral omeprazole formulations must be completely
protected from gastric fluid so that the active ingredient is
able to penetrate unharmed to the site of absorption in the
duodenum.
DE-A 1204363 describes a drug form consisting of three different
layers. The first layer is soluble in the stomach but insoluble
in the intestine. The second layer is soluble in water
(irrespective of the pH), and the third (outer) protective layer
is an enteric coating. However, the disadvantage of such a form
is that it is dissolved only slowly in the intestine and
therefore the active ingredient is likewise released only slowly.
However, a rapid release formulation is required in the case of
omeprazole.
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EP-A 240904 describes drug forms in which the active ingredient
is embedded as a molecular dispersion in a polymer matrix by
means of melt extrusion. Drug forms of this type are able to
release the active ingredient very rapidly. However, the
disadvantage of this form is that thermal stress occurs during
production, which leads to degradation in the case of omeprazole.
EP-0 496 437 describes pellet cores and tablets containing
omeprazole or an alkali metal salt of omeprazole together with an
alkaline reacting compound, and coated with a layer of
water-soluble film-forming excipients, which preferably have an
alkaline reaction, and with a final enteric film.
EP-A 0 239 200 describes the use of basic magnesium salts and/or
basic calcium salts for stabilizing benzimidazole derivatives.
The prior art described here shows that many approaches have been
made to preparing a maximally suitable formulation of a proton
pump inhibitor. This means specifically that a formulation is
sought which shows good chemical stability on storage and which
suppresses decomposition of the active ingredient in acidic
gastric fluid but, at the same time, releases the active
ingredient as quickly as possible in an alkaline medium.
It is an object of the present invention to find a presentation
which is suitable for oral administration of proton pump
inhibitors, which shows good chemical stability on storage, and
which suppresses decomposition of the active ingredient in acidic
gastric fluid but, at the same time, releases the active
ingredient as quickly as possible in an alkaline medium.
We have found that this object is achieved by solid preparations
in which the active substance is present in X-ray amorphous form
as a molecular dispersion in a polymer matrix, and a process for
production thereof.
In the preparations according to the invention, the acid-labile
proton pump inhibitor is embedded as a molecular dispersion in a
matrix consisting of one or more polymers.
Suitable polymers are: gelatin such as bovine gelatin,_ porcine
gelatin or fish gelatin, starch, dextrin, pectin, gum arabic,
ligninsulfonates, chitosan, polystyrenesulfonate, alginates,
casein, caseinate, methylcellulose, carboxymethylcellulose,
hydroxypropylcellulose, milk powder, dextran, whole milk or
skimmed milk or mixtures of these protective colloids. Also
suitable are homo- and copolymers based on the following
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monomers: ethylene oxide, propylene oxide, malefic anhydride,
lactic acid, glycolic acid, a- and B-aspartic acid,
N-vinylpyrrolidone, vinyl acetate, especially
polyvinylpyrrolidone with Fikentscher K values of from 12 to 100,
and copolymers of N-vinylpyrrolidone and vinyl acetate such as
VP/VAc-60/40. One of said gelatine types is particularly
preferably employed, in particular acid- or base-degraded gelatin
with Bloom numbers in the range from 0 to 250, very particularly
preferably gelatin A 100, A 200, B 100 and B 200, and low
molecular weight, enzymatically degraded gelatin types with Bloom
number 0 and molecular weights of from 15000 to 25000 D, such as,
for example, Collagel A and Gelitasol P (from Stoess, Eberbach)
and mixtures of these gelatin types.
Also suitable are acrylate-based polymers resistant to gastric
fluid of the Eudragit~ type.
The preparations additionally comprise low molecular weight
surface-active compounds. Particularly suitable as such are
amphiphilic compounds or mixtures of such compounds. In
principle, all surfactants with an HLB of from 5 to 20 are
suitable. Examples of corresponding suitable surface-active
substances are: esters of long-chain fatty acids with ascorbic
acid, mono- and diglycerides of fatty acids and their
ethoxylation products, esters of mono-fatty acid glycerides with
acetic acid, citric acid, lactic acid or diacetyltartaric acid,
polyglycerol fatty acid esters such as, for example, the
monostearate of triglycerol, sorbitan fatty acid esters,
propylene glycol fatty acid esters, 2-(2'-stearoyllactyl)lactic
acid salts and lecithin. Ascorbyl palmitate is preferably
employed.
The amounts of the various components are chosen according to the
invention so that the preparations contain from 1 to 90% by
weight, preferably 5 to 60% by weight, of active substance, from
1 to 95% by weight, preferably 10 to 90% by weight, of one or
more polymers and from 0 to 50% by weight, preferably 0 to 20% by
weight, of one or more low molecular weight stabilizers. The
percent by weight data relate to a dry powder.
The preparations may additionally comprise antioxidants and/or
preservatives to protect the active ingredient. Examples of
suitable antioxidants or preservatives are a-tocopherol,
t-butylhydroxytoluene, t-butylhydroxyanisole, lecithin,
ethoxyquin, methylparaben, propylparaben, sorbic acid, sodium
benzoate or ascorbyl palmitate. The antioxidants or preservatives
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can be present in amounts of from 0 to 10% by weight based on the
total amount of the preparation.
The preparations may also contain plasticizers to increase the
stability of the final product. Examples of suitable plasticizers
are sugars and sugar alcohols such as sucrose, glucose, lactose,
invert sugar, sorbitol, mannitol, xylitol or glycerol. Lactose is
preferably employed as plasticizer. The plasticizers can be
present in amounts of from 0 to 50% by weight.
Further pharmaceutical excipients such as binders, disintegrants,
flavorings, vitamins, dyes, wetting agents, additives to
influence the pH (cf. H. Sucker et al., Pharmazeutische
Technologie, Thieme-Verlag, Stuttgart 1978) can likewise be
introduced via the organic solvent or the aqueous phase.
The process according to the invention is carried out by
initially preparing a solution of the active substance, of the
polymer and, where appropriate, of the other abovementioned
substances in a suitable solvent. The total solids content of the
solution is between 0.5 and 40% by weight, particularly
preferably between 1 and 20% by weight.
Suitable solvents are water, organic solvents and homogeneous
mixtures of these components. Organic solvents preferably
employed are alcohols, esters, ketones and acetals. Methanol,
ethanol, n-propanol, isopropanol or acetone is used in
particular.
When water or aqueous solutions are used, the pH is adjusted to a
value > 7, preferably between 8 and 10, before dissolving the
active ingredient. The pH adjustment takes place using substances
which have a pKa of > 7. Metal hydroxides, metal carbonates,
metal phosphates, metal acetates are preferably employed. Sodium
hydroxide, magnesium hydroxide, calcium hydroxide, potassium
hydroxide, ammonium hydroxide, disodium hydrogen phosphate,
sodium dihydrogen phosphate, sodium carbonate, calcium carbonate
and magnesium carbonate are particularly preferably used.
The pH adjustment preferably takes place with aqueous ammonia.
The ammonium content of the finished dry powder is below the
detection limit for ammonia (detection limit 0.1% by weight).
005/49931 CA 02369951 2001-10-22
The solution prepared in this way is converted into a dry powder.
This is possible, for example, with the aid of a spray process.
The temperature at the spray head in this case is between 70 and
130°C, preferably between 80 and 110°C.
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It is likewise possible to convert the solution into a dry powder
by freeze drying or in a fluidized bed.
The solid omeprazole preparations according to the invention
allow faster release of active ingredient by comparison with a
formulation in which omeprazole is present in crystalline form.
The solid preparations according to the invention moreover show
good chemical stability. This also applies to preparations which
contain no detectable basic substances. Such good stability was
not to be expected from the prior art.
The solid preparations according to the invention can be produced
from a liquid solution by a spray process. Temperatures normally
leading to degradation of active ingredient occur in this
process. Surprisingly, no such degradation of active ingredient
occurs in this case.
The dry powders obtained according to the invention can be packed
into hard gelatin capsules which are resistant to gastric fluid
but soluble in the small intestine, or else be compressed to
tablets in conventional formulations.
The preparations according to the invention can also be employed
for combination drug forms, for example in combination with
nonsteroidal antiinflammatory drugs, analgesics, antibiotics such
as erythromycin or clarithromycin, or with motility improvers.
Examples
Production example 1'
Production of an omeprazole dry powder with an active ingredient
content in the region of 30%
a) Preparation of the solution
4.8 g of gelatin A 100 are dissolved in 600 g of deionized
water by stirring at 70°C. After cooling to room temperature,
120 g of acetone, 0.8 g of ascorbyl palmitate and 4 g of
lactose are stirred into the solution. The solution is then
adjusted to pH = 10 with 1 molar sodium hydroxide solution.
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4 g of omeprazole are then dissolved in the solution which
has been made alkaline.
Spray drying resulted in an amorphous dry powder with an
omeprazole content (determined by chromatography) of 29.3% by
weight.
b) X-ray wide-angle scattering
Figure 1 depicts the scattering plots for omeprazole (plot a)
and for the dry powder (plot b) from la. The omeprazole
starting material is crystalline, as proven by the X-ray
diagram which is distinguished by a series of sharp
interferences. In contrast to this, the scattering plot of
the dry powder shows only diffuse, broad inter-ference maxima,
as are typical of an amorphous material. The active
ingredient is accordingly in X-ray amorphous form in the dry
powder prepared in la. This also applies to the otherwise
crystalline excipients lactose and ascorbyl palmitate.
c) High-resolution 13C-NMR of solids
Figure 2 depicts the high-resolution 13C-NMR solids spectra of
omeprazole (plot a) and of the dry powder (plot b) from la.
The pure active ingredient omeprazole shows sharp signals as
are typical of crystalline substances. In contrast to this,
the 13C-NMR spectrum of the dry powder shows very broad
signals for the active ingredient, as are typical of an
amorphous material with a large number of realized
conformations and random packings of the molecules.
Beside the purely spectroscopic measurements, so-called
Tlrho(H) measurements were carried out with 13C detection.
This entails using the exchange of spin energy between 1H
nuclei ("spin diffusion") for gaining some information on a
scale of length of about 1 nm about spatial neighborhood
relationships of the individual components. A common
relaxation behavior (= parallel lines in a logarithmic plot
of the signal amplitudes vs. time) indicates that the
relevant structures are an average distance of < 1 nm apart,
i.e. are in a molecular mixture.
Figure 3 shows a plot of the Tlrho(H) behavior of omeprazole
(plot a) and of the matrix (plot b) from preparation example
la. The signal for omeprazole is derived from a typical
signal for omeprazole at 126.4 ppm, which is not overlapped
by a matrix signal (cf. Figure 2). The signal for the matrix
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is derived from a signal typical for the matrix at 172.7 ppm,
which is not overlapped by an omeprazole signal (cf.
Figure 2). It is very evident that the two lines are
parallel. This shows the presence of a molecular mixture of
active ingredient and matrix.
Figure 3 shows a plot of the Tlrho(H) behavior of omeprazole
(plot c) and of the matrix (plot d) in a physical mixture of
crystalline omeprazole and the same excipients and the same
composition as from preparation example la. The signal for
omeprazole is derived from a signal typical for omeprazole at
125.3 ppm, which is not overlapped by a matrix signal (cf.
Figure 2). The signal for the matrix is derived from a signal
typical for the matrix at 175.7 ppm, which is not overlapped
by an omeprazole signal (cf. Figure 2). It is very evident
that in this case the lines have a different gradient. This
shows that active ingredient and matrix are not in the form
of a molecular mixture.
Production example 2
Production of an omeprazole dry powder with an active ingredient
content in the region of 30%
a) Preparation of the solution
0.8 g of ascorbyl palmitate and 8.8 g of Kollidon 17 PF are
dissolved in a mixture of 600 g of water and 120 g of acetone
at room temperature. The pH of the solution is then adjusted
to 10 with 1 molar sodium hydroxide solution. 4 g of
omeprazole are then dissolved in the solution which has been
made alkaline.
Spray drying results in an amorphous dry powder with an
omeprazole content (determined by chromatography) of 29.2% by
weight.
b) X-ray wide-angle scattering
Figure 1 depicts the scattering plots for omeprazole (plot a)
and for the dry powder (plot c) from 2a. The omeprazole
starting material is crystalline, as proven by the X-ray
diagram which is distinguished by a series of sharp
interferences. In contrast to this, the scattering plot of
the dry powder shows only diffuse, broad interference maxima,
as are typical of an amorphous material. The active
ingredient is accordingly in X-ray amorphous form in the dry
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powder prepared in 2a. This also applies to the otherwise
crystalline excipient ascorbyl palmitate.
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Production example 3
Production of an omeprazole dry powder with an active ingredient
content in the region of 30%
a) Preparation of the solution
18 g of Kollidon 17 PF are dissolved in 300 g of 25% strength
ammonia solution at room temperature. Then 8 g of omeprazole
are dissolved in this solution.
Spray drying resulted in an amorphous dry powder with an
omeprazole content (determined by chromatography) of 30.7% by
weight. The ammonium content in the sample was 140 ppm.
b) X-ray wide-angle scattering
Figure 1 depicts the scattering plots for omeprazole (plot a)
and for the dry powder (plot d) from 3a. The omeprazole
starting material is crystalline, as proven by the X-ray
diagram which is distinguished by a series of sharp
interferences. In contrast to this, the scattering plot of
the dry powder shows only diffuse, broad interference maxima,
as are typical of an amorphous material. The active
ingredient is accordingly in X-ray amorphous form in the dry
powder prepared in 3a.
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Production example 4
Production of an omeprazole dry powder with an active ingredient
content in the region of 30%
a) Preparation of the solution
4.8 g of fish gelatin with molecular weight fractions from
103 to 10~ D are dissolved in 600 g of deionized water by
stirring at 70°C. After cooling to room temperature, 120 g of
acetone, 0.8 g of ascorbyl palmitate and 4 g of lactose are
stirred into the solution. The pH of the solution is then
adjusted to 9 with 25% strength ammonia solution. 4 g of
omeprazole are then dissolved in the solution which has been
made alkaline. .
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Spray drying resulted in an amorphous dry powder with an
omeprazole content (determined by chromatography) of 29.5% by
weight. The ammonium content in the sample was 120 ppm.
b) X-ray wide-angle scattering
Figure 1 depicts the scattering plots for omeprazole (plot a)
40
and for the dry powder (plot e) from 4a. The omeprazole
starting material is crystalline, as proven by the X-ray
10 diagram which is distinguished by a series of sharp
interferences. In contrast to this, the scattering plot of
the dry powder shows only diffuse, broad interference maxima,
as are typical of an amorphous material. The active
ingredient is accordingly in X-ray amorphous form in the dry
15 powder prepared in 4a. This also applies to the otherwise
crystalline excipients lactose and ascorbyl palmitate.
Production of enteric-coated capsules
20 70 mg of spray-embedded omeprazole were packed with 70 mg of
D-mannitol into a size 1 capsule. The hard gelatin capsules
packed in this way were given enteric coatings:
Coating formula:
25 129.5 g of Kollicoat MAE 30 DP (30% strength)
3.9 g of PEG 6000
1.8 g of PEG 400
9.1 g of talc
114.7 g of deionized water
The coating process took place in an Aeromatic Strea 1 with
granulating container insert using the following parameters:
Quantity of capsules: 20
Drying temperature: 30~C
Atomizer pressure: 2 bar
Blow-off pressure: 3.5 bar
Quantity of air: control setting 6 - 7
Pump (watson Marlow): setting 5 - 9
56.9 mg of coating were applied per capsule.
