U.S. patent application number 14/061578 was filed with the patent office on 2014-03-20 for pharmaceutical formulation for treating the upper digestive tract.
This patent application is currently assigned to Dr. Falk Pharma GmbH. The applicant listed for this patent is Dr. Falk Pharma GmbH. Invention is credited to Markus Proels, Rudolf Wilhelm.
Application Number | 20140079646 14/061578 |
Document ID | / |
Family ID | 39951664 |
Filed Date | 2014-03-20 |
United States Patent
Application |
20140079646 |
Kind Code |
A1 |
Wilhelm; Rudolf ; et
al. |
March 20, 2014 |
PHARMACEUTICAL FORMULATION FOR TREATING THE UPPER DIGESTIVE
TRACT
Abstract
The invention relates to an effervescent tablet for preparing a
mouth rinsing solution, wherein the effervescent tablet exhibits a
high release rate of budesonide. A high availability of the active
ingredient during use as a mouth rinsing solution on the inflamed
mucosa of the upper digestive tract is thereby achieved. The
advantage of the formulation according to the invention lies in the
bioavailability comparable to oral forms of administration, which
allows the formulation to be used safely over an extended period of
time.
Inventors: |
Wilhelm; Rudolf;
(Bischweier, DE) ; Proels; Markus;
(Freiburg/Breisgau, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Dr. Falk Pharma GmbH |
Freiburg |
|
DE |
|
|
Assignee: |
Dr. Falk Pharma GmbH
Freiburg
DE
|
Family ID: |
39951664 |
Appl. No.: |
14/061578 |
Filed: |
October 23, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13054844 |
Jan 19, 2011 |
8580300 |
|
|
PCT/EP2009/058320 |
Jul 2, 2009 |
|
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14061578 |
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Current U.S.
Class: |
424/44 |
Current CPC
Class: |
A61K 9/0095 20130101;
A61K 9/0007 20130101; A61P 29/00 20180101; A61P 1/00 20180101; A61K
31/58 20130101; A61P 1/04 20180101 |
Class at
Publication: |
424/44 |
International
Class: |
A61K 31/58 20060101
A61K031/58; A61K 9/00 20060101 A61K009/00 |
Claims
1. A solid pharmaceutical composition comprising a therapeutically
effective amount of budesonide in combination with an effervescent
mixture of a pharmaceutically acceptable acid in solid form and a
compound containing carbonate and/or hydrogen carbonate, wherein
said composition is formulated to rapidly dissolve in a specific
volume of liquid so as to generate an orally-administrable mouth
rinsing solution comprising a therapeutically effective amount of
dissolved budesonide suitable for the treatment of inflammatory
changes in the upper digestive tract.
2. The solid pharmaceutical composition according to claim 1,
wherein said tablet contains from 0.1 to 10 mg of budesonide per
composition.
3. The solid pharmaceutical composition according to claim 1,
wherein said tablet further comprises polyvinylpyrrolidone in a
concentration of from 0.5 to 10% by weight, based on the weight of
the composition.
4. The solid pharmaceutical composition according to claim 1,
wherein said tablet further comprises ducosate sodium in a
concentration of from 0.1.Salinity. to 5.0.Salinity. by weight,
based on the composition.
5. The solid pharmaceutical composition according to claim 1,
wherein said tablet contains an agent that produces a cooling
effect in the mouth in a concentration of from 0.1 to 1.0% by
weight, based on the composition.
6. An effervescent tablet containing budesonide, wherein said
tablet is formulated to rapidly dissolve in a specific volume of
liquid so as to generate an orally-administrable mouth rinsing
solution comprising a therapeutically effective amount of dissolved
budesonide suitable for the treatment of inflammatory changes in
the upper digestive tract.
7. The effervescent tablet according to claim 6, wherein said
tablet contains from 0.1 to 10 mg of budesonide per prepared
effervescent tablet.
8. The effervescent tablet according to claim 6, wherein said
tablet further comprises polyvinylpyrrolidone in a concentration of
from 0.5 to 10% by weight, based on the weight of the prepared
effervescent tablet.
9. The effervescent tablet according to claim 6, wherein said
tablet further comprises ducosate sodium in a concentration of from
0.1.Salinity. to 5.0.Salinity. by weight, based on the prepared
effervescent tablet.
10. The effervescent tablet according to claim 6, wherein said
tablet comprises an effervescent mixture of a pharmaceutically
acceptable acid in solid form and a compound containing carbonate
and/or hydrogen carbonate.
11. The effervescent tablet according to claim 6, wherein said
tablet contains an agent that produces a cooling effect in the
mouth in a concentration of from 0.1 to 1.0% by weight, based on
the prepared effervescent tablet.
12. An orally-administrable mouth rinsing solution comprising a
therapeutically effective amount of dissolved budesonide suitable
for the treatment of inflammatory changes in the upper digestive
tract prepared by dissolving the effervescent tablet of claim 1 in
a specific volume of liquid.
13. The orally-administrable mouth rinsing solution according to
claim 12, wherein said tablet contains from 0.1 to 10 mg of
budesonide per effervescent tablet.
14. The orally-administrable mouth rinsing solution according to
claim 12, wherein said tablet further comprises
polyvinylpyrrolidone in a concentration of from 0.5 to 10% by
weight, based on the weight of the effervescent tablet.
15. The orally-administrable mouth rinsing solution according to
claim 12, wherein said tablet further comprises ducosate sodium in
a concentration of from 0.1.Salinity. to 5.0.Salinity. by weight,
based on the effervescent tablet.
16. The orally-administrable mouth rinsing solution according to
claim 12, wherein said tablet comprises an effervescent mixture of
a pharmaceutically acceptable acid in solid form and a compound
containing carbonate and/or hydrogen carbonate.
17. The orally-administrable mouth rinsing solution according to
claim 12, wherein said tablet contains an agent that produces a
cooling effect in the mouth in a concentration of from 0.1 to 1.0%
by weight, based on the prepared effervescent tablet.
18. A method for the treatment of inflammatory changes in the upper
digestive tract, said method comprising (1) dissolving the solid
pharmaceutical composition of claim 1 in a specific volume of
liquid to generate a mouth rinsing solution comprising a
therapeutically effective amount of dissolved budesonide and (2)
orally administering said mouth rinse solution to a patient in need
thereof.
19. The method according to claim 18, characterized in that the
inflammatory changes of the upper digestive tract are localized in
the region of the oral cavity and/or pharynx.
20. The method according to claim 18, characterized in that the
inflammatory changes of the upper digestive tract are
non-infectious inflammations.
21. The method according to claim 18, characterized in that the
inflammatory changes of the upper digestive tract are the result of
chemotherapy.
22. The method according to claim 18, characterized in that the
inflammatory changes of the upper digestive tract are the result of
mucositis, an autoimmune disorder of the oral cavity, Crohn's
disease in the upper digestive tract or eosinophilic
oesophagitis.
23. The method according to claim 18, wherein said liquid is
water.
24. The method accordingly to claim 18, wherein said specific
volume of liquid added is 5 to 20 ml.
25. The method according to claim 18, further comprising (3)
gargling the mouth rinsing solution for a predetermined time
between 2 and 15 minutes and (4) expelling said mouth rinsing
solution from the mouth.
26. A method for the treatment of inflammatory changes in the upper
digestive tract, said method comprising (1) dissolving the
effervescent tablet of claim 6 in a specific volume of liquid to
generate a mouth rinsing solution comprising a therapeutically
effective amount of dissolved budesonide and (2) orally
administering said mouth rinse solution to a patient in need
thereof.
27. The method according to claim 26, characterized in that the
inflammatory changes of the upper digestive tract are localized in
the region of the oral cavity and/or pharynx.
28. The method according to claim 26, characterized in that the
inflammatory changes of the upper digestive tract are
non-infectious inflammations.
29. The method according to claim 26, characterized in that the
inflammatory changes of the upper digestive tract are the result of
chemotherapy.
30. The method according to claim 26, characterized in that the
inflammatory changes of the upper digestive tract are the result of
mucositis, an autoimmune disorder of the oral cavity, Crohn's
disease in the upper digestive tract or eosinophilic
oesophagitis.
31. The method according to claim 26, wherein said liquid is
water.
32. The method accordingly to claim 26, wherein said specific
volume of liquid added is 5 to 20 ml.
33. The method according to claim 26, further comprising (3)
gargling the mouth rinsing solution for a predetermined time
between 2 and 15 minutes and (4) expelling said mouth rinsing
solution from the mouth.
Description
PRIORITY
[0001] This application is a continuation of U.S. Ser. No.
13/054,844 filed Jan. 19, 2011, which corresponds to the national
phase of International Application No. PCT/EP2009/058320 filed Jul.
2, 2009, which, in turn, claims priority to European Patent
Application No. 08.013091.7 filed Jul. 21, 2008, the contents of
which are incorporated by reference herein in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to a pharmaceutical
formulation, namely an effervescent tablet, for treating the upper
digestive tract, which comprises as pharmaceutical active
ingredient budesonide or a pharmaceutically acceptable salt or
derivative thereof.
BACKGROUND OF THE INVENTION
[0003] Pharmaceutical formulations which contain budesonide and are
for oral administration with controlled release in the intestinal
tract are known from EP-A-0 720 473.
[0004] These formulations have been used for a relatively long time
in the treatment of intestinal diseases, such as Crohn's disease,
are effective (Bar-Meir, Gastroenterology, 1998, p. 835-840) and
have an improved safety profile (Andus, Digestive Diseases and
Sciences, 1 Feb. 2003, p. 373-378).
[0005] The use of glucocorticoids, in particular budesonide, is
generally known for the treatment of diseases which are associated
with inflammation processes. These diseases also include those of
the oral cavity, the pharynx and the oesophagus. The active
ingredient budesonide has been used successfully, for example in
GVHD (graft versus host disease) (Elad et al., Oral Surg. Oral Med.
Oral Pathol. and Radial Endod. 2003, 95, p. 308-311).
[0006] WO03/06629 describes lozenges containing an active
ingredient core which is sheathed by a water-soluble polysaccharide
(gellan gum). The active ingredient is inside the core and not
intermixed with the sheath. Glucocorticoids, for example budesonide
are mentioned as possible active ingredients. The tablet is
suitable for buccal use.
[0007] For treating inflammatory processes in the oral cavity, the
preparation of a drug form is desired which is reproducible as a
ready-for-use formulation, releases sufficiently high
concentrations of active ingredient at the inflammation site and
exhibits a local effect.
[0008] The direct use of the active ingredient following the
grinding up by pestle and mortar of capsules resistant to gastric
juice to treat GVHD (Elad, 2003) is known. This direct use of the
active ingredient mentioned in the prior art suffers from various
disadvantages, for example of not being a ready-for-use,
industrially producible formulation with a reproducible dosage.
Grinding up tablets also has the disadvantage that uniform high
concentrations of active ingredient are not provided at the
inflammation site.
[0009] The specific tablet formulation is used for buccal
administration, in particular with the objective of absorbing an
active ingredient buccally into the systemic circulation. Wetting
the entire region of the oral cavity with dissolved active
ingredient for local use is not possible.
[0010] The high instability of budesonide in dissolved form rules
out the production of a dissolved pharmaceutical preparation
containing budesonide. Over an extended period of time, such a
budesonide solution would not be stable without a precise pH
adjustment and the addition of preservatives and further
stabilisers.
[0011] An object of the present invention is to provide a
pharmaceutical formulation which can be administered orally and
which no longer suffers from the mentioned disadvantages.
[0012] Therefore, according to the invention, a formulation is
provided which exhibits a rapid, improved solubility for budesonide
when prepared as a mouth rinsing solution, results in a high local
concentration of active ingredient and furthermore allows a safe
use with few side effects over an extended period of time. In
addition, the effervescent tablet according to the invention allows
stable storage and simple handling.
SUMMARY OF THE INVENTION
[0013] It has been found that a specifically prepared mouth rinsing
solution, produced from an effervescent tablet, is particularly
suitable for the treatment. Unlike a tablet, such a mouth rinsing
solution can be used in equal measure in the entire oral cavity as
well as in the pharynx and in the oesophagus, since the active
ingredient is present in high quantities in dissolved form. The
effervescent tablet also affords significant advantages with regard
to long-time stability of the drug form up until use and a simple
and accurate dosage.
[0014] Likewise, an effervescent tablet affords significant
advantages in respect of the stability of the administration form
after opening.
[0015] The effervescent tablet according to the invention for the
preparation of a mouth rinsing solution which can be administered
orally contains budesonide. The IUPAC name of budesonide is
16,17-(butylidenebis(oxy))-11,21-dihydroxy-,
(11-.beta.,16-.alpha.)-pregna-1,4-diene-3,20-dione. In a preferred
embodiment, each effervescent tablet contains from 0.1 to 10 mg of
budesonide. Particularly preferably, budesonide is present in a
quantity of from 1 mg to 5 mg and most particularly preferably in a
quantity of approximately 3 mg per effervescent tablet.
[0016] The budesonide used in the effervescent tablet must satisfy
the quality and purity requirements imposed on a pharmaceutical
preparation. Micronised budesonide is preferably used. The size of
the budesonide particles plays an essential part in the dissolution
rate and the resorbability. Budesonide is preferably used in which
the particle size distribution is adjusted such that at least 90%
of the particles have a diameter of less than 20 .mu.m, preferably
less than 10 .mu.m. In a particularly preferred embodiment, 100% of
the particles have a diameter of less than 10 .mu.m, 95% of the
particles have a diameter of less than 5 .mu.m and 80% of the
particles have a diameter of less than 3 .mu.m. The particle
diameter is determined by conventional measuring methods.
[0017] To increase the solubility of budesonide in the mouth
rinsing solution prepared from the effervescent tablet according to
the invention, the effervescent tablet according to the invention
preferably contains polyvinylpyrrolidone in a concentration of from
0.5 to 10% by weight, more preferably in a quantity of between 1.0
and 3.0% by weight, in each case based on the total weight of the
prepared effervescent tablet.
[0018] Polyvinylpyrrolidone is a polymerisation product of
vinylpyrrolidone. A number of fractions with different molecular
sizes or molecular chain lengths are commercially available. The
molecular mass spectrum ranges from 10,000 to 350,000.
Polyvinylpyrrolidone with a molecular size of between approximately
15,000 and 150,000 is preferably used. A particular characteristic
of polyvinylpyrrolidones is the good solubility both in water and
in polar organic solvents, such as alcohols or glycerine.
[0019] Furthermore, the effervescent tablet according to the
invention preferably contains another solubiliser or emulsifier,
namely docusate sodium (sodium dioctylsulphosuccinate) in a
concentration of from 0.1 .Salinity. to 5 .Salinity., preferably
from 0.2 .Salinity. to 2.0 .Salinity., the quantities relating to
the weight of the prepared effervescent tablet.
[0020] In a most particularly preferred embodiment, the
effervescent tablet according to the invention contains both
polyvinylpyrrolidone and docusate sodium.
[0021] So that the effervescent tablet according to the invention
dissolves effectively following contact with water, it contains an
effervescent mixture comprising a pharmaceutically acceptable acid
in solid form and a compound containing carbonate and/or hydrogen
carbonate.
[0022] In the effervescent tablet according to the invention, the
pharmaceutically acceptable acid used is such an acid which is
available in solid form, does not pose any health threats and does
not produce an unpleasant taste. The acid which is preferably used
is citric acid. The effervescent mixture also contains a compound
which contains carbonate and/or hydrogen carbonate and which
releases carbon dioxide upon contact with acid, as a result of
which the effervescent tablet dissolves. This is preferably sodium
carbonate or sodium hydrogen carbonate.
[0023] In a preferred embodiment, the effervescent tablet according
to the invention also contains an agent which produces a cooling
effect in the mouth. In a preferred embodiment, this is butanamide
(N-2,3-trimethyl-2-isopropylbutanamide). This agent is preferably
used in a quantity of from 0.1 to 1.0, particularly preferably in a
quantity of between 0.3 and 0.8% by weight, based on the prepared
effervescent tablet.
[0024] The effervescent tablet according to the invention is
preferably used for the production of a medicament to prepare a
mouth rinsing solution which can be administered orally, to treat
inflammatory changes in the upper digestive tract.
[0025] When used, the effervescent tablet is dissolved in a
specific quantity of a liquid, preferably water, the quantity of
water required to dissolve the effervescent tablet amounting to
between 5 and 20 ml, preferably between 5 and 15 ml and
particularly preferably approximately 10 ml of water.
[0026] The inflammatory changes of the upper digestive tract
treated by the mouth rinsing solution which can be prepared by the
effervescent tablet are preferably inflammatory changes of the
digestive tract in the region of the oral cavity and/or pharynx. In
a usual method of application, the mouth rinsing solution is
produced by dissolving the effervescent tablet in water and then
the user gargles with this mouth rinsing solution for a
predetermined time which can be between 2 and 15 minutes,
preferably approximately 10 minutes, and rinses his mouth.
Thereafter, the user does not swallow the mouth rinsing solution,
but spits it out.
[0027] The inflammatory changes of the upper digestive tract are
preferably not infectious inflammations. They can have different
causes, for example radiotherapy, organ transplantation and/or
chemotherapy. In a preferred embodiment, the inflammatory changes
of the upper digestive tract are mucositis, an autoimmune disorder
of the oral cavity, Crohn's disease in the upper digestive tract
and eosinophilic oesophagitis.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1 shows a comparison of the quantity of budesonide
released in water from different effervescent tablet formulations.
Also shown is the quantity of released budesonide which can be
released from gastric juice-resistant capsules, ground up by pestle
and mortar, dissolved in water.
[0029] FIG. 2 shows budesonide plasma concentration time curves of
7 patients with chronically active oral graft-versus-host disease
after three different treatments with budesonide:
[0030] R=per os dose of 10 ml aqueous solution with 3 mg of
budesonide.
[0031] SD1=10 ml aqueous solution with 3 mg of budesonide as mouth
rinsing solution for 10 minutes.
[0032] MD1=multiple dosage for 7 days of a 10 ml aqueous solution
with 3 mg of budesonide, 3 times daily in a daily dose of 9 mg
budesonide as a mouth rinsing solution in each case for 10 minutes.
The last dose was given in the morning on the 7.sup.th day. The
curves are shown as an average.+-.standard deviation.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0033] Preferred embodiments of the present invention are
illustrated by the following examples.
Example 1
[0034] Surprisingly, it was found that the solubility of budesonide
effervescent tablets is significantly increased by the addition of
polyvinylpyrrolidone (PVP) and ducosate sodium. The composition of
different effervescent tablets is shown in Table 1. The composition
designated GO397X414 was investigated in more depth and proved to
be particularly suitable in the later experiments.
[0035] The following Table 1 summarises the formulations of the
tested effervescent tablets. The composition varies only in the
components Povidone K25 (polyvinylpyrrolidone) and docusate sodium
which were varied to improve the solubility of budesonide. Slight
differences in the individual formulations were compensated by
mannitol.
TABLE-US-00001 TABLE 1 Composition of the effervescent tablet
formulations Composition [mg] Step 1: Granulation Budesonide 3 3 3
3 3 3 Sodiumdihydro- 67 67 67 67 67 67 gencitrate Disodiumhydro- 15
15 15 15 15 15 gencitrate Sodiumhydrogen- 45 45 45 45 45 45
carbonate Povidone K25 (PVP) 2 2 -- -- 4 4 Docusate-sodium 0.05 --
0.05 -- -- -- Aspartam 1 1 1 1 1 1 Granules 133.05 133 131.05 131
135 135 Step 2: Final mixture Povidone K25 (PVP) -- -- -- -- -- 3
Mannitol 5.95 6 7.95 8 4 4 Macrogol 6000 5 5 5 5 5 5
Butanamide.sup.1 0.9 0.9 0.9 0.9 0.9 0.9 Magnesium-stearate 0.1 0.1
0.1 0.1 0.1 0.1 Final mixture 145 145 145 145 145 148 Effervescent
G0397X414 G0397X415 G0397X416 G0397X417 G0397X418 G0397X419 tablet
(Code) .sup.1Chemical name:
N-2,3-trimethyl-2-isopropylbutanamide
[0036] The solubility of budesonide of the individual effervescent
tablets was determined in accordance with the intended manner of
use by the patient. For this purpose, a respective effervescent
tablet was dissolved in 10 ml of water in a suitable polypropylene
measuring beaker. At the end of the effervescent reaction, the
content of dissolved budesonide was determined by an HPLC method. A
total of twelve determinations were made from each effervescent
tablet formulation. The solubility of pure budesonide in 10 ml of
water was determined simultaneously. For a better comparability,
the determined water solubility of budesonide was standardised to
1.0 or 100%. In this manner, it is possible to clearly see the
influence of the tested formulation ingredients on the solubility
of budesonide. The solubility values obtained are shown in FIG.
1.
[0037] Compared to the solubility of pure budesonide (see FIG. 1.
column "Budesonide API"), the addition of 1.4% of PVP into the
effervescent tablets significantly increases the water solubility
of budesonide by approximately 20% (see formulation
G0397.times.414). If PVP is absent (see column "G0397.times.416")
or if PVP and docusate sodium are absent (see column
"G0397.times.417"), the quantity of released budesonide is still
only within the region of the control mixture or is even lower. An
addition of 2.8% or 4.8% of PVP to the effervescent tablet
formulation again resulted in an increase in the quantity of
released budesonide (see columns "G0397X418 and G0397.times.419").
Grinding and dissolving gastric juice-resistant capsules described
in the prior art (FIG. 1, right-hand column) leads to poor
results.
Example 2
[0038] The addition of docusate sodium further improves the
usability of a mouth rinsing solution of budesonide: as a result,
the hydrophobic budesonide was made more easily wettable and a
greater proportion of the budesonide can dissolve (Table 2).
[0039] The intended use for the patient provides that the patient
dissolves the effervescent tablet in 10 ml of water in a
polypropylene measuring beaker and then uses the solution to rinse
his mouth. However, this presupposes that the content of the
measuring beaker can be removed approximately quantitatively and
that no appreciable budesonide residues remain (Table 2).
[0040] To verify the complete removal, therefore, after an
effervescent tablet had been dissolved, the mouth rinsing solution
was removed and the residue of budesonide remaining in the
measuring beaker was dissolved in 10 ml of methanol and determined
by an HPLC method. 12 determinations were again made from each
effervescent tablet formulation. Table 2 summarises the results of
the experiment. In this respect, the quantity of budesonide dosage
is stated which, after the mouth rinsing solution has been taken,
remains adhering to the measuring beaker and is not available to
the patient.
TABLE-US-00002 TABLE 2 Reside of budesonide remaining in the
measuring beaker after application Effervescent tablet (Code)
G0397X414 G0397X416 G0397X419 G0397X415 G0397X418 G0397X417
Budesonide residue 5% 6% 12% 13% 13% 25% in measuring beaker
[0041] The formulations with docusate sodium clearly show the least
adhesion to the measuring beaker material (see formulation codes
G0397X414 and G0397.times.416). When this ingredient is absent from
the formulation, the amount of dosage which remains as residue in
the vessel during an application significantly increases.
Example 3
[0042] The effervescent tablet according to the invention was
additionally optimised by the addition of
N-2,3-trimethyl-2-isopropylbutanamide ("cooling agent"). The use of
this auxiliary produces a cooling effect, thereby allowing an
improved, more pleasant use as a mouth rinsing solution which
increases the patient's adherence.
[0043] The solubility of the compositions stated in Table 1 was
determined and is shown in FIG. 1. The addition of PVP and ducosate
sodium increases the solubility of a budesonide effervescent tablet
by approximately 20%.
[0044] The preparation of this ready-for-use mouth rinsing
solution, based on a solid effervescent tablet now presents an
industrially producible pharmaceutical formulation which can be
dosed in a reproducible manner and is particularly suitable for use
in cases of inflammation in the upper digestive tract.
Example 4
[0045] The formulation (GO397X414) prepared in this way was tested
in vivo on patients with GVHD and the blood concentration was
measured as an indication of the availability of budesonide in the
mucosa. Surprisingly, it was found that when the selected,
optimised formulation was used as a mouth rinsing solution,
similarly low blood concentrations are generated as for the oral
dose (per os) of the same quantity of budesonide solution (FIG. 2),
although budesonide resorbed in the mouth is not subject to a
first-pass effect in the liver. Since budesonide resorbed in the
stomach/digestive tract is subject to a high first-pass effect in
which 90% of the absorbed budesonide is metabolised, this
comparable bioavailability of the mouth rinsing solution on the one
hand shows an effective concentration on the mucosal layers
concerned, and also a safe use which has few side effects because
comparatively low blood concentrations and not relatively high
blood concentrations are measured. Table 3 verifies this statement
by the comparability of the pharmacological data of the formulation
according to the invention with various oral forms of
administration.
[0046] In a clinical pilot study, the efficacy of the formulation
according to the invention was tested on 18 patients suffering from
oral chronic GVHD. The objective of the open, randomised phase II
study was to reduce the degree of severity of the oral chronic
GVHD. After using the budesonide effervescent tablet as a mouth
rinsing solution over a period of 8 weeks, it was possible to
achieve an objective reduction in the degree of severity of the
oral chronic GVHD, measured by the modified OMRS ("oral mucosa
rating scale", according to Schubert et al., Cancer, 1992, Vol. 69,
p. 2469-2477), in 11 of 18 patients (61%). As a definition of an
effective response rate, only those patients were counted for whom
the modified OMRS could be reduced by at least 50%, compared to the
starting value. This pilot study demonstrates in an impressive
manner the efficacy of the formulation according to the
invention.
[0047] Table 3 shows the resorption of 3 mg of budesonide in
healthy subjects and patients after a single dose. The data is
stated as averages.+-.standard deviation or as a median with the
spread in brackets.
TABLE-US-00003 TABLE 3 C.sub.max t.sub.max AUC.sub.0-tlast (ng/mL)
(h) (h * ng/mL) 7 patients, p.o. dose of 1.76 .+-. 1.38 1.7
(0.5-2.0) 5.90 .+-. 4.42 mouth rinsing solution 12 healthy
subjects, p.o. 1.23 .+-. 0.52 1.2 (0.3-1.7) 2.67 .+-. 1.09 dose of
mouth rinsing solution 8 healthy subjects, p.o.- 1.07 .+-. 0.63 5.0
(4.2-5.3) 3.15 .+-. 2.00 dose of a gastric juice- resistant capsule
7 patients, use as mouth 0.77 .+-. 0.23 2.0 (1.0-3.0) 3.61 .+-.
1.32 rinsing solution C.sub.max, peak level in the plasma;
t.sub.max, time of peak level; AUC.sub.0-tlast, area under the
plasma concentration time curve up to last measurable
concentration.
* * * * *