U.S. patent application number 14/722320 was filed with the patent office on 2015-09-24 for pharmaceutical composition for the sublingual administration of progesterone, and method for its preparation.
The applicant listed for this patent is Altergon S.A.. Invention is credited to Lorenzo Bellorini, Luca Nocelli, Giorgio Zoppetti.
Application Number | 20150265631 14/722320 |
Document ID | / |
Family ID | 40313810 |
Filed Date | 2015-09-24 |
United States Patent
Application |
20150265631 |
Kind Code |
A1 |
Bellorini; Lorenzo ; et
al. |
September 24, 2015 |
PHARMACEUTICAL COMPOSITION FOR THE SUBLINGUAL ADMINISTRATION OF
PROGESTERONE, AND METHOD FOR ITS PREPARATION
Abstract
A pharmaceutical composition is described for the sublingual
administration of progesterone in the form of a
rapidly-disintegrating tablet, which is capable of promoting a
greater bioavailability of the progesterone; a method for preparing
said pharmaceutical composition is also described.
Inventors: |
Bellorini; Lorenzo;
(Comerio, IT) ; Nocelli; Luca; (Luino, IT)
; Zoppetti; Giorgio; (Milano, IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Altergon S.A. |
Lugano |
|
CH |
|
|
Family ID: |
40313810 |
Appl. No.: |
14/722320 |
Filed: |
May 27, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12734078 |
Apr 7, 2010 |
9066858 |
|
|
PCT/EP2008/063595 |
Oct 10, 2008 |
|
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14722320 |
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Current U.S.
Class: |
514/58 |
Current CPC
Class: |
A61P 15/18 20180101;
A61K 9/0007 20130101; A61K 31/57 20130101; C08L 5/16 20130101; A61K
9/205 20130101; A61K 47/6951 20170801; A61K 9/0056 20130101; A61P
15/12 20180101; C08B 37/0015 20130101; A61K 47/12 20130101; A61K
9/2009 20130101; A61K 47/02 20130101; B82Y 5/00 20130101; A61K
9/006 20130101; A61K 31/00 20130101; A61P 5/24 20180101 |
International
Class: |
A61K 31/57 20060101
A61K031/57; A61K 9/00 20060101 A61K009/00; A61K 47/02 20060101
A61K047/02; A61K 47/48 20060101 A61K047/48; A61K 47/12 20060101
A61K047/12 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 10, 2007 |
IT |
MI2007A001971 |
Claims
1-23. (canceled)
24. A method to significantly increase the sublingual
bioavailability of a progesterone fast disintegrating tablet
without significantly modifying the tablet disintegration time,
characterized by including in said tablet: (a) progesterone
combined with a cyclodextrin, and (b) citric acid and sodium
bicarbonate, each present in an amount between 5 and 20% of the
total weight of the tablet composition.
25. The method according to claim 24, characterized in that said
tablet comprises citric acid amounting to 10% w/w of the total
weight of the composition.
26. The method according to claim 24, characterized in that said
tablet comprises bicarbonate amounting to 12% w/w of the total
weight of the composition.
27. The method according to claim 24, characterized in that said
cyclodextrin is chosen from either .beta.-cyclodextrin or
2-hydroxypropyl-.beta.-cyclodextrin.
28. The method according to claim 24, characterized in that the
molar ratio of said progesterone to said cyclodextrin is between 1
and 2.
29. The method according to claim 24, characterized in that the
content of cyclodextrin is between 27 and 40% w/w of the total
weight of the composition.
30. The method according to claim 24, characterized in that when
placed under the tongue, said tablet disintegrates completely
within a time approximately between 60 and 120 seconds.
31. A method to significantly increase the sublingual
bioavailability of a progesterone fast disintegrating tablet
without significantly modifying the tablet hardness, characterized
by including in said tablet: (a) progesterone combined with a
cyclodextrin, and (b) citric acid and sodium bicarbonate, each
present in an amount between 5 and 20% of the total weight of the
tablet composition.
32. The method according to claim 31, characterized in that said
tablet comprises citric acid amounting to 10% w/w of the total
weight of the composition.
33. The method according to claim 31, characterized in that said
tablet comprises bicarbonate amounting to 12% w/w of the total
weight of the composition.
34. The method according to claim 31, characterized in that said
cyclodextrin is chosen from either .beta.-cyclodextrin or
2-hydroxypropyl-.beta.-cyclodextrin.
35. The method according to claim 31, characterized in that the
molar ratio of said progesterone to said cyclodextrin is between 1
and 2.
36. The method according to claim 31, characterized in that the
content of cyclodextrin is between 27 and 40% w/w of the total
weight of the composition.
37. The method according to claim 31, characterized in that when
placed under the tongue, said tablet disintegrates completely
within a time approximately between 60 and 120 seconds.
Description
FIELD OF THE INVENTION
[0001] The present invention refers to a new pharmaceutical
composition for the sublingual administration of progesterone, and
to a method for its preparation.
STATE OF THE ART
[0002] Progesterone is a steroid hormone that is naturally secreted
by the ovaries in the second half of the menstrual cycle of fertile
women of reproductive age; it is used for therapeutic purposes,
e.g. in hormone replacement therapy for menopausal women, in oral
contraceptives and for regulating the menstrual cycle.
[0003] Various methods for administering progesterone are known,
from the parenteral to the vaginal, to the oral, the last of these
being by far the most readily acceptable and comfortable for the
patients, especially if they have to undergo lengthy periods of
treatment.
[0004] The therapeutic efficacy of progesterone is severely reduced
when it is administered orally, however, due to a more limited
bioavailability deriving from its solubility in water and its rapid
degradation by the liver; these two factors contribute to a very
poor absorption of the active ingredient in the gastrointestinal
tract.
[0005] To overcome these problems, it has been suggested that
progesterone be administered via absorption in the oral cavity,
where it is less affected by a rapid metabolism in the liver than
when it is absorbed in the gastrointestinal tract. Said mode of
administration generally gives rise to only modest haematic levels
of progesterone unless it is administered in the form of its
water-soluble derivative.
[0006] The U.S. Pat. No. 4,596,795, for instance, describes a
formulation in tablets for administering progesterone buccally or
sublingually in the oral cavity, in which the progesterone is
combined with specific beta-cyclodextrins. In fact, when combined
with these compounds, progesterone forms inclusion complexes that
are soluble in an aqueous environment, thereby favouring its
bioavailability.
[0007] In the case of its sublingual administration, this patent
indicates the need for the tablet to disintegrate, which takes
several minutes.
SUMMARY
[0008] According to the present invention, it has now surprisingly
been discovered that adding certain excipients to a composition
comprising progesterone and a cyclodextrin gives rise to a powder
that can be compressed to obtain a tablet which is sufficiently
compact for packaging but that nonetheless disintegrates rapidly
when administered sublingually, and that said
rapidly-disintegrating tablet is able, when administered
sublingually, to promote a greater bioavailability of the
progesterone than a tablet lacking said excipients.
[0009] By rapid disintegration, we mean a time preferably lasting
no more than two minutes.
[0010] The subject of the present invention is therefore a
pharmaceutical composition for the sublingual administration of
progesterone associated with a cyclodextrin, characterised in that
it is in the form of a rapidly-disintegrating tablet comprising
excipients capable of releasing CO.sub.2 in the sublingual
site.
[0011] For said purpose it preferably comprises a bicarbonate, such
as sodium bicarbonate, and a suitable acid, such as citric
acid.
[0012] According to the present invention, by progesterone
associated or combined with a cyclodextrin, we mean a complexing
derivative such as those described in U.S. Pat. No. 4,596,795.
[0013] A further object or the invention is a method used to
prepare the aforesaid pharmaceutical composition, which can be
achieved by means of the following stages: [0014] a) sieving the
excipients and the raw material; [0015] b) mixing; [0016] c)
compressing the mixture to produce said finished tablet.
[0017] Characteristics and advantages of the pharmaceutical
composition according to the present invention are illustrated in
more detail in the description that follows.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 shows a diagram comparing the concentration (ng/ml)
of progesterone in the serum against the time after the sublingual
administration of 20 mg of active ingredient using the tablets
prepared as in example 1 (invention) and example 2 (reference).
DETAILED DESCRIPTION OF THE INVENTION
[0019] Reference is made below to the non-limiting case in which
said excipients capable of releasing CO.sub.2 in the sublingual
site are citric acid and sodium bicarbonate.
[0020] The quantity of citric acid contained in the composition of
the invention is, for instance, comprised between 5 and 20% w/w of
the total weight of the composition, and preferably amounts to 10%
w/w.
[0021] The quantity of bicarbonate contained in the composition of
the invention is, for instance, comprised between 5 and 20% w/w of
the total weight of the composition, and preferably amounts to 12%
w/w.
[0022] The bicarbonate contained in the composition of the
invention is preferably sodium bicarbonate.
[0023] According to a preferred embodiment of the invention, the
molar ratio of the progesterone to the cyclodextrin is between 1
and 2.
[0024] A cyclodextrin suitable for use in the present composition
may be, for instance, either .beta.-cyclodextrin or
2-hydroxypropyl-.beta.-cyclodextrin; the composition of the
invention preferably contains
2-hydroxypropyl-.beta.-cyclodextrin.
[0025] The quantity of cyclodextrin contained in the composition
shall preferably be between 27 and 40% w/w of the total weight of
the composition.
[0026] In addition to the active ingredient (progesterone), a
cyclodextrin and the pair of excipients with an effervescent action
(citric acid and bicarbonate), the pharmaceutical compositions
according to the invention may comprise further pharmacologically
suitable excipients chosen from among those conventionally used in
pharmaceutical preparations to obtain a composition in the form of
a rapidly-disintegrating tablet.
[0027] The present pharmaceutical composition in tablet form,
though it is hard enough to enable it to retain its shape and
remain intact so that the product can be packaged and preserved,
when it is placed under the tongue it nonetheless disintegrates
rapidly, becoming completely disintegrated within a time generally
between 60 and 120 seconds.
[0028] Moreover, pharmacokinetic studies (described in more detail
in Example 3) have demonstrated an approximately 30% increase in
the bioavailability of the progesterone in the compositions
according to the present invention by comparison with similar
compositions for sublingual administration that lack the pair of
effervescent excipients, such as citric acid and sodium
bicarbonate.
[0029] The compositions according to the invention can be prepared
to contain various unit doses of progesterone, for instance,
between 5 and 30 mg of progesterone, and preferably amounting to 20
mg.
[0030] The following examples are given as a non-limiting
illustration of the present invention.
EXAMPLE OF THE PREPARATION METHOD 1
Formulation:
TABLE-US-00001 [0031] 1) hydroxypropyl-.beta.-cyclodextrin, batch
E0033 kg 13.5 Kleptose (HPBCD) 2) progesterone micron. batch
L00025494 kg 1.35 3) distilled water of 13.06.05 kg 55.4625
Method for Preparing the Solution to lyophilize:
[0032] 1) kg 42.2625 of distilled water are transferred to a
dissolver (A) with a capacity of 200 L;
[0033] 2) the first semiprocessed product is prepared in a separate
stainless steel container (B);
TABLE-US-00002 distilled water kg 6.6
hydroxypropyl-.beta.-cyclodextrin, Kleptose (HPBCD) kg 6.75
[0034] and agitated for 20 minutes at ambient temperature;
[0035] the deaerated solution appears clear and contains no
residues;
[0036] 3) progesterone micron. kg 0.675 is added to the solution
prepared according to step 2;
[0037] the mixture is agitated for 45 minutes at ambient
temperature;
[0038] the resulting solution is transferred to a dissolver
prepared according to step 1;
[0039] 4) the second semiprocessed product is prepared according to
steps 2 and 3 in a stainless steel container (B) and transferred to
a dissolver (A) prepared according to steps 1 and 3;
[0040] 5) the final solution is mixed for 10 minutes in a 200 L
dissolver; the resulting solution is clear and contains no air
bubbles; approximately 40 mL of solution are drawn off for
analyses;
[0041] the solution is placed in the lyophilizer;
[0042] 6) the solution is forced through a 0.46 .mu.m column filter
under a pressure of 2 bar of anhydrous air;
[0043] 7) the solution is placed on disposable high-density
polyethylene mats in a continuous flow (16--maintaining a bulk
thickness of 1 cm);
[0044] 8) the product is lyophilized;
[0045] 9) the resulting bulk product is ground in an oscillating
granulator and passed through a 1 mm sieve;
[0046] 13.9 kg of end product are obtained;
[0047] 10) the product is placed in three aluminium containers,
which are then sealed.
[0048] The resulting powder has the following characteristics:
[0049] Bulk humidity when unloaded from the mats 0.9%.
[0050] Humidity after grinding 1.5%.
[0051] Bulk density after pouring =0.26 g/ml
[0052] Bulk density after compacting =0.32 g/ml
[0053] Particle size distribution:
[0054] 95% between 50 and 800 .mu.m
[0055] mean =260 .mu.m
Example 1
Method for Preparing Tablets for the Sublingual Administration of
Progesterone According to the Invention
[0056] The single components are separately weighed and labelled as
follows:
TABLE-US-00003 Weight in g 1 Progesterone complex (as described
1507 in the example preparation method 1) 2 Polyvinylpyrrolidone CL
253.45 3 Citric acid anhydrous powder 445.25 4 Sodium bicarbonate
powder 548 5 Calcium silicate 616.5 6 Sorbitol 787.75 7 Sodium
stearyl fumarate 34.25 8 E951 137 9 Flavouring 226.05 TOTAL
4555.25
[0057] Ingredients 1), 2), 3), 4), 5), 6) and 9) are premixed and
sieved through a wire sieve with 1 mm net mesh holes and loaded in
a mixer.
[0058] Component 8) is separately sieved through a 0.5 mm wire
sieve and loaded in the mixer.
[0059] The ingredients are mixed for 25 minutes at a speed of 20
rpm/60''.
[0060] Component 9) is sieved through a 0.2 mm wire sieve and
loaded in the mixer.
[0061] Mixing proceeds with the other ingredients for 5 minutes at
a speed of 20 rpm/60''.
[0062] The powder is unloaded and compressed with a round punch 16
mm in diameter, setting a mean weight of 665 mg .+-.3% and a mean
hardness of 35 N .+-.3N.
[0063] The tablets are blister-packed in a suitable format and
placed in cardboard boxes.
[0064] The resulting tablets have the following
characteristics:
[0065] mean weight =660.4, mean titre =103.1% d.d., hardness =33N
and disintegration time =100 sec.
Example 2 (COMPARISON)
Method for Preparing Tablets for the Sublingual Administration of
Progesterone Without Citric Acid and Bicarbonate
[0066] The single components are separately weighed and labelled as
follows:
TABLE-US-00004 Weight in g 1 Progesterone complex (as described in
44 the example preparation method 1) 2 Polyvinylpyrrolidone CL 7.4
3 Calcium silicate 18 4 Sorbitol 52 5 Sodium stearyl fumarate 1 6
E951 4 7 Flavouring 6.6 TOTAL 133
[0067] Ingredients 1), 2), 3), 4) and 7) are premixed and sieved
through a wire sieve with 1 mm net mesh holes and loaded in a
mixer.
[0068] Component 6) is separately sieved through a 0.5 mm wire
sieve and loaded in the mixer.
[0069] The ingredients are mixed for 25 minutes at a speed of 20
rpm/60''.
[0070] Component 5) is sieved through a 0.2 mm wire sieve and
loaded in the mixer.
[0071] Mixing proceeds with the other ingredients for 5 minutes at
a speed of 20 rpm/60''.
[0072] The powder is unloaded and compressed with a round punch 16
mm in diameter, setting a mean weight of 665 mg .+-.3% and a mean
hardness of 35 N .+-.3N.
[0073] The tablets are blister-packed in a suitable format and
placed in cardboard boxes.
[0074] The resulting tablets have the following
characteristics:
[0075] mean weight =664, mean titre =101.1% d.d., hardness =32N and
disintegration time =90 sec.
Example 3
Pharmacokinetic Study
[0076] A preliminary pharmacokinetic study was conducted to compare
the administration of tablets according to the invention, obtained
as described in example 1, with those prepared for comparison as
described in example 2.
[0077] The diagram in the attached drawing (FIG. 1) compares the
concentration (ng/ml) of progesterone in the serum against the time
after the sublingual administration of 20 mg of active ingredient
using the tablets prepared as in example 1 (invention) and example
2 (reference).
[0078] The two curves plotted in the diagram represent the mean
(+SD) of the values obtained in three subjects treated as described
above.
[0079] Clearly, the curve relating to example 1 shows an
approximately 30% greater mean bioavailability than the curve
relating to example 2.
* * * * *