U.S. patent application number 11/483983 was filed with the patent office on 2007-02-22 for progestin co-micronized with a surfactant, pharmaceutical composition comprising same, methods for making same and uses thereof.
This patent application is currently assigned to Besins International Belgique. Invention is credited to Jerome Besse.
Application Number | 20070042038 11/483983 |
Document ID | / |
Family ID | 8860623 |
Filed Date | 2007-02-22 |
United States Patent
Application |
20070042038 |
Kind Code |
A1 |
Besse; Jerome |
February 22, 2007 |
Progestin co-micronized with a surfactant, pharmaceutical
composition comprising same, methods for making same and uses
thereof
Abstract
The invention concerns a progestin co-micronized with a
surfactant and a pharmaceutical composition comprising said
gestagenic. The invention also concerns methods for preparing
same.
Inventors: |
Besse; Jerome; (Listrac
Medoc, FR) |
Correspondence
Address: |
FOLEY AND LARDNER LLP;SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
Besins International
Belgique
|
Family ID: |
8860623 |
Appl. No.: |
11/483983 |
Filed: |
July 11, 2006 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10469441 |
Feb 10, 2004 |
|
|
|
PCT/FR02/00714 |
Feb 27, 2002 |
|
|
|
11483983 |
Jul 11, 2006 |
|
|
|
Current U.S.
Class: |
424/464 ;
264/109; 514/177 |
Current CPC
Class: |
A61P 15/12 20180101;
A61K 31/57 20130101; A61K 9/2054 20130101; A61K 9/2018 20130101;
A61K 9/145 20130101; A61K 9/2027 20130101 |
Class at
Publication: |
424/464 ;
264/109; 514/177 |
International
Class: |
A61K 31/57 20070101
A61K031/57; B27N 3/00 20060101 B27N003/00; A61K 9/20 20060101
A61K009/20 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 1, 2001 |
FR |
0102814 |
Claims
1. A progestin co-micronized with a surfactant.
2-17. (canceled)
Description
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
[0001] This application claims priority under 35 U.S.C. .sctn. 119
to French Application 0102814, filed Mar. 1, 2001. This application
is a continuation of U.S. application Ser. No. 10/469,441, filed
Feb. 10, 2004, which is incorporated herein by reference in its
entirety, and which is the U.S. National Stage of PCT/FR02/00714,
filed Feb. 27, 2004. This application claims priority under 35
U.S.C. .sctn. 120 to these U.S. and PCT applications.
FIELD OF THE INVENTION
[0002] The present invention relates, as a new product, to a
progestin co-micronized with a surfactant, to a pharmaceutical
composition containing same, to methods for preparing same, and
also to uses thereof.
BACKGROUND OF THE INVENTION
[0003] In the context of the present invention, the term
"progestin" is intended to mean any steroid having affinities for
progesterone receptors and capable of more or less fully
reproducing the biological effects of progesterone.
[0004] A progestin is a compound capable, by definition, of
maintaining gestation and of promoting implantation of the egg.
This biological role is reflected essentially by a change in the
vaginal mucosa (desquamation), in the endometrium (cell
proliferation, formation of the uterine lining), and in the
endocervical glandular epithelium (decrease in the production of
glairy mucus and thickening thereof).
[0005] The only property that all progestins have in common is
their endometrial action.
[0006] The effect on gestation is real for progesterone and very
inconstant with synthetic progestins.
[0007] Progestins comprise progesterone and also synthetic
progestins. The latter may be classified into three groups
(unofficial classification) according to their biological
activities (and their structure, which determines said activities);
the order of classification thus takes into account their
structural difference relative to physiological progesterone.
[0008] The first group comprises molecules similar to progesterone
or synthetic progestins 1 (SP1) (pregnanes), for example the
progesterone isomer (retroprogesterone), Medrogesterone,
norprogesterone derivatives(demegestone or promegestone). These
molecules have peripheral extragestative activity which is
virtually identical to progesterone, and have no androgenic
effects.
[0009] The second group comprises 17.alpha.-hydroxyprogesterone
derivatives or synthetic progestins 2 (SP2) (pregnanes), for
example cyproterone acetate and medroxyprogesterone acetate. These
molecules have more powerful and more intense peripheral gestative
activity than that of progesterone and, in addition, have an
androgenic effect.
[0010] The third group comprises the norsteroids or synthetic
progestins 3 (SP3) (estranes or norandrostanes). These are
19-nortestosterone derivatives, for example norethindrone. These
molecules have particularly powerful peripheral gestative activity
(this is the group of synthetic progestins which has the most
pronounced endometrial action) and also have an androgenic effect.
From these norandrostanes or estranes are derived molecules of the
gonane type containing a methyl group at C18 and an ethyl group at
C13. Examples that may be mentioned include norgestimate
(levonorgestrel), desogestrel (3-keto desogestrel) and gestodene.
These chemical modifications increase the endometrial power and
decrease the intrinsic androgenic activity of the molecule.
[0011] Progesterone is a hormone which is synthesized, in women,
essentially by the ovary during the post-ovulatory or luteal
(yellow body) phase and, to a lesser degree, by the adrenal glands
and the placenta during the second part of pregnancy. A
non-endocrine synthesis of progesterone, in particular in the
neurones, is also possible.
[0012] The consequence of insufficiency of progesterone secretion
in women is a loss of its biological effects: progestin effect;
anti-androgenic effect (action on the skin) and anti-estrogenic
effect (a consequence of which is hyperestrogenism: hot flushes,
psychogenic difficulties such as anxiety or depression, weight
gain, etc.). This progesterone insufficiency may lead to functional
impairment and various clinical manifestations, in particular:
[0013] premenstrual syndromes, [0014] menstrual irregularities
through disovulation or anovulation, [0015] benign mastopathies,
[0016] perimenopause and menopause.
[0017] The use of hormone replacement therapy is well established
to date for relieving menopausal symptoms. Given that it has been
demonstrated that progestins prevent the development of hyperplasia
and endometrial cancer, sequential or combined therapy with
estrogens and progestins is advised in menopausal women who have
not undergone a hysterectomy. Among progestins suitable for hormone
replacement therapy, micronized progesterone is preferably used due
to its lack of androgenic effect and its metabolic innocuity.
[0018] However, oral administration of progesterone suffers from a
serious handicap due to the considerable metabolizing thereof in
the liver.
[0019] Now, the oral administration method has clear advantages
compared to other methods of its administration. Specifically, it
is, firstly, more practical than vaginal administration and,
secondly, it allows a dose to be taken independently, which is
impossible with parenteral administration.
[0020] LABORATOIRES BESINS-ISCOVESCO have already proposed a
solution to this problem of progesterone degradation, in patent
application FR 76 36007. Specifically, they have developed a
formulation of soft capsules containing progesterone micronized in
oily suspension, which allows improved bioavailability of the
progesterone.
[0021] The method for preparing such capsules proves, however, to
be complex and expensive to carry out, and also requires
considerable know-how. Attempts have therefore been made to develop
alternative effective, but also economically viable, formulations
such as progesterone-based tablets (see patent applications FR 97
16168 and FR 98 02830).
[0022] However, there is still a need to find pharmaceutical
formulations containing progesterone or another progestin and
having improved bioavailability.
[0023] In general, the bioavailability of an active principle can
be improved by chemical means: administration of prodrugs,
complexation, combination with lipids or phospholipids, most often
in the presence of a surfactant; or by physical means such as
micronization.
[0024] Micronization is a well-known technique which can be carried
out either in hammer or ball mills or in gas jet micronizers. As
was recalled above, the micronization technique has already been
used (see BESINS patent FR 76 36007) to develop a composition based
on progesterone which is bioavailable and which can be administered
orally.
[0025] Patent application FR 2 757 397 also recalls this fact and
subsequently indicates, on page 2, that co-micronization of
phenofibrate in the presence of sodium lauryl sulfate has already
been described in patent EP 330 532. However, that patent
application underlines, at the same time, the fact that it is not
automatic and inescapable that the bioavailability of an active
principle is systematically improved by co-micronization in the
presence of a surfactant. Thus, the inventors of that patent
application recall that M. OTSUDA et al. (JPS 84, 1995, p. 1434-37)
studied the micronization of phenitoin in the presence of a
surfactant and that they showed that the solubility of phenitoin is
not improved in the case of co-micronization with a surfactant such
as sodium lauryl sulfate or a sucrose ester of stearic acid,
whereas it is multiplied by 30 compared to the mixture of powders
in the case of co-grinding with sodium deoxycholate.
[0026] The same authors underlined moreover--which is entirely
relevant--that even though micronization or grinding of a substance
in the presence of a surfactant or of a sugar can increase its
solubility, these parameters are not always sufficient. They thus
gave, as an example, the fact that the bioavailability of
micronized progesterone is not satisfactory and that it must be
improved, for example by mixing the micronized progesterone with
carnauba wax, a technique described in patent application WO
89/02742.
[0027] It is therefore perfectly established that the properties of
a substance treated by micronization or grinding, in particular its
solubility and its bioavailability, are not predictable,
contradictory results possibly being obtained, and that the same
pharmaceutical formulation can provide good results with one
substance and produce an opposite result with another
substance.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1 depicts the in vitro dissolution curves for 100 mg
and 200 mg progesterone tablets, respectively. The progesterone
tablets are co-micronized in the presence of sodium lauryl sulfate.
The progesterone tablets that are not co-micronized are used as
controls.
[0029] FIGS. 2 depicts the in vitro dissolution curves for the
formulations given in tables IV and V, respectively.
DETAILED DESCRIPTION
[0030] Now, it is to the applicant company's credit to have
succeeded in improving not only the solubility but also the
bioavailability of progestins, including most particularly
progesterone, by carrying out their co-micronization in the
presence of a surfactant, which was neither taught nor even
suggested by the documents of the prior art.
[0031] A subject of the invention is therefore, as a novel product,
a progestin co-micronized with a surfactant, and also a
pharmaceutical composition containing said co-micronized progestin.
Subjects of the invention are also the method for producing the
co-micronized progestin, the method for producing the
pharmaceutical composition comprising the co-micronized progestin,
and also the use of said progestin for preparing a medicinal
product intended to prevent or treat disorders or diseases caused
by a progestin insufficiency.
[0032] For the purpose of the present invention, the term
"surfactant" is intended to mean any product having both a
lipophilic component and a hydrophilic component. These products
are generally classified as ionic or nonionic. In accordance with
the present invention, an ionic surfactant is preferably used. Even
more preferentially, sodium lauryl sulfate is used.
[0033] Co-micronization of progesterone or of another progestin
with a surfactant, in particular sodium lauryl sulfate, makes it
possible to improve the solubility of the active principle,
allowing rapid in vitro dissolution profiles to be obtained.
Co-micronization also makes it possible to improve the wettability
of the progestin when it is administered per os thus facilitating
its absorption in vivo.
[0034] According to an advantageous embodiment of the invention,
the co-micronized progestin is progesterone and the surfactant is
sodium lauryl sulfate.
[0035] The surfactant content is at least equal to the critical
micellar concentration of the progestin/surfactant combination.
[0036] The co-micronized progestin in accordance with the invention
exhibits a progestin content of between 80.0% and 99.9%, preferably
between 90.0% and 99.5%, and even more preferentially between 95.0%
and 99.0%, and a surfactant content of between 0.1% and 20%,
preferably between 0.5% and 10.0%, and even more preferentially
between 1.0% and 5.0%, the percentages being expressed by weight of
solids.
[0037] When the progestin is progesterone, the
surfactant/progesterone ratio is between 1/200 and 1/20, preferably
between 1/150 and 1/40.
[0038] A subject of the invention is also a pharmaceutical
composition comprising the progestin co-micronized with a
surfactant as described above.
[0039] According to an advantageous embodiment, the pharmaceutical
composition in accordance with the invention exhibits a surfactant
content of between 0.001% and 5%, preferably between 0.002% and 3%,
and even more preferentially between 0.005% and 2%, relative to the
total solids.
[0040] When the co-micronized progestin is progesterone, the
surfactant content is then between 0.1% and 5%, preferably between
0.2% and 3%, even more preferentially between 0.2% and 2%, by
weight relative to the total solids of the pharmaceutical
composition.
[0041] The pharmaceutical composition according to the present
invention can be in the form, for example, of a soft capsule, of a
gelatin capsule, of a tablet, of a lyophilisate, of a powder or of
a granule, including microgranules. Preferably, the pharmaceutical
composition according to the invention is a tablet.
[0042] When it is a tablet, the pharmaceutical composition
according to the invention contains excipients for in particular
facilitating compression in order to obtain a tablet having good
hardness, disaggregation and dissolution characteristics.
[0043] As excipients which can be used in the tablet according to
the invention, mention may be made of diluents, disintegrating
agents, lubricants, binders and dyes conventionally used in this
application.
[0044] As examples of diluents, mention may be made of sugars,
starches, polyols and celluloses, and derivatives. Preferably, the
tablet according to the invention contains lactose and/or mannitol
as diluents.
[0045] As examples of disintegrating agents, mention may be made of
carboxymethylcelluloses, alginic acid and also its sodium salt, and
modified starches. Preferably, the tablet according to the
invention contains crosslinked sodium carboxymethylcellulose (also
referred to as sodium croscarmellose).
[0046] The preferred lubricant used in the context of the present
invention is magnesium stearate.
[0047] Among the preferred binders in the context of the production
of the tablet according to the present invention, mention may be
made of polyvinylpyrrolidones. Preferably, the tablet according to
the invention contains polyvidone K30.
[0048] The tablet according to the invention may also contain a
dye, such as, for example, the dye orange yellow S or Pigment Blend
PB 23028.
[0049] The pharmaceutical composition according to the invention
may also contain an estrogen or one of its derivatives.
[0050] In fact, estrogens, particularly 17.beta.-estradiol, are
prescribed in order to reduce the harmful consequences associated
with their disappearance during menopause, such as osteoporosis,
hot flushes or cardiovascular accidents. The long-term
administration of estrogens alone presents major risks given in
particular the possible carcinogenic role of this hormone. It is
usual to combine with it a treatment with a progestin in order to
avoid the risks of endometrial hyperplasia.
[0051] The estrogen which may be included in the pharmaceutical
composition according to the present invention can be selected from
the estrogens which are active per os, i.e. natural estrogens
(17.beta.-estradiol, estrone) or synthetic estrogens
(17.beta.-ethinylestradiol or estradiol valerate).
17.beta.-estradiol is preferably used.
[0052] The estrogen content of the pharmaceutical composition
according to the invention is between 0.05% and 5%, preferably
between 0.1% and 3%.
[0053] A subject of the invention is also a method for
co-micronization of a progestin with a surfactant. This
co-micronized material can be produced from a solid/solid mixture
(as in the case of the progesterone/sodium lauryl sulfate mixture)
using an airjet mill, such as the one marketed under the trade mark
ALPINE.
[0054] In the case of a solid/liquid co-micronized material
(example: progesterone/TWEEN 80), the co-micronization operation
can be carried out with a colloidal mill or else a ball mill.
[0055] The method for preparing the progestin co-micronized with a
surfactant is therefore characterized in that a mixture of a
progestin with a surfactant is prepared, and in that either a
grinding step is then carried out with an air jet mill, in the case
of a solid/solid co-micronization, or a grinding step is then
carried out with a colloidal mill or a ball mill, in the case of a
solid/liquid co-micronization.
[0056] When the pharmaceutical composition according to the
invention is in the form of a tablet, the method for preparing a
progestin-based tablet preferentially comprises the following
steps: [0057] preparing a first mixture of progestin and
surfactant, [0058] micronizing this first mixture in order to
obtain a progestin co-micronized with the surfactant, [0059]
preparing a wetting solution, [0060] wetting the progestin
co-micronized with the surfactant, with the wetting solution,
[0061] granulating the mixture obtained in order to obtain
granules, [0062] drying the granules and then calibrating, [0063]
adding to the calibrated granules disintegrating agents, diluents,
dyes, lubricants, [0064] compressing the mixture thus obtained in
order to obtain tablets.
[0065] The invention also relates to the use of a progestin
co-micronized with a surfactant as defined above, for preparing a
medicinal product intended for the treatment of a physiological
condition related to insufficiency of progesterone secretion, such
as menopause.
[0066] The invention will be understood more clearly from the
nonlimiting examples described below.
EXAMPLE 1
Preparation of Progesterone Co-Micronized with Sodium Lauryl
Sulfate
[0067] 1) 97 g of progesterone and 3 g of sodium lauryl sulfate are
mixed for 5 minutes in a mixer of the LODIGE type.
[0068] 2) The mixture obtained in step (1) is introduced into an
Alpine 200 AS airjet mill preset on the following parameters:
[0069] injection: 5.5 B [0070] ring: 3.0B [0071] rate: 35 kg/h
[0072] 3) This mixture is ground in order to obtain a co-micronized
material of progesterone/sodium lauryl sulfate.
EXAMPLE 2
Tablets Based on Progesterone Co-Micronized with A Surfactant
[0073] The formulations of progesterone tablets according to the
invention, containing 100 and 200 mg of progesterone, are given in
Table I below. TABLE-US-00001 TABLE 1 NAME OF THE UNIT AMOUNT BATCH
COMPONENT FUNCTION mg/tablet SIZE (kg) Micronized Active 55.000
progesterone* principle (sodium lauryl (progestin) 200 100 sulfate
(SLS))* (surfactant) 6.18 3.09 Povidone K30 Binder 9.60 4.80 2.561
Solution at 35% (m/m) Mannitol Diluent 29.84 14.92 7.981
Crosslinked Disintegrating 13.00 6.50 3.468 sodium agent
carboxymethyl cellulose Magnesium Lubricant 1.30 0.65 0.347
stearate *Progesterone/SLS are co-micronized according to example
1.
[0074] To prepare the tablets in question, the following procedure
was carried out:
Step 1: Preparation of the Wetting Solution
[0075] 4.756 kg of purified water are introduced into a container
of suitable volume. 2.561 kg of Povidone K30 are then introduced
into the purified water, gradually, and with stirring in a
deflocculating-type stirrer (RAYNERI) at a stirring rate of
approximately 1800 rpm and for 30 minutes until complete
solubilization of the Povidone K30.
Step 2: Granulation
[0076] 55.000 kg of co-micronized progesterone are introduced into
the tank of a LODIGE-type mixer.
[0077] The preceding mixture is wetted with the solutions from step
2, and granulation is then carried out until a satisfactory visual
appearance is obtained.
[0078] The conditions for the granulation are as follows:
TABLE-US-00002 Amount of purified water added as QS Satisfactory
final appearance of the grain % residual water content 6.8 Duration
of wetting (approximately 1 min) 30 sec Duration of granulation
(plowshare + blade) 5 min 30 sec Power absorbed (fine granulates)
(approximately 38%).
[0079] Wet decaking of the grain on leaving the granulator can be
carried out if necessary before drying on an ALEXANDERWERK rotary
calibrator or equivalent equipped with a stainless steel screen
greater than or equal to 3 mm in diameter.
Step 3: Drying
[0080] The grain from step 2 is dried until a satisfactory residual
water content is obtained.
[0081] The drying conditions are as follows: [0082] inlet air
temperature (approximately 55.degree. C.) [0083] outlet air
temperature: 39.degree. C. end at 42.degree. C. (at the end of
drying) [0084] duration: 10 min. Step 4: Calibration
[0085] The grain from 'step 3 is calibrated on a BOHLE equipped
with a screen of mesh size 1.0 mm, or equivalent.
[0086] The calibration conditions are as follows: [0087] duration:
12 min [0088] amount obtained: 55.040 kg [0089] % residual water
content of the calibrated grain.
[0090] Homogenization is carried out for 5 min at 5 rpm in a BOHLE
or equivalent.
Step 5: Mixing
[0091] The following are introduced into the MCG 600 tank of the
BOHLE PM 100 mixer of suitable capacity, or equivalent: [0092] the
calibrated grain from step 4: 54.740 kg [0093] croscarmellose:
3.298 kg [0094] mannitol: 7.590 kg
[0095] Mixing is carried out at a speed of 5 rpm for approximately
30 min.
Step 6: Lubrication
[0096] 0.330 kg of magnesium stearate are introduced into the
mixture from step 5:
[0097] Mixing is carried out at a speed of 5 rpm for approximately
10 min.
[0098] The net weight is 64.490 kg.
[0099] The mixture is stored in an air-tight container.
Step 7: Compression
[0100] The compressing machine of the KILIAN RTS 21 type, or
equivalent, is equipped with punches of 7R7.5-type format for
progesterone 100 mg and 9R10-type format for progesterone 200
mg.
[0101] The hopper of the compressing machine is fed with the
mixture from step 6.
[0102] The compression settings are adjusted so as to obtain
tablets with a mass of 130 mg, and with a satisfactory hardness and
thickness making it possible to guarantee a disintegration time of
less than 5 min.
EXAMPLE 3
Dissolving of the Progesterone Tablets Prepared According to the
Invention, In Vitro
[0103] 100 mg and 200 mg progesterone tablets are prepared
according to the method given in example 2, and the following
operations are carried out in order to determine the in vitro
dissolution curves (see FIG. 1).
[0104] The following material is used: [0105] SOTAX AT7 7-position
revolving-paddle dissolution device [0106] PERKIN ELMER lambda 20
spectrophotometer [0107] ISMATEC IPC 12 cassette pump [0108]
WINSOTAX data acquisition software.
[0109] The dissolving conditions are as follows: [0110] dissolving
medium: 1000 ml of aqueous solution of
.beta.-hydroxypropylcyclodextrin having the trade mark
KLEPTOSE.RTM. at 1% per cell [0111] rotation rate: 150 rpm [0112]
temperature: 37.degree. C..+-.0.5.degree. C. [0113] number of
cells: 7 [0114] circulation cell made of quartz with an optical
path: 0.1 cm.
[0115] A control is prepared, consisting of a tablet of micronized
progesterone: TABLE-US-00003 Progesterone 20 mg HPLC ethanol 20 ml
1% solution of KLEPTOSE .RTM. qs 200 ml
[0116] The agitation is carried out using rotating buckets.
Procedure
[0117] 1--The cells are placed in the waterbath at ambient
temperature. [0118] 2--1000 ml of 1% KLEPTOSE.RTM. solution are
transferred into each one of the 7 cells. [0119] 3--One tablet is
placed in 6 of the 7 rotating buckets. Cell 7 is used as an in-test
reference. [0120] 4--The rotating buckets are immersed in the
dissolving medium at a distance of 25 mm.+-.2 mm between the
rotating bucket and the bottom of the cell. [0121] 5--The buckets
are agitated at 150 rpm. [0122] 6--At each planned time interval,
the amount of medium necessary and sufficient to determine the
concentration of dissolved active principle is automatically
sampled from each one of the 7 cells. This measurement is carried
out with the device described above. [0123] 7--Each sample
collected is assayed by spectrophotometry (.lamda.=248 nm). [0124]
8--The percentage of released progesterone is determined.
[0125] The results are given in table II below and also in FIG.
1.
Legend:
[0126] GAL 207.07: 100 mg progesterone tablet batch 102
(progesterone/sodium lauryl sulfate co-micronization).
[0127] GAL 208.03:200 mg progesterone tablet batch 101
(progesterone/sodium lauryl sulfate co-micronization).
[0128] GAL 207.08: 100 mg progesterone tablet active principle not
co-micronized batch 00VR1108.01.
[0129] GAL 208.04: 200 mg progesterone tablet active principle not
co-micronized batch 00VR1110.01. TABLE-US-00004 TABLE II % of
dissolved progesterone (mean of 6 cells) GAL 207.08 GAL 208.04 Time
GAL 207.07 batch GAL 208.03 batch (in mm) batch 102 00VR1108.01
batch 101 00VR1110.01 0 0 0 0 0 5 42.97 32.35 40.31 32.06 10 62.43
50.29 60.37 49.42 15 72.26 60.64 69.74 59.90 30 85.59 78.21 82.35
77.21 45 90.79 87.45 88.21 86.18 60 93.38 92.81 91.48 90.99 90
95.95 98.09 94.85 95.61 120 97.32 100.26 96.49 97.71 150 98.02
101.26 97.45 98.88 180 98.46 101.81 97.31 99.56
EXAMPLE 4
Tablets According to the Invention Containing A Progestin
Co-Micronized with A Surfactant
[0130] The formulations of tablets according to the invention
containing either progesterone or levonogestrel are given in tables
III to V below. TABLE-US-00005 TABLE III NAME OF THE UNIT AMOUNT %
COMPONENT FUNCTION mg/tablet TABLET Micronized Progestin active 100
77.00 progesterone* principle LUTROL .RTM. F127* Surfactant 3.09
2.30 (poloxamer 407) (poloxamer) Kollidonr .RTM. 30 Binder 8.31
6.39 (Povidone K30) Pearlitol .RTM. 500DC Diluent 11.45 8.81
(Mannitol) AcDiSol .RTM. Disintegrating agent 6.50 5.00
(Crosscarmellose) Magnesium Lubricant 0.65 0.50 stearate
[0131] Progesterone/Lutrol are co-micronized according to the
protocol mentioned in example 1. TABLE-US-00006 TABLE IV NAME OF
THE UNIT AMOUNT COMPONENT FUNCTION mg/tablet % TABLET
Levonorgestrel* Progestin active 0.75 0.58 principle Sodium lauryl
Surfactant 0.023 0.02 sulfate (SLS) Mannitol 60 Diluent 102.303
78.69 Kollidon .RTM. 30 Binder 4.194 3.23 (Povidone K30) Pearlitol
.RTM. 500DC Diluent 15.58 11.98 (mannitol) AcDiSol .RTM.
Disintegrating 6.50 5.00 (Crosscarmellose) agent Magnesium
Lubricant 0.65 0.50 stearate *Levonorgestrel/SLS are co-micronized
according to the protocol mentioned in example 1.
[0132] TABLE-US-00007 TABLE V NAME OF THE UNIT AMOUNT COMPONENT
FUNCTION mg/tablet % TABLET Levonorgestrel* Progestin active 0.75
0.58 principle Lutrol .RTM. F127 Surfactant 0.023 0.02 (poloxamer
407) Mannitol 60 Diluent 102.3 78.69 Kollidon .RTM. 30 Binder 4.194
3.23 (Povidone K30) Pearlitol .RTM. 500DC Diluent 15.58 11.98
(mannitol) AcDiSol .RTM. Disintegrating 6.50 5.00 (Crosscarmellose)
agent Magnesium Lubricant 0.65 0.50 stearate *Levonorgestrel/Lutrol
are co-micronized according to the protocol mentioned in example
1.
[0133] FIG. 2 shows in vitro dissolution tests for the formulations
given in tables IV and V.
[0134] These curves demonstrate that the active principle
co-micronized is released in a very satisfactory manner.
* * * * *