TECHNICAL FIELD OF THE INVENTION
The present invention relates to improved dosage forms such as tablets and capsules and in
particular to a formulation for oral administration comprising a therapeutically effective
quantity of a selective estrogen receptor modulator, and more particularly Raloxifene, its
esters or ethers or a pharmaceutically acceptable salt or derivative thereof, in combination
with a super disintegrant, such as sodium starch glycolate as a dissolution enhancing agent
and a method for the preparation thereof.
BACKGROUND OF THE INVENTION
Osteoporosis constitutes a systemic skeletal disease characterized by low bone density and
deterioration of bone tissue. The consequence of this disease is a significant increase in
bone fragility, resulting to an increased susceptibility to fractures. The risk of osteoporosis
is significantly increased with ageing of the population, and furthermore, women are at
greater risk of osteoporosis than men. In women, bone loss is accelerated during the period
following menopause.
Treatment for osteoporosis is concentrated on slowing down or preventing bone loss and
on control of pain associated with the disease. There are different types of medicines used
to treat or prevent osteoporosis, including Raloxifene, bisphosphonates, hormone
replacement therapy and calcitonin. There are also several ways to prevent osteoporosis,
such as regular exercise and an adequate dietary intake of calcium, vitamin C & D and
protein.
Raloxifene constitutes an oral Selective Estrogen Receptor Modulator (SERM) that
belongs to the benzothiophene compounds and it is used as the active pharmaceutical
ingredient in compositions used for the prevention or treatment of osteoporosis in
postmenopausal women.
Menopause is a condition characterized by an imbalance between bone destruction and
bone formation, which is importantly related to progressive loss of estrogen. This
imbalance may also be associated with age-related impairment of osteoblasts or their
precursors.
The term "Selective Estrogen Receptor Modulators" (SERMs), such as Raloxifene, refers
to estrogen-like drugs, also known as "designer estrogens". This means that Raloxifene
possesses some, but not all, of the actions of estrogen. Raloxifene has been classified as a
SERM, because it prevents bone loss (like estrogen) and lowers serum cholesterol (like
estrogen), but it does not stimulate the uterus. Thus, Raloxifene acts like an estrogen by
stopping the progression of bone loss that is developed in women after menopause.
In fact, Raloxifene acts by reducing the bone resorption, resulting to a decrease in the
overall bone turnover. This action of Raloxifene is because of its binding to estrogen
receptors, regulating estrogen-regulated gene expression by at least two distinct pathways
which are ligand-, tissue-, and/or gene-specific.
Clinical studies have indicated that Raloxifene has estrogen-agonistic effects on bone
(increase in bone density) and on lipid (decrease in total and LDL cholesterol levels)
metabolism and estrogen-antagonistic effects on uterine endometrium and breast tissue.
This data denote that Raloxifene presents high tissue selectivity, causing fewer adverse
effects than typical estrogen therapy.
A particularly useful pharmaceutical^ acceptable salt of Raloxifene is the hydrochloride
salt, which can be easily prepared by reacting hydrogen chloride with a solution of
Raloxifene in an organic solvent, such as tetrahydrofuran or methanol.
Raloxifene hydrochloride is chemically designated as [6-hydroxy-2-(4-hydroxyphenyl)
benzothiophen-3-yl]-[4-[2-(l-piperidinyl) ethoxy] phenyl] methanone hydrochloride and
has the empirical formula of C28 H27 NO4 S-HC1. Its molecular weight is 510.05 g/mol, and
473.584g/mol as a free base.
The hydrochloride salt of Raloxifene has a very poor solubility in aqueous media, limiting
therefore its bioavailability. In addition, Raloxifene hydrochloride constitutes a highly
hydrophobic drug, fact that constitutes a significant barrier for its absorption.
Furthermore, the stability, the bioavailability and the release rate of pharmaceutical
compositions containing a selective estrogen receptor modulator and in particular,
Raloxifene or salt thereof can also be influenced by the selection of the excipients.
Various methods are already known for the industrial preparation of oral dosage forms
comprising a selective estrogen receptor modulator e.g. Raloxifene or salt thereof, as an
active ingredient due to its useful therapeutical properties. However, the prior art has
encountered substantial difficulties in the production of the oral solid formulations of a
desirable bioavailability due to the very poor solubility of said active ingredient.
EP 0 670 162 discloses a pharmaceutical composition with increased solubility in aqueous
media, which comprises Raloxifene hydrochloride, in combination with a surfactant, a
water-soluble diluent and a hydrophilic binder.
WO 2005/04917 discloses a pharmaceutical formulation with enhanced solubility, which
comprises a hydrophobic drug in particularly Raloxifene HCL and polyethylene glycol
(PEG), wherein the ratio of PEG to drug by weight is from about 0.2: 1 to about 10: 1.
Furthermore, US 2006/099252 discloses an oral solid pharmaceutical formulation with
increased dissolution rate, which comprises an active agent with low aqueous solubility,
particularly Raloxifene HC1, combined with starch at a concentration of greater than 25%
w/w.
Although each of the above patents represents an attempt to overcome the low aqueous
solubility and bioavailability problems associated with pharmaceuticals compositions
comprising a selective estrogen receptor modulator, there still exists a need for improving
the solubility of such pharmaceutical compositions.
SUMMARY OF THE INVENTION
It is, therefore, an object of the present invention to provide an improved solid dosage
formulation for oral administration containing a selective estrogen receptor modulator, and
in particular Raloxifene or salt thereof as an active ingredient, which overcomes the
deficiencies of the prior art and increases the dissolution rate of the active ingredient.
Another aspect of the present invention is to provide a solid dosage formulation for oral
administration containing a selective estrogen receptor modulator, and in particular
Raloxifene or salt thereof as an active ingredient, which is bioavailable and effective with
sufficient self-life and good pharmacotechnical properties.
Moreover, another aspect of the present invention is to provide a solid dosage formulation
for oral administration containing a selective estrogen receptor modulator, and in
particular Raloxifene or salt thereof as an active ingredient, which can be prepared in
dosage forms of different strength by proportionally adjusting the quantities of the
excipients and the active ingredient, thereby providing a pharmacotechnical linearity,
without affecting the dissolution profile and bioavailability of the active ingredient.
A further aspect of the present invention is to provide a method for the preparation of a
stable solid dosage formulation for oral administration containing a selective estrogen
receptor modulator, and in particular Raloxifene or salt thereof as an active ingredient,
permitting an enhanced release of the active medicament and used in the prevention and
treatment of osteoporosis in postmenopausal women with improved pharmacotechnical
characteristics of the composition.
In accordance with the above objects of the present invention, a pharmaceutical
composition for oral administration is provided comprising a selective estrogen receptor
modulator, and in particular Raloxifene, its esters or ethers or a pharmaceutically
acceptable salt or derivative thereof as an active ingredient, and an effective amount of a
super disintegrant such as sodium starch glycolate as an agent to enhance bioavailability
and to increase the drug release.
According to another embodiment of the present invention, a process for the preparation
of solid dosage forms for oral administration such as tablets, capsules and sachets,
containing a selective estrogen receptor modulator, and in particular Raloxifene, its esters
or ethers or a pharmaceutically acceptable salt or derivative thereof as an active ingredient
is provided, which comprises:
- Forming a first homogenous blend by mixing the total quantity of said active ingredient
with a total quantity of super disintegrant such as sodium starch glycolate as a dissolution
enhancing agent to facilitate the drug release and increase bioavailability, and optionally a
pH adjusting agent such as citric acid monohydrate;
- dissolving the total quantity of a surfactant such as Poloxamer 407 into purified water;
- adding the first blend into the formed solution;
- adding to the above kneaded mixture the total quantity of at least one optional excipient
such as a binder, a disintegrant, a lubricant, a colorant and/or a glidant until uniform and
wet granulating;
- drying the wet mass;
- sieving the dried material to achieve the desired granule size
- adding and mixing the dried material with at least one optional excipient of the external
phase such as a binder, a disintegrant, a lubricant, a colorant and/or a glidant until
uniform, and
- formulating the resulting mixture in a solid dosage form either by compressing it into a
desired tablet form or by filling capsules or sachets.
Further preferred embodiments of the present invention are defined in dependent claims 2
to 10 and 12 to 13.
Other objects and advantages of the present invention will become apparent to those
skilled in the art in view of the following detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows a dissolution diagram of the Raloxifene HCL compositions of examples 1, 2
and 3 according to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
For the purposes of the present invention, a pharmaceutical composition comprising an
active ingredient (a selective estrogen receptor modulator, and in particular Raloxifene or
salt thereof) is considered to have "low aqueous solubility" if said ingredient dissolves less
or more slowly than it does on its own and/or in known pharmaceutical compositions.
The term "pharmaceutically acceptable salt" refers to a salt that is not toxic at the specific
therapeutic dosage and to a salt that does not independently possess significant
pharmacological activity.
An excipient is considered to be "incompatible" with an active ingredient (a selective
estrogen receptor modulator, and in particular Raloxifene or salt thereof) if it inhibits the
dissolution rate of said active ingredient, that is to say, if said active ingredient (a selective
estrogen receptor modulator, and in particular Raloxifene or salt thereof) dissolves less or
slower in the presence of said excipient when compared with the dissolution rate of said
active ingredient (a selective estrogen receptor modulator, and in particular Raloxifene or
salt thereof) on its own. The terms "incompatibility", "compatible" and "compatibility"
are defined accordingly.
The active ingredient (a selective estrogen receptor modulator, and in particular
Raloxifene or salt thereof) contained in a dosage form is "bioavailable", if when
administered in a dosage form is released from the dosage form, absorbed and reaches, at
least the same, concentration levels in plasma as any of the marketed products containing
the same quantity of the same active ingredient and intended for the same use.
Although the pharmaceutical composition may be in various forms, the preferred solid
forms are tablets, capsules and caplets.
The improved solid pharmaceutical composition of the present invention is characterized
by physicochemical properties suitable for the tablet formulation by wet granulation, the
adequate release rate of the active ingredient (a selective estrogen receptor modulator, and
in particular Raloxifene or salt thereof) and the storage stability, by employing excipients
practically devoid the tendency of the active ingredient to degradation in humidity or
ambient temperature.
As already mentioned certain selective estrogen receptor modulators have low aqueous
solubility and their tendency gets stronger when they are formulated and mixed with
excipients or other active substances.
It has been surprisingly found that the object of the present invention is achieved by
employing a super disintegrant such as sodium starch glycolate, also called Primojel, as a
dissolution enhancing agent.
Sodium starch glycolate, a representative example of a cross-linked starch, is a modified
starch possessing very significant disintegrating properties, and is practically insoluble in
organic solvents. Chemically, Primojel constitutes a low substituted carboxy methyl
starch.
Sodium starch glycolate presents very good hydration capacity and very good flow
properties in comparison to other super disintegrants. Further, it presents the tendency to
absorb water rapidly, so it swells in a significant amount. Therefore, this rapid water
absorption by sodium starch glycolate molecules has as a result a significant increase in
the volume of granules resulting to rapid and uniform disintegration.
Sodium starch glycolate incorporated in a pharmaceutical composition facilitates the
breakup or disintegration of the content of the tablet into smaller particles that dissolve
more rapidly than in the absence of disintegrating agents.
Moreover, it presents the benefit to counterbalance the efficiency of the tablet binder, as
well as the physical forces that develop during the compression procedure for the
manufacture of a tablet.
Sodium starch glycolate is incorporated into the composition of the present invention by
internal addition (intragranular). During the internal addition method, the disintegrating
agent is mixed with other powders prior to wetting the powder mixture with the
granulating fluid. The result of this method is that the super disintegrant becomes
incorporated within the granules of the composition, resulting to a more effective
disintegration process.
Moreover, one of the main disadvantages of the selective estrogen receptor modulator, and
in particular Raloxifene HCL, is the fact that, they are very labile to acidic pH
environment, and consequently many limitations concerning the choice of excipients are
raised.
The lubricant should be very carefully selected because some of them are very
hydrophobic and affect negatively the disintegration and dissolution while it has been
shown to cause bioavailability problems. The manufacturing process should also be very
carefully determined because relatively high concentrations of lubricant and/or glidant
reduce crashing strength and increase disintegration time especially when associated with
prolonged mixing times.
In addition, the pH of the composition of the present invention was adjusted to 6.0 using
aqueous citric acid as needed. The molecule of citric acid has three carboxyl groups, each
of which loses a proton in a solution. Therefore, citrate ions are formed, which are
excellent buffers for controlling the PH of acidic solutions.
Moreover, any excipient may optionally be added to the above composition, provided that
they are compatible with the active ingredient of the composition, in order to overcome
problems associated with unfavorable pharmacotechnical characteristics of these
substances, and in order to increase the stability of the drug and the self-life of the
pharmaceutical product, and provide a product exhibiting excellent bioavailability.
The present invention can be applied in the formulation of tablets, capsules, caplets,
sachets or other solid dosage forms for oral or sub-lingual administration of an active
ingredient having solubility and bioavailability problems.
Furthermore, it is possible to prepare dosage forms of different strength using appropriate
quantity of the same composition, thereby limiting the cost of production and minimizing
the number, and consequently the cost, of clinical studies required for the approval of the
product by the authorities.
Therefore, in a first embodiment, the present invention provides a pharmaceutical
composition comprising from about 0.5% to30% by weight of Raloxifene or salt thereof
and from about 3% to 30% by weight of sodium starch glycolate. The weight ratio of
Raloxifene or salt thereof to sodium starch glycolate is preferably 10:1 to 1:60.
More preferred pharmaceutical compositions according to the present invention comprise
approximately 3% to 30%, more preferably 5% to 25% and most preferably 7% to 20% by
weight of sodium starch glycolate.
The preferred pharmaceutical compositions are in the form of solid dosage forms for oral
or sub-lingual administration such as tablets, capsules, caplets, troches, pastilles, pills,
lozenges and the like, in all shapes and sizes, coated or uncoated.
All percentages stated herein are weight percentages based on total composition weight,
unless otherwise stated.
Another embodiment of the present invention is the use of the wet granulation process for
the preparation of solid dosage forms for oral administration such as tablets, capsules and
sachets containing selective estrogen receptor modulator such as Raloxifene, its esters or
ethers or a pharmaceutically acceptable salt or derivative thereof as an active ingredient is
provided, which comprises:
with a total quantity of super disintegrate such as sodium starch glycolate as a dissolution
enhancing agent to facilitate the drug release and increase bioavailability, and optionally a
pH adjusting agent such as citric acid monohydrate;
- dissolving the total quantity of a surfactant such as Poloxamer 407 into purified water;
- adding the first blend into the formed solution;
- adding to the above kneaded mixture the total quantity of at least one optional excipient
such as a binder, a disintegrant, a lubricant, a colorant and/or a glidant until uniform and
wet granulating;
- drying the wet mass;
- sieving the dried material to achieve the desired granule size
- adding and mixing the dried material with at least one optional excipient of the external
phase such as a binder, a surfactant, a diluent, a disintegrant, a lubricant, a colorant and/or
a glidant until uniform, and
- formulating the resulting mixture in a solid dosage form either by compressing it into a
desired tablet form or by filling capsules or sachets.
The pharmaceutical compositions of the present invention may also contain one or more
additional formulation ingredients selected from a wide variety of excipients. According to
the desired properties of the composition, any number of ingredients may be selected,
alone or in combination, based upon their known uses in preparation of solid dosage form
compositions.
Such ingredients include, but are not limited to, diluents, binders, compression aids,
The optional excipients must be compatible with the selective estrogen receptor modulator
or the salt thereof so that it does not interfere with it in the composition.
Diluents may be, for example, calcium carbonate, calcium phosphate dibasic, calcium
phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline silicified
cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose anhydrous,
lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol sorbitol, starch,
pregelatinized starch, sucrose, talc, xylitol, maltose maltodextrin, maltitol.
Binders may be, for example, acacia mucilage, alginic acid, carbomer,
carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline
cellulose, powdered cellulose, ethyl cellulose, gelatin, liquid glucose, guar gum,
hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, sodium
alginate, starch paste, pregelatinized starch, and sucrose.
Disintegrants may be, for example, alginic acid, carbon dioxide, carboxymethylcellulose
calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose,
croscarmellose sodium, crospovidone, sodium docusate, guar gum, hydroxypropyl
cellulose, methylcellulose, polacrilin potassium, poloxamer, povidone, sodium alginate,
sodium glycine carbonate, sodium lauryl sulfate, starch, pregelatinized starch.
Surfactants may be, for example, poloxamer, pluronic, ethoxylated castor oil,
polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters,
polyoxyethylene sorbitan fatty acid esters, monoglycerides or ethoxylated derivatives
thereof, diglycerides or polyoxyethylene derivatives thereof, as well as sodium docusate or
sodium lauryl sulphate.
Glidants may be, for example, calcium silicate, powdered cellulose, starch, talc, colloidal
silicon dioxide.
Lubricants may be e.g. magnesium stearate, polyethylene glycol 4000, polyethylene glycol
6000, sodium lauryl sulfate, starch, talc.
The following examples illustrate preferred embodiments in accordance with the present
invention without limiting the scope or spirit of the invention:
EXAMPLES
Example l:Tablet of 60 mg Raloxifene HCL(Comp. 1)
Tablets of the above formulation were prepared according to the following manufacturing
process: Raloxifene HCL, sodium starch glycolate and citric acid monohydrate were
admixed to complete homogeneity. The total amount of Poloxamer 407 was dissolved in
the purified water and is stirred for an adequate period of time till it is completely
dissolved. The first blend was kneaded with the kneading solution described above till a
homogenous granular mass is produced. Subsequently, the total amount of
microcrystalline cellulose and the total amount of dibasic calcium phosphate were added
in the above mixture and mixed until a homogenous granular mass was produced. The
wetted mass was then dried, passed through a sieve to achieve the desired granule size and
further mixed with Mg stearate. Finally, it was formulated in a solid dosage form by
compressing it into a desired tablet form. Subsequently, the tablets were film-coated with
Opadry II white.
The produced tablets were tested for content uniformity, disintegration, water content and
dissolution proving that they are meeting the specifications.
Tablets of the composition 2 of Example 2 were prepared according to the manufacturing
process used in Example 1.
Example 3:Tablet of 60 mg Raloxifene HCL (Comp. 3)
Tablets of the composition 3 of Example 3 were prepared according to the manufacturing
process used in Example 1.
One of the most critical pharmacotechnical tests is the dissolution test as it is strongly
correlated with the bioavailability of the product. For the dissolution method an Apparatus
II (paddles) was run at 75rpm, 37°C ± 0.5 °C, for 30min, while as dissolution medium
500ml of HC1 0.01N was used.
Dissolution rate results for each composition tested are given in Table 1. The results show
that composition 1 is completely dissolved in about 30 minutes; however composition 2,
which does not comprise citric acid and composition 3 with less amount of sodium starch
glycolate are not completely dissolved in about 30 minutes.
Another object of the present invention was to prepare a pharmaceutical composition that
is stable, said active ingredient does not degradates and remains stable for a long period of
storage time. For this reason, prior to the clinical trials, composition 1 that exhibits the
desirable dissolution profile, was packed in PVC/PE/PVDC Aluminum blisters and
exposed to normal (25°C±2°C/60%±5% RH), intermediate (30°C±2°C/65%±5% RH) and
accelerated (40°C±2°C/75%±5% RH) stability studies according to the current ICH
guidelines. The stability results after twelve months (up to six months for accelerated
conditions) are shown in table 2 below.
TABLE 2: Stability results for composition 1 in normal, intermediate and accelerated
conditions
The results demonstrate that a very stable product is produced according to the method
described in the present invention.
The composition 1 described above was investigated for its scalability, while a process
validation was performed in order to prove the repeatability and accuracy of the
manufacturing process and the proposed formulation.
The validation process showed that the composition and the manufacturing process are
suitable in order to provide a repeatable and high quality product.
The results show a good stability of the product and compatibility between the drug
substance and the excipients proposed by the present invention. The excellent results
regarding the physicochemical characteristics, the excellent stability of the product as well
as the simple and economic manufacturing process indicate the advantages of the present
invention relative to the commonly used methods and excipients for the formulation of
Raloxifene HCL.
Another object of the present invention is to manufacture a pharmaceutical dosage form
that is "bioavailable", meaning that when administered is released from the dosage form,
absorbed and reaches, at least the same, concentration levels in plasma as any of the
marketed products containing the same quantity of the same active ingredient and intended
for the same use.
The bioavailability and pharmacokinetic profile of composition 1 of the present invention
was determined in "in-vivo" single dose studies. A single-dose study was conducted in 37
healthy volunteers using a pharmaceutical composition according to Example 1.
The reference product was 60 mg tablet (Evista) that consists of Raloxifene HCL,
anhydrous lactose, carnauba wax, crospovidone, hypromellose, lactose monohydrate, Mg
stearate, modified pharmaceutical glaze, PEG, polysorbate 80, PVP, propylene glycol and
titanium dioxide (product B).
In the pharmacokinetic analysis of composition 1 according to Example 1, Raloxifene and
its two metabolites Raloxifene-4'-glucorunide and Raloxifene-6'-glucorunide were
measured separately. Table 3 shows the main pharmacokinetic parameters obtained from
the studies.
TABLE 3: Pharmacokinetic analysis of 60mg dosage form of composition 1 vs. reference
product (B)
wherein:
C max= (peak concentration) is the highest concentration reached by the drug in plasma
after dosing;
AUCo-t = (area under the curve) the area under the plasma concentration versus time curve,
from time 0 to the last measurable concentration, as calculated by the linear trapezoidal
method.
AUCo-inf = (area under the curve) the area under the plasma concentration versus time curve
from time 0 to infinity. AUC inf is calculated as the sum of AUC 0-t plus the ratio of the last
measurable plasma concentration to the elimination rate constant.
Clinical trial results demonstrate that the composition manufactured according to the
present invention is bioavailable.
While the present invention has been described with respect to the particular
embodiments, it will be apparent to those skilled in the art that various changes and
modifications may be made in the invention without departing from the spirit and scope
thereof, as defined in the appended claims.
WE CLAIM :
1. A pharmaceutical composition for oral administration comprising a selective estrogen
receptor modulator or a pharmaceutical acceptable salt thereof, and in particular
Raloxifene, its esters or ethers or a pharmaceutically acceptable salt or derivative thereof
as an active ingredient, and an effective amount of a super disintegrant such as sodium
starch glycolate as a dissolution enhancing agent to facilitate the drug release and increase
bioavailability.
2. The pharmaceutical composition according to claim 1, wherein said super disintegrant
is sodium starch glycolate.
3. The pharmaceutical composition according to claim 2, wherein it comprises from about
0.5 to 30% by weight of said selective estrogen receptor modulator such as Raloxifene or
salt thereof, and from about 3 to 30 % by weight of said sodium starch glycolate.
4. The pharmaceutical composition according to claim 2, wherein the weight ratio of said
selective estrogen receptor modulator such as Raloxifene or salt thereof, to sodium starch
glycolate is preferably 10:1 to 1:60.
5. The pharmaceutical composition according to claim 1, wherein it comprises
approximately 0.5% to 30%, preferably 0.75% to 30% and most preferably 1% to 30% by
weight of said selective estrogen receptor modulator such as Raloxifene or salt thereof.
6. The pharmaceutical composition according to claim 2, wherein it comprises
approximately 3% to 30%, more preferably 5% to 25% and most preferably 7% to 20% by
weight of sodium starch glycolate.
7. The pharmaceutical composition according to any preceding claim, wherein said
selective estrogen receptor modulator is Raloxifene or pharmaceutical acceptable salt
thereof.
8. The pharmaceutical composition according to any preceding claim, wherein it further
comprises a pH adjusting agent, such as citric acid monohydrate.
9. The pharmaceutical composition according to any preceding claim, wherein it further
comprises at least one optionally excipient selected from the group consisting of diluents,
binders, disintegrants, lubricants, and glidants.
10. The pharmaceutical composition according to any preceding claim, wherein said
composition is in a solid dosage form such as a tablet, capsule or sachet comprising an
active ingredient such as Raloxifene or salt thereof.
11. A process for the preparation of a solid dosage form for oral administration, such as a
tablet, a capsule or a sachet, containing a selective estrogen receptor modulator, and in
particular Raloxifene, its esters or ethers or a pharmaceutically acceptable salt or
derivative thereof as an active ingredient is provided, which comprises:
- Forming a first homogenous blend by mixing the total quantity of said active ingredient
with a total quantity of super disintegrant such as sodium starch glycolate as a dissolution
enhancing agent to facilitate the drug release and increase bioavailability, and optionally a
pH adjusting agent such as citric acid monohydrate;
- dissolving the total quantity of a surfactant such as Poloxamer 407 into purified water;
- adding the first blend into the formed solution;
- adding to the above kneaded mixture the total quantity of at least one optional excipient
such as a binder, a disintegrant, a lubricant, a colorant and/or a glidant until uniform and
wet granulating;
- drying the wet mass;
- sieving the dried material to achieve the desired granule size
- adding and mixing the dried material with at least one optional excipient of the external
phase such as a binder, a disintegrant, a lubricant, a colorant and/or a glidant until
uniform, and
- formulating the resulting mixture in a solid dosage form either by compressing it into a
desired tablet form or by filling capsules or sachets.
12. The process according to claim 11, wherein said active ingredient is Raloxifene or salt
thereof.
13. The process according to claim 12, wherein said super disintegrant is sodium starch
glycolate.

The present invention relates to a pharmaceutical formulation of solid dosage forms
comprising a therapeutically effective amount of a selective estrogen receptor modulator,
and especially Raloxifene or a pharmaceutical acceptable salt thereof, in combination with
a super disintegrant such as Primojel, and a process for the preparation thereof by wet
granulation.