FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See Section 10 and Rule 13)
BIOENHANCED RALOXIFENE COMPOSITIONS


INTERNATIONAL SPECIALTY PRODUCTS (INDIA) PVT. LIMITED,
An Indian Company incorporated under the Companies Act 1956
C-211 Floral Deck Plaza,
Off Central road, M.I.D.C, Andheri (E),
Mumbai-400093, India

The following specification particularly describes the invention and the manner in which it is to be performed.



FIELD OF THE INVENTION
The present invention relates to a solid dispersion of raloxifene having improved dissolution profile and method of producing the same. More particularly, it relates to the solid dispersions 5 having enhanced bioavailability comprising (a) raloxifene; and (b) a water insoluble synthetic crosslinked homopolymer of N-alkenyl 2-pyrrolidone prepared by co-grinding (a) and (b). The solid dispersion of raloxifene prepared by co-grinding of raloxifene hydrochloride and 1- vinyl-2 -pyrrolidone is further characterized by about 6 fold increase in the AUC as compared to crystalline Raloxifene hydrochloride alone. The present invention further relates to 10 pharmaceutical composition comprising the said solid dispersion of raloxifene and method of producing the same.
DESCRIPTION OF THE PRIOR ART
15 Most of the highly crystalline drugs show poor dissolution and low solubility in water. Particularly, in pharmaceutical research the poor water solubility poses the main constraint for the product development. Relative to highly soluble compounds, low drug solubility often manifests itself in a host of in vivo consequences, including decreased bioavailability or internal absorption, increased chance of food effect, more frequent incomplete release from the dosage
20 form and higher inter patient variability. Poorly soluble compounds also present many in vitro formulation obstacles, such as severely limited choices of delivery technologies and increasingly complex dissolution testing with limited or poor correlation to the in vivo absorption.
Raloxifene, a selective estrogen receptor modulator (SERM) and chemically known as [6-25 hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(l-piperidinyl) ethoxy] phenyl]
methanone, is one of the exemplified poorly soluble drug, the development of which has been somewhat hampered by its physical characteristics. For example, the hydrochloride crystalline salt of raloxifene is very slightly soluble in water, which may negatively influence its bioavailability and manufacturing of dosage forms.


Clearly, any improvement in the physical characteristics of raloxifene and in closely related compounds would potentially offer a more beneficial therapy and enhanced manufacturing capabilities.
One of the approaches is disclosed in US pat. No. 6,713494, which provides an amorphous form 5 of raloxifene hydrochloride and methods of preparing it. However, it offer drug substance with limited physical stability, and tend to convert to crystalline forms over time, which can lead to improper dosing due to differences of the bioavailability and solubility of crystalline drug material compared to amorphous drug material.
Several other techniques are also known in the prior art to increase the bioavailability of such 10 drugs. One such attempt is to improve the solubility of the pure drug substance by the processes like particle size reduction, use of the water soluble polymers, wetting agents, formation of inclusion complexes, spray drying, spray congealing etc.
One of the common ways is to prepare a solid dispersion, in which molecules of a poorly soluble drug are dispersed in a high molecular weight carrier, at a solid state. Generally, solid dispersion 15 are prepared using tedious techniques such as water-in-oil emulsion, use of solvents evaporation or spray drying methods to improve dissolvability in water of a water-insoluble drug or a poorly water-soluble drug in a pharmaceutical composition. These techniques require continuous use of solvents which may be not recommended for human consumption.
20 Another well accepted practice is milling which routinely used to reduce the particle size of powder in order to enhance the bioavailability of poorly water soluble drugs, because the particle size and physiochemical properties of powdered drugs affect their dissolution rates. The method is also simple and easy to carry out. The milling can be carried out under either dry or wet conditions with various milling devices, such as ball mill, jet and hammer mills, cryo mills and
25 the like. However, the properties of milled product are dominated by the surface properties of the crystal face. In the case of poorly water soluble substances, the newly created surface is hydrophobic and thus poorly wettable. Due to aerophilicity of such hydrophobic substances, the dissolution rate is not increased as would expect from the increase in total surface area according to Noyes-Whitney equation. Thus if a pharmaceutical compound having low water solubility is
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milled in order to increase dissolution rate and bioavailability, the new surface has to be hydrophilized. The above behavior can be solved to an greater extent by Co-grinding suitable and compatible support material with drug as a carrier.
5 The U.S. Pat. No. 4,639,370 describes the use of co-grinding of polymers which are swellable but insoluble in water such as cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose and dextran; the low-solubility drugs studied include medroxyprogesterone acetate, griseofulvin and indomethacin.
10 WO 96/32931 filed by Vector Pharma International relates to mechanically activated composites having improved bioavailability prepared by high energy co-grinding the pharmaceutically active substances and sodium starch glycolate as a support material.
It is well known that both solid dispersion and co-milling of poorly soluble drugs with various
15 kinds of polymers are useful for solubilization and enhancement of bioavailability because the
crystalline drug is transformed into an amorphous form in a polymer network. The rationale
behind such a strategy is that a highly disordered amorphous material has a lower energetic
barrier to overcome to enter a solution than a regularly structured crystalline solid. However, one
skilled in the art cannot predict which polymers, if any, would be useful for preparing stable
20 amorphous dispersions for a particular drug product. A series of technologies designed to
increase the solubility of poorly water-soluble drugs were already disclosed and it is thought that
the nature and effect of a drug product is greatly affected by the interaction between a drug and a
matrix or a carrier, which disperse a drug into molecular state. However, since the compatibility
between a drug and a carrier is not easily predictable, each formulation should be regarded as
25 different thing depending on the nature of each drug (Phase behavior of amorphous molecular
dispersions 1: Determination of the degree and mechanism of solid solubility, Pharm. Res., 2004,
21(9), p. 1598).
The present invention thus provides a solid dispersion of raloxifene having increased dissolution
30 and enhanced bioavailability, prepared by Co-grinding of Raloxifene and N-alkylene-2-
pyrrolidone. The present invention when compared with the solid dispersion prepared by spray
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drying method, offers an advantages that the co-milling method did not require organic solvent processes involving environmental and health concerns or for fusion processes involving thermal instability and immiscibility. Further, use of the support material at the time of milling adds to the stability towards recrystallization. 5
SUMMARY OF THE INVENTION
It is an objective of the present invention to provide a solid dispersion of raloxifene having enhanced bioavailability comprising: 10 (a) raloxifene; and
(b) a water insoluble synthetic cross-linked homopolymer of N-alkenyl 2-pyrrolidone; wherein said solid dispersion is prepared by co-grinding (a) and (b).
The raloxifene relates to raloxifene or its pharmaceutically acceptable salts, esters, prodrugs, 15 solvates, hydrates, or derivatives thereof. Preferably, it is crystalline salt of raloxifene hydrochloride. Preferably, a water insoluble synthetic cross-linked homopolymer relate to 1-vinyl 2-pyrrolidone.
The process of co-grinding is carried out using a mechanically activated mill selected from the 20 group consisting of a roller mill, a ball mill, a bead mill, a millstone mill, a jet mill, and a hammer mill and the milling is done for the period of not more than 2 hours.
It is another object of the present invention to provide the solid dispersion of raloxifene having enhanced bioavailability wherein the weight ratio of raloxifene to homopolymer of N-alkenyl 2-25 pyrrolidone is from about 0.1:5 to about 5:1, preferably from about 1:5 to about 1:1.
It is yet another objective of the present invention to provide a solid dispersion having enhanced bioavailability characterized by about six folds increase in AUC and about five folds increase in dissolution as compared to the crystalline Raloxifene hydrochloride alone.
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Another objective of the present invention is to provide pharmaceutical composition comprising solid dispersion of raloxifene is further formulated into an oral solid dosage form.
BRIEF DESCRIPTION OF THE DRAWINGS:
5
Figure 1 is a Comparative DSC pattern of RAL 1, RAL 2, RAL 3 and Crystalline Raloxifene hydrochloride.
Figure 2 is a Comparative Dissolution Profile of RAL 1, RAL 2, RAL 3 and Crystalline 10 Raloxifene hydrochloride.
Figure 3 is a Pharmacokinetic Profiles of Ral 2 and Crystalline Raloxifene In Female Sprague Dawley Rats.
15 Figure 4 is a Comparative Dissolution Profile of Tablet Formulation of Ral 2 and Pure Crystalline Raloxifene Hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
20 The Co-ground solid dispersions of the present invention provide greatly enhanced characteristics to the poorly soluble drug raloxifene, such as substantially increased rate of dissolution, enhanced bioavailability, and higher peak level in plasma.
The inventors with their repetitive efforts have found that water insoluble synthetic cross linked homopolymer has high wettabilty and swellabilty and requires comparatively less grinding time as compared to the previously known support material. N-alkenyl 2-pyrrolidone, which is commonly known as crospovidone has the tendency to take-up water by wicking mechanism, further due to milling, reduction in particle size occurs, which further favors dispersion of crospvidone and RAL. The solid dispersion when introduced into aqueous medium shows enhanced dissolution results due to increase in surface area and homogeneity. Further quick and large water absorption capacity by crospovidone aids in dissolution and thus the increase in
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solubility. The increase in solubility may further be accelerated due to the reduction in crystallinity of the drug
The term "raloxifene," as used herein, refers to raloxifene or its pharmaceutically acceptable 5 salts, esters, prodrugs, solvates, hydrates, or derivatives thereof. Preferably, it is the crystalline salt of raloxifene hydrochloride. The said raloxifene has the aqueous solubility of not more than 0.0025mg/ml.
In general, the term "solid dispersion" refers to a system in a solid state comprising at least two 10 components, wherein one component is dispersed throughout the other component or components.
A solid that is in the "amorphous" solid state form means that it is in a non-crystalline state. Amorphous solids generally possess crystal-like short range molecular arrangement, but no long 15 range order of molecular packing as are found in crystalline solids. The solid state form of a solid, such as the drug substance in the amorphous dispersion, may be determined by Polarized Light Microscopy, X-Ray Powder Diffraction (XPRD), Differential Scanning Calorimetry (DSC), or other standard techniques known to those of skill in the art.
20 The amount of raloxifene in the solid dispersions of the present invention ranges from about 0.1:5 to about 5:1 by weight relative to the homopolymer. In a preferred embodiment, the amount of raloxifene ranges from about 1:5 to about 1:1.
The term "cross-linked homopolymer" as used herein, including the claims, refers to N-alkenyl-2-pyrrolidones, preferably it refers to 1- vinyl-2 —pyrrolidone. This class of polymer is well 25 experimented with wide range of drugs for improved performance and increased dissolution profile and are commercially available as Polyplasdone XL, Polyplasdone XL-10, and Polyplasdone INF-10, based on the particle size, sold by International Specialty Products (ISP. The preferred polymer in the present invention is Polyplasdone XL.
The solid dispersions are preferably prepared by physically mixing the raloxifene and the cross-30 linked homopolymer, followed by co-grinding the mixture in the mechanically activated ball mill
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for around two hours. The speed is maintained at 200 rpm using approximately 25 stainless steel ball.
In another aspect of the invention, pharmaceutically acceptable excipients generally used in the 5 art are combined with the solid dispersion powder to form a pharmaceutical composition. Such pharmaceutically acceptable excipients selected from the group consisting of diluents, disintegrants, fillers, bulking agents, vehicles, pH adjusting agents, stabilizers, anti-oxidants, binders, buffers, lubricants, antiadherants, coating agents, preservatives, emulsifiers, suspending agents, release controlling agents, polymers, colorants, flavoring agents, plasticizers, solvents, 10 preservatives, glidants, and chelating agents; used either alone or in combination.
The pharmaceutical compositions of the present invention are generally administered orally to patients, which include, but are not limited to, mammals, for example, humans, in the form of, for example, a hard or soft gelatin capsule, a tablet, a caplet, pills, granules or a suspension.
15
In another embodiment, the present invention relates to dosage forms comprising the pharmaceutical compositions described herein. Dosage forms include, but are not limited to, those selected from the group consisting of pills, hard or soft capsules, caplets, tablets, granules, and suspensions. Each dosage should contain the quantity of drug substance calculated to
20 produce the desired therapeutic effect. Typically, the pharmaceutical compositions will be administered in dosage units containing from about 30 mg to about 60 mg of the raloxifene by weight of the composition.
It will also be apparent to those skilled in the art that the pharmaceutical compositions of the 25 present invention can be administered with other therapeutic and/or prophylactic agents and/or medicaments that are not medically incompatible therewith.
The term "bioavailability" is generally measured using drug-serum concentration-time curves,
and includes such factors as rate of entry of the drug into the bloodstream, rate of achieving
30 maximum concentration, and area under the curve. See, e.g., J. Koch Weser (1974),
"Bioavailability of Drugs," New Engl. J. Med. 291:233-237. Many factors are known to affect
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18 AUG 2008

bioavailability of drugs. Such factors include the nature of the form of the drug (ester, salt, complex, etc.); the physical state, particle size and surface area; presence or absence of adjuvants with the drug, type of dosage form in which the drug is administered; and pharmaceutical processes used to make the dosage form. See, e.g., D.E. Cadwallader, (1971) "Biopharmaceutics 5 and Drug Interactions," (Roche combination.
The following examples will further illustrate the invention, without, however, limiting thereto.
Example 1: Preparation of solid dispersion of Raloxifene by co-grinding
10
Required quantities of Raloxifene and cross linked 1-vinyl 2-pyrrolidone were weighed to give different drug to 1-vinyl 2-pyrrolidone weight ratios and transferred to a jar of a Retsch ball mill and milled for 2 hours using 25 stainless steel balls. After every 30 minutes the direction of rotation of the jar was programmed to change automatically.
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Table 1: Composition of solid dispersion of Raloxifene prepared

Composition code Weight % Raloxifene HC1 Weight % of 1-vinyl 2-pyrrolidone
RAL 1 50 50
RAL2 16.6 83.4
RAL 3 83.4 16.6
After milling the prepared solid dispersions were stored appropriately in sealed aluminum packs.
20 Example 2 - Particle size determination
The solid dispersion as prepared under example I were subjected to particle size evaluation using Malvern Mastersizer 2000, using dry method (Sciroco-dry accessory of Mastersizer).
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Table 2: The particle size distribution:

d10 d50 d90 D(4,3)
Crystalline Raloxifene 7.32 37.31 125.47 65.66
RAL1 2.05 18.37 59.71 30.52
RAL 2 5.11 17.33 40.07 23.19
RAL 3 1.39 13.81 64.97 30.31
Example 3-DSC characterization
5 Thermal evaluation of the solid dispersion as prepared under example 1 was done using DSC (Q 1000 - TA). Pure crystalline Raloxifene was used as control. About 2-3 mg of the sample was weighed on to aluminum pans and crimped. The DSC of all the samples was recorded under nitrogen from 50 to 300 deg C at ramp rate of 10 deg C.
10 The DSC results showed that RAL 2 was completely amorphous, while RAL 1 was almost amorphous and RAL 3 was semi-crystalline
Example 4 - Dissolution studies of solid dispersions
15 The dissolution studies of the prepared solid dispersions as per Example 1 (equivalent to 30 mg of Raloxifene HC1, filled into size 00 capsules) and pure crystalline Raloxifene HC1 (30 mg filled in size 00 capsule) were carried out using USP apparatus II (Venkel VK7010) with sinkers (5 spiral stainless steel capsule sinker of 18 x 6 mm capacity). A peristaltic pump was coupled to a Cary 50 UV / visible spectrophotometer to provide a continuous flow of drug solution through
20 0.2-cm cuvettes. Dissolution was performed in 1000 ml of water at 37±0.5°C. Samples were programmed to be analyzed at 5, 10, 15, 30, 45 and 60 minutes at 285 nm.


Table 3: Comparative Dissolution Testing

Time(MIN) Crystalline Raloxifene RAL1 RAL 2 RAL 3
0 0 0 0 0
5 2 0 1 2
10 3 4 6 6
15 4 11 24 13
30 5 27 59 24
45 6 39 91 30
60 7 47 103 36
The results of dissolution testing, which are shown in Fig. 2, indicates that solid dispersion of the 5 present invention particularly RAL 2 have significantly greater dissolution as compared to pure crystalline drug substance.
Table 4: Analysis Of Comparative Dissolution Results

T50% T80%
Crystalline Raloxifene Not Achieved Not Achieved
RAL1 Not Achieved Not Achieved
RAL 2 25.58 30.09
RAL 3 Not Achieved Not Achieved
10 Example 5 - Pharmacokinetic study
The pharmacokinetics of RAL 2 as prepared under example 1 was compared with pure raloxifene HC1 using female Sprague Dawley rats using a parallel design. In total 12 rats were used for the study and were divided into 2 groups of 6 each. One group received the solid 15 dispersion (RAL 2) and the other group received the pure crystalline Raloxifene HC1.


This study was performed with approval from the Institutional Animal Ethics Committee (IAEC) in accordance with the requirement of Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), India.
5 Rats for the study were housed in polypropylene cages with stainless steel lids (one per cage). Environmental controls maintained the room temperature at 22 ± 3°C with a relative humidity of 40-70% and approximately 10-15 fresh air changes per hour. A 12 h dark/light cycle was maintained, and was interrupted only for study procedures. Temperature and relative humidity were recorded daily during the acclimatization and study periods. Animals were housed for at 10 least 5 days in the experimental unit before dosing. They were observed during the acclimatization period to ensure that they were in good health and suitable for the study
Individual oral dose was made for each rat in 2 mL BD syringes. For each dose, the syringe plunger was withdrawn fully and placed aside, the needle attachment port was blocked with tape,
15 and the barrel was placed vertically on a stand. Subsequently 1 mL of 1% aqueous gelatin solution (at room temperature) was pipetted into the syringe barrel and refrigerated. A weighed amount of drug material (target dose: mg/kg) was then layered, depending on weight of the individual rats on top of the gelatin; subsequently, a further aliquot of 0.7 mL of gelatin was layered on top of the suspended drug material within the dosing syringe using a pipette. Thus, the
20 drug was effectively sandwiched within 2 aliquots of gelatin gel. Total volume of the gelatin solution administered was approximately 1 ml per rat (the dead volume ~ 0.7 mL).
Blood samples were collected at pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 8 , 12 and 24 h (10 time points) following dose administration. Approximately 225 ml of whole blood was withdrawn from the
25 cannulated jugular vein, or the retro orbital plexus following light ether anesthesia, or from the tail vein. Blood samples were collected in labeled tubes containing sodium citrate solution as anticoagulant (25 uL per mL of 20 % w/v solution) and placed on ice until centrifugation. Plasma was separated by centrifugation of whole blood at 2500 g for 10 minutes at 4 °C within 0.5 h of sample collection. Separated plasma were then stored below -70°C until bioanalysis.
30 Plasma samples were analyzed by LC-MS/MS method following liquid-liquid extraction with
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TBME. Plasma pharmacokinetic parameters were calculated using the non-compartmental analysis tool of WinNonlin Enterprise software (Version 5.1.1).
Example 6 - Preparation of tablet compositions
5
Tablet formulations using RAL 2 and crystalline raloxifene HCI were prepared by wet granulation using a Pro-C-Ept high shear granulator as per the formula given below:
Table 5: Tablet Formulation of Crystalline Hydrochloride

Ingredients % by weight mg/tablet
Raloxifene 12.5 60
Lactose Anhydrous 77.9 374
Plasdone K29/32 5 24
Polysorbate 80 2.1 10
Polyplasdone XL 2 9.6
Magnesium stearate 0.5 2.4
Total Tablet weight 480
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Table 5: Tablet Formulation of RAL 2

Ingredients % mg/tablet
RAL 2 75 360*
Lactose Anhydrous 15.4 74
Plasdone K29/32 5 24
Polysorbate 80 2.1 10
Polyplasdone XL 2 9.6
Magnesium stearate 0.5 2.4
Total Tablet weight 480
Equivalent to 60 mg of raloxifene
The dissolution studies of the prepared tablets were carried out using USP apparatus II (Venkel 15 VK7010) as described in Example 4
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Table 5: Dissolution Study

Time(min) Raloxifene tablet Tablet Composition of RAL 2
0 0 0
5 1 16
10 8 54
15 17 64
30 27 70
45 32 70
60 35 71


WHAT IS CLAIMED:
1. A solid dispersion of raloxifene having enhanced bioavailability comprising:
(a) raloxifene; and
5 (b) a water insoluble synthetic cross-linked homopolymer of N-alkenyl 2-pyrrolidone ; wherein said solid dispersion is prepared by co-grinding (a) and (b).
2. The solid dispersion according to claim 1, wherein said raloxifene is the crystalline
hydrochloride salt of raloxifene.
10
3. The solid dispersion according to claim 1, wherein said homopolymer is cross- linked 1-vinyl
2-pyrrolidone.
4. The solid dispersion according to claim 1, wherein the weight ratio of raloxifene to
15 homopolymer of N-alkenyl 2-pyrrolidone is from about 0.1:5 to about 5:1.
5. The solid dispersion according to claim 4, wherein the weight ratio of raloxifene to
homopolymer of N-alkenyl 2-pyrrolidone is from about 1:5 to about 1:1.
20 6. The solid dispersion according to claim 1, wherein the enhanced bioavailability is characterized by about six fold increase in AUC as compared to crystalline raloxifene hydrochloride alone.
7. The solid dispersion according to claim 1, wherein said co-grinding is carried out using a
25 mechanically activated mill selected from the group consisting of a roller mill, a ball mill, a bead
mill, a millstone mill, a jet mill, and a hammer mill.
8. The solid dispersion according to claim 7, wherein said mechanically activated mill is a ball
mill and the co-grinding is carried out for a time period of not more than 2 hours.
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9. The solid dispersion according to claim 1, wherein said solid dispersion of raloxifene is further
formulated into a pharmaceutical composition comprising an oral solid dosage form.
10. The pharmaceutical composition according to claim 9, wherein the composition further comprises excipients selected from the group consisting of diluents, disintegrants, fillers, bulking agents, vehicles, pH adjusting agents, stabilizers, anti-oxidants, binders, buffers, lubricants, antiadherants, coating agents, preservatives, emulsifiers, suspending agents, release controlling agents, polymers, colorants, flavoring agents, plasticizers, solvents, preservatives, glidants, and chelating agents; used either alone or in combination.
11. A solid dispersion of raloxifene and a process of its preparation as described and illustrated in the examples herein.

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Dated this \8th Day of August, 2008
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1 8 AUG2008