RALOXIFENE SPRINKLE COMPOSITION

Field of the Invention

The present invention relates to a capsule composition comprising multiparticulates comprising a) a core comprising raloxifene, and b) a taste masking coating present in an amount of 0.5% to 40%w/w based on the core weight.

Background of the Invention
Raloxifene is indicated for the treatment of osteoporosis and breast cancer in postmenopausal women. It is commercially available as immediate release tablets (Evista®) in US. The development of raloxifene composition has been hindered, due to low water solubility, which can adversely affect the bioavailability and manufacturing process. US patent No. 6,458,811 discloses raloxifene having a mean particle size less than 25 micron, which allows the enhanced bioavailability and manufacturing process. It further disclose granular composition comprising raloxifene, which can be compressed into a tablet dosage form or can be filled into a capsule.

Raloxifene is known to possess a bitter taste as well is categorized under drug that should be handled as hazardous by NIOSH (US). Further, summary of product characteristic of Europe mentions that Evista® tablet “should not be crushed” as it may taste bad. Also, handling of uncoated granules and crushed tablet would be hazardous for the compounding pharmacist.

Thus, there exists a need in the art to formulate a composition of raloxifene which provides patient compliance for the patients having difficulty in swallowing. However, masking the bitter taste as well as achieving desired immediate release profile would be challenging for the drug having poor aqueous solubility.

Hence, the present inventors have now developed multiparticulates of raloxifene, which can be administered by sprinkling multiparticulates on the soft food and have a desired in-vitro release. The present invention would provide advantage for the patients who have difficulty in swallowing the conventional solid oral composition. Further, sprinkle composition of the present invention has high drug loading leading to a minimal total weight of the composition which can be easily handled and taken by the patients.

Summary of the Invention
The present invention relates to a capsule composition comprising multiparticulates comprising a) a core comprising raloxifene, and b) a taste masking coating present in amount of 0.5% to 40%w/w based on the core weight.

The present invention can be administered as an intact capsule as well as a sprinkle composition.

Detailed Description of the Invention
A first aspect of the present invention relates to a capsule composition of raloxifene comprising multiparticulates, wherein said capsules releases not more than 40% of raloxifene in 10 minutes, when measured in a United States Pharmacopeia (USP) type 2 dissolution apparatus, paddle at 50 rpm, at a temperature of 37°C ±0.5°C in1000 mL of pH 4.5 acetate buffer and 0.05% sodium lauryl sulfate.

A second aspect of the present invention relates to a capsule composition of raloxifene comprising multiparticulates, wherein said capsules release not more than 85% of raloxifene in 10 minutes, when measured in a United States Pharmacopeia (USP) type 2 dissolution apparatus, paddle at100 rpm, at a temperature of 37°C ±0.5°C in 1000 mL of water, 0.5% polysorbate and an enzyme.

According to one of embodiment of this aspect, the raloxifene may be present in an amount of about 10% to about 80% based on the total weight of composition. In particular, about 15% to about 80% based on the total weight of composition, wherein the capsule shell weight is not included into the total weight of composition.

A third aspect of the present invention relates to a capsule composition of raloxifene comprising multiparticulates having raloxifene in an amount of about 10% to about 80% based on the total fill weight of the capsule and said capsule is bioequivalent to the marketed raloxifene tablets.

According to one embodiment of this aspect, the total fill weight is less than about 600 mg. In particular, between about 75 mg to about 600 mg, wherein the capsule shell weight is not included into the total fill weight of the capsule.

According to another embodiment of this aspect, the capsule size is 0 or less. In particular, capsule size is 1 or less.

The bioequivalence is established by comparing pharmacokinetic parameters for example, AUC and Cmax of the intact capsule composition of the present invention with Evista® tablet in healthy human subjects.

The term “AUC” refers to the area under the time/plasma concentration curve after administration of raloxifene pharmaceutical composition.
The term “Cmax” refers to the maximum concentration of raloxifene in blood following the administration of raloxifene pharmaceutical composition.
According to another embodiment of this aspect, the capsules when administered to healthy subjects under fasting conditions provide a mean Cmax value in the range of about 2.5 to about 15 ng/mL/mg.

According to one of the embodiment of the above aspects, the multiparticulates have a bulk density of about 0.30 g/ml to about 0.80 g/ml.

According to another embodiment of the above aspects, the multiparticulates may be in the form of core and coating.

According to another embodiment of the above aspects, the coating is present in amount of 0.5% to 40%w/w based on the core weight.

According to another embodiment of the above aspects, the raloxifene has a particle size of D90 NMT 35µ.
According to another embodiment of the above aspects, the coated core have a particle size d90 of less than or equal to 900 µm.

The term “d90 value” as used in the application, means that 90% of the extended release coated cores have a volume diameter in the specified range when measured by a light scattering method such as a Malvern® Mastersizer.
According to another embodiment of the above aspects, the coating is a taste-masking coating.
According to another embodiment of the above aspects, the taste masking coating comprises taste masking polymer.

According to another embodiment of the above aspects, the taste-masking coating further comprises sweetener.

According to another embodiment of the above aspects, the multiparticulates are further blended with the lubricant.

According to another embodiment of the above aspects, the lubricant is present in an amount of 0.1-15% by total weight of the composition.

According to another embodiment of the above aspects, the multiparticulates are further blended with the disintegrants.

According to another embodiment of the above aspects, the capsule composition is stable when subjected to the stability conditions at a temperature of 40°C and RH of 75% for a period 6 months.

According to another embodiment of the above aspects, the sprinkle capsule composition when sprinkled on the soft food is not impacted by soft foods having different pH.
The term “stable” as used herein means that capsule composition when subjected to the stability conditions at a temperature of 40°C and RH of 75% for a period 6 months produce the raloxifene related compound C not more than 1%. Further, the multiparticulates are stable when sprinkled on to the soft food of different pH for at least 60 minutes.
According to another embodiment of the above aspects, the raloxifene is not present in an intimate contact with the alkaline excipient.

“Intimate contact” as used herein means that alkaline excipients are present in the core or the coating dispersion together with raloxifene.
Alkaline excipients as used herein for example calcium phosphate, magnesium phosphate aluminium phosphate, magnesum carbonate, croscarmellose or mixtures thereof.

The term “raloxifene” refers to raloxifene base as well as other pharmaceutically acceptable salts, in particular hydrochloride. It may be present in the sprinkle composition in an amount from about 20 mg to about 100 mg. Raloxifene may be present in an amount of about 15% to about 80% based on the total weight of composition.

The term “sprinkle composition” as used herein refers to a composition which can be sprinkled on to the soft food such as apple sauce, yoghurt, cottage cheese, pudding or drinks, and then administered orally to the patients. The composition may also be administered through NG/G-tube in patients who cannot swallow.

The term "multiparticulates" as used herein includes pellets, beads, granules, spheres or mini-tablets. These multiparticulates may be in the form of coated cores. Coated core may have single or multiple coating. Coated cores may be prepared by coating raloxifene, optionally along with other pharmaceutically acceptable excipients, onto an inert bead. Optionally, a seal coat layer may be present between the inert bead and said coating layer comprising raloxifene. Coated cores may be further coated preferably by taste-masking coating. The inert bead may be water-soluble, water-swellable, or water-insoluble. Examples of water-swellable cores include microcrystalline cellulose spheres such as Celphere®. Examples of water-soluble cores include sugar spheres made of glucose, mannitol, lactose, xylitol, dextrose, or sucrose. Examples of water-insoluble cores include glass beads or silicon dioxide beads. The inert cores have a particle size d90 of less than or equal to 800µm.

According to another embodiment of the above aspects, the coated cores are prepared by coating a raloxifene dispersion in an amount of 80-150% by total weight of the inert cores.

According to another embodiment of the above aspects, the raloxifene dispersion comprises the surfactant.

Alternatively, the multiparticulates may be in the form of matrix core, formulated by mixing raloxifene, optionally with other pharmaceutically acceptable excipients, followed by granulation, direct compression, or extrusion-spheronization. Optionally, matrix core may be coated.


A forth aspect of the present invention relates to a capsule composition comprising multiparticulates comprising
a) a core comprising raloxifene, and
b) a taste masking coating over the core
wherein the taste masking coating is present in an amount of about 0.5% to about 40%w/w based on the core weight.

The taste masking coating may comprises one or more taste masking polymers and coating additives. Pharmaceutically acceptable coating additives may be sweeteners, pore formers, plasticizers, anti-tacking agent, opacifiers, coloring agents, disintegrants, coating agent, and mixtures thereof.

Suitable taste masking polymers are selected from the group comprising water soluble/water swellable polymers such as hydroxyl ethyl cellulose, hydroxyl propyl cellulose, hypromellose, or water insoluble polymers such as ethyl cellulose, polycarbophil, polyacrylic acid, and mixtures thereof. Taste masking polymers may also be enteric such as cellulose acetate butyrate, cellulose acetate phthalate, ethyl vinyl phthalate, polyvinyl acetate phthalate, hydroxy alkyl cellulose phthalates, methacrylic acid/ethyl acrylate copolymers or mixtures thereof. In particular, the taste masking polymer is a water insoluble polymer, for example ethyl cellulose. In particular, the taste masking polymer is a water soluble polymer alone or in combination with water insoluble polymer. These may be present in the composition in the range from about 0.01% w/w to about 25% w/w of the composition.

Examples of pore formers include calcium carbonate, calcium phosphate, calcium saccharide, calcium succinate, calcium tartrate, ferric acetate, ferric hydroxide, ferric phosphate, magnesium carbonate, magnesium citrate, magnesium hydroxide, magnesium phosphate, hypromellose, e.g. HPMC E5, and mixtures thereof. These may be present in the composition in the range from about 0.01% w/w to about 15% w/w of the composition.

Examples of sweeteners include, but not limited to, sucrose, sucralose, sorbitol, xylitol, dextrose, fructose, maltitol, acesulfame potassium, aspartame, saccharin, saccharin sodium, maltitol, glucose, cyclamate, sodium cyclamate, and mixtures thereof. These may be present in the composition in the range from about 0.1% w/w to about 20% w/w of the total weight of the composition.

Examples of plasticizers include propylene glycol, triethyl citrate, tributyl citrate, dibutyl sebacate, acetyl tributyl citrate, glyceryl monostearate, triacetin, polyethylene glycol, diethyl phthalate, acetylated monoglycerides, diacetylated monoglycerides, cetyl alcohol, and mixtures thereof.

Examples of anti-tacking agent include talc, glyceryl monostearate, vegetable oil, waxes, a blend of magnesium stearate and sodium lauryl sulfate, boric acid, sodium benzoate, sodium acetate; sodium chloride, polyethylene glycol, sodium oleate, sodium lauryl sulfate, magnesium lauryl sulfate, corn starch, amorphous silicon dioxide, Vitamin E, Vitamin E TPGS, and mixtures thereof.

Examples of opacifiers include titanium dioxide, manganese dioxide, iron oxide, silicon dioxide, and mixtures thereof. These may be present in the composition in the range from about 0.01% w/w to about 15% w/w of the composition.

Suitable solvents are selected from the group comprising purified water, ethyl alcohol, isopropyl alcohol, acetone, and mixtures thereof.

The coating may be carried out by using any conventional coating techniques known in the art, such as spray coating using fluidized bed processor or pan coating.

The pharmaceutical composition may further comprise other pharmaceutically acceptable excipients. Examples of pharmaceutically acceptable excipients include binders, diluents, lubricants/glidants, disintegrants, surfactants, and mixtures thereof.

Examples of fillers or diluents include, but not limited to, lactose, sorbitol, calcium dihydrogen phosphate dihydrate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, starch, pregelatinized starch, and mixtures thereof.

Examples of binders include, but not limited to, corn starch, pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose, methyl cellulose, hydroxypropyl cellulose (HPC-L), methylcellulose, carboxymethyl cellulose sodium, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and mixtures thereof.

Examples of disintegrants include, but not limited to, cross-linked polyvinyl pyrrolidone, corn starch, and modified starches, agar-agar, calcium carbonate, sodium carbonate, alginic acids, croscarmellose sodium, sodium starch glycolate, microcrystalline cellulose, hydroxypropyl cellulose (L-HPC), and mixtures thereof. These may be present intragranularly or extragranularly. The disintegrant may be added at the lubrication stage.

Examples of lubricants and glidants include, but not limited to, colloidal anhydrous silica, stearic acid, magnesium stearate, glyceryl behenate, calcium stearate, sodium stearyl fumarate, stearic acid, talc, microcrystalline wax, yellow beeswax, white beeswax, and mixtures thereof.

Examples of surfactants include, but not limited to, sorbitan monostearate, polyoxythylene sorbitan monostearate, e.g., Polysorbate 60 or Polysorbate 80, non-ethoxylated glyceryl monostearate, cetomacrogol, cetostearyl alcohol, sodium stearoyl lactylate, lecithin, sodium lauryl sulphate and mixtures thereof.

The coloring agents and flavoring agents of the present invention may be selected from any FDA approved colors or flavors for oral use.

The term “about” as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.

The following examples represent various embodiments according to the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

Example 1:
Ingredients Quantity (mg)
Drug layered cores
Raloxifene hydrochloride 60.00
Sugar spheres 60.00
Polysorbate 80 04.00
Povidone 09.00
Sucralose 02.00
Purified water q.s.
Taste masking coating
Ethyl cellulose 03.88
Hypromellose 15.47
Talc 04.17
Magnesium stearate 02.00
Sucralose 00.50
Isopropyl alcohol q.s.
Purified water q.s.
Lubrication
Sodium stearyl fumarate 01.62
Colloidal silicon dioxide 01.62
Croscarmellose sodium 01.62

Manufacturing Process:
1. Raloxifene, povidone, polysorbate 80 and sucralose were dispersed in purified water to obtain a drug dispersion.
2. Sugar spheres were coated with the drug dispersion of step 1 to obtain drug layered core.
3. Hypromellose, ethyl cellulose, magnesium stearate, croscarmellose sodium, sucralose and talc were dispersed in a mixture of isopropyl alcohol and purified water to obtain a dispersion.
4. The drug coated cores of step 2 were coated with the dispersion of step 3 to obtain taste masked coated cores.
5. Sodium stearyl fumarate, croscarmellose sodium and colloidal silicon dioxide were mixed with taste masked coated cores to obtain lubricated coated cores.

Example 2: The lubricated coated cores of above Example 1 were filled in a capsule size 2.

Ingredients Quantity (mg/capsule)
Drug layered cores
Raloxifene hydrochloride 60.00
Sugar spheres 60.00
Polysorbate 80 04.00
Povidone 09.00
Sucralose 02.00
Purified water q.s.
Taste masking coating
Hypromellose 13.50
Sucralose 06.00
Talc 05.50
Magnesium stearate 02.00
Purified water q.s.
Lubrication
Sodium stearyl fumarate 01.62
Colloidal silicon dioxide 01.62
Croscarmellose sodium 01.62
Example 3:

Manufacturing Process:
1. Raloxifene, povidone, polysorbate 80 and sucralose were dispersed in purified water to obtain a drug dispersion.
2. Sugar spheres were coated with the drug dispersion of step 1 to obtain drug layered core.
3. Hypromellose, magnesium stearate, sucralose and talc were dispersed in a purified water to obtain a dispersion.
4. The drug coated cores of step 2 were coated with the dispersion of step 3 to obtain taste masked coated cores.
5. Sodium stearyl fumarate, croscarmellose sodium and colloidal silicon dioxide were mixed with taste masked coated cores.
6. The lubricated coated cores of step 5 were filled into suitable sized capsules.
7. The lubricated coated cores of step 6 were filled in a capsule size 2.

Example 4:
Ingredient mg/capsule
Raloxifene Hydrochloride USP 60.000
Sugar Spheres (40/60 mesh ASTM) 60.000
Polysorbate 80 4.000
Povidone 9.000
Sucralose 2.000
Taste masking coating
Ethyl cellulose 3.867
Hypromellose 15.465
Talc 4.168
Magnesium stearate 2.000
Sucralose 1.500
Iso Propyl Alcohol q.s
Purified water q.s
Lubrication
Sodium stearyl fumarate 1.620
Colloidal Silicon Dioxide 1.620
Croscarmellose sodium 1.620

Manufacturing Process:
1. Raloxifene, povidone, polysorbate 80 and sucralose were dispersed in purified water to obtain a drug dispersion.
2. Sugar spheres were coated with the drug dispersion of step 1 to obtain drug layered core.
3. Hypromellose, ethyl cellulose, magnesium stearate, sucralose and talc were dispersed in a mixture of isopropyl alcohol and purified water to obtain a dispersion.
4. The drug coated cores of step 2 were coated with the dispersion of step 3 to obtain taste masked coated cores.
5. Sodium stearyl fumarate, croscarmellose sodium and colloidal silicon dioxide were mixed with taste masked coated cores to obtain lubricated coated cores.
6. The lubricated coated cores of step 5 were filled in a capsule size 2.

Dissolution study of Example 1 in Dissolution Media I
The dissolution was performed in 1000 mL of pH 4.5 acetate buffer and 0.05% sodium lauryl sulfate in USP II apparatus at 50 rpm. The samples were analyzed by high performance liquid chromatography (HPLC)/ UV.
Dissolution study of Example 4 in Dissolution Media II
The dissolution was performed in 1000 mL of water, 0.5 % polysorbate and *pepsin in USP II apparatus at 100 rpm. The samples were analyzed by high performance liquid chromatography (HPLC)/ UV.

Table 1: Percentage release of Example 1 and Example 4 in the dissolution media I and II
Percent drug release Time (minutes)
10 20 30 45
Example 1
Dissolution media I 23 29 33 37
Example 4
Dissolution media II 75 88 94 97
Table 1 shows that Example 1 and 4 produces desired in-vitro profile in dissolution media I and dissolution media II.
*pepsin may be replaced with bromelain
Pharmacokinetic Parameters of Example 4 and Evista® tablet in Healthy Human Subjects
Pharmacokinetic study were conducted by orally administering in fasted condition to the healthy human subjects Example 4 capsule and Evista® tablet.
Single dose randomized, three treatment, four period, four sequence crossover study in healthy human subjects was carried out under fasted condition to determine pharmacokinetic parameters.
Table 2: Pharmacokinetic parameter for Example 4 and Evista®tablets
Pharmacokinetic parameters Ratio (T/R)
Cmax ( ng/mL) 111.13
AUC0-inf (ng.hr/mL) 112.66

Table 3:
Pharmacokinetic parameters Example 4
Mean Cmax ( ng/mL/mg) 7.0

Table 2 shows that Example 4 was found to be bioequivalent to the marketed raloxifene tablets.

Stability:
In vitro soft food studies
a) Related substances
A capsule of Example 4 was opened and multiparticulates were tested for RS after exposure to applesauce/chocolate pudding for 60 minutes.
The coated discrete units were found to be stable in applesauce/chocolate pudding with regard to related substances as given in Table 4.
Table 4: RS of multiparticulates after exposure to applesauce/chocolate pudding
Exposure time of 0 min
(applesauce) Exposure time of 60 min
(applesauce) Exposure time of 0 min
(chocolate pudding) Exposure time of 60 min
(chocolate pudding)
Impurity-C (Related Compound-C) 0.06 0.06 0.02 0.03
Total RS (%w/w) 0.15 0.17 0.13 0.13
b) Assay
Capsule of Example 4 was opened and multiparticulates were tested for assay after exposing in various soft foods for 60 minutes. The multiparticulates were found to be stable w.r.t. assay as given in Table 5.
Table 5: Assay of coated discrete units after exposing to various soft foods
Soft foods Exposure time-0 min Exposure time-60 min
Applesauce 101.7% 101.6%
Yoghurt 100.5 % 99.2 %
Pudding 98.3% 97.8%

Based on the in vitro soft food studies, it was concluded that the stability is not impacted by soft foods having different pH.

WE CLAIM:
1. A capsule composition comprising multiparticulates comprising
a) a core comprising raloxifene, and
b) a taste masking coating over the core
wherein the taste masking coating is present in an amount of about 0.5% to about 40%w/w based on the core weight.

2. The capsule composition according to claim 1 wherein the capsules release not more than about 85% of raloxifene in 10 minutes, when measured in a United States Pharmacopeia (USP) type 2 dissolution apparatus, paddle at 100 rpm, at a temperature of 37°C ±0.5°C in 1000 mL of water, 0.5% polysorbate and an enzyme.

3. The capsule composition according to claim 1 wherein the raloxifene is present in an amount of 15% to about 80% based on the total weight of composition.

4. The capsule composition according to claim 1 wherein the taste masking coating comprises taste masking polymer selected from the group consisting of water soluble, water swellable , water insoluble and combinations thereof.

5. The capsule composition according to claim 4 wherein the taste masking coating further comprises sweetener.

6. The capsule composition according to claim 1 wherein the total fill weight is about 75 mg to about 600 mg.

7. The capsule composition according to claim 1 wherein the multiparticulates are further blended with a lubricant present in an amount of 0.1-15% by total weight of the composition.

8. A capsule composition comprising multiparticulates comprising
a) a core comprising raloxifene, and
b) a taste masking coating over the core
wherein the composition is stable and is not in intimate contact with an alkaline excipients.

9. The capsule composition according to claim 8 wherein the capsule composition produces less than 1% of raloxifene impurity C.

10. The capsule composition according to claim 8 wherein the alkaline excipients is selected from the group consisting of calcium phosphate, magnesium phosphate, aluminum phosphate, magnesium carbonate, croscarmellose and mixture thereof.