Specification
FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
AN ORAL PHARMACEUTICAL COMPOSITION OF
DUTASTERIDE
GENEPHARM INDIA PRIVATE UMITED
A company incorporated under the laws of India having their office at
Regd. Off.: IB, Old Post Street, Kolkata-?00001
The following specification particularly describes the invention and the manner in
which it is to be performed
AN ORAL PHARMACEUTICAL COMPOSITION OF
DUTASTERIDE
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an oral composition of dutasteride. Dutasteride, a synthetic 4-azasteroid compound is an antiandrogen with the chemical name (5α, 17β) — N- {2, 5 bis (trifluoromethyl) phenyl} -3- oxo-4-azaandrost -1 -ene-17- carboxamide. Dutasteride is indicated for the treatment of symptomatic benign prostate hyperplasia (BPH) in men with enlarged prostate glands.
BACKGROUND OF THE INVENTION
Dutasteride, a synthetic 4-azasteroid compound is a selective
inhibitor of both the type 1 and type 2 isoforms of steroid 5a-reductase (5AR), an
intracellular enzyme that converts testosterone to 5_57% MG)
- Imwitor 742 (MG/DG/TG of C8 and C10 FA; 45-55% MG)
- Imwitor 928 (MG/DG/TG of saturated FA of coconut oil (mainly C12) min 40% MG)
(C) Long Chain Mono and Diglyceride blends
(Typically a mixture of MG, DG and smaller quantities of TG) * Typical products:
- Peceol ( Glyceryl monooleate HLB 3.3) Maisine 35-1 (Glyceryl monolinoleate HLB =
4)
(D) Propylene glycol esters:
Capryol PGMC (Propylene glycol caprylate HLB=5), Labrafat. PG propylene glycol dicaprylocaprate (HLB=2), Lauroglycol 90 Propylene glycol rhonolaurate (HLB= 5), Lauroglycol FCC Propylene glycol Jaurate (HLB=4), Labrafil M 1944 (PEG 300 oleic glycerides Oleoyl Macrogol-6 glycerides, HLB= 4), Labrafil ty 2125 (PEG 300 linoleic glycerides Linoleoyl Macrogol-6-g!ycerides, HLB=4)
The relative proportions of surfactant and co-surfactant in the Composition, formulation of the present invention can influence the solubilizing and dissolution properties of the
formulation. In general, the range of concentration of the surfactant/ co-surfactant broadly ranges from 15 to 96% (v/v) and more preferably ranges from approximately from 30 to 90% (v/v). The concentration of the co-surfactant broadly ranges from 10 to 80% (v/v).
The oil content in the oral composition of the present invention ranges from 4-60%, more preferably 4-44%.
The antioxidant used in oral composition of the present invention may be selected from butylated hydroxytoluence, butylated hydroxyl anisole, a-tocopherol ascorbic acid , ascorbyl palmitate sodium ascorbate, vitamin E, tartaric acid and the like.
The excipient used in oral composition of the present invention may be selected from diluents, binders lubricants, disintegrants, flavoring agents, coloring agents, stabilizers, glidants, plasticizers, preservatives and sweeteners.
The adsorbent used in oral composition of the present invention may be selected from kaolin, bentonite, hectorite, colloidal magnesium aluminium silicate, silicon dioxide, magnesium trisilicate, aluminium hydroxide magnesium oxide, talc, calcium — aluminium silicate, lactose.
Diluents may be selected from calcium-aluminum silicates (Sipernat 106 PQ), 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, pregelatmized starch ,sucrose,talc,xylitol,Tnaltosemaltodextrin,maltitol.
Binders may be selected from acacia, alginic acid, carbomer,carboxymethylcellulose calcium, carbomethylcellulose sodium,microcrystalline cellulose,powdered cellulose, ethyl cellulose, gelatin liquid glucose, guar gum, hydroxyethyl cellulos, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, maltodextrin,methy]cellulose,ploydextrose, polyethtylene oxide,povidone,sodium alginate, starch paste, pregelatinized starch, sucrose, tragacanth, low-substituted hydroxypropyl cellulose,glucose, sorbitol. Suitable fillers are preferably selected from atleast one of starch derivatives,such as corn starch, potato starch or rice starch.Polysaccharides such as dextrins, maltodextrins, dextrates, microcrystatline cellulose, powdered cellulose, mixture of microcrystalline cellulose and guar gum, coprocessed blends of microcrystalline cellulose; and polyhydric alcohols, such as xylitol and sorbitol.
Disintegrants may for example, example, alginic acid, carbon dioxide, carbonxymethylcellulose calcium carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmelose sodium, crospovidone, sodium docusate, gaur gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium , poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium laulyl sulfate, sodium starch glycolate, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose.
Glidants may be , for example, calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide.
Lubricants may be selected from magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulphate, talc, polyethylene glycol, and glyceryl behenate.
Suitable sweeteners may be selected from sugars such as sucrose, lactose and glucose; cyclamate and salts thereof; saccharin and salts thereof; and aspartame.
Flavouring agents may be selected from natural or synthetic flavours such as strawberry flavour, wild cherry flavour, green apple flavour, spearmint flavour and peppermint flavour.
According to another embodiment of the present invention is provided a process for the preparation of an oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt comprising mixing.
a) dutasteride or its pharmaceutically acceptable salt;
b) one or more surfactant (s) / co-surfactant (s);
c) one or more oil (s);
d) optionally antioxidant (s); and
e) optionally excipient (s) ;
at ambient temperature or heating at 25-75°C for less than an hour and cooling to ambient temperature.
The oral pharmaceutical composition of the present invention upon dilution with aqueous medium forms microemulsion with at least 95% particles having mean particle size below 200nm.
The admixture may be used as such or filled in capsules or adsorbed on an adsorbent and compressed into pellet or tablets or filled in capsules.
More specifically, a process for the preparation of an oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt comprising mixing.
a) dutasteride or its pharmaceutically acceptable salt;
one or more surfactant (s)/ co-surfactant(s);,
c) one or more oil (s);
d) optionally antioxidant (s); and
e) optionally excipient (s);
at ambient temperature or heating at 25-75°C for less than an hour and cooling to ambient temperature followed by filling in capsules or adsorbing on suitable adsorbent and filling in capsules or compressing into pellet or tablets.
The oral pharmaceutical composition of the present invention wherein the liquid composition, before adsorption on solid, upon dilution with aqueous medium forms microemulsion with at least 95% particles having mean particle size below 200nm.
The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope of the invention.
EXAMPLES
Example-1/2 and 3 (S/CoS ; = 6, Oil = 4%)
Ingredient Function mg / dosage
Dutasteride Active 0.5 mq
Cremophor EL (BASF) or Surfactant 82.24 mg
Polysorbate 80 or
Gelucire 44/14 (Gattefosse)
Capryol 90 (Gattefosse) hydrophilic surfactant 13.76 mg
Labrafil 1944 CS (Gattefosse) Oily phase 4.0 mg
Butylated hydroxyl toluene (BHT) Antioxidant 0.1 mg
Purified water Humectant 5.4 mg
Fill weight 106 mg
HPMC Hard capsule (V-caps) (Capsuqel) - size 4 • Size 4
Example-4 IS/CoS = 1, Oil - 44%
Ingredient Function mg / dosage
Dutasteride Active 0.5 mg
Cremophor EL (BASF) Surfactant 37.28 mg
Capryol 90 (Gattefosse) hydrophilic surfactant 18.72 mg
Labrafil 1944 CS (Gattefosse) Oily phase 44.0 mg
Butylated hydroxyl toluene (BHT) Antioxidant 0,1 mg
Fill weight 100.6 mg
HPMC Hard capsule (V-caps) (Capsugel) - size 4 Size 4
PROCEDURE: (Example 1-4) :
1. Weigh accurate amount of Dutasteride.
2. Add Surfactactant, hydrophilic surfactant and oily phase.
3. BHT added in step 2 solution and heated at about 60 C with stirring for 10 min -clear solution
4. Purified water {wherever applicable) added to above solution and mixing continued for 5 min — clear solution achieved. Cooled to ambient temperature (except for GeJucire containing mixture which was maintained at 40-45 C during filling in capsules)
5. Upon cooling at ambient temperature the solution of step 4 filled in size 4 HPMC capsules to desired fill weight.
EXAMPLES OF LIQUID/ SEMISOLID LOADED ON SOLID ADSORBENT AND POWDER FILLED IN HARD CAPSULES:
EXAMPLE-5, 6 and 7
Ingredient Function mg / dosage
Medicament of Example 1/2 or 3 SMEDDS concentrate 106 mg
Calcium-aluminium silicate, Stpernat 106 PQ ( Dequssa) Adsorbent 67 mg
MCC 101 Diluent/ adsorbent 77 mg
Crosscarmellose sodium (Acdisol) Disintegrant 10 mg
POWDER FILL WEIGHT 260 mg
HPMC Hard capsule (V-caps) (Capsugel) Size 0
EXAMPLE- 8 and 9
Ingredient Function Example 8
(mg / dosage) Example 9
(mg/
dosage)
Medicament of Example 4 SMEDDS concentrate 100.6 mg 100.6 mg
Lactose (DCL-ll) Water soluble diluent 150.0 mg 89.4 mg
Microcrystalline cellulose (MCC PH 102) Water insoluble diluent/ adsorbent 25.0 mg Nil
Crospovidone Disintegrant 15.0 mg 10.0 mq
Calcium-aluminiurn silicate, Sipernat 106 PQ ( Dequssa) Adsorbent 23.4 mg 60.0 mg
Colloidal silicone dioxide (Aerosil 200) Flow promoter/ adsorbent 6.0 mg Nil
POWDER FILL WEIGHT 320.0 mg 260.0 mg
HPMC Hard capsule (V-caps) (Capsuqel) Size 0 Size 0
EXAMPLE 10 (CONTROL FORMULATON, WET GRANULATION):
Ingredient Function mg / dosage
Dutasteride Mtcronised, Active 0.5 mg
Lactose powder grade Adsorbent 185.5 mg
Povidone K-30 Binder 6.0 mg
Purified water Binder solvent q.s.
Crosscarmellose sodium (Acdisol) Disintegrant 6.0 mg
Aerosil 200 Flow promoter 2.0 mg
POWDER FILL WEIGHT 200 mg
HPMC Hard capsule (V-caps) (Capsugel) Size 0
EXAMPLE 11: DISSOLUTION and GLOBULE SIZE COMPARISON OF ZERO DAY SAMPLE WITH AVODART
Dissloution/ Water/ 500 ml/ 37 + 0.5 ° C /Paddle 50 RPM
Time (min.) Example-1 Example-
2 Example-3 Example-4 AVODART * CONTROL
(Wet
Granulation
)
15 43.5 62.5 32.8 68.1 0 0 6.8
30 76.2 89.6 84 95.0 0 0 7.9
45 85.3 95.5 93.2 100.4 0 0 5.9
Assay 101.7% 103.7% — 99.6% 99.6% 111.5
* Avodart B.No. 053174B (expiry 6/2010) and 056959B (expiry: 4/2012) used for above evaluation
Dissloution/ 0.1N HC1 + 2% SLS/ 500 ml/ 37 + 0.5 ° C /Paddle 50 RPM
Time (min.) Example-1 Example-2 Example-3 Example-
4 AVODART
* CONTROL
(Wet
Granulation
)
15 85.6 86 52.7 76.5 93.9 21.1
# 62.2
30 94.6 89.8 83.4 94.9 99.6 42# 85.0
45 99.6 94.4 91.7 100.7 103.
5 46.6
# 93.6
* Avodart B.No. 053174B (expiry 6/2010) and 056959B (expiry: 4/2012) used for above
evaluation
# Crosslinking of Gelatin reported for Avodart - with Simulated gastric fluid with Pepsin
(Tier-11) dissolution value was 97.6% in 45 min
GLOBULE SIZE / VISUAL OBSERVATIOl NfS upon dilution in 0.1 N HCI
98% globul es less than 20 nm 20 nm 20 nm 36 nm about 1900 nm (Not ME) Not applicable
Visual Obser vation Clear, transparent Clear, transparent Clear
transparent Clear transparent HIGHLY TURBID Not applicable
EXAMPLE 12: DISSOLUTION and GLOBULE SIZE COMPARISON OF 3MONTH ACCELERATED STABILITY STUDY SAMPLE AT 40° C/75% RH
3M/ 40° C/75% RH - HDPE bottle
Dissloution/ Water/ 500 ml/ 37 + 0.5 ° C /Paddle 50 RPM
Time (min.) Example-1 Example-2 Example-3
15 58.7 66.2 55.6
30 89.6 80.0 85.2
45 96.5 84.2 90.9
3M7 40° C/75% RH - HDPE bottle
Dissloution/ 0.1N HC1 + 2% SLS/ 500 ml/ 37 + 0.5 ° C /Paddle 50
RPM
Time (min.) Example-1 Example-2 Example-3
15 79.6 77.4 46.9
30 102.2 90.6 84.2
45 104.9 99.8 87.6
3MZ 40° C/75% RH - HDPE bottle
VISUAL OBSERVATIONS upon dilution in 0.1 N HC1
Visual Observation Clear, transparent Clear, transparent Clear transparent
EXAMPLE 13: DISSOLUTION COMPARISON OF ZERO DAY SAMPLES
WITH AVODART
Dissloution/ Water/ 500 ml/ 37 + 0.5 ° C /Paddle 50 RPM
Time (min.) Example -5 Example -6 Example
-7 Examp le-8 Example -9 AVODAR T CONTROL
(Wet Granulation
)
15 34.4 29.9 37.4 35.3 20.2 0 6.8
30 43.7 42.4 50.1 38.4 19.2 0 7.9
45 48.5 47.9 52.7 48.1 22.8 0 5.9
Assay 104.7 105.9 — 95.7 ~ 99.6 111.5
Dissloution/ 0.1N HCl + 2% SLS/ 500 ml/ 37 + 0.5 ° C /Paddle 50 RPM
Time (min.) Example
-5 Examp le-6 Example
-7 Example -8 Example -9 AVODART
* CONTRO
L
(Wet
Granuiatio
n)
15 49.4 53.9 59.2 91.3 66.4 93.9 / 21.1# 62.2
30 66.5 56.5 74 95.1 83.1 99.6 / 42# 85.0
45 74.6 65 78.9 103 96.5 103.5/ 46.6# 93.6
* Avodart B.No. 053174B (expiry 6/2010) and 056959B (expiry: 4/2012) used for above
evaluation
# Crosslinking of Gelatin reported for Avodart - with Simulated gastric fluid with Pepsin
(Tier-It) dissolution value was 97.6% in 45min
We Claim
1. An oral pharmaceutical composition of dutasteride or its pharmaceutically
acceptable salt comprising admixture of
a) dutasteride or its pharmaceutically acceptable salt;
b) one or more surfactant (s) / co-surfactant (s);
c) one or more oil (s);
d) optionally antioxidant (s); and
e) optionally excipient (s) ;
wherein the composition upon dilution with aqueous medium forms microemulsion with atleast 95% particles having mean particle size below 200 nm.
2. An oral pharmaceutical composition as claimed in claim 1 wherein the admixture
is filled in capsules.
3. An oral pharmaceutical composition as claimed in claim 1 wherein the admixture
is adsorbed on suitable adsorbent and filled in capsules or compressed into pellets or tablets.
4. An oral pharmaceutical composition as claimed in claim I wherein the surfactant
has HLB value above 8.
5. An oral pharmaceutical composition as claimed in claim } wherein the co-surfactant has HLB value above 6.
6. An oral pharmaceutical composition as in claim I wherein the oil has HLB value below 6.
7. An oral pharmaceutical composition as in claim 1 wherein the antioxidant is
selected from butylated hydroxytoluence, butylated hydroxyl anisole,α-tocopherol ascorbic acid , ascorbyl palmitate sodium ascorbate, vitamin E and tartaric acid
8. An oral pharmaceutical composition as claimed in claim 1 wherein the excipient
is selected from diluents, binders, lubricants, disintegrants, flavoring agents, coloring agents, stabilizers, glidants, plasticizers, preservatives and sweeteners.
9. An oral pharmaceutical composition as claimed in claim 3 wherein the adsorbent
is selected from kaolin, bentonite, hectorite, colloidal magnesium aluminium silicate, silicon dioxide, magnesium trisilicate, aluminium hydroxide magnesium oxide, talc, calcium - aluminium silicate, lactose.
10. A process for the preparation of an oral pharmaceutical composition of
dutasteride or its pharmaceutically acceptable salt comprising mixing.
a. dutasteride or its pharmaceutically acceptable salt;
b. one or more surfactant (s) / co-surfactant (s);
c. one or more oil (s);
d. optionally antioxidant (s); and
e. optionally excipient (s);
at ambient temperature or heating at 25-75°C for less than an hour and cooling to ambient temperature.
11. A process as claimed in claim 10 wherein the composition upon dilution with
aqueous medium forms microemulsion with at least 95% particles having mean
particle size below 200nm.
I2.A process for the preparation of an oral pharmaceutical composition of dutasteride or its pharmaceutically acceptable salt comprising mixing. a) dutasteride or its pharmaceutically acceptable salt;
b) one or more surfactant (s) / co-surfactant (s);
c) one or more oil (s);
d) optionally antioxidant (s); and
e) optionally excipient (s) ;
at ambient temperature or heating at 25-75 C for less than an hour and cooling to ambient temperature followed by filling in capsules or adsorbing on suitable adsorbent and filling in capsules or compressing into pellet or tablets.
13. A process as claimed in claim 12 wherein the liquid composition, before adsorption on solid, upon dilution with aqueous medium forms microemulsion with atleast 95% particles having mean particle size below 200 nm.