FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Complete Specification
[See Sections 10 and rule 13]
TITLE: A NOVEL PHARMACEUTICAL COMPOSITION OF A LIPID
LOWERING COMPOUND
Applicant: (a) FTF Pharma Private Limited
(b) Address: opp. Sarjak Farm, Nr. B.P. Petrol Pump
Sarkhej-Rajkot highway
at village: Navapura, taluka: Sanand
dist.: Ahmedabad – 382210
Gujarat, India
(c) Nationality: Indian
The following specification particularly describes the invention and the manner in
which it is to be performed:
2
FIELD OF THE INVENTION
The present invention relates to liquid oral dosage form of lipid lowering
compound preferably statin products suitable for oral administration.
BACKGROUND OF THE INVENTION
Statins are HMG-CoA reductase inhibitors, a class of drug used to lower the
cholesterol level by inhibiting HMG-CoA reductase. Currently available in the
market either as tablets, capsules, or solutions for injection. An individual may
have difficulty swallowing the usual solid dosage form, and daily injections are
difficult to administer. For children dose management is difficult if tablet to cut or
crush because of no accuracy of dose. Based on that a patent application
US20120270933 claims liquid solution comprising statin and at least one
solubilizer with statement that liquid statin formulation are not available due to
poor solubility or insolubility
Still using solubilizer there is an increase in the unknown impurity. So to avoid
this in the present invention solubilizer is avoided.
OBJECT OF INVENTION
The primary object of present invention is to provide liquid oral dosage form of
lipid lowering compound.
Another object of present invention is to provide oral suspension / solution having
dose flexibility for patients who need special doses of the drug and have
difficulties in swallowing oral dosage forms.
Still another object of present invention is to provide oral suspension / solution
with improved taste having high patient compliance.
It is yet another object of present invention to provide process of preparation of
oral suspension / solution of statin products suitable for oral administration.
3
It is yet another object of present invention to provide oral suspension / solution of
atorvastatin products suitable for oral administration and process for preparation
thereof without use of stabilizer and buffering agent.
SUMMARY OF THE INVENTION
The present invention provides liquid oral dosage form of lipid lowering agent,
statin suitable for oral administration to human or animals. These formulations are
useful for administration of the lowest dose of statin for treatment of high
cholesterol level and any diseases due to high cholesterol. This liquid oral dosage
form formulation statins include atorvastatin, simvastatin, rosuvastatin etc. a
preferred is atorvastatin.
DETAIL DESCRIPTION OF THE INVENTION
The present invention relates to suspension of statin products suitable for oral
administration to humans or animals.
Statins are HMG-CoA reductase inhibitors, used for the treatment of high
cholesterol level or any disease due to high cholesterol level in human and
animals. Currently available doses of statins are either as tablets, capsules, or
solutions for injection. Present invention is liquid oral dosage form of statin for
oral administration without use of solubilise rand/or a stabiliser such as
antioxidant. Formulation of present invention is useful even to administer the
lowest dose of the composition.
This liquid oral dosage form formulation statins include atorvastatin, simvastatin,
rosuvastatin etc. wherein preferred is atorvastatin.
Statins are known for poor aqueous solubility and stability but present invention
provides dosage form without use of stabilizer, buffering agent and optionally
solubilizer.
4
Common formula of present invention comprises statin between of 0.1 and 5%
and at least one suspending agent between 0.2 and 6%. In addition the
composition comprises viscosity modifier, sweetener, flavors, colors,
preservatives and water.
In a preferred form of present invention excipients used can be selected from
vehicle, co-solvent, preservative, sweetener, chelating agent, buffer, flavoring
agent and sweetness/flavor enhancing agent.
Vehicles used in pharmaceutical formulations are mainly liquid bases which
carries drugs and other excipients in dissolved or dispersed state. Pharmaceutical
vehicles are of two types:
1) Aqueous vehicles
2) Oily vehicles
Aqueous vehicles can be selected from but not limited to purified water, hydroalcoholic,
polyhydric alcohols and buffers, while oily vehicles can be selected
from vegetable oils, oils, organic oily bases or emulsified bases.
Co-solvents are used to increase solubility of drugs that show low solubility in
water. It is also used to improve viscosity, taste and flavor. Co-solvent system
comprises of solvents selected from but not limited to propylene glycol, glycerin,
alcohol, polyhydric alcohol and water for injection which is used alone or in
combination.
Preservatives are included in pharmaceutical solutions to control the microbial
bioburden of the formulation having broad spectrum of antimicrobial activity,
must be chemically and physically stable over the shelf-life of the product and
have low toxicity. Preservative can be selected from group but not limited to
alcohol, benzyl alcohol, chlorbutol, chlorocresol, alkyl esters of paraben, phenol,
phenyl ethanol, sodium benzoate, antimicrobial solvents like propylene glycol,
chloroform.
.
5
Sweetener can be selected from but not limited to sucrose, liquid glucose,
glycerol, sorbitol, saccharin sodium, sucrose and aspartame to impart sweetness to
the formulation.
Chelating agent is used for drug stabilization, to maintain potency of active
ingredients and to stabilize colors and flavors. Chelating agent can be selected
from but not limited to citric acid monohydrate, disodium edetate, dipotassium
edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate,
tartaric acid and trisodium edetate.
pH of the formulation is between 5 and 10 can be controlled and optimize the
physicochemical performance of the formulation by using base or buffer can be
selected from but not limited to sodium acetate, sodium hydroxide, sodium citrate,
sodium phosphate and disodium phosphate.
Flavoring agents are mainly use to increase the palatability and enhance the
aesthetic qualities of the formulation. Flavoring agent can be selected but not
limited to oil based flavoring agent such as essential oils including peppermint oil,
orange oil, lemon oil etc.
In aspect of present invention, oral pharmaceutical solution of atorvastatin is
formulated which comprises of an active ingredient, atorvastatin and other
excipients selected from vehicle, co-solvent, preservative, sweetener, chelating
agent, buffer, flavoring agent and sweetness/flavor enhancing agent, wherein pH
of formulation is maintained between 5 and 10, more particularly between 6 and
9.
Oral liquid composition without use of stabilizer, buffering agent and optionally
solubilizer can be oral suspension or oral solution.
Examples
The present invention can be described by way of example or strategy only. It is
to be recognized that modifications falling within the scope and spirit of the
description or claims, which would be obvious to a person skilled in the art based
upon the disclosure herein, are also considered to be included within the scope of
this disclosure.
6
Composition is general for oral liquid dosage form of statin is as under:
Sr.
No.
Ingredients for Statin Oral
Solution
Range (%w/w)
1. Active Ingredient 2-10%
2. Solubilizer 0.0-15%
3. Co-solvent 0.0-15%
4. Suspending agent 0.0-10%
5. Complexing agent 0-5%
6. Sweetner 0-50%
7. Flavor
0.0-2%
8. Surfactant
0.0-0.2%
9. Vehicle
0.0-90%
For the composition of atorvastatin 1mg/ml, drug and excipients with its range are
shown below in table:
Strategy I & II
With antioxidant and without antioxidant
Sr.
No.
Ingredients
STRATEGY I STRATEGY II
20mg/5ml 20mg/5ml
1 Atorvastatin 20.00 20.00
2 Propylene Glycol 250.00 250.00
3
Carboxymethyl cellulose
sodium
33.33 33.33
4 Magnesium Aluminium silicate 66.67 66.67
5 Butylated hydroxyanisole 0.00 2.00
6 Purified water qs 5ml qs 5ml
7
Manufacturing process for (Strategy I)
1. Sodium Carboxymethyl Cellulose were slowly added in 30% W/W
purified water and stir well till clear solution was obtained.
2. Dispensed quantity of Magnesium Aluminium silicate was added in step1 ,
additional 20%w/w a purified water add in Step 1 and stir well till all solid
mass was get mixed properly.
3. API was added into propylene glycol and mixed properly where solubilizer
was used. This mixture was added in to step 2 and stirred through simple
stirrer properly to get homogenized suspension.
4. Add 50%w/w of remaining purified water for makeup the suspension.
Manufacturing process for (Strategy II)
1 Sodium Carboxymethyl Cellulose were slowly added in 30% W/W
purified water and stir well till clear solution was obtained.
2 Dispensed quantity Magnesium Aluminium silicate was added in STEP1 ,
additional 20%w/w a purified water add in Step 1 and stir well till all solid
mass was get mixed properly AT RPM(600-800).
3 BHA and API was added into propylene glycol and mixed properly where
solubilizer was used. This mixture was added in to step 2 and stirred through
simple stirrer properly to get homogenized suspension.
4 Add remaining purified water for makeup the suspension
8
Result achieved for strategy I and II based on stability are as under:
Trial Strategy I Strategy II
Stability
condition
Initial 3M 25/60 3M 40/75 Initial 3M25/60 3M40/75
Impurity A 0.05%
0.02
0.02
0.05
0.02
0.05
Impurity
C
0.01%
ND
ND
ND
ND
ND
Impurity
D
0.02%
0.01
0.01
0.03
0.01
0.01
Lactone 0.03%
0.1
0.06
0.04
0.05
0.05
Ester
ND
ND
ND
ND
ND
ND
Unknown
Impuritie
s
0.08
(RRT0.74
)
0.15
(RRT0.80
)
1.40
(RRT0.80
)
0.12
(RRT0.74
)
0.63
(RRT0.80
)
1.10
(RRT0.80
)
Total
Impuritie
s
0.53%
0.42%
2.1%
0.42
1.00
1.7
Conclusion:
On based of 3M 25/60 RS data of Strategy I & Strategy II, antioxidant having no
effective role.
Based on the results achieved with or without use of stabilizer we also tried for
avoiding buffering agent via strategy III and IV along with avoiding stabilizing
agent.
Strategy III & IV
With buffering agent without buffering agent
Sr.
No.
Ingredients for Atorvastatin Oral
Suspension
STRATEGY
III
STRATEGY
IV
20mg/5ml 20mg/5ml
1. Atorvastatin 20.00 20.00
2. Carboxymethyl cellulose sodium 33.33 33.33
3. Magnesium Aluminium silicate 66.66 66.66
9
4. Sucralose 50.00 50.0
5. Acesulfame K 5.00 5.0
6. Methyl parahydroxybenzoate 5 5
7. Ethyl parahydroxybenzoate 1 1
8. Potasium Di-Hydrogen Phosphate 0.959 -
9. Di-potasium Hydrogen Phosphate 0.078 -
10. Orange flavour 15.0 15.0
Purified water Up to 5ml Up to 5 ml
Manufacturing process for Strategy III
1. 50 %w/w Purified water was heated till the temperature reached to 80°C to
90°C. Dispensed quantity of Methyl parahydroxybenzoate and Ethyl
parahydroxybenzoate was added in to this and stirred to get clear solution.
Cool down solution at room temperature.
2. Add sucralose, Acesulfame K in step 1,stir well till clear solution.
3. Sodium Carboxymethyl Cellulose were slowly added in step 1, stir well till
clear viscous solution.
3 Magnesium Aluminium silicate were add in step 2 stir well till all solid mass
was get mixed properly.
4 Add and disperse Atorvastatin in 10%w/w purified water in separate
vessel mix properly for 30 min, with high speed homogenization. .
5 Step 4 is add in step 3, mix well through simple stirrer and get
homogenize suspension.
6 Add Potasium Di-Hydrogen Phosphate, Di-potasium Hydrogen Phosphate
in 20%w/w purified water, add slowly in step 5 to achieve pH 6.0-9.0
7 Add flavor in step 6.
10
8 Add purified water and makeup the volume.
Manufacturing process for Strategy IV
1 50 %w/w Purified water was heated till the temperature reached to 80°C. to
90°C. Dispensed quantity of Methyl parahydroxybenzoate (E218) and Ethyl
parahydroxybenzoate (E214) was added in to this and stirred to get clear
solution. Cool down solution at room temperature.
2 Add sucralose, Acesulfame K in step 1,stir well till clear solution.
3 Sodium Carboxymethyl Cellulose were slowly add in step 1,stir well till
clear viscous solution.
4 Magnesium Aluminium silicate were add in step 2 stir well till all solid mass
was get mixed properly.
5 Add and disperse Atorvastatin in 10%w/w purified water in separate
vessel mix properly for 30 min.
6 Step 4 is add in step 3,mix well through simple stirrer and get homogenize
medium.
7 Add flavor in step 6.
8 Add purified water and makeup the volume.
The results we achieved for strategy III and IV are as under:
Trial Strategy III Strategy IV
Stability condition Initial 3M 25/40 3M 40/25 Initial 3M 25/40 3M40/25
Impurity A ND 0.07 0.07 0.04 0.06 0.06
Impurity C ND ND ND ND ND ND
Impurity D 0.03 0.04 0.05 0.06 0.02 0.02
Lactone 0.05 0.08 0.11 0.18 0.1 0.08
Ester
ND ND ND ND ND ND
Unknown
Impurities
0.05(0.81)
0.25(0.78) 0.76(0.78) 0.07(0.80) 0.09(0.79) 0.12(0.79)
Total Impurities
0.1 0.62 1.4 0.57 0.44 0.44
Conclusion:
On based of 3M 25/40& 3M 40/25 RS data of Strategy III & Strategy IV stabilizer
buffering agent is having partial or no effective role.
11
Strategy V
For effective homogenization.
Sr. No. Ingredients for Atorvastatin Oral Suspension STRATEGY V
20mg/5ml
1. Atorvastatin 20.00
2. Carboxymethyl cellulose sodium 33.33
3. Magnesium Aluminium silicate 66.66
4. Sucralose 50.00
5. Acesulfame K 5.00
6. Methyl parahydroxybenzoate 5
7. Ethyl parahydroxybenzoate 1
8. Orange flavour 15.0
9. Purified water Up to 5ml
Manufacturing process for Strategy V
1 50 %w/w Purified water was heated till the temperature reached to 80°C. to
90°C. Dispensed quantity of Methyl parahydroxybenzoate (E218) and Ethyl
parahydroxybenzoate (E214) was added in to this and stirred to get clear
solution. Cool down solution at room temperature.
2 Add sucralose, Acesulfame K in step 1, stir well till clear solution.
3 90 % quantity of Sodium Carboxymethyl Cellulose were slowly add in step
1,stir well till clear viscous solution.
4 Magnesium Aluminium silicate were add in step 2 stir well till all solid mass
was get mixed properly.
5 In a separate vessel take 10% v/v of purified water and remaining qty of
sodium carboxymethyl cellulose and disperse Atorvastatin. Homogenize
12
through high speed for 30 min, achieve particle size d90 1micon-15
micron.
6 Step 5 is add in step 4, mix well through simple stirrer and get
homogenize medium.
7 Add flavor in step 6.
8 Add purified water to make up and homogenize through high speed for 45
min.
Trial results: Based on the homogenization trials final formulation with different
Particle size distribution were evaluated with Reference marketed product (Lipitor
40 mg Film coated tablet). And the results of the bio equivalence study is as
mentioned below:
BE STUDY I: Formulation particle size (D90-22.39μm)
Pharmacokinetic
Parameters
(Units)
Ln- transformed
90% Confidence
Interval
(Parametric)
Geometric Least Squares Mean
Test Product
(T)
Reference
Product (R)
T/R (%) Lower Upper
Cmax (ng/mL) 36.1290 53.2937 67.79 52.49 87.56
AUC0-t
(ng.hr/mL)
164.7519 176.0092 93.60 86.32 101.50
BE STUDY II: Formulation particle size (D90- 6.02μm)
Pharmacokinetic
Parameters
(Units)
Ln- transformed
90% Confidence
Interval
(Parametric)
Geometric Least Squares Mean
Test Product
(T)
Reference
Product (R)
T/R (%) Lower Upper
Cmax (ng/mL) 55.6268 61.7538 90.08 63.43 127.92
AUC0-t
(ng.hr/mL)
212.8483 215.5457 98.75 82.91 117.61
Formulation particle size (d90- 6.02μm)
13
Conclusion:
Based on above data stabilizer, buffering agent having partial or no effective role,
effective particle size for bioequivalence it can be achieved from effective
homogenization, the result comes from BE study as above.
Observation from study 2:
The ratios of geometric least squares means of test product (T) and reference product (R)
for Ln-transformed pharmacokinetic parameters (Cmax and AUC0-t) of atorvastatin were
found to be 90.08% and 98.75% respectively. The 90% confidence intervals for the ratio
of geometric least squares means for Ln-transformed pharmacokinetic parameters (Cmax
and AUC0-t) of atorvastatin were found to be 63.43 – 127.92% and 82.91 – 117.61%
respectively. The 90% confidence intervals for the ratio of geometric least squares means
for Ln-transformed pharmacokinetic parameter AUC0-t are within the acceptable
bioequivalence interval of 80.00 – 125.00% but that of Cmax is not within the acceptable
bioequivalence interval of 80.00 – 125.00%.
From the study it was concluded that effective homogenization- particle size reduction
method is required to produce the product having comparative pharmacokinetic profile to
Innovator product (Lipitor)
The same strategy and manufacturing process can be applicable to all HMG-CoA
reductase inhibitors like simvastatin, rosuvastatin.
Further also tried for atorvastatin oral solution without usinf stabilising and
buffering agent. Few strategies are mentioned below:
Atorvastatin oral solution
Sr.
No.
Ingredients for
Atorvastatin Oral
Solution
STRATEGY
I
II III IV
20mg/5ml 20mg/5ml 20mg/5ml 20mg/5ml
1. Atorvastatin 20.00 20.0 20.0 20.00
2. Propylene glycol 250 - 150 -
3. Ethanol - - 5%v/v 20%v/v
14
4. HPBCD - - - 400
5. Sorbitol solution 300 300 300 300
6. Peppermint flavor 0.5 0.5 - 0.5
7. Orange flavor - 0.5 0.5 -
8. Polysorbat 80 1 3 - -
9. Glycerine Up to 5 ml - - Up to 5
ml
10. Purified water - Up to 5 ml Up to 5 ml -
Manufacturing process strategy I
1. Add atorvastatin in Propylene glycol mix well till clear solution obtained.
2. Add sorbitol solution in 50 % v/v of total quantity of glycerine mix well to
obtain homogeneous mixture.
3. Add step 2 in to step 1 mix well.
4. Add polysorbate 80 in step3 to obtain clear viscous solution.
5. Add peppermint in step 4 and mix well till homogenious solution obtain.
6. Make up the volume with glycerine pH of solution (4.0-7.0)
Manufacturing process strategy II
1 Add atorvastatin in purified water mix well than add polysorbate 80 and mix
well till clear solution obtain.
2 Add sorbitol solution in Step 1 stirr well till clear solution.
3 Add Orange flavor in step 2 stirr well till clear solution.
4 Make up the volume with purified water pH of solution (5.0-9.0)
Manufacturing process strategy III
1 Add atorvastatin in ethanol mix well in separate vessel.
2 Add propylene glycol in step 1 till clear solution obtain.
3 Add sorbitol solution in 50% purified water in separate vessel mix well to
obtain homogeneous mixture
4 Add Orange flavor in step 3 stirr well till clear solution.
5 Step 1 add in step 4 stirr well till clear solution obtain.
15
6 Make up the volume with purified water. Ph of solution (5.0-8.0)
Manufacturing process strategy IV
1 Add atorvastatin in ethanol mix well in separate vessel.
2 Add HPBCD in step 1 stirr well till complete complaxation obtain.
3 Add sorbitol solution in 50% purified water in separate vessel mix well to
obtain homogeneous mixture.
4 Add peppermint flavor in step 3 stirr well till clear solution.
5 Step 1 add in step 4 stirr well till clear solution obtain.
7 Make up the volume with glycerine. pH of solution (4.0-7.0)
The same strategy can be applicable to all other HMG-CoA reductase inhibitors
like simvastatin, rosuvastatin, etc.
16
We claim,
1. Liquid oral dosage form of lipid lowering agent without use of stabilizer,
buffering agent and optionally solubilizer.
2. Liquid oral dosage form of lipid lowering agent as claimed in claim 1,
wherein lipid lowering agent is statin products.
3. Liquid oral dosage form of lipid lowering agent as claimed in claim 1,
wherein statin products can be atorvastatin, rosuvastatin or simvastatin.
4. Liquid oral dosage form of lipid lowering agent as claimed in claim 1,
wherein particle size of stain is D90 less than about 50 micron.
5. Liquid oral dosage form of lipid lowering agent as claimed in claim 1,
wherein particle size of stain is D90 less than about 10 micron,
6. Liquid oral dosage form of lipid lowering agent as claimed in claim 1,
wherein pH of the formulation is between 5 and 10.
7. Liquid oral dosage form of lipid lowering agent as claimed in claim 1,
wherein composition comprises complexing agent 0-5%, surfactant 0-0.2%,
sweetener 0-50%, preservative 0.01-0.5%, solubilizer 10-15%, suspending
agent 0-10%, co-solvent 0-15%, flavouring agent 0-2% and vehicle 0-90%.
8. Liquid oral dosage form of lipid lowering agent atorvastatin is suspension
without use of stabilizer, buffering agent and solubilizer comprises
atorvastatin 0.1-2%, suspending agent 0.1-1.0 %, sweetener 0.1-2%,
preservative 0.01-0.5%, flavor 0.01-2.0% and vehicle q.s..
9. Process for preparation of liquid oral dosage form of lipid lowering agent as
claimed in claim 8, comprises
Step 1
•Heat 50 %w/w Purified water till the temperature reached to 80°C to 90°C.
•Add dispensed quantity of methyl parahydroxybenzoate and ethyl
parahydroxybenzoate into it and stir to get clear solution.
•Cool down solution at room temperature.
17
Step 2
•Add sucralose, Acesulfame K in step 1, stir well till clear solution.
Step 3
•Add slowly sodium carboxymethyl cellulose in step 1, stir well till clear
viscous solution.
•Add magnesium aluminium silicate in step 2, stir well till all solid mass get
mixed properly.
Step 4
•Add and disperse atorvastatin in 10%w/w purified water in separate vessel
mix properly for 30 min.
Step 5
•Add outcome of step 4 in step 3, mix well through simple stirrer and get
homogenize medium.
Step 6
•Add potasium di-hydrogen phosphate, di-potasium hydrogen phosphate in
20%w/w purified water, add slowly in step 5 to achieve pH 6.0-9.0
Step 7
•Add flavor in step 6.
•Add purified water and makeup the volume.