FIELD OF THE INVENTION
The present invention relates to stable solid oral pharmaceutical compositions of
carvedilol or a pharmaceutically acceptable salt thereof.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 4,503,067 describes a compound, which is known as carvedilol. This
compound is a novel multiple action drug useful in the treatment of mild to moderate
hypertension. Carvedilol is known to be both a competitive non-selective P-adrenoceptor
antagonist and a vasodilator. The vasodilatory actions of carvedilol result primarily from
ai-adrenoceptor blockade, whereas the P-adrenoceptor blocking activity of the drug
prevents reflex tachycardia when used in the treatment of hypertension. These multiple
actions of carvedilol are responsible for the antihypertensive efficacy of the drug. Also,
carvedilol, as a consequence of its antioxidant action in attenuating oxygen free radical-
initiated lipid peroxidation, is useful in organ protection, in particular, cardio protection.
Additionally, carvedilol is useful in the treatment of congestive heart failure.
US patent application 2004/0234602 discloses use of stabilizing agents like antioxidants
suitable for use also in situation where the active substance is subject to oxidation: acids
(ascorbic acid, erythorbic acid, etidronic acid, gallic acid, hypophosphorous acid,
nordihydroguairetic acid, propionic acid etc.), phenols (e.g. BHA, BHT, t-butyl
hydroquinone, dodecyl gallate, octyl gallate, 1,3,5-trihydroxybenzene), organic and
inorganic salts (calcium ascorbate, sodium ascorbate, sodium bisulphite, sodium
metabisulfite, sodium sulfite, potassium bisulphite, potassium metabisulphite), esteres
(calcium ascorbate, dilauryl thiodipropionate, dimyristyl thiodipropionate, distearyl
thiodipropionate), pyranon (maltol), and vitamin E (tocopherol, D-cc-tocopherol, DL-oc-
tocopherol, tocopheryl acetate, d-oc-tocopheryl acetate, dl-oc-tocopheryl acetate.
A need exists in the art for methods to stabilize solid oral pharmaceutical dosage forms
comprising carvedilol or a pharmaceutically acceptable salts thereof. These stabilized
pharmaceutical dosage forms would allow for longer storage periods, and would allow
the amount of components to remain constant over the storage period.

OBJECT OF THE INVENTION
An object of the invention is to provide stable solid pharmaceutical compositions for oral
administration comprising carvedilol or a pharmaceutically acceptable salt thereof
It is an object of the invention to provide a process for manufacturing a stable solid oral
dosage form containing carvedilol or a pharmaceutically acceptable salt thereof, which is
packed in the packaging configuration comprising moisture permeation inhibitory
packaging.
It is an object of the invention to provide a method of preparing a pharmaceutical dosage
form, the method comprising encasing a pharmaceutical dosage form comprising
carvedilol or a pharmaceutically acceptable salt thereof in a container essentially
impervious to moisture and comprising a desiccant.
It is an object of the invention to provide a pharmaceutical kit, the pharmaceutical kit
comprising (a) a container impervious to moisture, wherein the container contains a
desiccant, and (b) a pharmaceutical dosage form comprising carvedilol or a
pharmaceutically acceptable salts thereof, wherein the pharmaceutical dosage form is
encased in the container.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to stable solid oral pharmaceutical compositions of
carvedilol or a pharmaceutically acceptable salt thereof.
Carvedilol or a pharmaceutically acceptable salt thereof is preferably carvedilol
phosphate. Carvedilol phosphate is either amorphous or crystalline in nature or mixture
thereof
Stabilization in a package form is provided in order to improve the stability of the solid
dosage form of the present invention at storage or transportation. The stabilization of the
solid dosage form containing carvedilol or a pharmaceutically acceptable salt thereof,

compound of the present invention can be improved by using package form such as
package suppressing the permeation of moisture.
Suitable packaging material comprises a high-density polyethylene (HDPE) container.
The container can additionally contain a desiccant. A desiccant is any drying agent that
removes moisture from the air. Desiccants include, but are not limited to, silica gel, clay
desiccants, calcium sulfate, calcium chloride, calcium oxide, zeolite, activated alumina,
activated charcoal and combinations thereof
The moisture permeation inhibitory packaging is material is preferably
hydroxypropylmethylcellulose (HPMC) based capsule.
The stable solid oral pharmaceutical compositions of the present invention are those
known to a person ordinarily skilled in the art. These may comprises of pellets, beads,
granules, spheroids, mini tablets and capsules. The stable solid oral pharmaceutical
composition of the present invention is a sustained release, controlled release, extended
release, modified release, pulsed release, immediate release dosage form or combination
thereof
Controlled release compositions of carvedilol phosphate are prepared and tested for
related substances by storing in HDPE container with desiccant and without desiccant.
EXAMPLES:
Example 1: Controlled Release Composition of Carvedilol Phosphate
Stage I: Drug Loading

S.No. Name of Ingredient Quantity
(mg)
1 Carvedilol Phosphate 8.0
2 Sugar Spheres NF 190.00
3 Hydroxypropylmethylcellulose 2.6
4 Dichloromethane Q.S.
5 Methanol Q.S.

Prepare a solution of hydroxypropylmethylcellulose & carvedilol phosphate in methanol
and dichloromethane. This solution is sprayed onto sugar spheres.
Stage II: Extended Release Coating

S.No. Name of Ingredient Quantity
(mg)
1 Stage I pellets
2 Ethyl cellulose 10.0
3 Hydroxypropylmethylcellulose 15.0
4 Triethyl citrate 2.5
5 Dichloromethane Q.S.
6 Isopropyl Alcohol Q.S.
Prepare a solution of ethyl cellulose and hydroxypropylmethylcellulose in isopropyl
alcohol, dichloromethane and triethyl citrate. Spray this solution onto pellets of stage I.
Stage III: Immediate Release Drug Loading

S.No. Name of Ingredient Quantity
(mg)
1 Stage II pellets
2 Carvedilol Phosphate 18.0
3 Hydroxypropylmethylcellulose 5.8
4 Dichloromethane Q.S.
5 Methanol Q.S.
Prepare a solution of carvedilol phosphate, hydroxypropylmethylcellulose in
dichloromethane and methanol. Spray this solution onto pellets of stage II.
Stage IV: Enteric Coating

S.No. Name of Ingredient Quantity
(mg)
1 Stage III pellets
2 Hydroxypropylmethylcellulose
phthalate 39.2
3 Triethyl citrate 3.9
4 Dichloromethane Q.S.
5 Isopropyl Alcohol Q.S.
Prepare a solution of hydroxypropylmethylcellulose phthalate in dichloromethane and
isopropyl alcohol. Add triethyl citrate and spray this solution onto pellets of stage III.
Stage V: Immediate Release Drug Loading

S.No. Name of Ingredient Quantity
(mg)
1 Stage IV pellets
2 Carvedilol Phosphate 14.0
3 Hydroxypropylmethylcellulose 4.5
4 Dichloromethane Q.S.
5 Methanol Q.S.
Prepare a solution of carvedilol phosphate and hydroxypropylmethylcellulose in
dichloromethane and methanol. Spray this solution onto pellets of stage IV.
Stage VI: Protective Coating

S.No. Name of Ingredient Quantity
(mg)
1 Stage V pellets
2 Hydroxypropylmethylcellulose 17.9
3 Dichloromethane Q.S.
4 Isopropyl Alcohol Q.S.
Prepare a solution of hydroxypropylmethylcellulose in dichloromethane and isopropyl
alcohol. Spray this solution onto pellets of stage V.
Carry out the assay of pellets to calculate the fill weight. Based on 100% assay, these
pellets are filled into hard gelatin capsules.
Example 2: Controlled Release Composition of Carvedilol Phosphate
Stage I: Drug Loading

S.No. Name of Ingredient Quantity
(mg)
1 Carvedilol Phosphate 80.0
2 Sugar Spheres NF 200.0
3 Povidone 20.0
4 Talc 20
5 Methanol , Q.S.
Dissolve povidone and carvedilol phosphate in methanol. Talc is dispersed in it. Spray
this solution onto sugar spheres.

Stage II: Barrier Coating

S.No. Name of Ingredient Quantity
(mg)
1 Stage I pellets
2 Hydroxypropylmethylcellulose 16.25
3 Triethyl citrate 1.63
4 Methanol Q.S.
Prepare a solution of hydroxypropylmethylcellulose in methanol. Add triethyl citrate and
spray this solution onto pellets of stage I.
Stage III: Enteric Coating

S.No. Name of Ingredient Quantity
(mg)
1 Stage II pellets
2 Eudragit 24.0
3 Hydroxypropylmethylcellulose 10.29
4 Triethyl citrate 3.43
5 Talc 24.0
6 Isoproply Alcohol Q.S.
7 Dichloromethane Q.S.
Disperse eudragit in dichloromethane. Disperse hydroxypropylmethylcellulose in
isopropyl alcohol. These two dispersions are mixed to get a clear solution. Add triethyl
citrate and sprayed onto pellets of stage II.
Carry out the assay of pellets to calculate the fill weight. Based on 100% assay, these
pellets are filled into hard gelatin capsules.
Example 3: Controlled Release Compositions of Carvedilol Phosphate
Stage I: Drug Loading

S.No. Name of Ingredient Quantity
(mg)
1 Carvedilol Phosphate 64.0
2 Sugar Spheres NF 172.00
3 Povidone 16.0
4 Talc 16.0
5 Methanol Q.S.

Dissolve povidone & carvedilol phosphate in methanol and talc is dispersed in it. This
solution is sprayed onto sugar spheres.
Stage II: Barrier Coating

S.No. Name of Ingredient Quantity
(mg)
1 Stage I pellets
2 Hydroxypropylmethylcellulose 13.6
3 Triethyl citrate 1.4
4 Methanol Q.S.
Prepare a solution of Hydroxypropylmethylcellulose in methanol. Add tirethyl citrate to
this solution and sprayed onto the pellets of stage I.
Stage III: Enteric Coating

S.No. Name of Ingredient Quantity
(mg)
1 Stage II pellets
2 Eudragit 20.09
3 Hydroxypropylmethylcellulose 8.61
4 Triethyl citrate 2.87
5 Talc 20.09
6 Dichloromethane Q.S.
7 Isopropyl Alcohol Q.S.
Disperse Hydroxypropylmethylcellulose in isopropyl alcohol. Separately, disperse
eudragit in dichloromethane. Add these two dispersions and stirred to get a clear solution.
Add tirethyl citrate and talc. Spray this solution onto the pellets of stage II.
Stage IV: Barrier Coating

S.No. Name of Ingredient Quantity
(mg)
1 Stage III pellets
2 Hydroxypropylmethylcellulose 16.93
3 Triethyl citrate 1.69
4 Dichloromethane Q.S.
5 Isopropyl Alcohol Q.S.
Prepare a solution of Hydroxypropylmethylcellulose in isopropyl alcohol. Add triethyl
citrate to dichloromethane. Add these solutions and sprayed onto the pellets of stage III.

Stage V: Immediate Release Drug Loading

S.No. Name of Ingredient Quantity
(mg)
1 Stage IV pellets
2 Carvedilol Phosphate 16.0
3 Povidone 4.0
4 Talc 4.0
5 Methanol Q.S.
Dissolve povidone and carvedilol phosphate in methanol. Disperse talc in it and sprayed
onto pellets of stage IV.
Stage VI: Protective Coating

S.No. Name of Ingredient Quantity
(mg)
1 Stage V pellets
2 Hydroxypropylmethylcellulose 19.11
3 Triethyl citrate 1.91
4 Methanol Q.S.
Dissolve Hydroxypropylmethylcellulose in methanol. Add triethyl citrate and spray this
solution onto pellets of stage V.
Carry out the assay of pellets to calculate the fill weight. Based on 100% assay, these
pellets are filled into hydroxpropylmethylcellulose-based capsules.
Extended release compositions of carvedilol phosphate are subjected to stability studies
at 40°C± 2°C & 75± 5 % relative humidity and tested for related substances by storing in
HDPE containers with and without desiccant and the results are enumerated in Tables 1 -
6.
Table 1: Stability Study of Example I by storing in HDPE container without Desiccant
for Related Substances Study (40°C± 2°C & 75± 5 % RH)

Related Substance Initial 2 month
Impurity A BDL BDL
Impurity B 0.040 0.060
Impurity C 0.027 0.049
Impurity D BDL 0.111
Impurity E BDL BDL
Unknown 0.038 0.370
Total Impurity 0.105 0.697

Table 2: Stability Study of Example 1 by storing in HDPE container with 1 g silica as
desiccant for Related Substances Study (40°C± 2°C & 75± 5 % RH)

Related Substance Initial 2 month
Impurity A BDL BDL
Impurity B 0.040 0.061
Impurity C 0.027 0.034
Impurity D BDL 0.035
Impurity E BDL BDL
Unknown 0.038 0.063
Total Impurity 0.105 0.240
Table 3: Stability Study of Example 2 by storing in HDPE container without Desiccant
for Related Substances Study (40°C± 2°C & 75± 5 % RH)

Related Substance Initial 1 month
Impurity A 0.060 0.079
Impurity B 0.012 0.011
Impurity C 0.033 0.078
Impurity D 0.002 0.002
Impurity E BDL BDL
Unknown 0.025 0.048
Total Impurity 0.167 0.345
Table 4: Stability Study of Example 2 by storing in HDPE container with 1 g silica as
desiccant for Related Substances Study (40°C± 2°C & 75± 5 % RH)

Related Substance Initial 1 month
Impurity A 0.060 0.067
Impurity B 0.012 0.013
Impurity C 0.033 0.073
Impurity D 0.002 0.002
Impurity E BDL BDL
Unknown 0.025 0.041
Total Impurity 0.167 0.276
Table 5: Stability Study of Example 3 by storing in HDPE container without Desiccant
for Related Substances Study (40°C± 2°C & 75± 5 % RH)

Related Substance Initial 1 month
Impurity A BDL 0.112
Impurity B 0.010 0.016
10

Impurity C BDL BDL
Impurity D BDL BDL
Impurity E BDL BDL
Unknown 0.045 0.075
Total Impurity 0.084 0.254
Table 6: Stability Study of Example 3 by storing in HDPE container with 1 g silica as
desiccant for Related Substances Study (40°C± 2°C & 75± 5 % RH)

Related Substance Initial 1 month
Impurity A BDL 0.094
Impurity B 0.010 0.014
Impurity C BDL BDL
Impurity D BDL BDL
Impurity E BDL BDL
Unknown 0.045 0.054
Total Impurity 0.084 0.191
The results from Tables 1-6 reveal that suitable moisture permeation inhibitory packaging
materials make the solid oral dosage form of carvedilol phosphate more stable. The total
impurity is high when these solid oral dosage forms are packed in a HDPE container
without desiccant as compared to a HDPE container with desiccant.
Further, the use of HPMC based capsule having low moisture content of 3-8% as
compared to gelatin capsule containing 13-14% moisture makes the solid oral dosage
forms of carvedilol phosphate more stable (Tables 5 & 6).
In another embodiment, the present invention also relates to a process for manufacturing
a stable solid oral dosage form containing carvedilol or a pharmaceutically acceptable salt
thereof, which is packed in the packaging configuration comprising moisture permeation
inhibitory packaging.
In another embodiment, the present invention also relates to a method of preparing a
stable solid oral pharmaceutical dosage form, said method comprising, encasing a
pharmaceutical dosage form comprising carvedilol or pharmaceutically acceptable salt
thereof in a container comprising a desiccant.
11

In another embodiment, the present invention also relates to a pharmaceutical kit
comprising: (a) a container impervious to moisture, wherein said container comprises a
desiccant; and (b) a solid oral pharmaceutical dosage form comprising carvedilol or a
pharmaceutically acceptable salt thereof, wherein said pharmaceutical dosage form is
encased in said container.
12

We Claim:
1. A stable solid oral pharmaceutical composition comprising carvedilol or a
pharmaceutically acceptable salt thereof, which is packed using a suitable
packaging material along with a desiccant.
2. A stable solid oral pharmaceutical composition of claim 1, wherein the
pharmaceutically acceptable salt of carvedilol is carvedilol phosphate.
3. A stable solid oral pharmaceutical composition of claim 2, wherein carvedilol
phosphate is either amorphous or crystalline or mixture thereof
4. A stable solid oral pharmaceutical composition of claim 2, wherein carvedilol
phosphate is amorphous.
5. A process for manufacturing a stable solid oral dosage form containing carvedilol
or a pharmaceutically acceptable salt thereof, which is packed in the packaging
configuration comprising moisture permeation inhibitory packaging.
6. A process for manufacturing a stable solid oral dosage form of claim 5, wherein
the moisture permeation inhibitory packaging is hydroxypropylmethylcellulose-
based capsule.
7. A method of preparing a stable solid oral pharmaceutical dosage form, said
method comprising, encasing a pharmaceutical dosage form comprising
carvedilol or pharmaceutically acceptable salt thereof in a container comprising a
desiccant.
8. A pharmaceutical kit comprising: (a) a container impervious to moisture, wherein
said container comprises a desiccant; and (b) a solid oral pharmaceutical dosage
form comprising carvedilol or a pharmaceutically acceptable salt thereof, wherein
said pharmaceutical dosage form is encased in said container.
9. The stable solid oral pharmaceutical compositions of claim 1, wherein the suitable
packaging material is a high-density polyethylene container.
10. The stable solid oral pharmaceutical compositions of claim 1, wherein the
desiccant is selected from the group comprising silica gel, molecular sieve, clay
desiccants, calcium sulfate, calcium chloride, calcium oxide, zeolite, activated
alumina, activated charcoal and combinations thereof
13

11. The stable solid oral pharmaceutical compositions of claim 1, is in the form of
pellets, beads, granules, spheroids, mini tablets and capsules.
12. The stable solid oral pharmaceutical composition of claim 1, is a sustained
release, controlled release, extended release, modified release, pulsed release,
immediate release dosage form or combination thereof.
Dated this 4* day of March 2008.

Dr. Sanchita Ganguli
of S. Majumdar & Co.
Applicant's Agent
14

A stable solid oral pharmaceutical composition comprising carvedilol or a pharmaceutically acceptable salt thereof, which is packed using a suitable packaging material along with a desiccant. A process for manufacturing a stable solid oral dosage form containing carvedilol or a pharmaceutically acceptable salt thereof, which is packed in the packaging configuration comprising moisture permeation inhibitory packaging. A method of preparing a stable solid oral pharmaceutical dosage form, said method comprising, encasing a pharmaceutical dosage form comprising carvedilol or pharmaceutically acceptable salt thereof in a container comprising a desiccant. A pharmaceutical kit comprising a container impervious to moisture, wherein said container comprises a desiccant; and a solid oral pharmaceutical dosage form comprising carvedilol or a pharmaceutically acceptable salt thereof, wherein said pharmaceutical dosage form is encased in said container