Title of Invention

NOVEL MEDICINAL CAPSULES CONTAINING AT LEAST TWO DRUGS HAVING MULTIPLE RELEASE PROFILES METHODS FOR MANUFACTURE THEREOF

Abstract A novel encapsulation process for providing multiple release profile of ingredients and capsules containing at least two drugs with multiple release profile are disclosed.
Full Text FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"NOVEL MEDICINAL CAPSULES CONTAINING AT LEAST TWO DRUGS HAVING MULTIPLE RELEASE PROFILES METHODS FOR
MANUFACTURE THEREOF"
We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956 of "Zydus Tower", Satellite Cross Roads, Ahmedabad - 380 015, Gujarat, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of invention
The present invention relates to a novel medicinal capsule containing at least two drugs having multiple release profiles as well as encapsulation process for providing multiple release profiles of ingredients.
Background of the invention
Filling of liquids into gelatin capsules has been a commercial practice in pharmaceutical manufacturing. The gelatin capsules are either soft gelatin capsules or hard gelatin capsules. However, filling of two layers for achieving different release patterns of the drugs contained therein is not possible with soft gelatin capsules using current technology. Two layered filling for achieving different release patterns of the drugs contained therein has not been reported before using hard gelatin capsules.
Objects of the invention
It is therefore, an important object of the present invention to provide two or more but at least two drugs in a single capsule having identical or multiple release profiles. Summary of the invention
This invention discloses a process for the preparation of a liquid-filled hard gelatin capsule containing two or more layers capable of independently controlling the release of the drugs contained therein. The invention also relates the hard gelatin capsules containing at least two drugs exhibiting multiple release profiles.
The expression "multiple release profile" in the context of the present invention simply means that two or more drugs which may be present in the capsule have their own release profiles which are independent of each other. Such release profile may be sustained release for one and immediate release for the other or immediate release for both or sustained release for both.
The invention is based on the discovery that with judicious manipulation of LabrafH M1944CS, Liquid Paraffin, Bees Wax, Loratadinc, and polyethylene glycol, particularly, PEG 400 and PEG 6000, a gelatin capsule containing at least two drugs with multiple release profiles may be obtained. In other words, the invention relates to a gelatin medicinal capsules containing at least two drugs with the following properties:
1. A combination of release patterns - one layer designed for immediate release of the drug contained therein and the other layer designed for sustained release of the drug contained therein.
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2. Both layers providing sustained release of the drugs contained there in respectively.
3. Both layers providing immediate release of the drugs contained there in respectively.
Thus, according to the present invention, there is provided a medicinal capsule containing at least two drugs having multiple release profiles, said first drug exhibiting immediate release while the second drug exhibiting delayed release said capsule comprising of a bottom layer consisting of said second drug dispersed in mixture of labrafll, liquid paraffin and bees wax and a top layer consisting of said first drug dispersed in a mixture of polyethylene glycol 400 (PEG 400) and polyethylene glycol 400 (PEG 6000).
Preferably, the first drug comprises loratidine and said second drug comprises pseudoephedrine sulfate.
The present invention also provides a method for the manufacture of a medicinal capsule containing at least two drugs having multiple release profiles, said first drug exhibiting immediate release while the second drug exhibiting delayed release said method comprising melting a mixture of labrafll, liquid paraffin and bees wax, adding to said melt said second drug and allowing it to cool, melting a mixture of PEG 400 and PEG 6000, dispersing said first drug in said mixture and allowing it to cool, filling said mixture containing said second drug in a capsule to form a bottom layer containing said second drug and filling the mixture containing said first drug to form a top layer containing said first drug and sealing said capsule.
Preferably, said mixtures are allowed to cool to a temperature of about 37±2^C In another preferred feature, said bottom layer is allowed to cool to room temperature before the addition of said top layer.
Preferably, said capsule is sealed with aqueous gelatin solution.
In another embodiment, the present invention provides a medicinal capsule containing at least two drugs having multiple release profiles, both said drugs exhibiting delayed release said capsule comprising of a bottom layer consisting of said second drug dispersed in mixture of melted hard paraffin and liquid Paraffin and a top layer consisting of said first drug dispersed in propylene glycol.
In yet another embodiment, the present invention provides a medicinal capsule containing at least two drugs having multiple release profiles, both said drugs exhibiting
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delayed release said capsule comprising of a bottom layer consisting of said second drug dispersed in mixture of melted labrafil, liquid paraffin and bees and a top layer consisting of said first drug dispersed in propylene glycol.
Detailed description
The present invention will now be described using two model drugs, pseudoephedirne and loratadine with reference to the accompanying drawings and following examples. In the drawings,
Fig 1. shows the dissolution pattern of Loratidine and Pseudoephedrine, wherein the former exhibits immediate release pattern while the latter exhibits delayed release.
Fig. 2. shows the dissolution pattern of Loratidine and Pseudoephedrine, wherein both the drugs exhibit delayed release profiles.
Fig. 3 shows the dissolution pattern of Loratidine and Pseudoephedrine, wherein both the drugs exhibit delayed release.
Fig. 4. shows the dissolution pattern of Loratidine and Pseudoephedrine, wherein the former exhibits immediate release while the latter exhibits delayed release.
Fig. 5 shows the dissolution pattern of Loratidine and Pseudoephedrine, wherein the former exhibits immediate release while the latter exhibits delayed release.
Fig. 6. shows the dissolution pattern of Loratidine and Pseudoephedrine, wherein the former exhibits immediate release while the latter exhibits delayed release.
Fig. 7 shows the dissolution pattern of Loratidine and Pseudoephedrine, wherein the former exhibits immediate release while the latter exhibits delayed release.
The present invention will now be described with reference to the following Examples using loratidine and pseudoephedrine as two model drugs. It will however, be apparent to a person skilled in the art that the invention will work equally with different drugs.
Example 1
A - Pseudoephedirne Layer
mg/capsule
Pseudoephedrine Sulfate 120 mg
Labrafil M1944CS 40 mg
Liquid Paraffin 175 mg
4

Bees Wax

10 mg

B - Loratadine Layer
Loratadine l0mg
PEG 400 100 mg
PEG 6000 10MG
Total 465 mg
Weighed quantities of labrafil, liquid paraffin and bees wax were transferred into a beaker and melted on a hot water bath. Weighed quantity of pseudoephedrine sulfate was transferred into above mixture and stirred well. The mixture was allowed to cool to
37±2°C. Weighed quantities of PEG 400 and PEG 6000 were transferred in a beaker and melted on a hot water bath. Loratadine was dispersed in the mixture and allowed to cool
to 37±2^C. Pseudoephedrine layer was filled into size 1 capsule and allowed to cool to room temperature. Thereafter, loratadine layer was filled in the capsule. The filled capsule was sealed using aqueous gelatin solution.
Dissolution test : The release of the two drugs was monitored by a dissolution test at 37°C using water as the dissolution and apparatus 1 at 50 RPM.
Results : The dissolution of loratadine was 98.8% in 60 min., as any immediate release formulation and that of pseudoephedrine was 61.4% at 12h as shown in Figure 1.
Example 2
A - Pseudoepnedirne Layer

mg/capsule
Pseudoephedrine Sulfate 180 mg
Liquid Paraffin 342 mg
Hard Paraffin 18 mg
B - Loratadine Layer
Loratadine 10 mg
Polyethylene Glycol 400 100 mg
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Total

650 mg

Weighed quantities of liquid paraffin and hard paraffin were transferred into a glass beaker and melted on a hot water bath. Weighed quantity of pseudoephedrine sulfate was transferred up to the above mixture and stirred well and allowed to cool down to 37 ± 2°C. Loratadine was dispersed in a beaker containing Propylene Glycol and stirred well. Pseudoephedrine layer was filled into a hard gelatin capsule followed by loratadine layer.
Dissolution Test: The release of the two drugs was monitored by a dissolution test at37 C using water as the dissolution medium and apparatus 1 at 50 RPM.
As shown in Fig. 2 only 37.6% of loratadine and 24.5% of pseudoephedrine sulfate were released at the end of 6 h.. This shows that sustained release of both ingredients can be achieved from liquid-filled capsules.
Example 3
mg/capsule
180 mg
175mg
175
10 mg
A - Pseudoephedirne Layer
Pseudoephedrine Sulfate LabrafilM1944CS Liquid Paraffin Bess Wax
B - Loratadine Layer
Loratadine 10 mg
PEG 400 100 mg
Total 650 mg
Weighed quantities of labrafil, liquid paraffin and bees wax were transferred into a glass beaker and melted on a hot water bath. Weighed quantity of pseudoephedrine sulfate was transferred up to the above mixture and stirred well and allowed to cool down to 37 ± 2 C. Loratadine was dispersed in a beaker containing Propylene Glycol and stirred well. Pseudoephedrine layer was filled into a hard gelatin capsule followed by loratadine layer.
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Dissolution test ; The release of the two drugs was monitored by a dissolution test at 37°C using water as the dissolution medium and apparatus 1 at 50 RPM.
The release of both ingredients is sustained as demonstrated in Figure 3. Loratadine release is not 100% in 60min as seen in some other examples and by 6 h it only reaches 74.8%. Pseudoephedrine release after 6h is 55.98%.

Exam Die 4
A - Pseudoephedirne Layer
mg/capsule
Pseudoephedrine Sulfate 120 mg
LabrafilM1944CS 175mg
Liquid Paraffin 175 mg
Bees Wax 10 mg
B - Loratadine Layer
Loratadine 10 mg
PEG 400 100 mg
PEG 6000 10 mg
Total 600 mg
Weighed quantities of labrafil, liquid paraffin and bees wax were transferred into a glass beaker and melted on a hot water bath. Weighed quantity of pseudoephedrine sulfate was transferred up to the above mixture and stirred well and allowed to cool down to 37 ± 2°C. PRG 400 and PEG 6000 were heated in a water bath to melting, Loratadine was dispersed in it and stirred well. The mixture was allowed to cool down to 37 ± 2°C. Pseudoephedrine layer was filled into a hard gelatin capsule followed by loratadine layer.
Dissolution test : The release of the two drugs was monitored by a dissolution test at 37 C using water as the dissolution medium and apparatus 1 at 50 RPM.
Results : The dissolution of loratadine from this formula is 98% in 60 min., typical of immediate release formulations. Pseudoephedrine release was drastically reduced, less than 20% of the drug of the drug in 6h as shown in Figure 4.
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Example 5
A - Pseudoephedirne Layer
mg/capsule
Pseudoephedrine Sulfate 120 mg
Labrafil Ml 944 CS 75mg
Liquid Paraffin 175 mg
Bees Wax l0mg
B - Loratadine Layer
Loratadine 10 mg
PEG 400 100 mg
PEG 6000 10 mg
Total 500 mg
Weighed quantities of labrafil, liquid paraffin and bees wax were transferred into a glass beaker and melted them on a hot water bath. Weighed quantity of pseudoephedrine Sulfate was transferred up to the above mixture and stirred well and allowed to cool down to 37 ± 2°C. PEG 400 and PEG 6000 were heated in a water bath to melting, Loratadine was dispersed in it and stirred well. The mixture was allowed to cool down to 37 ± 2°C. Pseudoephedrine layer was filled into a hard gelatin capsule followed by loratadine layer.
Dissolution test : The release of the two drugs was monitored by a dissolution test at 37 C using water as the dissolution medium and apparatus 1 at 50 RPM.
Results : In dissolution of loratadine was found to be 92.1% in 60 min., again typical of immediate release formulations. Pseudoephedrine release is 27.5% by 12h as shown in Figure 5.
Example 6
A - Pseudoephedirne Layer
mg/ capsule
Pseudoephedrine Sulfate 120 mg
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LabrafilM1944CS 25mg
Liquid Paraffin 175 mg
Bees Wax 10 mg
B - Loratadine Layer
Loratadine 10 mg
PEG 400 100 mg
PEG 6000 10 mg
Total 450 mg
Weighed quantities of labrafil, liquid paraffin and bees wax were transferred into a glass beaker and melted on a hot water bath. Weighed quantity of pseudoephedrine sulfate was transferred up to the above mixture and stirred well and allowed to cool down to 37 ± 2°C. In a water bath, PEG 400 and PEG 6000 were heated to melting. Loratadine was dispersed in it and stirred well. The mixture was allowed to cool down to 37 ± 2°C. Pseudoephedrine layer was filled into a hard gelatin capsule followed by loratadine layer.
Dissolution test : The release of the two drugs was monitored by a dissolution test at 37°C using water as the dissolution medium and apparatus 1 at 50 RPM
Results : The dissolution results showed that loratadine release was 97.4% in 60 min. Pseudoephedrine release was 43.8% after lh and 82.2% after 6h as shown in Figure 6.
Example 7
A - Pseudoephedirne Layer

mg/capsule
Pseudoephedrine Sulfate 120 mg
Labrafil M1944CS 40 mg
Liquid Paraffin 175 mg
Bess Wax 10 mg
B - Loratadine Layer
Loratadine 10 mg

PEG 400 100 mg
PEG 6000 l0mg
Total 465 mg
Weighed quantities of labrafll, liquid paraffin and bees wax were transferred into a glass beaker and melted on a hot water bath. Weighed quantity of pseudoephedrine sulfate was transferred up to the above mixture and stirred well and allowed to cool down to 37 ± 2°C. In. a water bath, PEG 400 and PEG 6000 were heated to melting, followed by dispersion therein of loratadine. The mixture was stirred well and allowed to cool down to 37 ± 2 C. Pseudoephedrine layer was filled into a hard gelatin capsule followed by Loratadine layer.
Dissolution test : The release of the two drugs was monitored by a dissolution test at 37 C using water as the dissolution medium and apparatus 1 at 50 RPM.
Results : The dissolution results showed that loratadine release was 98.7% in 60 min. Pseudoephedrine release was 79.2% after 24h as shown in Figure 7
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We claim:
1. A medicinal capsule containing at least two drugs having multiple release profiles, said first drug exhibiting immediate release while the second drug exhibiting delayed release said capsule comprising of a bottom layer consisting of said second drug dispersed in mixture of labrafil, liquid paraffin and bees wax and a top layer consisting of said first drug dispersed in a mixture of polyethylene glycol 400 (PEG 400) and polyethylene glycol 400 (PEG 6000).
2. A medicinal capsule as claimed in claim 1 wherein said first drug comprises loratidine and said second drug comprises pseudoephedrine sulfate.
3. A method for the manufacture of a medicinal capsule containing at least two drugs as claimed in claim 1 or 2 which comprises melting a mixture of labrafil, liquid paraffin and bees wax, adding to said melt said second drug and allowing it to cool, melting a mixture of PEG 400 and PEG 6000, dispersing said first drug in said mixture and allowing it to cool, filling said mixture containing said second drug in a capsule to form a bottom layer containing said second drug and filling the mixture containing said first drug to form a top layer containing said first drug and sealing said capsule.
4. A method as claimed in claim 3 wherein said mixtures are allowed to cool to a temperature of about 37±2°C.
5. A method as claimed in claim 3 or 4 wherein said bottom layer is allowed to cool to
room temperature before the addition of said top layer.
6. A method as claimed in any one of claims 3 to 5 wherein said capsule is sealed with aqueous gelatin solution.
7. A medicinal capsule containing at least two drugs having multiple release profiles, both said drugs exhibiting delayed release said capsule comprising of a bottom layer consisting of said second drug dispersed in mixture of melted hard paraffin and liquid paraffin and a top layer consisting of said first drug dispersed in propylene glycol.
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8. A medicinal capsule as claimed in claim 1 wherein said first drug comprises loratidine and said second drug comprises pseudoephedrine sulfate.
9. A method for the manufacture of a medicinal capsule containing at least two drugs as claimed in claim 7 or 8 which comprises melting a mixture of hard paraffin and liquid paraffin, adding to said melt said second drug and allowing it to cool, dispersing said first drug in propylene glycol, filling said mixture containing said second drug in a capsule to form a bottom layer containing said second drug and filling the mixture containing said first drug to form a top layer containing said first drug and sealing said capsule.
10. A method as claimed in claim 9 wherein said mixture is allowed to cool to a temperature of about 37±2^C.
11. A method as claimed in claim 9 or 10 wherein said bottom layer is allowed to cool to
room temperature before the addition of said top layer.
12. A method as claimed in any one of claims 9 to 11 wherein said capsule is sealed with aqueous gelatin solution.
13. A medicinal capsule containing at least two drugs having multiple release profiles, both said drugs exhibiting delayed release said capsule comprising of a bottom layer consisting of said second drug dispersed in mixture of melted labrafil, liquid paraffin and bees and a top layer consisting of said first drug dispersed in propylene glycol.
14. A medicinal capsule as claimed in claim 1 wherein said first drug comprises loratidine and said second drug comprises pseudoephedrine sulfate.
15. A method for the manufacture of a medicinal capsule containing at least two drugs as claimed in claim 13 or 14 which comprises melting a mixture of labrafil, liquid paraffin and bees wax, adding to said melt said second drug and allowing it to cool, dispersing said first drug in propylene glycol, filling said mixture containing said second drug in a capsule to form a bottom layer containing said second drug and
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filling the mixture containing said first drug to form a top layer containing said first drug and sealing said capsule.
16. A method as claimed in claim 15 wherein said mixture is allowed to cool to a temperature of about 37±2°C.
17. A method as claimed in claim 15 or 16 wherein said bottom layer is allowed to cool to room temperature before the addition of said top layer.
18. A method as claimed in any one of claims 15 to 17 wherein said capsule is sealed with aqueous gelatin solution.
19. A medicinal capsule containing at least two drugs having multiple release profiles substantially as herein described with reference to the foregoing examples.
20. A method for the manufacture of a medicinal capsule containing at least two drugs having multiple release profiles substantially as herein described with reference to the foregoing examples.

ABSTRACT
A novel encapsulation process for providing multiple release profiles of ingredients and capsules containing at least two drugs with multiple release profiles are disclosed.

Documents:

314-mum-2006-abstract(06-03-2006).pdf

314-mum-2006-abstract-(6-3-2006).doc

314-mum-2006-abstract.doc

314-mum-2006-abstract.pdf

314-mum-2006-cancelled page(06-03-2006).pdf

314-mum-2006-claim(granted)-(06-03-2006).pdf

314-mum-2006-claims(granted)-(6-3-2006).doc

314-mum-2006-claims.doc

314-mum-2006-claims.pdf

314-mum-2006-correspondence(21-04-2008).pdf

314-mum-2006-correspondence(ipo)-(04-07-2008).pdf

314-mum-2006-correspondence-received.pdf

314-mum-2006-description (complete).pdf

314-mum-2006-drawing(06-03-2006).pdf

314-mum-2006-drawings.pdf

314-mum-2006-form 1(06-03-2006).pdf

314-mum-2006-form 1(11-08-2006).pdf

314-mum-2006-form 18(11-08-2006).pdf

314-mum-2006-form 2(granted)-(06-03-2006).pdf

314-mum-2006-form 2(granted)-(6-3-2006).doc

314-mum-2006-form 3(06-03-2006).pdf

314-mum-2006-form 5(06-03-2006).pdf

314-mum-2006-form-1.pdf

314-mum-2006-form-2.doc

314-mum-2006-form-2.pdf

314-mum-2006-form-26.pdf

314-mum-2006-form-3.pdf

314-mum-2006-form-5.pdf

314-mum-2006-power of attorney(06-03-2006).pdf

abstract 1.jpg

abstract1.jpg


Patent Number 222065
Indian Patent Application Number 314/MUM/2006
PG Journal Number 40/2008
Publication Date 03-Oct-2008
Grant Date 16-Jul-2008
Date of Filing 06-Mar-2006
Name of Patentee CADILA HEALTHCARE LIMITED
Applicant Address ZYDUS TOWER, SATELLITE CROSS ROADS, AHMEDABAD - 380 015,
Inventors:
# Inventor's Name Inventor's Address
1 VENKATARAM SURESH CADILA HEALTHCARE LIMITED, OF R&D CENTRE, 2/2 SOUTHCROSS ROAD, BASAVANAGUDI BANGALORE 560 004
PCT International Classification Number A61K35/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA