FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
AND
THE PATENT RULES, 2003
COMPLETE SPECIFICATION [SECTION 10; RULE 13]
"SOFT CAPSULAR PREPARATION OF ARTEMETHER AND LUMEFANTRINE AND PROCESS TO MANUFACTURE SAME"
APPLICANT: GUJARAT LIQUI PHARMACAPS PVT. LTD., NATIONALITY: AN INDIAN COMPANY INCORPORATED UNDER THE
COMPANIES ACT, 1956.
ADDRESS: PLOT NO.'S 662-666, GIDC, WAGHODIA, VADODARA-391
760, GUJARAT, INDIA
THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED: -

FIELD OF INVENTION:
This invention relates to a soft capsular preparation of Artemether and Lumefantrine and process of manufacturing the said preparation (hereinafter called "the medicament"). The medicament is useful for a treatment of uncomplicated infection with Plasmodium falciparum including strains from multi-drug-resistant Plasmodium falciparum malaria.
BACKGROUND OF THE INVENTION :
Approximately one million children die from malaria each year. Malaria is a leading cause of mortality and morbidity in developing areas of the world, and remains a major health problem in endemic regions. Resistance to available drugs is increasing, thus creating a clear need for new drugs that are well tolerated and simple to use. The use of Artemether-Lumefantrine in the treatment of uncomplicated infections with Plasmodium falciparum is known. However their use alone may result in development of resistance to these life saving drugs. According to the new WHO malaria treatment guidelines, uncomplicated falciparum malaria must be treated with artemisinin combination therapy (ACT) and not by artemisinin alone or any other mono therapy correctly in combination with other anti-malarial drugs is not only effective in curing malaria, but also the parasite is highly unlikely to become drug resistant. Artemether is fast acting drug with a short half-life. Lumefantrine acts slowly and has a longer half-life.

PRIOR ART
In the prior art, the medicament is available in a tablet (solid form). However, as Artemether is sparingly soluble in water and as Lurnefantrine is insoluble in water, the medicament does not dissolve in body fluid easily and efficaciously. Excipients are therefore mixed with and / or added with the medicament. However, excipients which are in liquid form at room temperature cannot be used with the medicament in a tablet form and therefore there is a limitation on the selection of excipients. The excipients which are liquids at room temperature and which are highly desirable for dissolution of a hydrophobic medicament in body fluids cannot be used with the medicament in tablet form. The bioavailability of the medicament in the tablet form is less than the desired limits resulting in a major disadvantage.
PCT/IB2007/052436 describes high dose oral pharmaceutical composition tablet of Artemether and Lurnefantrine for the treatment of malaria. However, in this the consumption of high dosage by a person of low body weight would be harmful. Hence this tablet has limited use and can be recommended only to a person having healthy body weight.
US5968987 describes halofantrine lipids free base in the treatment of malarial infection which are taken as injectables as well as in oral forms. In this case there is single active ingredient (of lurnefantrine group) for the treatment and the parasite becomes resistant after prolonged use of single active ingredient. The WHO however, recommends ACT treatment. Further, intra venous is a painful procedure and also rapture of vein occurs and contamination of blood are not ruled out.

US 6329,552 describes oral tablet containing Artemether and Lumefantrine for the treatment of malaria. In this there are two layers of the tablet having one active ingredient in each layer.
One of the major problems encountered in the above prior art is the lack of desired bioavailability of the medicament in the plasma of the blood. Further, the problem experienced in the above prior art in making the medicament in a tablet form is the selection of the binding agent. It is found that the binding agents have a tendency to bind the medicament powder rather strongly or coercively with the result the complete disintegration of the tablet in body fluids is complicated and difficult with the ageing of the tablet and also liquid excipients cannot be used, as active ingredient being insoluble in nature.
BRIEF DESCRIPTION OF THE INVENTION:-
The present invention obviates the aforesaid drawbacks by proposing to manufacture the medicament in soft gelatin capsules. Soft gelatin capsules are hermetically sealed one piece capsule with a liquid or semisolid fill of the medicament within it. They consist of two major components, the gelatin shell and the medicament which is filled within it. A medicament which is filled within the soft gelatin capsule is in a liquid form. It could be a non aqueous solution or suspension. This invention proposes soft capsular preparation of Artemether and Lumefantrine comprising Artemether 3 to 10 % w/w, Lumefantrine 30 to 60 % w/w, non-aqueous

vehicle 17 to 30 % w/w, preservative less than 1 % w/w, viscosity imparting agent 15 to 30 % w/w, suspending agent 1 to 7 % w/w and emulsifying agent 0.7 to 4 % w/w and a process to manufacture the said preparation comprising of the following steps:
(a) Artemether. Lumefantrine. Preservatives and Solid Suspending Agents are milled and sifted.
(b) Non-aqueous vehicle, viscosity imparting agent and liquid suspending agents are filtered to remove the foreign particles.
(c) (i) Preservatives are dissolved in non-aqueous vehicle ;
(ii) Emulsifying agents are warmed and / or melted and added into
mixture in (i) above;
(iii) Viscosity imparting agent is added to mixture of (ii) above and
the resultant mixture is stirred.
(iv) Suspending agent is added and mixed with the mixture in (iii)
above;and
(v) The mixture of (a) above and (c) (iv) above is homogenized.
(d) The mixture in (v) above is the encapsulated in soft gelatin.

3. PROCESS TO MANUFACTURE THE MEDICAMENT
The problem faced in manufacturing the medicament is interalia in the selection of the excipients. The excepients should not only be harmonious with the medicament but also be compatible with the soft gelatin capsule. With this issue, the present invention proposes to use the following excipients with the medicament.

Sr. No. Excipients Ingredients % w/w
1. Non-aqueous vehicle such as Liquid Paraffin. 17 to 30
2. Known preservatives such as Butylated Hydroxy Toluene and / or Butylated Hydroxy anisole Upto 1% .
3. Viscosity imparting agent like Soya bean oil 15 to 30
4. Suspending Agent like Titanium dioxide 1 to 7
5. Emulsifying agent such as Bees Wax and / or Soya Lecithin and / or Xanthan Gum. 0.7 to 4
Further, according to a preferable embodiment of this invention, the suspending agents are Titanium dioxide and / or Talc and / or Dibasic Calcium Phosphate and / or Sodium Carboxy Methyl Cellulose and / or Simethicone and / or Colloidal Silicon dioxide.

In a preferable embodiment of the invention, the medicament is made in the following manner:-
a) The medicament and some of the solid components of the above excipients

are milled and sifted preferably through 60 to 100 mesh sieve.

b) The excipients which are in the liquid are carfully filtered to remove the

foreign particles.

c) The addition of all the solid and liquid excipients and its final mixing with the medicament is carried preferably in a suitable mixer equipped with planetary movement of its agitators along with high speed homogenizer to ensure proper particle size to achieve micro suspension.
i) The preservatives are added into non aqueous vehicle. If required the
preservative is heated to dissolve into non aqueous vehicle.
ii) Emulsifying agent is melted and added into aforesaid mixture in (i).
iii) Viscosity imparting agent is then added to mixture of (ii) above and the
resultant mixture is stirred at slow speed, for 2 to 10mintes
iv) Suspending agent is added and mixed, with the mixture in (iii) above.
v) The finely powdered medicament is then added to mixture in (iv) above
and the entire mass is homogenized for 10 to 20 minutes in a mixer equipped
with planetary movement of its agitators along with high speed homogenizer.

vi) The mixture in (v) above, in then passed through ultra, micronizer to
obtain the final mixture.
The above medicament is in the form of homogenized liquid micro
suspension.
EXAMPLE:
The preparation according to this invention was made as per the aforesaid procedure but using different combinations of the excipients etc.
The results achieved are given below in tabular form. It only explains/describes the present invention. The following, however, in no way limit the scope of the invention.
Table No. I (Optimized Fill in the Formulation)

Ingredients F1 F2 F3 F4 F5 F6 F7
Artemether 20 mg 20 mg 20 nig 20 mg 20 mg 20 mg 20 mg
Lumefantrine 120 mg 120 mg 120 mg 120 mg 120 mg 120 mg 120mg
Capmul MCM 50% 65% 35% 99.07% - - -
Macrogol 400 49.07 % 34.70% 64.7% - 56.07% - -
Light Liquid Paraffin - - - - 40% 56.07% 40 to 50% of X
Butylated Hydroxy
Toluene 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01 to 0.1% of X

Butyl ated
Hydroxy
Anisole 0.02% 0.02% 0.02% 0.02% 0.02% 0.02%
Soybean Oil - - - - 40% 40 to 50% ofX
Titanium Dioxide - - - - - - 3 to 7% of X
Bees Wax - - - - 5% 3% 2 to 5% of X
Results Unsati sfactor y fill Unsatisfa ctory fill Separat ion of Paste Separat ion of Paste Very hard paste Unsatisfac tory
Suspensio n of Paste, Optimized Paste
In the column F7, 'X' is the total of all the excipients, non-aqueous vehicle, preservative, viscosity imparting agent, suspending agent, emulsifying agent etc. It is thus found that the medicament containing composition in F-7 above is most desirable and efficacious.
II. PROCESS TO MANUFACTURE SOFT GELATIN CAPSULE :
According to this invention, gelatin capsule composition from which soft gelatin capsules are made comprises the following:-

Sr. No. Ingredients % w/w
1. Gelatin 40 to 50
2. Plasttcizers 10 to 25

3. Preservatives 0.05 to 0.5
4. Color As per requirement
5. Purified Water 30 to 45
In a preferable embodiment of this invention, plasticizers comprise of glycerine (2 to 6% w/w), sorbitol (5 to 15 w/w) and polyethylene glycol weight (1 to 5 %w/w)
Further, according to a still preferable embodiment of this invention, preservatives are Methyl paraben and/or Propyl paraben (each of 0.05. to 0.5% w/w).
Gelatin Capsule according to above composition is made as follows:
The process for making the gelatin capsule involves following critical steps:-
1. Bloom strength and gel strength of the gelatin is to be preserved through out
the process.
2. This is possible only when the soaking of the gelatin in the plasticizer and
water mixture is done at a certain temperature followed by warming of soaked mass
at a certain critical temperature.

3. If the soaking and warming temperatures are not religiously controlled the gelatin will loose all its capsule forming properties and the process of encapsulation will be complicated.
4. In a preferable embodiment, according to this invention, the gelatin should be soaked in mixture of purified water and preservative at temperature between 7 to 15°C
EXAMPLE:
The gelatin capsule was made as per the aforesaid procedure but using different combinations of the ingredients. The results achieved are given below in tabular form. The following, however, in no way limits the scope of the invention.
Table No. 2 (Gelatin Shell Compositions)

Sr. No. Ingredients Shell formulae

P1 P2 P3
01. Gelatin 45% 45% 40 to 50%
02. Glycerin (Plasticizer) 20% 3% 2 to 6%
03. Sorbitol (Plasticizer) - 17% 5 to 15%
04. Polyethylene Glycole (Plasticizer) 6% 7% 1 to 5%
05. Methyl Paraben 0.2 0.2 0.05 to 0.5%
06. Propyl Paraben 0.1 0.1 0.05 to 0.5%

07. Colour 0.015% 0.015% As per requirement
08. Purified Water 34.5% 34.24% 30 to 45%
Result Incomplete dissolution Incomplete dissolution Complete dissolution of shell and release of fill content
It was noticed that the complete dissolution of shell and release of fill content was achieved when the gelatin shell composition was as per P-3 above.
Ill - ENCAPSULATION PROCESS
During encapsulation process the following critical parameters need to be adhered to according to this invention.
i) The gelatin mass must have a viscosity between 8000 to 20,000 cps.
ii) The gelatin ribbon which will be created from this mass must have a ribbon thickness ranging from 0.6 to 0.9 mm, preferably 0.7 to 0.8 mm.
iii) The above process is prepared under highly controlled temperature and humidity environment.
Post encapsulation, the solid gelatin capsules are subject to continuous rolling in dehumidifying conditions for a period ranging 30 to 60 hours, preferably 40 to 50 hours.

SYNERGY OF COMPOSITION :
EVALUTION OF THE PRESENT INVENTION
I. LOSS ON DRYING OF THE CAPSULE SHELL
Soft gelatin capsule shells normally contain 6% to 13% of water and the Loss on Drying of the shell was found to be within the limits as depicted in below. Loss on drying: Wt. ofPetri dish=43.1393g
Wt. of Petri dish + 5 empty soft gelatin capsules = 44-7708g Wt. of 5 empty soft gelatin capsules taken = 1.6315 After drying at 105°c for 2 hours;
Wt. of Petri dish +5 empty soft gelatin capsules = 47,643g Wt. of 5 empty soft gelatin capsules = 1.5037g Lossin wt. = 0.1278

II. DISINTEGRATION TEST FOR SOFT GELATIN CAPSULES
Disintegration test determines whether tablets and capsules disintegrate within a prescribed time when placed in an immersion fluid under prescribed experimental conditions. Disintegration is defined as the state in which no residue of the tablet or capsule, except fragments of undissolved coating or capsule shell, remains on the

screen of the test apparatus or, if any other residue remains, it consists of a soft mass having no palpably firm, unmoistened core.
Although there are no official limits specified, ideally a disintegration time within 30 minutes is considered ideal for soft gelatin capsules. The present invention disintegrates within a maximum of about 25 minutes (min) as shown below
Table No: 3 Disintegration Times of the Invented Capsules

Media Temp Soft Soft Soft Soft Soft Soft Avg
gell gel 2 gel 3 gel 4 gel 5 gel 6 DT
Water 37 ± 14 15 13 14 15 14 14.17
2 °C mins mins Mins mins mins mins mins
0.1N 37 ± 12 13 12 12 13 13 12
HCL 2°C mins mins Mins mins mins mins mins
Acetate 37 ± 17 17 18 17 16 17 17
pH4.5 2°C mins mins Mins mins mins mins mins
Phosphate 37 ± 18 20 21 25 22 20 21
pH 6.8 2°C mins mins Mins mins mins mins mins
Modified 37 ± 16 18 21 18 19 21 18
Media 2°C mins mins Mins mins mins mins mins
HI. DISSOLUTION STUDIES OF ARTEMETHER AND LUMEFANTRINE SOFT GELATIN CAPSULES ACCORDING TO THIS INVENTION :
Dissolution testing has become increasingly important in the pharmaceutical industry. Dissolution testing provides information on batch homogeneity and conformity, and is routinely used for quality control purposes. In addition, conclusions about the in vivo behavior of the product can be drawn from its in-vitro dissolution behavior. Therefore, the dissolution test has become an

indispensable tool in the development of new solid oral dosage forms and the assessment of the physical stability of the formulation. For marketed products dissolution data are of great importance to justify variations and can be under certain conditions a waiver for bioavailability studies. To generate reliable dissolution data a careful development of the dissolution test method is required.
Optimization of Media for Dissolution for Lumfantrine

Time
in
min % CDR
(Water with pepsin+ 2% SLS) % CDR (0.1N HCI with pepsin +2% SLS) % CDR
(pH 4.5 Acetate buffer with pepsin+2% SLS) % CDR
(Ph 6.8
phosphate buffer with pepsin +2% SLS) % CDR (0.1 N HCI with 3% Benzalkonium chloride )
0 0.0 0.0 0.0 0.0 0.0
15 68.5 75.5 67.2 75.5 70.7
30 75.6 81.5 73.5 81.5 83.7
45 79.8 84.3 76.0 82.3 88.9
60 87.2 86.8 85.8 84.8 90.7
CDR:- Cumulative Drug Release SLS: - Sodium Lauryl Sulphate

Optimization of Media for Dissolution for Artemether

Time in min % CDR
(Water with pepsin+ 2% SLS) % CDR
(O.IN HCl with pepsin +2% SLS) % CDR
(pH 4.5 Acetate buffer with pepsin +2% SLS) %CDR
(pH 6.8 phosphate buffer with pepsin +2% SLS) % CDR (0.1 N HCl with 3% Benzalkonium chloride)
0 0.0 0.0 . 0.0 0.0 0.0
15 62.4 71.4 70.4 72.6 70.4
30 72.8 80.9 79.6 83.4 85.6
45 80.5 83.6 82.4 86.9 90.5
60 88.9 89.1 87.1 90.1 93.1
COMPARATIVE DISSOLUTION STUDIES OF INVENTED CAPSULE AND TABLET IN PRIOR ART
The dissolution study of the invented capsule and the tablet containing Artemether and Lumefantrine known in the prior art was carried out. The comparative results of dissolution of "Artemether" and "Lumefantrine" were found to be as under.
Report of Dissolution of Artemether
RT Area % of Drug Release
Standard 7.058 1595871 -
Tablet in Prior Art
Sample 30 minutes 7.139 2704 54%

Sample 60 minutes 7.107 4307 87.44%
Sample 90 minutes 7.021 4548 92.33%
Sample 120 minutes 6.949 4610 93.59%
Invented Capsule
Sample 30 minutes 6.927 2410 48.92%
Sample 60 minutes 6.927 3658 74.26%
Sample 90 minutes 6.924 4390 89.12%
Samplel 20 minutes 6.909 4427 94.87%
It may be noted that Peak Inhibitory Concentration (Threshold) of Artemether is at 120 minutes after oral administration.
Report of Dissolution of Lumefantrine
Tablet in Prior Art % of Drug Release
Sample 0 minutes 00
Sample 15 minutes 65.7
Sample 30 minutes 82.8
Sample 45 minutes 90.65
Sample 60 minutes 92.70
Invented Capsule
Sample 0 minutes 0.0
Sample 15 minutes 70.7
Sample 30 minutes 83.7
Sample 45 minutes 88.9
Sample 60 minutes 93.7
It may be noted that Peak Inhibitory Concentration (Threshold) of Lumefantrine is at 60 minutes after oral administration.

STABILITY DATA OF INVENTED CAPSULES:
This includes accelerated stability test and real time stability test.
After complete packaging, a statistically significant number of packed sample of the
present invented capsule were retained for stability studies.
The invented capsule was evaluated under storage conditions (with appropriate tolerances) so as to test its thermal stability and, if applicable, its sensitivity to moisture. The storage conditions and the lengths of studies chosen were sufficient to cover storage, shipment, and subsequent use.
STABILITY STUDY REPORT (REAL TIME)

Name of Product Invented Capsule Batch No GL/10/810
Description of the pack 3x8 capsules Mfg. Date MAY-2010
Test methods As per In house Specification Exp, Date APRIL-2012
Storage Conditions 30°C ± 2°C & RH 75% ±5%
Test Limit Result of analysis

Initial After 3 months After 6 months After 9 months
Description A pink colored, oval shaped, soft gelatin capsule contains yellow paste Complies Complies Complies Complies
Avg. fill wt. 325 mg ± 5 % 330 mg 328 mg 321 mg 318mg
Disintegration time NMT 60 min. 12 min 25 sec 13 min 48 sec 15 min 38
sec 16 min 42 sec
Uniformity of weight To comply with the test as per BP Complies Complies Complies Complies

ASSAY :
Artemether 90% to 110% 96.05 % 95.48% 94.89% 94.23%
Lumefantrine 90% to 110% 96.26% 95.84% 95.23% 95.04%
The results show that there are no significant chemical changes when the product is kept at temperature of 30 ± 2°C & Relative Humidity (RH) 75 %±5 %
STABILITY STUDY REPORT (ACCELERATED)

Name of Product Invented Capsule Batch No GL/10/810
Description of the pack 3x8 capsules Mfg. Date MAY-2010
Test methods As per In house Specification Exp. Date APRIL-2012
Storage Conditions 40°C ± 2°C & RH 75% ± 5%

Test Limit Result of analysis

Initial After 1 month After 2 months After 3 months After 6 months
Description A pink colored, oval shaped, soft gelatin capsule contains yellow paste Complies Complies Complies Complies Complies
Avg. fill wt. 325 mg ± 5 % 330 mg 323 mg 327 mg 320 mg 322 mg
Disintegration time NMT 60 min. 12 min 25 sec 13 min 21 sec 14 min 53 sec 16 min 11 sec 18 min 37 sec
Uniformity of weight To comply with the test as per BP Complies Complies Complies Complies Complies
ASSAY:
Arteinether 90% to 110% 96.05 % 95.67% 94.53% 94.24% 93.89%
Lumefantrine 90% to 110% 96.26% 95.71% 95.20% 94.76% 93.21%

The results show that there are no significant chemical changes when the product is kept at temperature of 40°C ± 2°C & Relative Humidity (RH) 75% ± 5 %.
ADVANTAGES:
1. It is found that the medicament in the form of liquid micro suspension
remains homogenous through out the process of encapsulation. This is so vital
because any kind of heterogeneity will result in non uniform dosage which in turn
will give rise to low concentration or high concentration of medicine in the soft gel
and both such situations are dangerous to the patient especially because both these
drugs are highly potent.
2. A low concentration will result in the organism namely Plasmodium falciparum develop drug resistance and higher concentration wall result in side effects.
3. It is found that more than 85% of Lumefantrine in soft gelatin capsule according to this invention dissolves or mixes with simulated body fluid within a period of 45 minutes which is far above the recommended dissolution parameters. It is also found that more than 65% of Artemether in soft gelatin capsule dissolves or mixes with simulated body fluid within a period of 3 hours as per recommended parameters.
4. Bioavailability of Artemether and Lumefantrine in the invented capsule is, at their respective threshold, higher than the tablet in the prior art.

WE CLAIM :-
1. Soft Capsular preparation of Artemether and Lumefantrine comprising Artemether 3 % to 10 % w/w, Lumefantrine 30 % to 60 % w/w, non-aqueous vehicle 17 % to 30 % w/w, preservative less than 1 % w/w, viscosity imparting agent 15 % to 30 % w/w, suspending agent 1 % to 7 % w/w and emulsifying agent 0.7 % to 4 % w/w. (the medicament).
2. Soft Capsular preparation of Artemether and Lumefantrine claimed in Claim 1 above wherein, Non-aqueous vehicle is liquid paraffin.
3. Soft Capsular preparation of Artemether and Lumefantrine claimed in Claim 1 above wherein preservatives are Butylated Hydroxy Toluene and / or Butylated Hydroxy Anisole and / or Sodium Benzoate and / or Methyl Paraben and / or Propyl Paraben.
4. Soft Capsular preparation of Artemether and Lumefantrine claimed in Claim 1 above wherein, viscosity imparting agent is Edible Oil.
5. Soft Capsular preparation of Artemether and Lumefantrine claimed in Claim 1 above wherein, suspending agent is Titanium dioxide and / or Talc and / or Dibasic Calcium Phosphate and / or Sodium Carboxy Methyl Cellulose and / or Simethicone and / or Colloidal Silicon dioxide.

6. Soft Capsular preparation of Artemether and Lumefantrine claimed in Claim 1 above wherein, emulsifying agent is Bees Wax and / or Soya Lecithin and / or Xanthan Gum.
7. A Process to manufacture preparation claimed in Claims 1 to 6 above comprising the following steps :
a) Artemether, Lumefantrine, Preservatives and Solid
Suspending Agents are milled and sifted.
b) Non-aqueous vehicle, viscosity imparting agent and liquid
suspending agents are filtered to remove the foreign particles.
c) (i) Preservatives are dissolved in non-aqueous vehicle ;
(ii) Emulsifying agents are warmed and / or melted and added
into mixture in (i) above;
(iii) Viscosity imparting agent is added to mixure of (ii) above
and the resultant mixture is stirred.
(iv) Suspending agent is added and mixed with the mixture in
(iii) above; and
(v) The mixture of (a) above and (c) (iv) above is homogenized.
d) The mixture in (v) above is encapsulated in soft gelatin.
8. A Process claimed in Claim 7 above wherein, suspending agent is finely sub-divided before mixing it with the mixture in (c) (iii) above.

9. A Process claimed in Claim 8 above wherein, mixture in (c) (v) above is passed
through ultra micronizer to obtain the particle size of 100 to 200 microns.
10. A Process claimed in Claim 7 to 9 above wherein in step (c) (iii), the resultant
mixture is stirred at slow speed for a period up to 10 minutes.
11.A Process claimed in Claim 7 to 10 above wherein in step (c) (v) the resultant mass is homogenized at high speed for 10 to 20 minutes in a mixer having planetary movement of its agitators.
12. A Process claimed in Claim 1 to 6 above wherein, gelatin shell composition comprises the following:

Sr. No. Ingredients % w/w
1. Gelatin 40 to 50
2. Plasticizers 10 to 25
3. Preservatives 0.05 to 0.5
4. Color As per requirement
5. Purified Water 30 to 45
13. A Process claimed in Claim 12 above wherein, Plasticizers comprises glycerin 2 to 6 % w/w, sorbitol 5 to 15 % w/w and polyethylene glycol of low molecular weight 1 to 5
% w/w.

14. A Process claimed in Claim 12 above wherein,the Preservatives are Methyl paraben and / or Propyl paraben.
15. A Process claimed in Claim 12 above wherein,the Bloom Strength of the Gelatin shell composition is 170 to 180 grams.
16. A Process claimed in Claim 12 above wherein,the Viscosity of the Gelatin shell composition is 8,000 to 20,000 cps.
17. A Process claimed in Claim 12 above wherein, the Gelatin is bovine gelatin of
type A.
18. A process to encapsulate the medicament characterized in that the Gelatin
ribbon thickness of the capsule is between 30 to 36 thou.