DESC:4. DESCTRIPTION

FIELD OF THE INVENTION

The present invention relates to the field of pharmacology and drug delivery. More specifically it relates to oral dispersible formulations of tadalafil.

BACKGROUND OF THE INVENTION

Oral dispersible drug delivery systems can improve acceptance and compliance in patients with dysphasia. These dispersible films offer several advantages like, convenient dosing, fast disintegration or dissolution followed by quick effect which is desirable in some cases such as pain, no water needed, no risk of choking, enhanced stability, improved patient compliance, difficulties caused from swallowing tablets are circumvented, that is especially advantageous for pediatric and geriatric patients are in diseases with nausea or vomiting.

Oral films are the newer technologies in the manufacturing of orally dispersible dosage forms. They are thin elegant films of edible water-soluble polymers of various sizes and shapes like square, rectangle or disc. The films may be flexible or brittle, opaque or transparent. They are designed to provide rapid disintegration on the tongue without the need for water. Orally dispersible films have a large specific surface area for disintegration. The films alleviate the danger/ fear of chocking, easy to handle and administer, maintain a simple and conventional packaging that is easy to manufacture thus overcoming the short falls of oral fast dispersible tablets.

The immediate dissolution in saliva is due to special matrix made from water soluble polymers it has usually low tack for ease of handling and application. Flexibility and strength of are selected to facilitate manufacturing process and process like rewinding, die cutting and packaging. Oral dispersible films are placed on the patient tongue or any mucosal tissue, which gets instantly wetted by saliva. The strip hydrates and adheres on to the site of application. It then rapidly disintegrates and dissolves to release drug for oral mucosal absorption, or for gastric absorption on swallowing. Dispersible powder forms that dissolve in water/ liquids is also another method of oral drug intake.

Tadalafil is a phosphodiesterase 5 inhibitor, these stop a particular enzyme (phosphodiesterase type 5 [PDE5]) found in blood vessel walls, from working properly. Furthermore, these help control blood flow to the pulmonary arteries and by stopping the PDE5 inhibitor, it causes the blood vessels to relax. In turn these increases the blood flow to the lung helping in decreasing the blood pressure

Tadalafil also helps decrease the smooth cell proliferation which might contribute in the size reduction of prostate and relieves the obstruction that has been anatomically developed which produces urinary symptoms of benign prostatic hyperplasia.

Polyethylene oxide acts as a water-soluble polymer which helps in rapid dispersible of the film with the use of saliva in the oral cavity. Sucralose, mannitol, maltodextrin and peppermint flavoring contributes in providing an edible formulation that is pleasant to consume and to disintegrate in the oral cavity.

The patent WO2012053006A2 relates to an oral film having reduced adherence to oral cavity comprising water-soluble polymer as an essential polymer base in combination with film former for easy drug delivery including tadalafil. The composition and method of preparation of the present invention is different from the abovementioned patent.

The patent EP2698146B1 (ablet Formulations Comprising Tadalafil and Dapoxetine) relates to an oral tablet formulation of dapoxetine, tadalafil, comprising crospovidone and dibasic calcium phosphate. The composition and method of preparation of the abovementioned patent is different from our present invention.

There are many other patents which provide different types of formulations for oral dispersible films. However there still exists a need to develop a formulation and a method for a film which targets on ailments like erectile dysfunction, benign prostatic hyperplasia, and pulmonary arterial hypertension.

OBJECTIVE OF THE INVENTION

The main objective of our present invention is to provide the method of formulation of orally dispersible films of tadalafil.

The second objective of the present invention is to provide easy to administer, easy to use, and effective way of consuming tadalafil.

SUMMARY OF THE INVENTION

The following summary is provided to facilitate a clear understanding of the new features in the disclosed embodiment and it is not intended to be a full, detailed description. A detailed description of all the aspects of the disclosed invention can be understood by reviewing the full specification, the drawing and the claims and the abstract, as a whole.

In one aspect of the present invention, it provides two different formulations with varying ingredients and its proportions which are used in the composition. The method includes adding each ingredient in a container one at a time with constant stirring for about 450-500 RPM.

In another aspect of the present invention is after the addition of the ingredients, a Wet slurry stir is done for 20 min to get uniform dispersion and which is subjected to vacuum degassing to obtain bubble free slurry.

In yet another aspect of the present invention is, the Wet slurry is processed at the parameters of Dr. Knife thickness of 300 to 350 microns with the Temperature 90±3°C in-direct drying for 18 min. The dried casted electrolyte film ready to drink is slit into 25mm x 40mm in 10mg dose and 25mm x 20mm for 20mg dose.

BRIEF DESCRIPTION OF THE DRAWINGS

The manner in which the present invention is formulated is given a more particular description below, briefly summarized above, may be had by reference to the components, some of which is illustrated in the appended drawing It is to be noted; however, that the appended drawing illustrates only typical embodiments of this invention and are therefore should not be considered limiting of its scope, for the system may admit to other equally effective embodiments.

Throughout the drawings, the same drawing reference numerals will be understood to refer to the same elements and features.

The features and advantages of the present invention will become more apparent from the following detailed description a long with the accompanying figures, which forms a part of this application and in which:

Fig 1: Block diagram describing the preparation process of oral dispersible film formulation of tadalafil, in accordance with our present invention;
Fig 2: Block diagram describing the preparation process of oral electrolyte film of tadalafil, in accordance with our present invention;
Fig 3: Graph diagram describing the comparative dissolution profile of one embodiment (oral dispersible film), in accordance with our present invention;
Fig 4 Graph diagram describing the comparative dissolution profile of one embodiment (oral electrolyte film), in accordance with our present invention;

REFERENCE NUMERALS

100 Weighed required quantity of Polyoxyl 40 Hydrogenated Castor Oil in container.
101 Add Weighed quantity of purified water in a container to above step-1 under stirring at 450 RPM for 2min.
102 Add Weighed quantity of sodium lauryl sulphate to above step-2 under stirring at 450 RPM for 2min.
103 Add Weighed quantity of Tadalafil to above step-3 under stirring at 450 RPM for 5min.
104 Add Weighed quantity of sucralose to above step-4 under stirring at 450 RPM for 2min.
105 Add Weighed quantity of maltodextrin to above step-5 under stirring at 500 RPM for 3min.
106 Add Weighed quantity of Polyethylene oxide to above step-6 under stirring at 450 RPM for 5min.
107 Add Weighed quantity of 13% HPMC solution to the above step – 7 under stirring at 500rpm for 10mins.
108 Add Weighed quantity of glycerol to above step-8 under stirring at 500 RPM for 2min.
109 Add Weighed quantity of Triethyl citrate to above step-9 under stirring at 500 RPM for 2min.
110 Add Weighed quantity of Polyethylene Glycol to above step-10 under stirring at 500 RPM for 2min.
111 Add Weighed quantity of Tartrazine to above step-11 under stirring at 500 RPM for 5min.
112 Add Weighed quantity of peppermint Flavour to above step-12 under stirring at 500 RPM for 3 min.
113 Finally, above step- 13 Wet slurry stirred at 500 RPM for 20 min to get uniform dispersion.
114 Above step wet slurry after completion of mixing subjected to vacuum degassing for 15mins to obtain bubble free slurry.
115 Cast the Wet slurry at process parameters of Dr. Knife thickness of 300 to 350 microns; Temperature 90±3°C; In-direct drying for 18 min.
116 Slit the dried cast film into 25mm x 40mm for 20mg dose.
117 Slit the dried cast film into 25mm x 20mm for 10mg dose.
200 Weighed required quantity of Polyoxyl 40 Hydrogenated Castor Oil in container.
201 Add Weigh quantity of purified water in a container to above step-1 under stirring at 450 RPM for 2min.
202 Add Weighed quantity of sodium lauryl sulphate to above step-2 under stirring at 450 RPM for 2min.
203 Add Weighed quantity of tadalafil to above step-3 under stirring at 450 RPM for 5min.
204 Add Weighed quantity of sucralose to above step-4 under stirring at 450 RPM for 2min.
205 Add Weighed quantity of mannitol to above step-5 under stirring at 500 RPM for 3min.
206 Add Weighed quantity of Polyethylene oxide to above step-6 under stirring at 450 RPM for 5min.
207 Add Weighed quantity of 13% HPMC solution to the above step – 7 under stirring at 500rpm for 10mins.
208 Add Weighed quantity of Glycerol to above step under stirring at 500 RPM for 5min.
209 Add Weighed quantity of yellow iron oxide to above step under stirring at 500 RPM for 5min.
210 Add Weighed quantity of peppermint Flavour to above step under stirring at 500 RPM for 3 min.
211 Finally, above step- 12 Wet slurry stirred at 500 RPM for 20 min to get uniform dispersion.
212 Above step wet slurry after completion of mixing subjected to vacuum degassing for 15mins to obtain bubble free slurry.
213 Cast the Wet slurry at process parameters of Dr. Knife thickness of 300 to 350 microns; Temperature 90±3°C; In-direct drying for 18 min.
214 Slit the dried cast film into 25mm x 40mm for 20mg dose and Slit the dried cast film into 25mm x 20mm for 10mg dose.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to orally dispersible formulations of Tadalafil. The formulation consists of tadalafil, sucralose, polyethylene oxide, hydroxypropyl methylcellulose as its key ingredients in the current embodiment of our present invention.

Polyethylene oxide is a water-soluble polymer for the rapid dispersal of the film with the use of saliva in the oral cavity used in one embodiment of our present invention. Flavoring like, but not limited to, sucralose, mannitol, maltodextrin and peppermint provide a pleasant consumption experience for one embodiment of our present invention.

Hydroxypropyl Methylcellulose used comprises 14.33% - 28.65% of the present formulation, which acts a thickening agent. While Polyoxyl 40 hydrogenated castor oil is chosen in one embodiment of our present invention, due to its in-water content, glycerol is one other component that has been used in different formulations, this ingredient acts as plasticizer, a solvent, a humectant or an emollient.

Table 1 showing the ingredients with % values for one embodiment of the formulation
S. No. Ingredients Function %w/w
1 Tadalafil Active 12.5 – 25
2 Sucralose Sweetening Agent 2.89 - 5.76
3 Maltodextrin Diluent 2.89 - 5.76
4 Polyethylene oxide Film forming Agent 1.93 - 3.85
5 Hydroxypropyl Methylcellulose Film forming Agent 14.07 - 28.14
6 Glycerol Plasticizer 2.81 - 5.63
7 Triethyl citrate Plasticizer 1.93 - 3.87
8 Polyethylene Glycol Plasticizer 0.96 - 1.93
9 Polyoxyl 40 Hydrogenated Castor Oil solubilizing agents 3.13 - 6.25
10 Sodium Lauryl Sulphate Solubilizing agents 3.75 - 7.5
11 Tartrazine Colouring Agent 0.03-0.06
12 Peppermint flavour Flavouring Agent 3.13-6.25
13 Purified Water* Vehicle q.s.
Total 100.00%

Formulation for one embodiment of our present invention:

A method of preparation of one embodiment of our present invention, the tadalafil orally dispersible films comprise of the following steps, as shown in fig 1:

* Water gets evaporated during the coating prosses, and traces of water content will remain product
1. Weighed required quantity of Polyoxyl 40 Hydrogenated Castor Oil in container. (100)
2. Add Weigh quantity of purified water in a container to step-1 under stirring at 450 RPM for 2min. (101)
3. Add Weighed quantity of sodium lauryl sulphate to step-2 under stirring at 450 RPM for 2min. (102)
4. Add Weighed quantity of Tadalafil to step-3 under stirring at 450 RPM for 5min. (103)
5. Add Weighed quantity of sucralose to step-4 under stirring at 450 RPM for 2min. (104)
6. Add Weighed quantity of maltodextrin to step-5 under stirring at 500 RPM for 3min. (105)
7. Add Weighed quantity of Polyethylene oxide to step-6 under stirring at 450 RPM for 5min. (107)
8. Add Weighed quantity of 13% HPMC solution to the step – 7 under stirring at 500rpm for 10mins. (108)
9. Add Weighed quantity of glycerol to step-8 under stirring at 500 RPM for 2min. (109)
10. Add Weighed quantity of Triethyl citrate to step-9 under stirring at 500 RPM for 2min. (110)
11. Add Weighed quantity of Polyethylene Glycol to step-10 under stirring at 500 RPM for 2min. (111)
12. Add Weighed quantity of Tartrazine to step-11 under stirring at 500 RPM for 5min. (112)
13. Add Weighed quantity of peppermint Flavour to above step-12 under stirring at 500 RPM for 3 min. (113)
14. Finally, step- 13 Wet slurry stirred at 500 RPM for 20 min to get uniform dispersion. (114)
15. Above step wet slurry after completion of mixing subjected to vacuum degassing for 1mins to obtain bubble free slurry. (115)
16. Cast the Wet slurry at process parameters of Dr. Knife thickness of 300 to 350 microns; Temperature 90±3°C; In-direct drying for 18 min. (117)
17. Slit the dried casted film into 25mm x 40mm for 20mg dose. (118)
18. Slit the dried casted film into 25mm x 20mm for 10mg dose. (118)
The final product of one embodiment of our present invention is thus obtained.
The films thus obtained as one embodiment of our present invention are evaluated for disintegration time, folding endurance, water content Assay as shown in fig 3. The films are subjected to stability study under 40°C ± 2°C and 75% ± 5% RH condition for six months and evaluated below test parameters and results are tabulated.
Sample- 1:
Stability Data
S. No. Test Parameters Limits Results
Initial 1month 3months 6months
1 Disintegrating time NMT 60sec 10 9 9 9
2 Folding Endurance NLT 10 150 150 150 150
3 Water content NMT 12% 4.05 4.96 5.59 6.96
4 Assay 90 – 110% 101.8 100.0 98.1 102.3
5 Dissolution NLT 40% at 10min 94.0 97.0 97.0 96.0
NLT 80% at 30min 100.0 99.0 98.0 97.0
6 Related substances Any secondary peak
(NMT 0.2% w/w) Not Detected Not Detected Not Detected Not Detected
Sum of secondary peaks (NMT 0.3%w/w) Not Detected Not Detected Not Detected Not Detected

Comparative Dissolution (Fig 3):
Comparative Dissolution Profile (media - 0.5% SLS)
Time points % Drug Release
Reference Product- Tablet
(Tazzle 20 mg tablet)
B. No: T2220202 Test Product- Film
B. No: TAD/P/ODS/0007-IPD/014
0 0 0
10 94 94
15 96 100
20 96 100
30 96 100
45 96 101

Comparative Disintegration Time:
Comparative Disintegration Time
N= 6 Reference Product- Tablet
(Tazzle 20 mg tablet) B. No: T2220202 Test Product- Film
B. No: TAD/P/ODS/0007-IPD/014
1 74 sec 10 Sec
2 72 Sec 11 Sec
3 77 Sec 9 Sec
4 81 Sec 8 Sec
5 76 Sec 9 Sec
6 71 Sec 10 Sec
Average: 75 Sec Average: 10 Sec

Another embodiment of our present invention is given below, along with evaluatory results given below:

Table 2: Ingredient list for another embodiment of our present invention
S. No. Ingredients Function %w/w
1 Tadalafil Active 10.42 - 20.83
2 Sucralose Sweetening Agent 3.13 - 6.25
3 Mannitol Diluent 5.10 - 10.20
4 Polyethylene oxide Film forming Agent 2.86 - 5.73
5 Hydroxypropyl Methylcellulose Film forming Agent 14.33 - 28.65
6 Glycerol Plasticizer 2.60 - 5.21
9 Polyoxyl 40 Hydrogenated Castor Oil Solubilizing agents 5.21 - 10.42
10 Sodium Lauryl Sulphate Solubilizing agents 4.17 - 8.33
11 Yellow iron oxide Colouring Agent 0.036 - 0.73
12 Peppermint Flavour Flavouring Agent 1.82 - 3.65
13 Purified Water* Vehicle q.s
Total 100.00%
* Water gets evaporated during the coating prosses, and traces of water content will remain product

Formulation 2
Another embodiment of our present invention, a ready to drink oral electrolyte film is prepared by the following steps, as shown in fig 2:
1. Weighed required quantity of Polyoxyl 40 Hydrogenated Castor Oil in container. (200)
2. Add Weighed quantity of purified water in a container to step-1 under stirring at 450 RPM for 2min. (201)
3. Add Weighed quantity of sodium lauryl sulphate to step-2 under stirring at 450 RPM for 2min. (202)
4. Add Weighed quantity of tadalafil to step-3 under stirring at 450 RPM for 5min. (203)
5. Add Weighed quantity of sucralose to step-4 under stirring at 450 RPM for 2min. (204)
6. Add Weighed quantity of mannitol to step-5 under stirring at 500 RPM for 3min. (205)
7. Add Weighed quantity of Polyethylene oxide to step-6 under stirring at 450 RPM for 5min. (206)
8. Add Weighed quantity of 13% HPMC solution to the step – 7 under stirring at 500rpm for 10mins. (207)
9. Add Weighed quantity of Glycerol to step-8 under stirring at 500 RPM for 5min. (208)
10. Add Weighed quantity of Yellow iron oxide to step-9 under stirring at 500 RPM for 5min. (209)
11. Add Weighed quantity of peppermint Flavour to step-10 under stirring at 500 RPM for 3 min. (210)
12. Finally, step- 11 Wet slurry stirred at 500 RPM for 20 min to get uniform dispersion. (211)
13. Above step wet slurry after completion of mixing subjected to vacuum degassing for 15mins to obtain bubble free slurry. (212)
14. Cast the Wet slurry at process parameters of Dr. Knife thickness of 300 to 350 microns; Temperature 90±3°C; In-direct drying for 18 min. (213)
15. Slit the dried casted film into 25mm x 40mm for 20mg dose and into 25mm x 20mm for 20mg dose. (214)
Thus, the oral electrolyte film version embodiment of our present invention is obtained using the abovesaid formulation. Water gets evaporated during the coating processes and traces of water content will remain product.
This electrolyte formulation embodiment of our present invention is evaluated for disintegration time, folding endurance, water content Assay as shown in fig 4. The films are subjected to stability study under 40°C ± 2°C and 75% ± 5% RH condition for six months and evaluated below test parameters and results are tabulated and given as under sample 2.
Sample- 2:
Stability Data
S. No. Test Parameters Limits Results
Initial 1month 3months 6months
1 Disintegrating time NMT 60sec 10 16 12 15
2 Folding Endurance NLT 10 150 150 150 150
3 Water content NMT 12% 4.1 5.48 5.94 5.65
4 Assay 90 – 110% 99.1 97.9 97.1 97.0
5 Dissolution NLT 40% at 10min 98.0 95.0 97.0 95.0
NLT 80% at 30min 100.0 100.0 98.0 97.0
6 Related substances Any secondary peak
(NMT 0.2% w/w) Not Detected Not Detected Not Detected Not Detected
Sum of secondary peaks (NMT 0.3%w/w) Not Detected Not Detected Not Detected Not Detected

Comparative Dissolution (fig 4):
Comparative Dissolution Profile (Media - 0.5% SLS)
Time points % Drug Release
Reference Product- Tablet
B. No: T2220202 (Tazzle 20 mg tablet) Test Product- Film
B. No: TAD/P/ODS/0007-IPD/012
0 0 0
10 94 98
,CLAIMS:5. CLAIMS:
I/We claim:
1. Oral dispersible strip of Tadalafil comprising:
Tadalafil (Active ingredient) (12.5–25%w/w),
Sucralose (Sweetening Agent) (2.89 - 5.76 %w/w),
Maltodextrin (Diluent) (2.89 - 5.76 %w/w),
Polyethylene oxide (Film forming Agent) (1.93 - 3.85 %w/w),
Hydroxypropyl Methylcellulose (Film forming Agent) (14.07 - 28.14 %w/w),
Glycerol (Plasticizer) (2.81 - 5.63%w/w),
Triethyl citrate (Plasticizer) (1.93 - 3.87%w/w),
Polyethylene Glycol (Plasticizer) (0.96 - 1.93 %w/w),
Polyoxyl 40 Hydrogenated Castor Oil (solubilizing agents) (3.13 - 6.25 %w/w), Sodium Lauryl Sulphate (solubilising agents) (3.75 - 7.5 %w/w),
Tartrazine (Colouring Agent) (0.03-0.06 %w/w),
Peppermint flavour (Flavouring Agent) (3.13-6.25%w/w), and
Purified Water* (Vehicle) (q.s. %w/w)
2. The method of preparation of the orally dispersible strip of tadalafil comprising of the steps:
a. Weighed required quantity of Polyoxyl 40 Hydrogenated Castor Oil in container. (200)
b. Add Weigh quantity of purified water in a container to above step-1 under stirring at 450 RPM for 2min. (201)
c. Add Weighed quantity of sodium lauryl sulphate to above step-2 under stirring at 450 RPM for 2min. (202)
d. Add Weighed quantity of tadalafil to above step-3 under stirring at 450 RPM for 5min. (203)
e. Add Weighed quantity of sucralose to above step-4 under stirring at 450 RPM for 2min. (204)
f. Add Weighed quantity of mannitol to above step-5 under stirring at 500 RPM for 3min. (205)
g. Add Weighed quantity of Polyethylene oxide to above step-6 under stirring at 450 RPM for 5min. (206)
h. Add Weighed quantity of 13% HPMC solution to the above step – 7 under stirring at 500rpm for 10mins. (207)
i. Add Weighed quantity of Glycerol to above step-9 under stirring at 500 RPM for 5min. (208)
j. Add Weighed quantity of yellow iron oxide to above step-10 under stirring at 500 RPM for 5min. (209)
k. Add Weighed quantity of peppermint Flavour to above step-11 under stirring at 500 RPM for 3 min. (210)
l. Finally, above step- 12 Wet slurry stirred at 500 RPM for 20 min to get uniform dispersion. (211)
m. Above step wet slurry after completion of mixing subjected to vacuum degassing for 15mins to obtain bubble free slurry. (212)
n. Cast the Wet slurry at process parameters of Dr. Knife thickness of 300 to 350 microns; Temperature 90±3°C; In-direct drying for 18 min. (213)
o. Slit the dried cast film into 25mm x 40mm for 20mg dose. (214)
p. Slit the dried cast film into 25mm x 20mm for 10mg dose. (214)