Description:FIELD OF THE INVENTION
The present invention relates to the composition of an oral dispersible film of Nifedipine comprising film forming agent, plasticizer, saliva stimulating agent, sweetener, solvent and a flavouring agent.
The invention also relates to the process of preparing an oral dispersible film of Nifedipine, useful in the treatment of hypertension and angina.
BACKGROUND OF THE INVENTION
Nifedipine (I) is chemically named as 3, 5-pyridinedicarboxylic acid, 1, 4-dihydro-2, 6-dimethyl-4-(2-nitrophenyl)-dimethyl ester and its structural formula is:

Nifedipine (I)
It has a molecular weight of 346.3. Nifedipine is a yellow crystalline substance, partially insoluble in water but soluble in ethanol.
Nifedipine is a drug belonging to a class of pharmacological agents known as the calcium channel blockers. Nifedipine is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) which inhibits the trans-membrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The contractile processes of vascular smooth muscle and cardiac muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Nifedipine selectively inhibits calcium ion influx across the cell membrane of vascular smooth muscle and cardiac muscle without altering serum calcium concentrations.
PROCARDIA XL is a registered trademark for Nifedipine GITS tablets. Nifedipine GITS (Gastrointestinal Therapeutic System) Tablet is formulated as a once-a-day controlled-release tablet for oral administration to provide 30, 60, or 90 mg of Nifedipine.
PROCARDIA capsules are formulated as soft gelatin capsules for oral administration, each containing 10 mg Nifedipine.
Friedrich et al. in US3485847; a first disclosure of the compound Nifedipine as 4-Aryl-1, 4-Dihydropyridines, which is useful in the treatment of angina pectoris.
Nadine et al. in US10828254B2 relates to an oral film dosage form includes a high viscosity polymer in an amount of from 1% to 5% by dry weight to reduce, modulate and/or control Cmax of an active agent. The high viscosity polymer has a viscosity of from 100 cps to 500 cps as determined at 2% concentration in water by weight at 25°C using a Brookfield LVF viscometer with spindle no. 2 at 60 rpm.
Lee et al. in US20180000725A1 relates to orally dissolving film of Nifedipine and provide a convenient means of administration and a desirable fast drug action.
Fugate et al. in IN20232102908A relates to the formulation of Nifedipine by using Lepidium sativum (also known as cress seeds) polymer in the form of buccal film for buccal mucoadhesive drug delivery. Cress seed polymer alone and in combination with HPMC shows excellent mucoadhesive property with controlled release of drug. A formulation of Nifedipine by using natural polymer for buccal mucoadhesive drug delivery consists of Nifedipine, a natural polymer, plasticizer, permeation enhancer and solvent.
A few prior arts as non-patent literature have been located viz, Raju et al. (Int. Res J Pharm. App Sci., 2012; 2(6): 18-32) fabricated the buccal mucoadhesive tablets of Nifedipine with the objective of avoiding first-pass metabolism and prolonging the duration of action. In this, Carbopol (cp934), Hydroxyl Propyl Methyl Cellulose (HPMC E15) or/and Sodium Carboxy Methyl Cellulose as mucoadhesive polymers are employed in the formulations (NaCMC).
Chaudhari et al. (IJPSR, 2014; Vol. 5(2): 588-595) investigated the potential of the liquisolid approach and improved the in-vitro dissolving property of the poorly water-soluble Nifedipine. Nifedipine is suspended in PEG 400 along with Avicel PH 102 as a carrier, Aerosil 200 as a coating material and sodium starch glycolate as a disintegrating agent to create various liquisolid tablets.
Usually tablets and capsules are widely used dosage forms of Nifedipine for delivery of formulations.
It is noted in the prior arts that Nifedipine (pharmaceutical active ingredient) has a low bioavailability due to first pass metabolism and/or low water solubility upon oral administration. Apart from this some patients like paediatrics and geriatrics may found difficulty in swallowing them and sometimes also feel fear of chocking. Hence, there is a long felt need of a fast dissolving oral film. Oral dissolving films are the best alternative in comparative to the prior disclosed dosage forms as the oral films can disintegrate or dissolve in the oral cavity without need of water during administration.
Oral dissolving film is designed as a very thin film and gets instantly wet by saliva while placed on the tongue. Subsequently it disintegrates or dissolves once hydrated and release medicaments immediately. It gives fast absorption and thereby early bioavailability of drug due to high surface area, high blood flow and permeability to pre-gastric mucosa. Oral film facilitates drug administration to paediatrics, old age and non-cooperating patients. For better bioavailability it is essential to improve solubility of poorly water soluble drug. After dissolution of oral film in saliva, it moves down towards pharynx then due to swallowing reaches to the region of stomach and simultaneously it also shows absorption in these regions. Thus pre-gastric absorption starts before stomach. Due to this, first pass metabolism is avoided which leads to increase the bioavailability as compared to other dosage forms.
Many geriatric and paediatric patients feel difficulty in swallowing solid dosage forms like tablets or capsules. Therefore, ease of delivery of dosage forms is of paramount importance, especially in emesis like conditions where patients find difficulty to gulp the tablets or capsules.
In the recent years, orally disintegrating drug delivery systems have been developed to resolve these issues. Orally disintegrating tablet (ODT) is an example of this type of drug delivery system, is a solid dosage form that is placed in oral cavity and allowed to disperse in the mouth before swallowing. But ODT products are fragile, friable and water is also required to sallow them. On the other hand, mouth dissolving films resolve these types of issues. This mouth dissolving film dosage form is the thin film of polymer which dissolves rapidly when placed on the tongue which ultimately leads to the improved patient’s compliance.
In order to overcome the patient’s compliance, oral dissolving films provide large surface area that leads to rapid disintegration and dissolution in the oral cavity due to which it promotes the systemic absorption of active pharmaceutical ingredient. The film increases the systemic bioavailability of the drugs, as it bypasses the hepatic first pass metabolism. Drug can be protected from degradation by gastro-intestinal (GI) enzymes and the acidic environment besides, there is rapid onset of action and minimum side effects, easy self- administration, no need of chewing and swallowing and taste masking is possible. It prolongs the residence time of the dosage form at the site of absorption, hence increases the bioavailability. Ease of administration to paediatric, geriatric patients and also to the patients who are mentally retarded, disabled or non-cooperative. Ease of transportation, storage and consumer handling. However, the main limitation of the buccal films is that higher doses may not be incorporated easily, owing to film’s physicochemical, taste masking and other usability concerns.
Despite the successful development of the fast dissolving oral dosage films, there still exists need to work on to minimize the time for the dissolution of the films in the mouth depending on product specific requirements and patients compliance/safety reasons as the fast dissolving oral films can provide an improved absorption profile of the pharmaceutical active agent.
The review of plethora of the Prior arts specific to Nifedipine dosage forms; it appears inadequate to arrive on adequate solution for formulating an oral film dosage form.
In order to overcome the existing drawback in the prior-arts, present inventors have successfully developed the oral film formulation of Nifedipine, which is not only provide stable pharmaceutical composition but also amenable to scale up for industrial scale. .
SUMMARY OF INVENTION
In one aspect of the present invention, it relates to the composition of an oral dispersible film of Nifedipine.
The composition of an oral dispersible film of Nifedipine according to present invention comprising,
a) a film forming agent is selected from hydroxypropyl methylcellulose E-15, pullulan, polyvinyl pyrollidone k-90 or gelatine in an amount ranging between 50-55%w/w;
b) a plasticizer is selected from polyethylene glycol 400, glycerol or triethyl citrate in an amount ranging between 23-28%w/w;
c) a saliva stimulating agent is selected from citric acid monohydrate, tartaric acid, ascorbic acid or malic acid in an amount ranging between 3-4%w/w;
d) a sweetener is selected from sucralose, aspartame or saccharin in an amount ranging between 1-2%w/w;
e) a solvent is selected from acetone, ethanol, isopropyl alcohol, methylene dichloride or a mixture thereof and
f) a flavouring agent is selected from mango, raspberry or cherry.
In another aspect of the present invention, it also relates to the unique process of preparing said oral dispersible film of Nifedipine.
Different features of the unique process of preparing said oral dispersible film of Nifedipine according to the present invention are summarized herein below individually.
The unique process for preparing a composition of an oral dispersible film of Nifedipine, wherein said process of preparing pharmaceutical composition comprising the steps of:
a) mixing of Hydroxypropyl methylcellulose E-15 with Isopropyl alcohol;
b) dissolving Nifedipine in acetone separately;
c) slow mixing of step b) into step a) for 5-15 minutes;
d) dissolving citric acid monohydrate with sucralose in ethanol separately;
e) slow mixing of step d) into step c) and add Polyethylene Glycol 400;
f) sonicate the solution and add flavouring agent for 5-20 minutes and
g) drying the solution to get the oral dispersible film.
Various other specific aspects of the invention are further detailed in the description part of the specification, wherever appropriate.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an illustration of in vitro Dissolution data for Oral dispersible film of Nifedipine.

DETAILED DESCRIPTION
As set forth herein, the embodiments of the present invention provide unique pharmaceutical composition of an Oral dispersible film of Nifedipine. Individual embodiments of the present invention are detailed herein below separately.
In one embodiment according to present invention, it provides a composition of an oral dispersible film of Nifedipine comprising-
a) a film forming agent is selected from hydroxypropyl methylcellulose (HPMC) E-15, Pullulan, polyvinyl pyrollidone k-90 or gelatin in an amount ranging between 50-55% w/w;
b) a plasticizer is selected from polyethylene glycol 400, glycerol or triethyl citrate in an amount ranging between 23-28% w/w;
c) a saliva stimulating agent is selected from citric acid monohydrate, tartaric acid, ascorbic acid or malic acid in an amount ranging between 3-4% w/w;
d) a sweetener is selected from sucralose, aspartame or saccharin in an amount ranging between 1-2% w/w;
e) a solvent is selected from acetone, ethanol, isopropyl alcohol, methylene dichloride or a mixture thereof and
f) a flavouring agent is selected from mango, raspberry or cherry.
Hence, the said composition of an oral dispersible film of Nifedipine comprising of one or more pharmaceutically acceptable excipients used in the preparation of oral film are film forming agent, plasticizer, saliva stimulating agent, sweetener, solvent and flavouring agent.
The film forming agent used in the oral dispersible film of Nifedipine is selected from hydroxypropyl methylcellulose E-15 (HPMC E-15), Pullulan, polyvinyl pyrollidone k-90 or gelatine in an amount ranging between 50-55% w/w.
In a particular embodiment, hydroxypropyl methylcellulose E-15 is used, which has shown the excellent mechanical properties for film.
The hydroxypropyl methyl cellulose E-15 is used in an amount ranging between 50-55 %w/w. However, by exceeding this quantity it is observed to deform the spread ability, consistency and uniformity of the film. The lower range quantity as per the inventor’s observation may provide failures in long term mechanical properties of film.
The plasticizer used in the step b) of the present process are selected from polyethylene glycol 400, glycerol or triethyl citrate and is observed to perform best in an amount ranging between 23-28 %w/w.
As the inventors of the present invention observed that the use of the inappropriate quantity of the plasticizer may lead to cracking, splitting and peeling of the film. It is also reported that the use of the particular plasticizer also affects the absorption rate of the drug.
In a particular embodiment, the plasticizer used is polyethylene glycol 400 in the pharmaceutical composition of the present invention. It is best optimized to be used in an amount ranging between 23-28 %w/w, which shown the improvement in film flexibility and strength. Apart from this, it also reduced the brittleness property of the mouth dissolving/dispersible film.
The saliva stimulating agent used in the step c) of the present process is selected from citric acid monohydrate, tartaric acid, ascorbic acid or malic acid and is optimized in an amount ranging between 3-4 %w/w.
In a particular embodiment, the invention provides that the composition of oral dispersible film of Nifedipine comprising saliva stimulating agent used is citric acid monohydrate. The advantage of the saliva stimulating agent in the pharmaceutical composition of an oral dissolving film is to increase the saliva stimulation to release of saliva for faster disintegration and dissolution of the film.
In a particular embodiment, sweetener used in the pharmaceutical composition is selected from sucralose, aspartame or saccharin in an amount ranging between 1-2 %w/w. Sweetener increases the palatability of the film.
In a particular embodiment the composition of an oral dispersible film of Nifedipine comprising of a solvent is selected from acetone, ethanol, isopropyl alcohol, methylene dichloride or a mixture thereof.
In a particular embodiment, a flavouring agent used in the pharmaceutical composition is selected from mango, raspberry or cherry.
In a particular embodiment, the present invention relates to a composition of oral dispersible film of Nifedipine, wherein said composition comprising solvent casting method is selected among the various conventional methods (i.e. Solvent Casting Method, Hot Melt Extrusion Technique) and solvent is selected as acetone, ethanol, isopropyl alcohol, methylene dichloride or a mixture thereof.
In a particular embodiment, it provides to a process of preparing of an oral dispersible film of Nifedipine comprising the steps of:
a) mixing of Hydroxypropyl methylcellulose E-15 with Isopropyl alcohol;
b) dissolving Nifedipine in acetone separately;
c) slow mixing of step b) into step a) for 5-15 minutes;
d) dissolving citric acid monohydrate with sucralose in ethanol separately;
e) slow mixing of step d) into step c) and add Polyethylene Glycol 400;
f) sonicate the solution and add flavouring agent for 5-20 minutes and
g) drying the solution to get the oral dispersible film.
In an embodiment according to the present invention in step a) mixing of Hydroxypropyl methyl celullose E-15 with Isopropyl alcohol and allowed to swell in a beaker, in step b) of the present invention Nifedipine dissolved in acetone separately in a beaker later on in step c) slow mixing of step b) into step a) for 5-15 minutes and let it rest for 3-8 minutes.
According to the present invention of step d) dissolving citric acid monohydrate with sucralose in ethanol separately in a beaker until clear solution is obtained.
Further according to the present invention of step e) involves the slow mixing of step d) into step c) and stir for 10-15 minutes for uniform mixing of content and add Polyethylene Glycol 400, stir for another 5-15 minutes and then volume is marked up with Methylene dichloride.
According to the present invention of step f) sonicate the prepared solution for 5-20 minutes and add mango flavour and again sonicate for 3-8 minutes.
According to the present invention of step g) poured the prepared solution into petridish that has been greased with glycerin in such a way that no air bubbles comes during pouring and let the solution in air dry for 24 hours. After drying removed the film carefully from the petri dish and cut into 2 x 2 cm2 of square shape films. Wrapped each film with aluminum foil to store the prepared films.
Based on context of discussion, the term "%w/w" refers to the relative value to total weight of granules or to total weight of pharmaceutical composition and “%v/v” refers to volume by total volume percentage.
Certain specific aspects and embodiments of the present application will be explained in more details with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.
EXAMPLES
Examples 1: Composition of oral dispersible film of Nifedipine
INGREDIENTS Quantity mg/ Unit %w/w of Film
Nifedipine 20.00 17.27
HydroxyPropyl Methyl Celullose E-15 60.50 52.24
Polyethylene Glycol 400 29.00 25.03
Citric acid monohydrate 4.32 3.73
Sucralose 2.00 1.73
Acetone + Ethanol + IPA+ MDC q.s
Mango flavour q.s
Core weight 115.82 100

Manufacturing process of oral dispersible film of Nifedipine comprising the steps of:
a) mixing of HydroxyPropyl Methyl Celullose E-15 with Isopropyl alcohol.
b) dissolving Nifedipine in acetone separately.
c) slow mixing of step b) into step a) for 5-15 minutes.
d) dissolving citric acid monohydrate with sucralose in ethanol separately.
e) slow mixing of step d) into step c) and add Polyethylene Glycol 400, stir for 5-15 minutes and markup with Methylene dichloride.
f) sonicate the solution and add Mango Flavour for 5-20 minutes.
g) drying the solution to get the oral dispersible film.

Examples 2: Composition of oral dispersible film of Nifedipine
INGREDIENTS Quantity mg/ Unit %w/w of Film
Nifedipine 30.00 18.31
HydroxyPropyl Methyl Celullose E-15 73.60 44.90
Polyethylene Glycol 400 48.00 29.28
Citric acid monohydrate 8.00 4.88
Sucralose 4.32 2.63
Acetone + Ethanol + IPA+ MDC q.s
Mango flavour q.s
Core weight 163.92 100

Manufacturing process of oral dispersible film of Nifedipine comprising the steps of:
a) mixing of HydroxyPropyl Methyl Celullose E-15 with Isopropyl alcohol.
b) dissolving Nifedipine in acetone separately.
c) slow mixing of step b) into step a) for 5-15 minutes.
d) dissolving citric acid monohydrate with sucralose in ethanol separately.
e) slow mixing of step d) into step c) and add Polyethylene Glycol 400, stir for 5-15 minutes and markup with Methylene dichloride.
f) sonicate the solution and add Mango Flavour for 5-20 minutes.
g) drying the solution to get the oral dispersible film.

Evaluation parameters of oral dispersible film of Nifedipine:
1) Organoleptic properties:
Table 1: Organoleptic properties
Sr. No. Property Description
1. Description Square shaped, smooth oral dispersible film
2. Colour Yellow to light yellow
3. Odour Characteristic mango flavour
4. Taste Sweet to slightly sour

2) Thickness:
Measurement is taken from at least three films from three different location, and the results are given as mean and the standard deviation.
3) Weight:
Weight variability is calculated by weighing them individually on a sensitive scale.
4) Surface pH:
Film is kept in contact with 1 ml of distilled water (pH 6.6±0.2) for 15 minutes at room temperature to allow them to swell. The pH is measured by placing an electrode in contact with the film surface and letting it acclimatize for 1 minute.
5) Disintegration Time:
The film is subjected for disintegration or complete dispersion using disintegration test apparatus in 900 ml water at constant frequency rate between 29 to 32 cycles per minute.
6) Folding Endurance:
The value of folding endurance is determined by to how many times the film could be folded in the same position without breaking or cracking.
7) Swelling Index:
Individually weighted film was kept in a petridish filled with simulated physiological fluid. After then, the film was weighed and periodically checked for weight growth until it stabilises.
%S = [(Xt-Xo)/Xo] x 100
Where, Xt=weight of area of swollen film after time t, and
Xo=original film weight.
8) Percentage Moisture Absorption or Uptake:
Once each sample has been individually weighed, it is placed in desiccators with an aluminium chloride solution and exposed to moisture for three days. The formula below is used to determine the film % moisture absorption capacity once they have been weighed.
% Moisture uptake = (Final weight–Initial weight)/Initial weight x 100
9) Percentage Moisture Loss:
The films are carefully weighed and stored in desiccators with anhydrous calcium chloride. The Films are removed and weighed after three days.
% Moisture loss = (Initial weight–Final weight)/Initial weight x 100
Table 2: Result of Oral dispersible film of Nifedipine (n=3)
S. No. Test Mean ± Standard Deviation

1. Thickness (mm) 0.46±0.009428
2. Weight (g) 0.91±0.026246
3. Surface pH 6.58±0.004714
4. Disintegration Time (min) 2.50±0.002612
5. Folding Endurance
Time 176.6±7.586537
6. Swelling Index (%)
(After 2 Hours) 46.4±0.329983
7. Percentage Moisture Uptake (%) 7.57±0.053124
8. Percentage Moisture Loss (%) 12.23±0.204993

In vitro dissolution study
The dissolution study in USP apparatus II paddle at 100 RPM for 60 minutes and dissolution medium 900ml of 1.2 pH Gastric Fluid With 0.5% SLS at 37°C.

Table 03: Dissolution in 900ml of 1.2 pH Gastric Fluid With 0.5% SLS at 37°C, Paddle II 75 RPM
Time
(Minutes) Cumulative % of Drug Dissolved (20 mg)
Avg. % RSD
5 10.87 15.13
10 21.11 13.60
20 38.96 21.53
30 69.58 2.05
45 91.39 8.16
60 101.07 10.22

The above mentioned examples, which are provided by the way of illustration, should not be constructed as limiting the scope of the invention with respect to parameter/s, ingredient/s and quantities used in any manner.
, Claims:We claim
1. An oral dispersible film of Nifedipine comprising:
a) a film forming agent is selected from hydroxypropyl methylcellulose E-15, pullulan, polyvinyl pyrollidone k-90 or gelatine in an amount ranging between 50-55% w/w;
b) a plasticizer is selected from polyethylene glycol 400, glycerol or triethyl citrate in an amount ranging between 23-28% w/w;
c) a saliva stimulating agent is selected from citric acid monohydrate, tartaric acid, ascorbic acid or malic acid in an amount ranging between 3-4% w/w;
d) a sweetener is selected from sucralose, aspartame or saccharin in an amount ranging between 1-2% w/w;
e) a solvent is selected from acetone, ethanol, isopropyl alcohol, methylene dichloride or a mixture thereof and
f) a flavouring agent is selected from mango, raspberry or cherry.
2. A process for preparing of oral dispersible film of Nifedipine comprising the
steps of:
a) mixing of Hydroxypropyl methylcellulose E-15 with Isopropyl alcohol;
b) dissolving Nifedipine in acetone separately;
c) slow mixing of step b) into step a) for 5-15 minutes;
d) dissolving citric acid monohydrate with sucralose in ethanol separately;
e) slow mixing of step d) into step c) and add Polyethylene Glycol 400;
f) sonicate the solution and add flavouring agent for 5-20 minutes; and
g) drying the solution to get the oral dispersible film.
3. A process as claimed in claim 2, wherein pharmaceutical composition is film with thickness ranging between 0.30 to 0.60 mm.
4. A process as claimed in claim 2, wherein the film of Nifedipine is having active content of 10 to 30 mg.
5. A process as claimed in claim 2, wherein the film of Nifedipine is having active content of 20 mg in 4cm2.