Description:FIELD OF INVENTION
The present invention relates to the field of pharmaceutical dosage form for pediatric and geriatric patients wherein the dosage form is orodispersible film of Carbamazepine.
In particular, the present invention relates to an orodispersible film composition comprising Carbamazepine, which is an anti-epileptic agent for pediatric and geriatric patients. It also relates to its unique process for preparing orodispersible film.
BACKGROUND OF THE INVENTION
Carbamazepine is chemically named as 5 H-dibenz [b,f]azepine-5-carboxamide and its structural formula is:

Carbamazepine (I)
Carbamazepine is a white to off-white powder, partially insoluble in water and soluble in alcohol and in acetone. Its molecular weight is 236.27.
Carbamazepine is a dibenzazepine derivative and it is widely used as anticonvulsant and specific analgesic for trigeminal neuralgia. Tablets and capsules are widely used dosage forms of Carbamazepine for delivery of formulations.
Tegretol® is the registered trademark for Carbamazepine and it is available for oral administration as chewable tablets and suspension. Tegretol® is formulated as chewable tablets to provide 100 mg and 200mg of Carbamazepine. Its suspension provides the 100 mg/5 mL of Carbamazepine. Extended release (XR) tablets of Tegretol® provide 100, 200 and 400 mg of Carbamazepine.
CARBATROL® and EQUETR® are the registered trademarks for extended release (XR) capsule formulation of Carbamazepine with 100, 200 and 300mg strength. Dosage varies person to person as per the age group of the patient.
Walter Schindler et al. in US2948718A; is the first disclosure of the compound Carbamazepine as N-heterocyclic, which is having anti-convulsive activity and therefore is suitable for the use as anti-epileptica.
Paiement et. al. in US10828254B2; disclosed the oral film dosage formulations and processes for preparing oral film dosage forms and more particularly to the preparation of oral film dosage forms that exhibit enhanced bioavailability.
Park et. al. in US9492379B2; disclosed the quickly soluble oral film dosage of Carbamazepine for masking a nasty taste, in particular, a quickly soluble oral film dosage comprising a stevioside based sweetener and a high potency sweetener in a ratio by weight (w/w) of 1:3 to 3:1, which may efficiently mask a bitter or nasty taste of a medicine and may be quickly dissolved in a mouth without water.
Parthasarathy et al. (Asian Pac J Trop Biomed 2013 Dec; 3 (12):995-1002); disclosed the formulation of buccal patches of Carbamazepine and study of permeation through porcine buccal mucosa.
It is noted in the prior arts that Carbamazepine (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 pediatric and geriatric 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 pediatric, 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 pediatric 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 pediatric, 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 Carbamazepine 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 an alternative cost effective oral film formulation of Carbamazepine and processes of making the same, which is not only provide stable pharmaceutical composition but also amenable to scale up for industrial scale.
SUMMARY OF THE INVENTION
In one aspect of present invention, it relates to the composition of an orodispersible film of Carbamazepine.
The composition of an orodispersible film of Carbamazepine according to present invention comprising,
a) a film forming agent selected from hydroxypropyl methylcellulose E-5, polyvinyl pyrollidone k-90 or gelatin in an amount ranging between 30-35% (w/w);
b) a saliva stimulating agent selected from citric acid monohydrate, tartaric acid, ascorbic acid or malic acid in an amount ranging between 2-4% (w/w);
c) a plasticizer selected from polyethylene glycol-400, glycerol or triethyl citrate in an amount ranging between 38-42% (w/w);
d) a sweetening agent selected from sucralose, aspartame or saccharin in an amount ranging between 1-3% (w/w);
e) a solvent selected from acetone, ethanol, isopropyl alcohol, dichloromethane or a mixture thereof; and
f) a flavouring agent selected from mango, raspberry or cherry.
In another aspect of the present invention, it also relates to the unique process for preparing said orodispersible film of Carbamazepine.
Different features of the unique process of preparing said orodispersible film of Carbamazepine according to the present invention are summarized herein below individually.
The unique process for preparing a composition of an orodispersible film of Carbamazepine, wherein said process of preparing pharmaceutical composition comprising the steps of:
a) mixing Carbamazepine, hydroxypropyl methylcellulose E-5 and Isopropylalcohol;
b) mixing dichloromethane into step- a) mixture for a time duration of 5-15 minutes;
c) prepare a solution of sucralose, citric acid monohydrate and colouring agent in ethanol separately;
d) mixing of step- c) solution into step-b) and add polyethylene glycol -400 followed by stirring for a time duration ranging between 10-30 minutes;
e) optionally homogenize the solution and add flavouring agent; and
f) drying the resultant mixture to get the orodispersible 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 orodispersible film of Carbamazepine.
DETAILED DESCRIPTION
As set forth herein, the embodiments of the present invention provide unique pharmaceutical composition of orodispersible film of Carbamazepine. Individual embodiments of the present invention are detailed herein below separately.
In one embodiment according to present invention, it provides a composition of an orodispersible film of Carbamazepine comprising-
a. a film forming agent selected from hydroxypropyl methylcellulose E-5, polyvinyl pyrollidone k-90 or gelatin in an amount ranging between 30-35% (w/w);
b. a saliva stimulating agent selected from citric acid monohydrate, tartaric acid, ascorbic acid or malic acid in an amount ranging between 2-4% (w/w);
c. a plasticizer selected from polyethylene glycol-400, glycerol or triethyl citrate in an amount ranging between 38-42% (w/w);
d. a sweetening agent selected from sucralose, aspartame or saccharin in an amount ranging between 1-3% (w/w);
e. a solvent selected from acetone, ethanol, isopropyl alcohol, dichloromethane or a mixture thereof; and
f. a flavouring agent selected from mango, raspberry or cherry.
Hence, the said composition of an orodispersible film of Carbamazepine; 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 orodispersible film of Carbamazepine is selected from hydroxypropyl methylcellulose E-5 (HPMC E-5), Pullulan, polyvinyl pyrollidone k-90 or gelatine in an amount ranging between 30-35% w/w.
In a particular embodiment, hydroxypropyl methylcellulose E-5 is used, which has shown the excellent mechanical properties for film.
The hydroxypropyl methyl cellulose E-5 is used in an amount ranging between 30-35%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 saliva stimulating agent used in the step b) 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 2-4 %w/w.
In a particular embodiment, the invention provides that the composition of orodispersible film of Carbamazepine 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.
The plasticizer used in the step c) 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 38-42%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 38-42%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.
In a particular embodiment, sweetener used in the pharmaceutical composition is selected from sucralose, aspartame or saccharin in an amount ranging between 1-3 %w/w. Sweetener increases the palatability of the film.
In a particular embodiment the composition of an orodispersible film of Carbamazepine comprising of a solvent is selected from acetone, ethanol, isopropyl alcohol, dichloromethane 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 orodispersible film of Carbamazepine, 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, dichloromethane or a mixture thereof.
In a particular embodiment, it provides to a process for preparing of an orodispersible film of Carbamazepine comprising the steps of:
a. mixing Carbamazepine, hydroxypropyl methylcellulose E-5 and Isopropylalcohol;
b. mixing dichloromethane into step- a) mixture for a time duration of 5-15 minutes;
c. prepare a solution of sucralose, citric acid monohydrate and colouring agent in ethanol separately;
d. mixing of step- c) solution into step-b) and add polyethylene glycol -400 followed by stirring for a time duration ranging between 10-30 minutes;
e. optionally homogenize the solution and add flavouring agent; and
f. drying the resultant mixture to get the orodispersible film.
In an embodiment according to the present invention in step a) mix hydroxypropyl methyl celullose E-5 with Carbamazepine and add isopropyl alcohol in a beaker, in step b) slow mixing of dichloromethane into step a) and continuously stirring until clear solution is not obtained.
According to the present invention of step c) dissolving citric acid monohydrate and colouring agent with sucralose in ethanol separately in a beaker and transfer the ethanolic solution into step b) and mix the resultant solution uniformly.
According to the present invention of step d) add Polyethylene Glycol 400 and flavouring agent into the uniform solution of step c) under properly stirring. Allow it to rest for 5-15 minutes.
According to the present invention of step e) homogenize the above prepared solution of step d) with sonicator for 5-20 minutes.
According to the present invention of step f) 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 3 cm2 of rectangular 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 detail 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
Example 1: Composition of orodispersible film of Carbamazepine
Ingredients Quantity mg/ Unit %w/w of Film
Carbamazepine 100 21.62%
Hydroxypropyl Methylcellulose E-5 156.25 33.78%
Propyl Ethylene Glycol 187.50 40.54%
Citric acid monohydrate 12.50 2.70%
Sucralose 6.25 1.35%
IPA + Ethanol + MDC q.s.
Mix fruit flavour q.s.
Blue lake colour q.s.
Core weight 462.50 100

Manufacturing process of orodispersible film of Carbamazepine comprising the steps of:
a. mix Carbamazepine, hydroxypropyl methylcellulose E-5 and Isopropylalcohol;
b. mix dichloromethane into step- a) mixture for 5-15 minutes;
c. add sucralose, citric acid monohydrate and colouring agent in ethanol separately;
d. mixing of step - c) solution into step-b) and add polyethylene glycol-400 stir for 10-20 minutes;
e. homogenize the solution and add flavouring agent; and
f. drying the resultant mixture to get an orodispersible film.
Example 2: Composition of orodispersible film of Carbamazepine
Ingredients Quantity mg/ Unit %w/w of Film
Carbamazepine 20.00 3.36
Pullulan 156.25 26.26
Propyl Ethylene Glycol-400 137.50 23.10
Citric acid monohydrate 50.00 8.40
Sucralose 25.00 4.20
Purified water q.s.
Orange flavour q.s.
Propylene Glycol 206.25 34.66
Core weight 595.00 100

Manufacturing process of orodispersible film of Carbamazepine comprising the steps of:
a. mix purified water, citric acid monohydrate, sucralose and Pullulan for 5-15 minutes;
b. mix Carbamazepine , propylene glycol and PEG-400;
c. mix step - b) into step - a) mixture
d. add flavouring agent; and
e. drying the resultant mixture to get the orodispersible film.
Evaluation parameters of orodispersible film of Carbamazepine:
1) Organoleptic Properties:
Table 1: Organoleptic Properties
Sr. No. Property Description
1. Description Rectangular shape, smooth surface, orodispersible film
2. Colour Transparent to slightly opaque
3. Odour Characteristic mix fruit
4. Taste Sweet to slightly sour

2) Thickness
Measurements are taken from at least three films from 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 1ml 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 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 stabilizes.
%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 film are removed and weighed after three days.
% Moisture loss = (Initial weight–Final weight)/Initial weight x 100
Table 2: Result of orodispersible film of Carbamazepine (n=3)
S. No. Test Mean ± Standard Deviation

1. Thickness (mm) 0.60±0.004714
2. Weight (g) 0.97±0.012472
3. Surface pH 6.58±0.008164
4. Disintegration Time (min) 2.30±0.3
5. Folding Endurance 174.3±2.494438
6. Swelling Index (%)
(After 2 Hours) 44.1±0.205480
7. Percentage Moisture Uptake (%) 8.57±0.053124
8. Percentage Moisture Loss (%) 12.9±0.471192

In vitro dissolution study
The dissolution study in USP apparatus type-II paddle at 50 RPM for 60 minutes and dissolution medium 900ml of distilled water at 37°C.
Table 03: Dissolution in 900ml of distilled water at 37°C, Paddle II 50 RPM
Time
(Minutes) Cumulative % of Drug Dissolved (100 mg)
10 35.57
20 67.09
30 74.44
45 79.16
60 83.57

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 or quantities used in any manner.
, Claims:We Claim
1. An orodispersible film composition of Carbamazepine comprising:
a. a film forming agent selected from hydroxypropyl methylcellulose E-5, polyvinyl pyrollidone k-90 or gelatin in an amount ranging between 30-35% (w/w);
b. a saliva stimulating agent selected from citric acid monohydrate, tartaric acid, ascorbic acid or malic acid in an amount ranging between 2-4% (w/w);
c. a plasticizer selected from polyethylene glycol-400, glycerol or triethyl citrate in an amount ranging between 38-42% (w/w);
d. a sweetening agent selected from sucralose, aspartame or saccharin in an amount ranging between 1-3% (w/w);
e. a solvent selected from acetone, ethanol, isopropyl alcohol, dichloromethane or a mixture thereof; and
f. a flavouring agent selected from mango, raspberry or cherry.
2. A process for preparing of orodispersible film composition of Carbamazepine comprising the steps of:
a. mixing Carbamazepine, hydroxypropyl methylcellulose E-5 and Isopropylalcohol;
b. mixing dichloromethane into step- a) mixture for a time duration of 5-15 minutes;
c. prepare a solution of sucralose, citric acid monohydrate and colouring agent in ethanol separately;
d. mixing of step- c) solution into step-b) and add polyethylene glycol -400 followed by stirring for a time duration ranging between 10-30 minutes;
e. optionally homogenize the solution and add flavouring agent; and
f. drying the resultant mixture to get the orodispersible film.
3. The process as claimed in claim 2, wherein pharmaceutical composition is film
possessing a thickness ranging between 0.65mm to 0.80mm.
4. The process as claimed in claim 2, wherein the film of Carbamazepine is having active content of 50 to 100 mg.
5. The process as claimed in claim 2, wherein the film of Carbamazepine is having active content of 100 mg in 6 cm2.