Fast Dissolving Oral Films of Pramipexole HCl monohydrate: Preparation and in vitro evaluation

 

A. Srinivas1, D.V.R.N.Bhikshapathi2*

1Research Scholar, Mewar University, Chittorgarh, Rajasthan, India

2Research Supervisor, Mewar University, Chittorgarh, Rajasthan, India

*Corresponding Author E-mail: dbpathi71@gmail.com

 

ABSTRACT:

Pramipexole (2-amino- 4, 5, 6, 7-tetrahydro-6-propylaminobenzthiazole- dihydrochloride) is a novel, highly active, full dopamine receptor agonist used in the treatment of Parkinson’s disease (PD). Present work aimed at preparing quick onset of action which is beneficial in (PD), aiding in the enhancement of bioavailabity and is very convenient for administration without the problem of swallowing and using water. Pramipexole HCl mouth dissolving films of 27 formulations were prepared by solvent casting method using 33 response surface method where 33 indicates 3 variables and 3 levels of polymers (HPMC E15, Kollidon 30) of different grades and plasticizer (Propylene Glycol) (low, middle and high concentrations) by using Design of experiment software. Among the prepared formulations PF24 showed minimum disintegration time 10 sec, maximum drug was released i.e. 99.21±1.87% of drug within 10 min when compared to the other formulations and finalized as optimized formulation. FTIR and SEM data revealed that no interactions takes place between the drug and polymers used in the optimized formulation. The in vitro dissolution profiles of marketed product and optimized formulation was compared and found to be the drug released was 93.78±1.53 after 50 min. Therefore it can be a good alternative to conventional Pramipexole HCl for immediate action. In vitro evaluation of the Pramipexole HCl fast dissolving films confirmed their potential as an innovative dosage form to improve delivery and quick onset of action of Pramipexole HCl for the treatment of Parkinson’s disease where the quick onset of action is desired, also improved patient compliance.

 

KEYWORDS: Pramipexole HCl monohydrate, fast dissolving oral films, disintegration time, Kollidon 30.

 


INTRODUCTION:

The main aim of any drug delivery system is the successful delivery of the drug, in which almost 90% of the drugs are administered to the body for the treatment of various disorders and diseases as it is regarded as the safest, most convenient and most economical method of drug delivery having the highest patient compliance [1,2,3]. About 60% of all dosage forms available are the oral solid dosage form. The lower bioavailability, long onset time and dysphagia patients turned the manufacturer to the parenterals and liquid orals. But the liquid orals have the problem of accurate dosing mainly and parenterals are painful drug delivery, so most patient incompliance.

 

Each pharmaceutical company wants to formulate the novel oral dosage form which has the higher bioavailability, quick action and most patient compliance [4]. Many pharmaceutical companies have directed their research activity in reformulating existing drugs into new dosage forms. One such relatively new dosage form is the oral strip, a thin film that is prepared using hydrophilic polymers that rapidly dissolves on the tongue or buccal cavity[5, 6].

 

Fast dissolving drug delivery system is easy to administer and provides better patient compliance in the elderly, pediatric, mentally retarded, nauseated and uncooperative patients[7]. This delivery system consists of the solid dosage forms that dissolve quickly i.e. within a matter of seconds in the oral cavity without the administration of water. The delivery system consists of a very thin oral strip which is simply placed on the patient’s tongue or any other oral mucosal tissue and instantly gets wetted by saliva[8]. The film rapidly hydrates onto the site of application. It then rapidly dissolves and disintegrates to release the medication for oro-mucosal absorption. Fast dissolving oral thin films are widely accepted by patients and also to the caregiver for their ease-of-delivery, portability and accurate dosing[9]. They also provide quick onset of action within few seconds as the oro-mucosal absorption of drug occurs directly from the site of administration to the systemic circulation avoiding first pass metabolism to produce the desired effect[10].

 

Rapidly dissolving films (RDF) were initially introduced in the market as breath fresheners and personal care products such as dental care strips and soap strips. However, these dosage forms are introduced in the United States and European pharmaceutical markets for therapeutic benefits. The first of the kind of oral strips (OS) were developed by the major pharmaceutical company Pfizer who named it as Listerine® pocket packs™ and were used for mouth freshening [11].

 

Pramipexole (2-amino- 4, 5, 6, 7-tetrahydro-6-propylaminobenzthiazole- dihydrochloride) is a novel, highly active, full dopamine receptor agonist which acts on the D2 receptor family with a preferential affinity for the D3 type14, 15. Pramipexole antagonizes the reserpine induced akinesia and neuroleptic-induced catalepsy. The above data show that due to stimulation of dopamine D2 postsynaptic receptors, pramipexole appears to have a high antiparkinsonian potential. It has been investigated as a monotherapy in the treatment of PD [12].

 

Fast dissolving oral films are the novel approach in oral drug delivery systems. It promises patient compliance especially in case of pediatrics and geriatrics patients. They can also be used when quick action is required. They possess many advantages over conventional dosage form and can also be used in cases of dysphagia, Parkinson's disease, mucositis or vomiting [13].

 

The present study is aim to formulate and characterize the fast dissolving oral films of Pramipexole HCl monohydrate by solvent casting method for rapid onset of action in the management of Parkinson’s disease and also to improve the bioavailability of the drug.

 

MATERIALS AND METHODS:

Materials:

Pramipexole HCl monohydrate pure drug was generous gift from Aurobindo Pharma Limited, Hyderabad, India.  Hydroxy Propyl Methyl Cellulose (E 50) was received by Nectar life sciences, Hyderabad, Kollidon 30, Propylene glycol, mannitol and Aspartame was gifted from MSN Labs, Hyderabad. Pineapple flavor was purchased from SD FINE CHEM LTD, Mumbai. All other chemicals used were of analytical grade.


 

Table 1: Formulation of fast dissolving oral films containing Pramipexole HCl

F.NO

Pramipexole HCl (mg)

HPMC

E 50 (mg)

Kollidon 30 (mg)

Propylene Glycol

(ml)

Mannitol

(mg)

Aspartame

(mg)

Pine apple Flavor (ml)

Water

(ml)

PF1

8

150

120

60

40

20

0.1

Q.S

PF2

8

150

140

60

40

20

0.1

Q.S

PF3

8

125

120

30

40

20

0.1

Q.S

PF4

8

100

120

80

40

20

0.1

Q.S

PF5

8

150

120

60

40

20

0.1

Q.S

PF6

8

125

160

60

40

20

0.1

Q.S

PF7

8

125

120

100

40

20

0.1

Q.S

PF8

8

125

160

100

40

20

0.1

Q.S

PF9

8

150

120

100

40

20

0.1

Q.S

PF10

8

150

160

80

40

20

0.1

Q.S

PF11

8

100

140

60

40

20

0.1

Q.S

PF12

8

100

140

100

40

20

0.1

Q.S

PF13

8

150

140

80

40

20

0.1

Q.S

PF14

8

125

140

80

40

20

0.1

Q.S

PF15

8

100

140

80

40

20

0.1

Q.S

PF16

8

100

140

60

40

20

0.1

Q.S

PF17

8

150

140

60

40

20

0.1

Q.S

PF18

8

125

140

100

40

20

0.1

Q.S

PF19

8

150

160

60

40

20

0.1

Q.S

PF20

8

150

140

100

40

20

0.1

Q.S

PF21

8

150

160

80

40

20

0.1

Q.S

PF22

8

125

160

60

40

20

0.1

Q.S

PF23

8

100

160

100

40

20

0.1

Q.S

PF24

8

125

145

60

40

20

0.1

Q.S

PF25

8

125

160

80

40

20

0.1

Q.S

PF26

8

125

120

80

40

20

0.1

Q.S

PF27

8

125

140

80

40

20

0.1

Q.S

 


Formulation and development of fast dissolving film [14]:

Procedure:

Fast dissolving oral films of Pramipexole HCl monohydrate were prepared by the solvent casting method. The water soluble polymers were soaked in half quantity of distilled water for overnight to obtain a uniform dispersion. Aqueous solution I was prepared by adding plasticizer to above polymeric solution and was allowed to stir for 4 hours and kept for 1 hour to remove all the air bubbles entrapped. Aqueous solution II was prepared by dissolving the Pramipexole HCl monohydrate, Mannitol, aspartame in specific proportion in remaining amount of distilled water.

 

Both aqueous solutions I and II were mixed and stirred for 1 hour and kept for 30min for sonication. Then the mixture solution was casted onto a plastic Petri dish having surface area of 63.642cm2 and it was dried in the oven at 500C for 24 hour. The film was carefully removed from the Petri dish, checked for any imperfections, and cut according to the size required for testing (2×2 cm2).

 

Response surface methodology [15]:

Twenty seven formulations (F1-F27) were prepared by solvent casting method using 33 response surface method  where 33 indicates 3 variables and 3 levels of polymers (HPMC E50, Kollidon 30) of different grades and plasticizer (Propylene Glycol) (low, middle and high concentrations) by using Design of experiment software. The composition of the films for 16 doses (each dose is 0.5mg of Pramipexole HCl monohydrate) are mentioned in the Table 1.

 

Evaluation of films:

Thickness uniformity [16]:

The thickness of the patch was measured using digital Vernier Calliper with a least count of 0.01 mm. The thickness was measured at different strategic points of the film and average was taken and SD was calculated.

 

Weight uniformity [17]:

Weight variation is studied by individually weighing randomly selected films and calculating the average weight. And standard deviation was calculated.

 

Drug Content uniformity [18]:

Drug content determination of the film was carried out by dissolving the films of required size in pH 6.8 phosphate buffer using magnetic stirrer for 1hour. The drug concentration was then evaluated spectrophotometrically at λmax of 268 nm. The determination was carried out five times for all the formulations and average with standard deviation was recorded.

Folding endurance [19]:

Folding endurance was determined by repeated folding of the film at the same place till the strip breaks. The number of times the film is folded without breaking was computed as the folding endurance value.

 

Surface pH of film [20]:

The pH was determined by dissolving a film in 2 ml of pH 6.8 phosphate buffer and then the pH of the obtained solution was measured by pH meter. The average of three determinations for each formulation was done.

 

Tensile strength [21]:

Tensile strength is the maximum stress applied to a point at which the strip specimen breaks. Film strip of dimension 2 × 2 cm2 and free from air bubbles or physical imperfections was held between two clamps positioned at a distance of 3 cm apart. A cardboard was attached on the surface of the clamp via a double sided tape to prevent the film from being cut by the grooves of the clamp. During measurement, the strips were pulled at the bottom clamp by adding weights in pan till the film breaks. The force was measured when the films broke.  It is calculated by the applied load at rupture divided by the cross-sectional area of the strip as given in the equation below:

                                                 Load at Failure

Tensile strength (gm)  =   -----------------------------------

                                         Strip thickness X Strip Width

 

In vitro Disintegration Time [22]:

The film size required for dose delivery (2X2 cm2) was placed on a glass Petri dish containing 10 ml of pH 6.8 phosphate buffer. The time required for the film to break was noted as in vitro disintegration time.

 

In vitro drug release studies [23]:

Dissolution profile of Fast dissolving oral films of Pramipexole HCl monohydrate was carried out in a beaker containing 30ml of the stimulated salivary fluid pH (6.8) as a dissolution medium, maintained at 37±5ºC.The medium was stirred at 100rpm.Aliquotes of the medium were withdrawn at regular intervals of 1 min. And the same amount was replaced with fresh medium. Samples were analyzed for cumulative percentage drug release spectrophotometrically at 268nm. Three trials were carried out for all the samples and average was taken.

 

Introduction to Design of Experiments (DOE)[24, 25]:

DOE is an essential piece of the reliability program pie. It plays an important role in Design for Reliability (DFR) programs, allowing the simultaneous investigation of the effects of various factors and thereby facilitating design optimization. This article introduces the concept of DOE. Future articles will cover more DOE fundamentals in addition to applications and discussion of DOE analyses accomplished with a soon-to-be-introduced ReliaSoft software product.

 

Drug excipient compatability studies:

The drug excipient compatibility studies were carried out by Fourier Transmission Infrared Spectroscopy (FTIR) method and Differential Scanning Colorimetry (DSC) method.

 

Fourier Transform Infrared Spectroscopy (FTIR):

FTIR spectra for pure drug, physical mixture and optimized formulations were recorded using a Fourier transform Infrared spectrophotometer. The analysis was carried out in Shimadzu-IR Affinity 1 Spectrophotometer. The IR spectrum of the samples was prepared using KBr (spectroscopic grade) disks by means of hydraulic pellet press at pressure of seven to ten tons.

 

SEM studies:

The surface characteristics of film were determined by scanning electron microscopy (SEM) (HITACHI, S-3700N). Photographs were taken and recorded at suitable magnification.

 

 

 

Stability Studies:

The stability study of the optimized fast-dissolving films was carried out under different conditions according to ICH guidelines. The film was packed in the aluminium foil and stored in a stability chamber for stability studies. Accelerated Stability studies were carried out at 40 0C / 75% RH for the best formulations for 6 months. The patches were characterized for the drug content and other parameters during the stability study period

 

RESULTS AND DISCUSSION:

Preparation of Pramipexole HCl films:

It was aimed to prepare fast dissolving oral films of Pramipexole HCl with the dose of 0.5 mg per 4 cm2 film. Total 27 formulations were prepared using different polymers and the resulting films were shown in Figure 1.

 

Figure 1: Pramipexole hydrochloride films


 

Evaluation parameters

Table 2: Physico-chemical properties of FD Films of Pramipexole HCl monohydrate

F.NO

Thickness

(mm)

Tensile Strength (gm/cm2)

Folding

Endurance

Drug content

(%)

Surface pH

DT

(Sec)

PF1

0.14±0.05

11±0.13

115±1.14

95.11±0.63

6.8±0.037

13±1.23

PF2

0.11±0.14

15±0.27

118±1.22

98.45±0.06

6.5±0.011

12±1.51

PF3

0.15±0.36

13±0.10

112±1.17

96.16±0.17

6.8±0.039

13±1.40

PF4

0.12±0.90

14±0.16

113±1.69

97.16±1.01

6.7±0.012

14±1.19

PF5

0.15±0.23

15±0.78

117±1.18

96.21±0.22

6.6±0.019

13±1.25

PF6

0.12±0.14

14±0.58

115±1.19

97.27±0.39

6.8±0.035

14±1.87

PF7

0.16±0.64

11±0.34

111±1.13

96.18±0.89

6.5±0.040

16±1.63

PF8

0.13±0.28

13±0.66

115±1.15

96.77±0.58

6.5±0.077

17±1.37

PF9

0.16±0.19

15±0.48

116±1.28

96.75±0.63

6.7±0.011

16±1.19

FP10

0.14±0.11

13±0.96

115±1.29

98.89±0.47

6.6±0.087

15±1.24

PF11

0.15±0.18

15±0.75

119±1.49

95.47±0.38

6.6±0.017

14±1.19

PF12

0.15±0.20

14±0.12

118±1.69

96.81±0.22

6.7±0.060

16±1.40

PF13

0.16±0.13

12±0.49

115±1.29

98.45±0.47

6.6±0.089

14±1.73

PF14

0.13±0.29

13±0.18

114±1.41

97.65±0.11

6.8±0.028

15±1.87

PF15

0.14±0.59

14±0.59

115±1.64

97.57±0.24

6.6±0.040

15±1.35

PF16

0.12±0.12

13±0.37

116±1.30

98.85±0.39

6.5±0.096

13±1.81

PF17

0.11±0.13

13±0.39

115±1.38

95.56±0.44

6.8±0.029

12±1.56

PF18

0.14±0.20

10±0.13

115±1.58

98.68±0.47

6.5±0.022

16±1.12

PF19

0.16±0.15

12±0.14

118±1.17

96.34±0.55

6.7±0.019

13±1.33

PF20

0.12±0.26

13±0.77

115±1.30

95.31±0.24

6.8±0.049

16±132

PF21

0.13±0.39

12±0.30

117±1.49

98.23±0.87

6.8±0.041

14±1.27

PF22

0.14±0.49

11±0.19

112±1.51

97.36±0.61

6.7±0.085

14±1.61

PF23

0.12±0.58

13±0.10

113±1.51

95.45±0.38

6.7±0.062

16±1.49

PF24

0.10±0.98

15±0.14

126±1.23

99.29±0.62

6.9±0.046

10±1.31

PF25

0.15±0.46

12±0.37

110±1.41

97.36±0.55

6.8±0.014

16±1.39

PF26

0.13±0.59

13±0.44

116±1.54

95.38±0.45

6.7±0.025

14±1.40

PF27

0.14±0.50

15±0.58

116±1.30

97.89±0.13

6.6±0.051

15±1.77

Values are expressed in mean± SD :( n=3)


This is essential to ascertain uniformity in the thickness of the film as this is directly related to the accuracy of dose in the strip. Low SD values in the film thickness measurements ensured uniformity of thickness in each formulation. Differences in thickness of films may due to differences of viscosities of polymeric solutions. The average thickness of the formulation PF1 to PF27 ranged from 0.10±0.98 to 0.16±0.64 mm. The Tensile Strength measures the ability of film to withstand rupture. It was found to be satisfactory. Tensile Strength of formulation PF1 to PF27 was found to have folding endurance in the range of 10±0.13 to 16±0.14. The folding endurance measures the ability of film to withstand rupture. It was found to be satisfactory. The results indicated that the films would not break and would maintain their integrity with general folding when used. Folding endurance of formulation PF1 to PF27 was found to have folding endurance in the range of 110±1.41 to 126±1.23. Homogeneous uniform drug distribution is one of the important characteristic of a fast dissolving film that ensures the uniform reproducible release of the drug from the film. Drug content uniformity (%) of formulations PF1 to PF27 was in the range of 95.11±0.63 to 99.29±0.62. Estimation of drug content indicated that the drug is uniformly distributed throughout the films, evidenced by the low values of the SD. The surface pH of fast dissolving oral films was determined in order to investigate the possibility of any side effects In vivo. As an acidic or alkaline pH may cause irritation to the oral mucosa. The surface pH of films PF1 to PF27 was found to be in the range of 6.6±0.011 to 6.9±0.046. It assured that there will not be any kind of irritation to the mucosal lining of the oral cavity. Disintegration time (Sec) of the formulations PF1 to PF27 was found to be in the range of 10±1.31 to 17±1.37. Formulation PF24 was shown low disintegration time, folding endurance, drug content uniformity and best tensile strength when comparative with other formulations. The results are summarized in Table 2.

 

In Vitro dissolution studies:

Figure 3: Cumulative % drug released of formulation of PF8-PF13

 

Figure: 5 Cumulative % drug released of formulation of PF21-PF27

 

Being the fast disintegrating formulations the release rates of all the formulations were very rapid. It was noticed that the films got hydrated rapidly and began to dissolute the drug within minutes. This may be due to the water solubility of the drug and the polymer. From the above dissolution studies PF24 is considered as a optimized formulation based on in vitro release studies 99.21±1.87 after 10 min and other evaluation parameters. The drug release from marketed product was found to be 93.78±1.53 after 50 min (Figure 2, 3, 4 and 5).

Design of Experiment:

This method is mainly used to explain the effect of one factor on other. To know whether this effect is significant or not, if significant how it influences the response. In this present work the effect of one factor (Propylene Glycol) on other two factors (HPMC E 50, Kollidon 30) is explained.

 

Figure: 6 Response surface plot showing the influence of amount of polymer and Plasticizer on the release profile of Pramipexole HCl monohydrate for % Cumulative drug release.  

 

Figure: 7 Response surface plots showing the influence of amount of polymer and Plasticizer on Tensile Strength of Pramipexole HCl monohydrate

 

In the above graph (Figure 6) the effect of Propylene Glycol on % cumulative drug release is examined and it clearly indicates that there is a very significant effect of Propylene Glycol on % cumulative drug release. From the in vitro drug release study observed that as concentration of polymer increase, % drug release was decreased and as the concentration of plasticizer increase, % drug release was increased. But prediction of results of % drug release, response surface plot was plotted for graphical representation of results. So, figure showed common effect of plasticizer and polymer concentration. We can conclude from the contour plot for formulation batch PF1 to PF27 that, % drug release was decreased as the concentration of polymer increased and % drug release was increased as the plasticizer concentration increased.

 

There is a negligible effect on Tensile Strength of formulations because both the polymers in formulations have excellent Tensile Strength and there is slightly influence on Tensile Strength by Propylene Glycol (Figure 7). 

 

Figure: 8 Response surface plot showing the influence of amount of polymer and Plasticizer on Disintegration Time of Pramipexole HCl monohydrate

 

Disintegration time observed that as concentration of polymer increase, Disintegration Time was decreased and as the concentration of plasticizer increase, Disintegration time was increased (Figure 8).

 

DRUG EXCIPIENT COMPATABILITY STUDIES:

Fourier Transform Infrared Spectroscopy (FTIR)

FT-IR:

The major peaks obtained in the FTIR studies of pure drug Pramipexole like Benzothiazole, C=C, N-H and aromatic C-H stretching’s remained unchanged when mixed with the polymers and in the formulation.

 

Overall there was no alteration in peaks of Pramipexole pure drug (Figure 9) and optimized formulation (Figure 10), suggesting that there was no interaction between drug and excipients. There is additional peaks appeared or disappeared hence no significant changes in peaks of optimized formulation was observed when compared to pure drug indicating absence of any interaction.


 

Figure: 9 FT-IR spectra of Pramipexole hydrochloride monohydrate pure drug

 

Figure: 10 FT-IR spectra Pramipexole optimized formulation (PF24)

 


SEM studies:

SEM of Pramipexole Hydrochloride mouth dissolving film shows the rough and uneven surface with circular pits with the absence of particles suggesting the presence of the drug in dissolved state in the polymer HPMC. They further ensure the loss of crystallinity when formulated as a film comprising amorphous HPMC (Figure 11).


 

Figure: 11 Scanning electron micrograph of Pramipexole HCl optimized mouth dissolving films PF24

 


Stability studies:

Table 3: Stability Studies of Pramipexole HCl optimized formulation PF24

Parameters

Temperature Maintained at 40 ±20C ; Relative Humidity (RH) Maintained at 75%±5%RH

Initial

After 1 month

After 2 months

After 3 months

Drug Content (%)

99.29±0.62

98.05±1.17

97.89±1.12

97.45±1.06

In Vitro Drug Release (%)

99.21±1.87

98.10±1.13

97.83±1.45

97.33±1.27

Tensile Strength

15±0.14

15±0.17

14±0.23

14±0.58

Disintegration Time

10±1.31

11±1.11

11±1.53

12±1.21

 


There were no physical changes in appearance and flexibility. After subjecting the optimized formulation (PF24) to the Accelerated Stability Studies, the results were shown that there were no major changes in Drug Content, In Vitro Drug Release, Tensile Strength and Disintegration Time. Hence the formulation was found to be stable (Table 3).

 

CONCLUSION:

An attempt was made to formulate and evaluate twenty seven formulations (F1-F27) of Pramipexole HCl mouth dissolving films by solvent casting method using 33 response surface method where 33 indicates 3 variables and 3 levels of polymers (HPMC E15, Kollidon 30) of different grades and plasticizer (Propylene Glycol) (low, middle and high concentrations) by using Design of experiment software.

 

Among the prepared formulations PF24 showed minimum disintegration time 10 sec, maximum drug was released i.e. 99.21±1.87% of drug within 10 min when compared to the other formulations and finalized as optimized formulation. FTIR and SEM data revealed that no interactions takes place between the drug and polymers used in the optimized formulation. The in vitro dissolution profiles of marketed product and optimized formulation was compared and found to be the drug released was 93.78±1.53 after 50 min. Therefore it can be a good alternative to conventional Pramipexole HCl for immediate action. In vitro evaluation of the Pramipexole HCl fast dissolving films confirmed their potential as an innovative dosage form to improve delivery and quick onset of action of Pramipexole HCl. Therefore, the oral fast dissolving film is considered to be potentially useful for the treatment of Parkinson’s disease where the quick onset of action is desired, also improved patient compliance.

 

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Received on 19.09.2017         Modified on 15.10.2017

Accepted on 01.11.2017      © RJPT All right reserved

Research J. Pharm. and Tech. 2018; 11(3): 1001-1008.

DOI: 10.5958/0974-360X.2018.00187.7