INTRODUCTION:

Sacubitril sodium is a selective neprilysin inhibitor indicated for the treatment of hypertension. Sacubitril is a prodrug that is activated to Sacubitrilat by deethylation via esterases¹. Sacubitrilat inhibits the enzyme neprilysin² which is responsible for the degradation of atrial and brain natriuretic peptide, two blood pressure-lowering peptides that work mainly by reducing blood volume³. In addition, neprilysin degrades a variety of peptides including bradykinin an inflammatory mediator exerting potent vasodilator action.

As one possible solution to the problem of swallowing conventional solid dosage forms, a few major pharmaceutical companies have developed fast-dissolving intraoral tablets. The major drawback of these conventional fast dispersing and/or dissolving tablets is their physical solid form. The fear of swallowing, chewing, or choking on such solid shaped articles is still a concern in certain populations. In addition, the fragility/friability of wafer- like, porous and low-pressure moulded tablets fabricated by various manufacturing processes, which require special and expensive packaging to protect the dosage forms. The oral fast dissolving films are thin films for oral mucosal delivery that overcome the shortfalls of conventional fast-dissolving intraoral tablets. The film alleviates the danger/fear of choking, easy to handle and administer, maintains a simple and convenient packaging, alleviates unpleasant taste, and is straightforward to manufacture^{4, 5}. The oral route remains the perfect route for the administration of therapeutic agents because the low cost of therapy and ease of administration lead to high levels of patient compliance. Oral dosage forms are more popular than other dosage form. Oral fast dissolving film is relatively a new dosage form in which thin film is prepared using hydrophilic polymers, which rapidly dissolves on tongue or oral cavity. Oral Fast dissolving film (FDF) is also known as mouth dissolving films (MDF), oral strips, oral dispersible films (ODF). buccal mucosa offers many advantages like relatively large surface area of absorption, easy accessibility, simple delivery devices, avoiding hepatic first pass metabolism and feasibility of controlled drug delivery⁶. Buccal ﬁlms are ﬂexible, comfortable compared to the tablets and can circumvent shorter residence time of oral gels⁷.

On placing fast dissolving films in the mouth, saliva serves to rapidly dissolve the dosage form. The saliva containing the dissolved or dispersed medicament is then swallowed and the drug is absorbed in the normal way. Some drugs are absorbed from the mouth, pharynx and oesophagus as the saliva passes down into the stomach and it may produce rapid onset of action. In such cases bioavailability of drug is significantly greater than those observed from conventional tablets dosage form.

Following oral administration, Sacubitril Sodium is well absorbed and undergoes substantial first-pass metabolism; the systemic bioavailability of Sacubitril Sodium is approximately 60%. In view of these facts this drug can be considered as a suitable candidate for fast dissolving oral film. In this study, an attempt is made to investigate the feasibility of fast dissolving oral films as a medium for the fast delivery of Sacubitril Sodium with better bioavailability and enhanced patient compliance.

MATERIAL AND METHODS:

Materials:

Sacubitril sodium was obtained as a gift sample from Strides Arcolabs, Bengaluru. HPMC –E5, propylene glycol, Glycerine, Tween-80 and Sorbitol were purchased from Sigma-Aldrich.

Method:

Oral fast dissolving films of Sacubitril Sodium were prepared by solvent casting method^.Flat, square-shaped, aluminum foil-coated glass molds having a surface area of 25 cm² were fabricated for casting the films. Compositions of circular cast films of various formulations were mentioned in Table-1.

Preparation of casting solutions:

The weighed quantity of polymer [Table 1] was kept for swelling overnight in distilled water and dissolved (heated, if necessary). The drug and sorbitol were dissolved in distilled water and added to the above mentioned polymer solution along with propylene glycol as a plasticizer, mixed thoroughly to form a homogenous mixture. The volume was made up to 10ml with distilled water. Entrapped air bubbles were removed by applying vacuum.

Preparation of fast-dissolving films:

The casting solution (10ml) was poured into glass molds and dried at 40°C in a vacuum oven for 24 h for solvent evaporation. The patches were removed by peeling and cut into a square dimension of 5cm × 5cm (25cm²). These patches were kept in a desiccator for 2 days for further drying and wrapped in aluminium foil, and packed in self-sealing covers. Fast-dissolving films were prepared with different polymers and ratios by maintaining the concentration of the plasticizer and sweetener constant [Table 1]⁸.

Characterization Parameters:

Film Thickness:

The thickness of 3 films of each formulation was performed by screw gauge at different position of the film and the average thickness was calculated⁹ [Table 2].

Uniformity of weight:

It is desirable that films should have nearly constant weight. It is useful to ensure that a film contains the proper amount of excipients and API. Weight variation was determined for all the films. The film (4cm²) was cut at five different places in the cast film. The weight of each filmstrip was taken and the weight variation was calculated¹⁰ [Table 2].

Surface pH:

The film to be tested was placed in a petridish and moistened with 0.5ml of distilled water and kept for 1 hour. The pH was noted after bringing the electrode of the pH meter in contact with the surface of the formulation and kept for 1minute to allow equilibrium condition. The average of three determinations for each formulation was done¹¹ [Table 2].

Dissolving Time:

The dissolving time was determined by placing the film in a beaker containing 50ml of phosphate buffer (pH6.8). The time required by the film to dissolve completely was noted [Table 2].

Folding Endurance:

Folding endurance of the film is essential to study the elasticity of the film during storage and handling. The folding endurance of the films was determined by repeatedly folding one film at the same place till it broke. This is considered to reveal good film properties. A film (3 X 2cm) was cut evenly and repeatedly folded at the same place till it breaks. All determinations were performed in triplicate. The number of times the film could be folded at the same place without breaking/cracking gave the value of folding endurance¹² [Table 2].

Drug Content:

Sacubitril Sodium content in the fast dissolving film was calculated by UV-spectrophotometric method based on the measurement of absorbance at 230nm in 0.1N HCl solution. A circular film of 2.5cm diameter was cut and kept in 25ml of 0.1N HCl solution overnight so that the drug from fast dissolving film diffuses out. After suitable dilution the absorbance of the films was measured using a Shimadzu UV–1700 double beam spectrophotometer (Shimadzu Corporation, Japan). This method was repeated 3 times ^13,14. The results were shown in Table 2.

Disintegration Time:

5cm² film was placed in the basket, raised and lowered it in such a manner that the complete up and down movement at a rate to achieve equivalent to thirty times a minute was set. Time taken by film to break and dissolve was measured as in-vitro disintegration time¹¹[Table 3].

In-Vitro Dissolution Studies:

The film samples were subjected to in-vitro dissolution studies using USP Type II dissolution apparatus at 37±2°C and 50rpm speed in 900ml dissolution medium. The different dissolution medium like 0.1N HCl and Simulated saliva were used for the study. Simulated saliva pH 6.8 was prepared by using sodium chloride (8 g/l), potassium phosphate monobasic (0.19g/l), sodium phosphate dibasic (2.38g/l). Film (dimension: 3cm x 2 cm) was submerged into the dissolution media and appropriate aliquots were withdrawn at 1, 2, 3, 4, 5, 7, 10, 15 and 20 minute time intervals. The samples were filtered through what man filter paper and analysed spectrophotometrically at λ max of drug (Model UV-1700 UV-Visible spectrophotometer, Shimadzu, Japan). Sink conditions were maintained throughout the experiment^15,16 [Table 3]. The comparative release profile of various formulations of Sacubitril Sodium was shown in figure 1.

FTIR Studies:

FTIR spectra of pure Sacubitril sodium, HPMC-E5 and physical mixture of polymer with drug [Figures 1-3] were recorded on Agilent FTIR spectrophotometer. The instrument was operated under dry air purge and the scans were collected with resolution of 4cm^-1 over the region 4000-400cm^-1. The scans were evaluated for the presence of principle peaks of drug^{17, 18}. The results were shown in figures 2 -4.

Differential scanning calorimetry (DSC) study:

Differential Scanning Calorimetry (DSC) can be used to investigate and predict physicochemical interaction between components in a formulation thus helps in selecting suitable chemically compatible excipients. Any interaction would be indicated in the thermogram of a mixture by the appearance of one or more new peaks or the disappearance of one or more peaks corresponding to those of the components. Any polymorphic change in the drug causes changes in the melting point, bioavailability and release kinetics. The DSC thermogram was obtained for pure Sacubitril sodium, HPMC-E5, PEG 400 and their physical mixture [Figures 5-7]. In physical mixture those excipient were added that were expected to be used in the development of formulation. DSC thermograms of Sacubitril Sodium and Sacubitril Sodium containing films (only K3) were recorded on a thermal analyzer (DSC, Q200, and VA 24.2). The samples were heated from 30° to 300°at a heating rate of 10°/min in an inert nitrogen atmosphere. The temperature calibrations were performed periodically using indium as a standard and thermograms obtained were observed for any interaction¹⁹.

RESULTS AND DISCUSSION:

Fast-dissolving films of Sacubitril Sodium were prepared by the solvent casting method on glass molds, using HPMC-E5 as polymer. Propylene glycol was used as a plasticizer and Sorbitol as a sweetener. Distilled water was used as a solvent for HPMC-E5. Tween80 at suitable concentrations in an increasing order along with this polymer concentration was included in some formulations as Tween80 maintains the pH range of oral cavity thus making the drug available for systemic circulation from oral cavity. The effect of the concentration ratio of polymers and nature of polymers was studied by preparing various formulations of fast-dissolving films. In the preparation, the addition of ingredients, particularly propylene glycol and sorbitol was followed after the careful evaluation of films for physical characteristics. In all these formulations, a constant amount of drug (50mg) was maintained. The casting solution (10ml) was poured into 25cm² molds, so that each square centimeter contains approximately 0.8 mg of the drug. Polymers were used in different concentrations and the concentration of other ingredients such as plasticizer and sweetener were kept constant. Fast-dissolving films of Sacubitril Sodium were evaluated for various parameters. In the present study, eight formulations were prepared by varying the polymer concentration.

Effect of the polymer concentration:

Different formulations (F1, F2, F3, F4, F5, F6, F7 and F8) were prepared using HPMC-E5 in different concentrations to study the effect of polymers/concentration on the physicochemical properties.

Table 1: Composition of fast dissolving films

Formulation Code	Sacubitril sodium (mg)	HPMC-E5 (mg)	Propylene glycol (ml)	Tween 80(ml)	Glycerine (ml)	Sorbitol (mg)	Distilled water qs(ml)
F₁	50	100	0.5	^_	0.5	0.5	10
F₂	50	200	0.5	^_	0.5	0.5	10
F₃	50	300	0.5	^_	0.5	0.5	10
F₄	50	400	0.5	^_	0.5	0.5	10
F₅	50	400	0.5	0.05	0.5	0.5	10
F₆	50	300	0.5	0.05	0.5	0.5	10
F₇	50	200	0.5	0.05	0.5	0.5	10
F₈	50	100	0.5	0.05	0.5	0.5	10

Table 2: Physical Characterization of film formulations

Formulation Code	*Thickness (mm)**	Weight Variation* (mg)	Drug Content (%)	Folding endurence	Surface pH *	Dissolving time (sec)	*Disintegration time (sec)**
F₁	0.72±0.031	72.5±0.091	90.72	154	6.4±0.018	58	89.66±5.50
F₂	0.74±0.056	73.2±0.065	90.88	308	6.7±0.020	56	77.53±7.02
F₃	0.76±0.055	75.9±0.097	92.33	263	6.6±0.016	54	69.66±7.23
F₄	0.78±0.020	74.8±0.080	97.44	298	6.8±0.011	53	62.64±5.50
F₅	0.77±0.020	77.8±0.097	98.52	250	6.8±0.021	50	62.25±3.60
F₆	0.75±0.154	76.4±0.015	95.62	268	6.6±0.015	51	67.66±5.23
F₇	0.74±0.145	79.2±0.154	93.68	254	6.5±0.025	51	75.53±4.02
F₈	0.73±0.091	80.2±0.045	94.78	300	6.9±0.014	52	80.45±4.50

Dissolution was also found to be improved due to salivary stimulation in the presence of the sweetener (sorbitol).

Table 3: In-vitro dissolution profile of fast dissolving films

S.No.	Time (sec)	Cumulative % of Drug Release
S.No.	Time (sec)	F₁	F₂	F₃	F₄	F₅	F₆	F₇	F₈
1	50	48±0.82	54±0.56	56±0.66	52±0.64	58±0.45	56±0.99	56±0.97	50±0.07
2	100	53±0.52	58±1.10	61±0.91	56±0.22	63±0.65	61±0.65	59±0.93	56±0.03
3	150	63±1.22	61±0.87	66±1.01	59±0.45	68±0.15	66±0.55	65±1.08	63±0.31
4	200	69±1.08	68±0.52	70±0.25	61±0.59	77±0.36	75±0.87	69±1.04	69±0.58
5	250	76±0.55	76±0.48	75±0.55	66±0.21	88±0.58	80±0.93	75±0.98	76±0.64
6	300	83±0.86	81±0.21	78±0.88	72±0.11	92±0.47	86±0.57	85±1.52	82±0.42
7	350	87±0.92	85±0.11	82±0.69	82±0.83	95±0.15	92±0.97	89±0.50	88±0.54

Fig.1: Comparative invitro dissolution profile of films

Stability Studies:

Stability studies of all the formulations were carried out at different temperatures. Physical appearance of film and drug content was evaluated for four weeks²⁰. When the oral film preparation was stored in an aluminum package under normal condition or in a chamber controlled at 40°C and 75% in humidity for 4–13 weeks, no apparent changes in the drug content, form or color of preparations were observed. The contents of films were fairly stable ranging from 98.4% to 101.7% during 13 weeks after storage at 30°C and 60% humidity (normal condition), or from 98.0% to 100.4% during the same periods after storage at 40°C and 75% RH humidity (accelerated condition). As there was no change in the of films, it may be concluded that fast dissolving film of Sacubitril Sodium can be formulated, which provides better compliance than conventional drug delivery system of Sacubitril Sodium.

FTIR studies conducted on pure drug and mixture of drug and polymer showed that there is no marked interaction between drug and excipient selected. The graphs obtained indicate that the drug is compatible with the polymer used.

Fig. 2: FT-IR Spectrum of Polymer HPMC-E5

Fig. 3: FT-IR Spectrum of Drug Sacubitril Sodium

Fig.4: FT-IR Spectrum of Sacubitril + HPMCE5

The DSC study revealed that the melting point of HPMC-E5 and Sacubitril Sodium was found to be 269.38^oC and 140.98^oC respectively. In the DSC thermogram of drug-HPMC-E5 mixture, it was shown that the melting points of HPMC-E5 and the drug were 267.66^oC and 133.05^oC respectively which clearly indicates there is only a slight variation in the melting points of polymer and the pure drug and showed that good compatibility with polymers. These studies concluded that there is no excipient incompatibility.

Fig. 5: DSC thermo gram of Polymer HPMC-E5

Fig6: DSC thermo gram of Drug Sacubitril Sodium

Fig. 7: DSC thermo gram of drug+polymer

CONCLUSION:

Based on the encouraging results, the fast-dissolving films of Sacubitril Sodium can be considered suitable for clinical use in the treatment of Hypertension and other conditions of heart disorders, where a quicker onset of action for a dosage form is desirable along with the convenience of administration. The method of preparation was found to be simple and requires minimum excipients, thus making the product cost-effective. Among all HPMC-Sacubitril films, extent of drug release was greater in F5 film. It was observed that with the increased content of polymer, the rate and extent of drug release was faster. This was because of water soluble polymer that results in increased wettability and penetration of water into the film matrices and hence increased diffusion of the drug. Among all the eight formulations F₁, F₂, F₃, F₄, F₅, F₆, F₇, F_8,it was shown that the presence of tween80 in constant concentration in the formulations F₅,F₆,F₇ and F₈enhanced the drug release. From the present investigation it can be concluded that oral fast dissolving films have shown superior drug release. The films prepared by HPMC-E5 and propylene glycol had shown good mechanical strength, drug release, disintegration time and stability. Sacubitril sodium administered in the form of fast dissolving films will be potential novel drug dosage form for geriatric and also for general population by providing faster release and better patient compliance. There fore it can be a good alternative to conventional anti hypertensive tablets.

ACKNOWLEDGEMENT:

The authors express deep gratitude to Strides Arcolabs, Bengaluru, for providing the gift sample of the drug Sacubitril sodium. The authors are also immensely grateful to Sree Vidyanikethan College of Pharmacy, A. Rangampet, Tirupati for providing all the facilities required to carry out the research work.

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Received on 03.06.2019 Modified on 11.08.2019

Research J. Pharm. and Tech. 2020; 13(8):3553-3558.

DOI: 10.5958/0974-360X.2020.00628.9