Formulation, optimization and evaluation of levocetirizine dihyrochloride oral thin strip

Abstract

The aim of present research was to develop a fast releasing oral polymeric film, with good mechanical properties, instant disintegration and dissolution, producing an acceptable taste when placed on tongue. Solvent casting method was used to prepare oral films. Levocetirizine dihydrochloride, an antihistaminic was incorporated to relieve the symptoms of allergic rhinitis. The polymers selected were HPMC E 15 and PVA. Propylene glycol was the plasticizers used. Nine batches of films with drug were prepared using different combinations of polymers and plasticizer concentration. The resultant films were evaluated for weight variation, content uniformity, folding endurance, thickness, surface pH, in vitro disintegration and in vitro dissolution. The optimized films which disintegrated in less than 30 sec, releasing 85-98% of drug within 2 minutes. The percentage release was varying with concentration of plasticizer and polymer. The films made with HPMC: PVA (1:2) released 96% of drug in 1 min, which was the best release amongst all.

Among the delivery routes, the oral route is the most acceptable from patient compliance aspects. Many elderly people have difficulty taking medicines because of their reduced swallowing capability. Commercially available swallowing-assistive jelly has been developed as a functional food to help people swallow medicines and is used by children, the elderly, and those who have a difficulty taking medicine.[1] To improve patient compliance, recently developed medicines have been produced as a jelly formulation or disintegrating oral tablet. Although the jelly formulation is favored by people who have difficulty taking medicine, it lacks versatility in terms of stability because of its high moisture and the added cost.[2]

Orally disintegrating tablets (ODTs) have gained popularity during the last few years. To accelerate fast disintegration, many ODTs are fragile, which causes problems during manufacturing, storage, handling and administration. On the contrary, ODFs are flexible but still robust to mechanical forces. Whereas lyophillization is a common process for manufacturing ODTs, the manufacturing of ODFs is based on the technology for producing transdermal patches, which is less expensive than lyophillization. Superior to liquid formulations such as drops or syrups, ODFs offer the convenience of accurate dosing.[3] As the drug is released within seconds into the oral cavity, a rapid onset of action could be achieved. If the drug is absorbed through the oral mucosa, first-pass metabolism can be avoided for some drugs, which may improve bioavailability. Buccal absorption may be particularly beneficial, for example, for patients suffering from migraine. However, some patients may experience drowsiness, owing to the fast onset of action.[4–7] Many pharmaceutical firms 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.[8–10] Different terms can be found in the literature, for example, wafer, oral film, thin strip, orally dissolving film, flashrelease wafer, quick dissolve film and melt-away film. Melt-away film and melting film are rather inappropriate terms because the films are not melting but dissolving, or at least disintegrating in saliva. Therefore, the term ‘soluble film’ (in some cases ‘oral soluble film’) is preferred by the FDA, whereas the European Medicines Agency (EMA) is using ‘orodispersible film’ (ODF).[3,5–7]

Oral Thin Strip of Levocetirizine Dihydrochloride were developed employing Hydroxypropyl Methylcellulose and Polyvinyl Alchol as film formers. The effect of binary mixture of polymers on physicochemical parameters including thickness, folding endurance, drug content, and in vitro dissolution was evaluated. in vitro dissolution study showed that binary mixture of PVA and Hydroxypropyl Methylcellulose (HPMC), at 2:1 ratio provided highest drug release in 30 sec to 1 minute. Based on the above observations, it can be reasonably concluded that blend of PVA–HPMC polymers are better suited for the development of Oral Thin Strip of Levocetirizine Dihydrochloride

Materials and Methods

Levocetirizine dihydrochloride was obtained from Sunrise Remedies Pvt Ltd. Ahmedabad. HPMC E-15, Polyvinyl alcohol and Propylene glycol (PG) and polyethylene Glycol 400 (PEG400) were purchased from Sigma chemicals. All other chemicals used were of analytical grade.

Formulation

Oral thin Strip with varied mixture composition of HPMC E15 and PVA were prepared by casting drug dispersion in water and subsequent evaporation of solvent in an open glass mould and dried at 40°C for 9 hrs. Propylene glycol (10% w/w) was added as a plasticizer and Citric acid as saliva stimutating agent, Aspartame as sweetner. Solvent was evaporated slowly at room temperature and controlled evaporation was assured by covering glass mould with an inverted funnel. After complete removal of the solvent, film were removed and kept in desiccators till further use.

Results and Discussion

Cellulose derivatives are known for their good film forming properties and have excellent acceptability. Hence various cellulose derivatives namely HPMC, HPC, CMC, Gelatin, PVA, were used as primary film former. Various trials were taken to formulate the quick dissolving films (QDF) where in all the polymers at different concentrations were assessed. Film containing HPMC and PVA were transparent where as HPC, Gelatin and CMC films were opaque in their appearance. Citric acid amount was also varied from 30-80 mg. Film with 30 mg Citric acid were selected. Since, increase in the amount of citric acid resulted in distortion of films. As all batches do not have uniform amount of ingredients in it, hence their weight and thickness were varied.

Levocetirizine Dihydrochloride in combination with HPMC E-15 and PVA produced smooth, flexible and transparent Oral Thin Strip. Prepared strips were evaluated for different parameter like weight uniformity, folding endurance, % drug content, % drug release. From the result, it was observed that all the formulation shows good weight uniformity and % drug content. As concentration of polymer increase, decrease in folding endurance. HPMC E 15 alone shows lesser folding endurance 155±5.5. While only Polyvinyl alcohol containing film shows greater folding endurance 452 ± 3.2. As concentration of polymer increase, drug release was decreased. Only HPMC E15 containing film shows 92% drug release in 3 min. While only PVA containing film showed 93% drug release in 3 min. Maximum drug release of 98.32% ± 0.35 in 30sec was shown by patch containing 2:1 ratio of PVA: HPMC in combination. In addition, this combination shows folding endurance of 249±4.2.

Conclusion

The fast dissolving films containing levocetirizine dihydrochloride were prepared with an aim to have rapid onset of action and increased bioavailability in allergic conditions. Various cellulose derivatives were employed for their film forming properties of which HPMC and PVA showed promising physicochemical properties as compare to all other grades therefore, it was selected for further studies. Prepared films were transparent with smooth surface and acceptable mechanical properties. It can be concluded that Oral thin strip of Levocetirizine dihydrochloride can prepared using the polymer combinations of HPMC E15: PVA (1:2). When the concentration of polymer increase drug release decreases.