ENCLOSURE - I

6. BRIEF RESUME OF INTENDED WORK

6.1 Need for the study

Among the various routes, the oral route is the most acceptable for the patients. About 60% of the total dosage forms are administered by oral route. In particular to the pediatric and Geriatric patients have difficulty in swallowing or chewing solid dosage forms, so, 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 cavity1.

Fast-dissolving films are generally constituted of plasticized hydrocolloids or blends, which can be laminated by solvent casting or hot-melt extrusion2. Mouth dissolving film, a new drug delivery system for the oral delivery of the drugs, was developed based on the technology of the transdermal patch. The delivery system consists of a very thin oral strip, which is simply placed on the patient’s tongue or any oral mucosal tissue, instantly wet by saliva the film rapidly hydrates and adheres onto the site of application. It then rapidly disintegrates and dissolves to release the medication for oromucosal absorption or with formula modifications. The quick dissolving aspects allow for gastrointestinal absorption to be achieved when swallowed. In contrast to other existing, rapid dissolving dosage forms, which consist of liophylisates, the rapid films can be produced with a manufacturing process that is competitive with the manufacturing costs of conventional tablets3.

Lisinopril dihydrate is an oral long-acting angiotensin converting enzyme inhibitor. It is a white to off-white, crystalline powder, soluble in water, sparingly soluble in methanol and practically insoluble in ethanol. Effective half-life of accumulation following multiple dosing is 12 hours. Approximately 25%, but widely variable between individuals (6 to 60%) in all doses tested (5-80 mg); absorption is unaffected by food. It does not appear to be bound to serum proteins other than ACE. It melts at approximately 160ºC4. It is used in the treatment of hypertension and symptomatic congestive heart failure. May be used to slow the progression of renal disease in hypertensive patients with diabetes mellitus and microalbuminuria or overt nephropathy5.

Oral films has faster onset of action and hence can be used as a drug delivery system for Lisinopril dihydrate in the treatment of hypertension. The aim of present study is to develop taste masked orally disintegrating /dispersible films of Lisinopril dihydrate to increase patient compliance, ease of administration, safety and appropriate dosing.

ENCLOSURE- II

6.2 REVIEW OF LITERATURE

Aditya D et al6 investigated triclosan (TC) containing fast dissolving films for local delivery to oral cavity. They found that poloxamer 407 and hydroxypropyl-β-cyclodextrin (HPBCD) improved solubility of TC. Use of poloxamer 407 and HPBCD resulted in significant improvement in the solubility of TC. Fast dissolving films containing TC-HPBCD complex and TC-Poloxamer 407 were formulated and were evaluated for the in vitro dissolution profile and in vitro microbiological assay. Films containing TC-Poloxamer 407 exhibited better in vitro dissolution profile and in vitro antimicrobial activity as compared to the films containing TC-HPBCD complex. Eugenol containing films improved the acceptability of TC-Poloxamer 407 films with respect to taste masking and mouth freshening without compromising the in vivo dissolution time.

Puttipipatkhachorn S et al7 conducted studies on four different grades of chitosan to prepare films. Salicylic acid and theophylline were incorporated into cast chitosan films as model acidic and basic drugs, respectively. Crystalline characteristics, thermal behavior, drug–polymer interaction and drug release behaviors of the films 13 were studied. The results of Fourier transform infrared and solid-state C NMR spectroscopy demonstrated the drug– polymer interaction between salicylic acid and chitosan, resulting in salicylate formation, whereas no drug–polymer interaction was observed in theophylline-loaded chitosan films. Most chitosan films loaded with either salicylic acid or theophylline exhibited a fast release pattern, whereas the high viscosity chitosan films incorporated with salicylic acid showed sustained release patterns in distilled water.

Yoshinori I et al8 prepared fast dissolving oral thin film containing dexamethasone and base materials including microcrystalline cellulose, polyethylene glycol, hydroxypropylmethyl cellulose, polysorbate 80 and low-substituted hydroxypropyl cellulose. This preparation showed excellent uniformity and stability, when stored at 40̊C and 75% in humidity for up to 24 weeks. The film was disintegrated within 15 sec after immersion into distilled water. The dissolution test showed that approximately 90% of dexamethasone was dissolved within 5 min. The results suggested that the fast dissolving oral thin film containing dexamethasone is likely to become one of choices of dexamethasone preparations for antiemesis during cancer chemotherapy.

Hirokazu O et al9 examined the penetration rate of Lidocaine (LC) through excised oral mucosa from hamster cheek pouch and the in vitro release rate of LC from film dosage forms with hydroxypropylcellulose (HPC) as a film base. The addition of glycyrrhizic acid (GL) to the HPC films increased the LC release rate almost GL-content-dependently, while an optimum GL content was observed for the LC penetration rate. No LC penetration was observed from an acidic aqueous solution (pH 3.4) of LC, suggesting only unionized LC can substantially penetrate through the mucosa. A significant relationship between the penetration rate of LC and the release rate of unionized LC was found, suggesting that the in- vitro dissolution study is a useful tool to predict the penetration rate taking the unionized drug fraction into consideration.

FrancescoC et al10 developed a fast-dissolving film made of low dextrose equivalent maltodextrins (MDX) containing nicotine hydrogen tartrate salt (NHT). MDX with two different dextrose equivalents (DEs), namely DE 6 and DE 12, were selected in order to evaluate the effect of polymer molecular weight on film tensile properties. The addition of NHT and taste-masking agents affected film tensile properties; however, the effect of the addition of these components can be counterweighted by modulating the glycerine content and/or the MDX molecular weight. The feasibility of NHT loaded fast-dissolving films was demonstrated.

Oral AY et al11 formulated Copper (II) oxide thin films by a sol–gel-like method on microscope glass substrates. Precursor solutions were prepared by dissolving copper acetate in isopropyl alcohol. Various stabilizers and additives were used to enhance the solubility of copper acetate and to strengthen the adhesion between the films and the glass substrates. It was observed that the films crystallized to CuO with tenorite structure after heat treatment at 600̊C for 30 min. The general appearances of the films were uniform and brownish black in color. The microstructures of the films were substantially affected by the chemistry of the precursor solutions. The optical band gaps of the films were between 1.6 and 1.75 eV.

Nadia G et al12 carried out research to assess the bioequivalence between Rapid film , a new patented delivery system, versus the traditional orodispersible tablet (ODT). A randomized, two-way, single dose, crossover, bioequivalence study was conducted in 24 fasting, healthy volunteers with two formulations of ondansetron. Plasma samples were analysed by a validated LC–MS/MS method during a collection period of 24 h post-dosing. The analysis of variance (ANOVA) on the targeted pharmacokinetic parameters did not show any significant difference between the two formulations and 90% confidence intervals (CIs) fell within the common acceptance range of 80–125%, satisfying the bioequivalence criteria.

Renuka M et al13 developed rapid dissolving films of cetirizine hydrochloride using pullulan as film forming polymer, by solvent casting method. The prepared films were evaluated for the effect of type of casting surface and plasticizer on film separation and taste masking properties. A type of casting surface played a critical role in film formation and separation. The film exhibited satisfactory thickness, mechanical properties like tensile strength, % elongation and elastic modulus. In vitro dissolution studies, in vivo disintegration studies and surface morphology using SEM were also performed.

Kulakarni AS et al14 investigated different polymers for use in the formulation of fast dissolving strips by solvent casting method. The different polymers employed for the formulation are HPMC E-15, HPMC K4M, HPMC E-5, PVA, PVP, Gelatin, Eudragite RL100 and pullulan with different excipients such as carrageen, Guar gum, PEG-400 and Glycerin. Among all polymers pullulan and HPMC E-15 showed desired film forming capacity. Hence by various studies it was concluded that among the two polymers pullulan is the best film forming agent.


ENCLOSURE-III

6.3 OBJECTIVE OF THE STUDY

The present work is planned with the following objectives.

  1. To prepare orodispersible films containing Lisinopril by solvent casting method using different biodegradable polymers.
  2. To evaluate the prepared oral film for drug content, tensile property, film thickness.
  3. To carry out drug-polymer interaction studies in prepared films.
  4. To determine the effect of different concentration and composition of polymers on the release profile of drugs.
  5. To perform in vitro dissolution studies.

ENCLOSURE-IV

7. MATERIALS AND METHODS

7.1 Source of data

The primary data will be collected by performing various tests and investigations in the laboratory. The secondary data will be collected by referring various national and International journals, books, Pharmacopeia’s and websites.

ENCLOSURE -V

7.2 METHOD OF COLLECTION OF DATA

The physico-chemical parameters of the model drug and the polymers will be determined in our laboratory using standard methodology.

  1. Compatibility between drug and excipients will be studied using techniques such as FTIR etc.
  2. Preparation of Lisinopril dihydrate orodispersible films by methods like solvent casting.
  3. To characterize the polymers used.
  4. Instruments like dissolution test apparatus and UV/IR spectroscopy are used to collect above data.

5.  The in vitro release data shall be analyzed statistically.


enclosure VI

LIST OF REFERENCES:

  1. Basani G, Subash VK, Guru S, madhusudan Rao Y. Overview on fast dissolving films. Int J Pharm Pharm Sci 2010; 2(3):29-33.
  2. Francesco C, Irma EC, Paola M, Francesca S, Luisa M. Fast dissolving films made of maltodextrins. Eur J Pharm Biopharm 2008; 70:895–900.
  3. Arun A, Amrish C, Vijay S, Kamla P. Fast Dissolving Oral Films: An Innovative Drug Delivery System and Dosage Form. Int J of Chem Tech Research 2010; 2(1): 576-583.
  4. Goodman, Gilman’s. The pharmacological basis of therapeutics.10th. .ed. 2001; 1975.
  5. Government of India, ministry of Health and Family Welfare. Indian Pharmacopeia 2007; 2:334 1306.
  6. Aditya D, Mangal N. Formulation and Evaluation of Fast Dissolving Films for Delivery of Triclosan to the Oral Cavity. AAPS Pharm Sci Tech 2008; 9(2):210-215.
  7. Puttipipatkhachorn S, Nunthanid J, Yamamoto K, Peck GE. Drug physical state and drug–polymer interaction on drug release from chitosan matrix films. J Control Release 2001; 75:143–153.
  8. Yoshinori I, Hiroyoshi S , Kazumi T , Misao N, Katsuhiko M , Tadao T ,Hirotaka Y , Naoki I , Kazuyuki H , Mayumi Y , Yasutomi K. Preparation of a fast dissolving oral thin film containing dexamethasone, A possible application to antiemesis during cancer chemotherapy. Eur J Pharm Biopharm 2009; 73:361–365.
  9. Hirokazu O, Hirohisa T, Kotaro I, Kazumi D. Development of polymer film dosage forms of lidocaine for buccal administration I. Penetration rate and release rate. J Cont Rel 2001; 77: 253–260.
  10. FrancescoC, IrmaEC, PaolaM, SusannaB, Francesca S, ChiaraGMG, LuisaM. Nicotine Fast Dissolving Films Made of Maltodextrins: A Feasibility Study. J Ame Asso Pharm Sci 2010; 820-832.
  11. Oral AY, Men E¸ Aslanc MH, Ba E¸ saran. The preparation of copper (II) oxide thin films and the study of their microstructures and optical properties. Materials Chemistry and Physics 2004; 83:140–144.
  12. Nadia G, Valentina R, Nunzia CM, Armin B, Peter K. Rapidfilm: An innovative pharmaceutical form designed to improve patient compliance. Int J Pharm 2010; 393:55–60.
  13. Renuka M, Avani A. Formulation and characterization of rapidly dissolving films of cetirizine hydrochloride using pullalan as a film forming agent. Ind J Pharm Edu Res 2011; 45(1):71-77.
  14. Kulakarni AS, Deokule HA, Mane MS, Ghadge DM. Exploration of different polymers for use in the formulation of oral fast dissolving strips. J Curr Pharm Res 2010; 2(1):33-35.