Development of thin film formulations for poorly soluble drugs

(1)

DISSERTATIONS | KRISTIINA KORHONEN | DEVELOPMENT OF THIN FILM FORMULATIONS FOR POORLY... | No 416

uef.fi

PUBLICATIONS OF

THE UNIVERSITY OF EASTERN FINLAND Dissertations in Health Sciences

ISBN 978-952-61-2488-9 ISSN 1798-5706

Dissertations in Health Sciences

THE UNIVERSITY OF EASTERN FINLAND

KRISTIINA KORHONEN

DEVELOPMENT OF THIN FILM FORMULATIONS FOR POORLY SOLUBLE DRUGS

Polymeric thin films are attracting considerable interest due to their extensive

and exciting pharmaceutical applications.

They can be delivered via different routes, they have tailorable drug release properties and they are patient-friendly. The aim of this study

was to develop amorphous thin films and to characterize their mechanical and release

properties and physical stability during storage under different conditions

KRISTIINA KORHONEN

(2)

(3)

Development of Thin Film Formulations for

Poorly Soluble Drugs

(4)

(5)

(6)

(7)

KRISTIINA KORHONEN

Development of Thin Film Formulations for Poorly Soluble Drugs

To be presented by permission of the Faculty of Health Sciences, University of Eastern Finland for public examination in Mediteknia, Kuopio, on Friday, June 9^th 2017, at 12 noon

Publications of the University of Eastern Finland Dissertations in Health Sciences

Number 416

School of Pharmacy, Faculty of Health Sciences University of Eastern Finland

Kuopio 2017

(8)

Grano Oy Jyväskylä, 2017

Series Editors:

Professor Tomi Laitinen, M.D., Ph.D.

Institute of Clinical Medicine, Clinical Radiology and Nuclear Medicine Faculty of Health Sciences

Professor Hannele Turunen, Ph.D.

Department of Nursing Science Faculty of Health Sciences

Professor Kai Kaarniranta, M.D., Ph.D.

Institute of Clinical Medicine, Ophthalmology Faculty of Health Sciences

Associate Professor (Tenure Track) Tarja Malm, Ph.D.

A.I. Virtanen Institute for Molecular Sciences Faculty of Health Sciences

Lecturer Veli-Pekka Ranta, Ph.D. (pharmacy) School of Pharmacy

Faculty of Health Sciences

Distributor:

University of Eastern Finland Kuopio Campus Library

P.O.Box 1627 FI-70211 Kuopio, Finland http://www.uef.fi/kirjasto

ISBN (print): 978-952-61-2488-9 ISBN (pdf): 978-952-61-2489-6

ISSN (print): 1798-5706 ISSN (pdf): 1798-5714

ISSN-L: 1798-5706

(9)

Author’s address: School of Pharmacy Faculty of Healt Sciences University of Eastern Finland KUOPIO

FINLAND

Supervisors: Docent Riikka Laitinen, Ph.D.

Schoolof Pharmacy Faculty of Healt Sciences University of Eastern Finland KUOPIO

FINLAND

Associate Professor (Tenure Track) Ossi Korhonen, Ph.D.

School of Pharmacy Faculty of Healt Sciences University of Eastern Finland KUOPIO

FINLAND

Professor Jarkko Ketolainen, Ph.D.

School of Pharmacy Faculty of Healt Sciences University of Eastern Finland KUOPIO

FINLAND

Reviewers: Professor Georgios Imanidis, Ph.D.

School of Life Sciences

University of Applied Sciences NW Switzerland and

Department of Pharmaceutical Sciences University of Basel

BASEL

SWITZERLAND

Senior Researcher Tapani Viitala, Ph.D.

Faculty of Pharmacy, Division of Pharmaceutical Biosciences University of Helsinki

HELSINKI FINLAND

Opponent: Professor Jyrki Heinämäki, Ph.D.

Institute of Pharmacy, Faculty of Medicine University of Tartu

TARTU ESTONIA

(10)

(11)

Korhonen, Kristiina

Development of Thin Film Formulations for Poorly Soluble Drugs University of Eastern Finland, Faculty of Health Sciences

Publications of the University of Eastern Finland. Dissertations in Health Sciences 416. 2017. 95 p.

ISBN (print):978-952-61-2488-9 ISBN (pdf):978-952-61-2489-6 ISSN (print): 1798-5706 ISSN (pdf):1798-5714 ISSN-L:1798-5706

ABSTRACT

Polymeric thin films are used to achieve a systemic and local drug effect via the buccal, sublingual, ocular, vaginal and transdermal routes. Thin films have many advantages such as convenient administration, the potential for tailored personalized medication and low unit dose cost. For example as the population ages, many elderly patients experience problems swallowing tablets and thus thin films are interesting alternatives to oral dosage forms. Thin film formulations usually consist of drug, polymers and plasticizers. For example, the choice and qualities of the polymer e.g. its molecular weight, can influence the film’s properties such as its mechanical strength, drug release rate and disintegration time.

Thin films are usually manufactured by solvent casting or solid extrusion methods. The in vitro evaluation of thin film formulations includes physical, and mechanical testing.

The overall aim of this work was to formulate a poorly soluble drug perphenazine (PPZ) into a thin polymeric film where the drug would exist in an amorphous form. The specific aims were: (1) to develop a spraying method to manufacture thin polymer-drug films with good mechanical and drug release properties and to optimize manufacturing conditions by the Design of Experiments, (2) to observe in real time the physical changes occurring in the films during drug dissolution by applying a novel multi-parametric surface plasmon resonance method (MP-SPR), (3) to explore the mechanical and physical properties of the thin films during storage under different conditions of temperature and humidity.

It was found that a pneumatic airbrush can be used to manufacture thin polymer-PPZ- films with good mechanical and release properties. The systematic evaluation of the effect of the formulation and process variables revealed that the amounts of drug and the film thickeners (polyvinylpyrrolidone (PVP), Soluplus^®) were the two main variables affecting the mechanical properties of the films. Moreover, it was found that the amount of PVP enhanced the dissolution rate of drug and the release of drug followed a square root of time kinetics. The MP-SPR method was utilized for the first time to acquire real-time information about the physical changes occurring in the films during drug dissolution. In addition, this technique can be used to study and optimize drug release from thin drug delivery systems.

The physical stability of thin films was evaluated under three different storage conditions with different methods. High temperature and humidity were found to induce drug crystallization especially in binary phase systems. Instead, in low temperature and dry condition, the drug remained amorphous. Crystallization of the drug was found to have an impact on the films’ mechanical properties and the in vitro drug release from the films.

In conclusion, well designed, wide-ranging studies are crucial in the manufacture of drug delivery systems. Temperature and relative humidity can destabilize amorphous drug formulations during manufacturing and storage, and thus it is important to control these parameters. In addition to traditional methods, new techniques, such as MP-SPR, can be exploited to monitor the changes occurring in thin films during drug dissolution.

National Library of Medicine Classification:QV 778, QV 779, QV 785, QV 786.5

Medical Subject Headings: Technology, Pharmaceutical; Drug Delivery Systems; Drug Compounding;

Polymers; Solubility; Drug Liberation; Drug Stability; Drug

(12)

(13)

Korhonen, Kristiina

Ohutkalvovalmisteiden kehittäminen huonosti vesiliukoisille lääkeaineille Itä-Suomen yliopisto, terveystieteiden tiedekunta

Publications of the University of Eastern Finland. Dissertations in Health Sciences 416. 2017. 95 s.

ISBN (nid.):978-952-61-2488-9 ISBN (pdf):978-952-61-2489-6 ISSN (nid.):1798-5706 ISSN (pdf):1798-5714 ISSN-L:1798-5706

TIIVISTELMÄ

Polymeerisiä ohutkalvovalmisteita käytetään systeemisen ja paikallisen vaikutuksen saamiseksi suun, kielenaluksen, silmän, emättimen ja ihon kautta. Ko. valmisteilla on useita etuja, kuten helppo annostelu, yksilöllisesti toteutettava lääkitys ja alhainen yksikköhinta.

Esimerkiksi väestön ikääntyessä monilla iäkkäillä potilailla on ongelmia tablettien nielemisen kanssa. Siksi ohutkalvot ovat kiinnostava vaihtoehto suun kautta annosteltaville lääkevalmisteille. Ohutkalvovalmisteet koostuvat yleensä lääkeaineesta, polymeeristä ja pehmentimestä. Muun muassa polymeerin valinta ja sen ominaisuudet voivat vaikuttaa kalvon ominaisuuksiin, kuten mekaaniseen lujuuteen, hajoamisaikaan ja lääkeaineen vapautumiseen. Ohutkalvovalmisteet valmistetaan yleensä valamalla tai puristamalla.

Kalvojen in vitro -testaus sisältää mm. fysikaalisen ja mekaanisen testauksen.

Tämän tutkimuksen tarkoituksena oli formuloida niukkaliukoisesta perfenatsiinista (PPZ) ohutkalvovalmiste, jossa lääkeaine on amorfisessa muodossa. Tutkimuksen tavoitteita olivat: (1) kehittää ohuille kalvoille valmistusmenetelmä paineilmalla toimivan kynäsumuttimen avulla sekä valmistaa koesuunnittelua apuna käyttäen käsittelyä kestäviä ja kontrolloidusti lääkeainetta vapauttavia lääkeaine-polymeerikalvoja, (2) tutkia lääkeaineen vapautumiseen yhteydessä tapahtuvia fysikaalisia muutoksia reaaliaikaisesti käyttäen uutta moniparametrista pintaplasmoniresonanssi -menetelmää (MP-SPR), (3) tutkia tapahtuuko lääkeaine-polymeerikalvojen mekaanisissa ja/tai fysikaalisissa ominaisuuksissa muutoksia lämpötilan ja kosteuden vaikutuksesta säilytyksen aikana.

Tutkimuksessa havaittiin, että kynäsumutin sopii ohuiden polymeeri-PPZ-kalvojen valmistamiseen sekä ko. kalvoilla olivat hyvät mekaaniset ja vapautumisominaisuudet.

Kalvojen koostumuksen ja valmistusolosuhteiden arviointi osoitti, että lääke- ja apuaineiden (polyvinyylipyrrolidoni (PVP), Soluplus^®) määrät olivat tärkeimmät kalvojen mekaanisiin ominaisuuksiin vaikuttavat tekijät. PVP:n määrä lisäsi PPZ:n liukenemista ja PPZ:n vapautuminen noudatti ajan neliöjuuri -kinetiikkaa. Tutkimuksessa käytettiin ensimmäistä kertaa MP-SPR-menetelmää, jolla saatiin reaaliaikaista tietoa kalvoissa tapahtuvista fysikaalisista muutoksista. Ohutkalvovalmisteiden fysikaalista säilyvyyttä tutkittiin vuoden ajan. Korkean lämpötilan ja kosteuden todettiin aiheuttavan PPZ:n kiteytymistä erityisesti kaksifaasisissa kalvoissa. Sen sijaan alhaisessa lämpötilassa ja kosteudessa PPZ pysyi amorfisena. PPZ:n kiteytymisen havaittiin vaikuttavan kalvojen mekaanisiin ominaisuuksiin ja PPZ:n in vitro vapautumiseen kalvoista.

Hyvin suunnitellut ja laaja-alaiset tutkimukset ovat tärkeitä lääkevalmisteiden suunnittelussa ja valmistuksessa. Lämpötila ja suhteellinen kosteus voivat vaikuttaa lääkeaineen amorfisuuteen ja niitä on tärkeä valvoa valmistuksen ja varastoinnin aikana.

Perinteisten menetelmien lisäksi uusia menetelmiä, kuten MP-SPR:tä, voidaan hyödyntää tutkittaessa ohutkalvovalmisteissa tapahtuvia muutoksia.

Luokitus:QV 778, QV 779, QV 785, QV 786.5

Yleinen suomalainen asiasanasto: farmasian teknologia; lääkeaineet; annostelu; ohutkalvot; polymeerit;

liukoisuus; fysikaaliset ominaisuudet; vapautuminen; säilyvyys; stabiilius; varastointi

(14)

(15)

Acknowledgements

The present study was carried out in the School of Pharmacy, University of Eastern Finland, Kuopio during the years 2013-2016. The work was conducted as a part of the Doctoral Programme in Drug Research.

My supervisors were Docent Riikka Laitinen (Ph.D.), Associate Professor (Tenure Track) Professor Ossi Korhonen (Ph.D.) and Professor Jarkko Ketolainen (Ph.D.). I express my sincere gratitude to my principal supervisor, Riikka. You have a positive attitude and you have always been there for me to support me in the ups and down of reseach. I sincerely appreciate my second supervisor Ossi. You have such great ideas. In addition, I express my gratitude to my third supervisor Jarkko for giving me the chance to undertake this doctoral thesis and for his support during the study.

Professor Georgios Imanidis, Ph.D., from the School of Life Sciences, University of Applied Sciences NW Switzerland and Department of Pharmaceutical Sciences, University of Basel, and Senior Researcher Tapani Viitala, Ph.D., from the Faculty of Pharmacy, Division of Pharmaceutical Biosciences, University of Helsinki, are greatly appreciated for reviewing this thesis. Their valuable comments helped to improve the content of thesis. I am honoured that Jyrki Heinämäki (Ph.D.), from the Institute of Pharmacy, Faculty of Medicine, University of Tartu, has agreed to be the opponent of my dissertation on the occasion of its public examination. I am very grateful to Ewen MacDonald (Ph.D.) for proofreading this thesis.

I warmly wish to thank my co-authors Niko Granqvist, Ph.D, Mirja Poikolainen (former Savolainen) M.Sc. (Pharm) and Elina Smolander M.Sc. (Pharm.). Niko, I am very grateful to you for introducing me to multi-parametric surface plasmon resonance, and for your advice and contribution to article II. Mirja and Elina, I am very thankful for your valuable assistance.

I wish to thank all my colleagues and friends in the university during these years. I am especially grateful to Tarja Toropainen, Ph.D. (Pharm.) and Piia Siitonen Ph.D. (Pharm.) for sharing many things related to reseach and teaching. I also wish to thank Päivi Tiihonen, B.Sc. (Pharm.) for many cheerful moments.

I owe my warmest thanks to my whole family and relatives. I am very grateful to my parents Leila and Seppo, and my parents-in-law Sirkka and Matti for their support during these years. I want to thank all my friends near and far that have been part of my life throughout these years. After this, I will have more time for you.

Finally, but not least, I want to thank my family, Pasi and my children Eveliina, Katariina and Mikko. This thesis is dedicated to you.

Kuopio, April 2017

Kristiina Korhonen

(16)

(17)

List of the original publications

This dissertation is based on the following original publications:

I Korhonen K, Poikolainen M, Korhonen O, Ketolainen J and Laitinen R.

Systematic evaluation of a spraying method for preparing thin Eudragit-drug films by design of experiments. Journal of Drug Delivery Science and Technology 35:

241-251, 2016.

II Korhonen K, Granqvist N, Ketolainen J and Laitinen R. Monitoring of drug release kinetics from thin polymer films by multi-parametric surface plasmon resonance. International Journal of Pharmaceutics 494: 531-536, 2015.

III Korhonen K, Smolander E, Korhonen O, Ketolainen J and Laitinen R. Effect of storage on the physical stability of thin Eudragit-perphenazine films. European Journal of Pharmaceutical Sciences 104: 293-301, 2017.

The publications were reused with the permission of the copyright owners.

(18)

(19)

Abbreviations

A Surface area

ATR Attenuated total reflectance BEMA BioErodible MucoAdhesive BCS Biopharmaceutical

classification system co Initial drug concentration cs Solubility of the drug in the

polymer carrier

D Drug diffusivity in the polymer carrier

DoE Design of experiments DSC Differential scanning

calorimetry EC Ethylcellulose

EDQM European Directorate for the Quality of Medicines &

Health Care

eMC electronic Medicines Compendium EPO Eudragit^® E PO

EU European Union

δ Solubility parameter FDA U.S. Food and Drug

Administration

FTIR Fourier-transformed infrared spectroscopy

GI Gastrointestinal HEC Hydroxyethylcellulose

HPC Hydroxypropylcellulose HPLC High-performance liquid

chromatography HPMC Hydroxypropylmethyl-

cellulose

ICH International Council for Harmonisation

k Rate constant

logP Octanol-water partition coefficient

Mt Cumulative amount of drug released at time t

Mw Molecularweight

M^∞ Cumulative amount of drug released at infinity

MC Methylcellulose

MLR Multiple linear regression – analysis

Mp Melting point

MP-SPR Multi-parametric surface plasmon resonance M^w Molecular weight

n Indicative of the mechanism of drug release

NaCMC Sodium

carboxymethylcellulose ODF Orodispersible film PAA Polyacrylic acid

(22)

PC Polycarbophil PEG Polyethylene glycol PEO Polyethylene oxide Ph. Eur. European Pharmacopeia PLM Polarized light microscopy PPZ Perphenazine

PSA Pressure sensitive adhesive PVA Polyvinyl alcohol

PVP Polyvinylpyrrolidone RH Relative humidity RLPO Eudragit^® RL PO

SEM Scanning electron microscopy SPR Surface plasmon resonance

t Time

Tg Glass transition temperature USP United States Pharmacopeia

W Weight

XRPD X-ray powder diffraction

(23)

(24)

(25)

1 Introduction

Pharmaceutical thin films consist of diverse film preparations that are intended for several administration routes and have different drug release properties. According to the definitions in the United States Pharmacopeia 36^th Edition (USP 2012): “Film is used to describe a thin, flexible sheet of material, usually composed of a polymer. Films are used in various routes of administration of a material in rapidly dissolving form“. In addition, films can contain one or more layers, and a layer may or may not contain a drug substance. Instead, the FDA (U.S. Food and Drug Administration) classifies film dosage forms as films (i.e. a thin layer), soluble films and extended release films (FDA 2015). In addition, a wafer is defined as a thin slice of material containing a drug. The European Pharmacopeia 9^th Edition (Ph. Eur. 2016) does not provide an exact definition of the term “film”.

Films (Figure 1.1) are usually administered oromucosally but they can also be used cutaneously/transdermally, vaginally and ocularly (Qi et al. 2013, Machado et al. 2015, Boateng and Popescu 2016, Chan et al. 2016, Senta-Loys et al. 2016). In USP 36^th edition, monographs to buccal, oral and sublingual films can be found. Instead, the Ph. Eur. has a monograph about Oromucosal preparations, which are divided into several subcategories for example into orodispersible films (ODFs) and mucoadhesive preparations. According to the definitions of Ph. Eur.: “ODFs are single- or multilayer sheets of suitable materials, to be placed in the mouth where they disperse rapidly”. In addition, “Mucoadhesive preparations contain one or more active substances intended for systemic absorption through the buccal mucosa over a prolonged period of time. They may be supplied as mucoadhesive buccal tablets, as buccal films or as other mucoadhesive solid or semi-solid preparations. They usually contain hydrophilic polymers, which on wetting with the saliva produce a hydrogel that adheres to the buccal mucosa; in addition, buccal films may dissolve. Buccal films are single- or multilayer sheets of suitable materials”.

Moreover, oromucosal preparations can be sub-divided into those intended to achieve a systemic effect and those which are local preparations. If they are to achieve a systemic effect, the preparations have to be designed to be absorbed from different locations on the oral mucosa (for example sublingual preparations). When a local effect is intended, the preparations are designed for application to a specific site within the oral cavity (for example, gingival preparations).

Overall, there is no official classification and this explains why there are different definitions. Figure 1.1 is a schematic presentation of pharmaceutical thin film preparations and their routes of administration. In the literature, several terms are used for pharmaceutical thin films depending on the disintegration time or their design or their route of administration (Borges et al. 2015a, Silva et al. 2015). For example, oral films have been divided into three types according to their properties i.e. dissolution: flash release, mucoadhesive melt-away wafers and mucoadhesive sustained release wafers (Garsuch and Breitkreutz 2009, Nagaraju et al. 2013). Typically, oral thin films have a thickness of 20–500 µm. Thin films, which have thicknesses of only a few micrometers, have also been developed (Qi et al. 2013).

(26)

Figure 1.1. Pharmaceutical thin film preparations and their routes of administration (light grey according to Ph.Eur.).

Pharmaceutical thin films may represent interesting alternatives to traditional dosage forms (Barnhart 2008, Susarla et al. 2013, Silva et al. 2015). Thin films have many advantages such as convenient administration without an applicator or liquid, low unit dose cost, portability and ease of storage (Barnhart 2008, Repka et al. 2011, de Araujo Pereira and Bruschi 2012, Trastullo et al. 2016). Moreover, thin films have other advantages which are also related to route of administration such as bypassing first-pass metabolism, tailored (fast or controlled) release, precise dosage, and site specific and/or local action (Repka et al. 2011, de Araujo Pereira and Bruschi 2012, Susarla et al. 2013). It has been estimated that as many as 24% of patients using oral medication experience problems on a daily basis swallowing solid oral dosage forms, such as large tablets (Shiele et al. 2012). Therefore, thin oral films would be a good choice for pediatric patients and geriatric patients and patients being treated with oral chemotherapeutics all of whom have difficulties swallowing tablets i.e. this would be a good way to improve patient compliance (Barnhart 2008, Reiner et al. 2010a).

However, there are some disadvantages; high doses cannot be incorporated into a thin film.

In addition, a film has to be handled with dry hands and one must also avoid touching the film with fingers (or the tongue) after its placement into the mucosal surface.

Thin films are usually produced by casting or by solid extrusion (Barnhart 2008). The formulation and manufacturing of thin films encounters many challenges (Bala et al. 2013).

It may be difficult to achieve the small thickness of the film and to ensure dose uniformity.

Furthermore, packaging of films is difficult and it requires special equipment. However, it has been stated that preparation methods for thin films have the potential for scaling-up, continuous processing and cost effective manufacturing (Dixit and Puthli 2009, Susarla et al.

2013).

There are several evaluation methods which can be used to characterize thin films.

However, new, more sensitive characterization methods and in addition, comprehensive and long term evaluations of stability of thin films are needed. The focus of this thesis is on the formulation, manufacturing and evaluation of thin pharmaceutical films. In the experimental section, a novel spraying method was evaluated and used, and the manufacturing conditions were optimized by the Design of Experiment (DoE) protocol to achieve thin polymer-drug films with good mechanical and drug release properties. The properties of thin films and the physical stability of the drug were investigated with different analytical methods in order to identify the optimal formulation for a poorly soluble model drug, perphenazine.

(27)

2 Background of the Study

The background of the study will provide a general insight into different route of administrations, formulations, manufacturing methods and evaluation methods of thin films.

2.1 ROUTES OF ADMINISTRATION OF THIN FILMS

Pharmaceutical thin films are versatile with regards to the route of drug administration.

Thin films can be administered oromucosally, cutaneously/transdermally, vaginally and ocularly (Nagaraju et al. 2013, Machado et al. 2015, Chan et al. 2016).

The thin mucoadhesive films deliver drugs through the oral mucosa - sublingual, gingival, palatal or buccal mucosa - after which the drug is absorbed systemically or can exert a local effect (Salamat-Miller et al. 2005, Repka et al. 2011, Kianfar et al. 2012, Silva et al. 2015). In addition, the advantages of mucosal delivery are its rapid access to the systemic circulation since the mucosa is highly vascularized, avoiding first pass drug metabolism and pre-systemic elimination of the drug in the gastrointestinal (GI) tract. The oral mucosa surface area is about 100 cm² (Rossi et al. 2005).The thickness of the sublingual mucosa is 100–200 µm, in the buccal mucosa, it is thicker - 500–800 µm (Patel et al. 2011, Lam et al.

2014). Thus, the most readily permeable area is the sublingual mucosa i.e. rapid action is possible whereas for sustained release, the buccal region is a better option (Salamat-Miller et al. 2005, Laffleur 2014). The permeability of the buccal mucosa is less than that in the intestine but approximately 4–4 000 times greater than that of the skin (Shojaei 1998, Salamat-Miller et al. 2005, Hearnden et al. 2012). In addition to the good permeability of oral mucosa, physiological aspects of the oral cavity such as pH (between 6.5 and 6.9), fluid volume and enzyme activity are important (Patel et al. 2009). The possible enzymatic degradation of drug in saliva has to be taken into consideration. However, buccal mucosa has relatively low enzymatic activity (Repka et al. 2011). Some other disadvantages may be encountered; too rapid elimination of drugs, non-uniform distribution of drugs in saliva and tongue movements (Kianfar et al. 2012). The main barrier in the oral mucosa is the outermost part of the epithelium (Figure 2.1) (Patel et al. 2011, Hearnden et al. 2012, Laffleur 2014). There are three main mechanisms of diffusion across the oral mucosa i.e. passive diffusion (both paracellular and transcellular), carrier-mediated diffusion, and endocytosis.

Passive diffusion is the primary mechanism but a drug can use simultaneously other transport mechanisms. However, depending on the nature of drug, it may be possible to target one particular transport mechanism i.e. a lipophilic drug may prefer the transcellular pathway.

The drug can also be absorbed into the systemic circulation after orodispersible films are placed in the mouth but their contents are swallowed and absorbed from the GI tract (Borges et al. 2015a). However, changes in GI pH, unpredictable GI transit, the presence of intestinal flora and digestive enzymes may influence drug efficacy (Patel et al. 2011).

Dissolvable films can also be considered as gastro-retentive dosage forms for example to treat gastrointestinal disorders where the dissolution of the films could be triggered by the pH (Nagaraju et al. 2013).

The main advantages of the vaginal route are the possibility to bypass first-pass metabolism, its relatively large surface area, rich blood supply, ease of administration without an applicator, high permeability for low molecular weight (Mw) drugs and accurate dose administration (de Araujo Pereira and Bruschi 2012, Zhang et al. 2014a, Machado et al.

2015). The vaginal wall consists of three layers: the epithelial layer, the muscular layer and

(28)

tunica adventitia (de Araujo Pereira and Bruschi 2012, Machado et al. 2015). The vagina is elastic and possesses numerous folds; it secretes a large amount of fluids. However, these fluids may alter the absorption characteristics of a vaginal product and thus reduce the efficacy of the drug. Moreover, other disadvantages are personal hygiene and local irritation.

Figure 2.1.The structure of the oral mucosa and diffusion across the oral mucosa (Hearnden et al. 2012).

Figure 2.2.The structure of the cornea (Gause et al. 2016).

The cornea consists of three layers: the outer layer is the epithelium, followed by the stroma and on the inside there is the endothelium (Figure 2.2) (Gause et al. 2016). The epithelium has a high lipid content and is mainly composed of cells with tight junctions, thus it exhibits significant resistance to the transport of hydrophilic drugs. Instead, there is a hydrophilic stroma that poses a significant resistance barrier to lipophilic drugs. Thus, a drug needs to have an appropriate balance between lipid and water solubilities for effective corneal permeation. By increasing the contact time, one can extend drug delivery, reduce systemic effects, increase bioavailability and thus improve patient compliance (Boateng and Popescu 2016). Ocular inserts and contact lenses (both dosage forms are thin ocular films) have been developed to maintain the drug on the surface of the eye for a relatively longer time than can be achieved with eye drops (Bernards et al. 2013, Guzman-Aranguez et al.

(29)

2013, Clavalho et al. 2015). Moreover, erodible and mucoadhesive thin films have been claimed to make possible topical ocular drug delivery (Hermans et al. 2014, Chan et al.

2016). Moreover, visual clarity should be maintained and no irritation, inflammation and infection should occur while using ocular films (Boateng and Popescu 2016).

Figure 2.3.The structure of the skin and penetration pathways (Alexander et al. 2012).

Transdermal delivery is a route often used for topical drug delivery because of the large surface area of skin and its easy accessibility (Hearnden et al. 2012). Even if transdermal delivery in general is favored by patients as it is self-administrable and painless, patient compliance can be impaired e.g. due to repetitive daily applications of ointments; the use of thin films can overcome these problems (Lunter and Daniels 2012, Frederiksen et al. 2015).

However, the greatest challenge in the development of transdermal delivery systems has been finding ways to overcome the highly impermeable, keratinized and outermost layer of the skin, the stratum corneum (Figure 2.3) (Hearnden et al. 2012). Most drug molecules permeate across the stratum corneum by intercellular, intracellular (transcellular) and follicular pathways (Alexander et al. 2012). In addition, the penetration through the skin depends on other factors, for example the condition of the skin, area of application and contact time.

2.2 FORMULATION OF THIN FILMS

The typical thin film is composed of 5–30% w/w of drug, at least 45% w/w polymer, 0–

20% w/w plastizers (Dixit and Puthli 2009) and 0–40% w/w of other excipients (Jyoti et al.

2011). For example, the surface area of an orally dissolving thin film depends on the required dose and drug loading (Bala et al. 2013). The area is generally between 2 and 8 cm². If the films have a larger surface area, this often leads to rapid disintegration and dissolution (Sievens-Figueroa et al. 2012, Krull et al. 2015a). The area of vaginally dissolving films should not exceed 8 cm² (Reiner et al. 2010b). The thickness of the thin films usually varies between 20 µm and 500 µm, depending on their composition. The thickness of ODFs should be less than 100 µm in order to maintain good wettability and achieve rapid dissolution on contact with saliva (Repka et al. 2011). If the thickness of a film is more than 70 µm, then it may cause an unpleasant feeling in the mouth (Garsuch and Breitkreutz 2009). However, the exact thickness of thin films on the market is usually not known. The mass of

(30)

immediate-release ODF is in a range of 50–200 mg which is four times smaller than the mass of rapidly disintegrating tablets (i.e. 200–750 mg) (Barnhart 2008). The structure of thin films is either a single layer or a multilayer system (Subedi et al. 2010, Preis et al. 2015, Anandhakumar et al. 2016). Multilayer systems can be used to modify disintegrating and drug-releasing properties. Moreover, a fast release layer combined with a sustained release layer is capable of achieving both rapid and sustained effects (Repka et al. 2011). The backing layer ensures a unidirectional drug release when the film is attached to mucosal tissue (Patel et al. 2011, Preis et al. 2014a). The appearance of the thin films has an influence on the acceptance of the dosage form from the patient's perspective (Patel et al. 2011, Woertz and Kleinbudde 2015a). A low-dose film with a smooth surface is more desirable than films with rough surfaces. It may be possible to achieve a burst effect of drug from thin films i.e.

rapid action followed by sustained release (Garg et al. 2010).

The high flexibility and low adhesion properties of the film ensure that the film is both physically desirable and easily handled (Bangalore 2009, Woertz and Kleinbudde 2015a).

Thus, films cannot be fragile or sticky, they must be easily removed from packaging and placed on a mucosal surface or onto skin. Thin films are packed into single or multiple dose packages not only due to their moisture sensitivity but also to provide mechanical protection (Garg. et al. 2010, Nagaraju et al. 2013). However, single dose packages are preferred since thin films can stick to each other thus resulting in overdosing (Barnhart 2008). Some kind of secondary package may be needed with multiple dose packaging (Garg.

et al. 2010, Nagaraju et al. 2013). The shelf life of films is typically up to 2 years and storage conditions are usually at room temperature, under 30 °C.

It is a challenging task to develop good thin films. For example, disintegration time, mechanical strength and stability of the drug in the formulation have to be considered as well as the features specific to the administration route, such as palatability (taste, smell, texture and aftertaste) of the formulation (Cilurzo et al. 2011, Liew et al. 2012). A factorial design can be employed to study the effect of independent variables for example the influence of polymers on characteristics of the film which in turn helps define the crucial steps in formulation development as these consequently may help to rationalize time and resources (Landová et al. 2014, Visser et al. 2015a, Parhi and Suresh 2016).

2.2.1 Film-forming polymers

The polymers used in film formulations should possess the following properties: non- toxicity and non-irritating, inexpensive, good wetting and spreading ability, adequate shelf life, good peel, shear, and tensile strength (Hearnden et al. 2012, Bala et al. 2013) and they should not cause any secondary infections or retard the disintegration time of the film. The polymer should also be tasteless and biodegradable. An ideal mucoadhesive polymer should display strong and rapid adhesion to mucosa, and an ability to overcome the highly hydrated, enzymatic and non-static environmental conditions of the oral or vaginal cavity (de Araujo Pereira and Bruschi 2012).

The thin films contain variable compositions of ingredients in order to achieve the desired properties (Borges et al. 2015a). The film former concentration can be in the range of 5–99% w/w and films can be composed of one or more polymers (Bangalore 2009). The type or grade and concentration of the polymer determines the characteristics of the film, such as its mechanical strength (Irfan et al. 2016). In flash release or mucoadhesive melt-away wafers/thin films, the polymer should be a soluble hydrophilic polymer (Barnhart 2008). For example, the water soluble polymer content is typically 40–50% w/w in oral films since this ensures their rapid disintegration while maintaining good mechanical properties for the films (Jyoti et al. 2011). If one increases the molecular weight of the film-forming polymer, the disintegration rate of the films is decreased. Instead, in mucoadhesive sustained release wafers, the polymers should be low- or non-soluble. There are several water soluble polymers in use, for example methylcellulose (MC) and hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), sodium alginate and maltodextrins (Sinko 2011, Handbook of

(31)

Pharmaceutical Excipients 2016). Water-insoluble polymers form a swellable network through covalent or ionic bonds via a crosslinking agent (Lee et al 2000, Morales and McConville 2011). There are also several water-insoluble polymers for example chitosan, ethylcellulose (EC) and polycarbophil (PC).

Polymers can also be classified according to their origin i.e. natural, semi-synthetic and synthetic polymers (Lee et al. 2000, Sinko 2011, Gu and Burgess 2014). Pectin, starch and sodium alginate are examples of natural polymers (Lee et al. 2000, Salamat-Miller et al. 2005, Handbook of Pharmaceutical Excipients 2016) whereas cellulose derivates, poly(acrylic acid)-based polymers, polyethylene oxide (PEO), PVP and polyvinyl alcohol (PVA) are synthetic polymers. The most commonly used film-forming polymers in drug formulations are shown in Table 2.1.

In general, mucoadhesion occurs via chain interlocking, conformational changes and secondary chemical interactions and they are induced by interdiffusion or interpenetration of mucoadhesive polymer chains and mucus glycoprotein chains (Madsen et al. 1998).

Polymers can be divided according to the way that they bind to the mucosa: ionic polymers, neutral polymers and thiomers (Lee et al. 2000, Laffleur 2014). The most effective anionic polymers seem to be polyacrylates and sodium carboxymethylcellulose (NaCMC) (Morales and McConville 2011, Laffleur 2014). Their carboxy group is responsible for the mucoadhesion. Instead, cationic polymers undergo ionic interactions with anionic substructures in mucosa; the most important cationic polymers are chitosan and polylysine.

In the case of non-ionic polymers, mucoadhesion is independent of the pH value and they are less adhesive than anionic or cationic polymers. For example, PEOs are able to create hydrogen bonds with surrounding fluids. There are other examples of non-ionic polymers e.g. PVA, PVP, PC and celluloses such as hydroxyethylcellulose (HEC)(Morales and McConville 2011). A few polymers are amphiphilic i.e. they have both anionic and cationic substructures. Thiomers have thiol groups on their polymeric backbones and they are able to form covalent bonds with the mucus gel layer (Bernkop-Schnurch and Steininger 2000).

For example, PC and chitosan-thioglycolic acid are anionic and cationic thiolated polymers, respectively (Laffleur 2014). Furthermore, several properties of the polymer such as its molecular weight, polymer chain flexibility, concentration and extent of swelling can influence its mucoadhesive function (Lee et al. 2000, Salamat-Miller et al. 2005). For example, low-molecular weight polymers can penetrate through the mucus layer. In addition, the rheological properties of the polymeric formulations are likely to have an impact on their bioadhesion and thus on their overall retention duration (Eouani et al. 2001).

Chain interlocking, conformational changes and secondary chemical interactions are induced by interdiffusion or interpenetration of mucoadhesive polymer chains and mucus glycoprotein chains (Madsen et al. 1998). The changes in the rheological properties of the interfacial region may be produced to strengthen the adhesive joint. Pressure sensitive additives (PSA) used in transdermal films adhere to the skin (Subedi et al. 2010). The PSAs most widely used in transdermal films are acrylic, rubber and silicone based adhesives.

Starch is useful due to its wide availability, biodegradability and low cost (Mali et al.

2004). However, pure starch films are usually brittle, tacky and lack adequate strength. If the glass transition temperature (Tg) is lowered by adding a plasticizer or by increasing the moisture content, the polymer will become more flexible and thus the films are more extensible, but also weaker (Koch et al. 2010). Several starch derivatives such as maltodextrin, hydroxypropyl starches, pre-gelatinized starches and pullulan, have been developed to overcome the dissolution problems and poor mechanical properties of pure starch (Borges et al. 2015a, Krull et al. 2015b).

Cellulose derivates are also widely used (Table 2.1)(Morales and McConville 2011).

Hydroxypropylmethylcellulose (HPMC) is a good film former with different grades available (Irfan et al. 2016). In HPMC, the higher hydroxypropoxyl/methoxyl ratio (commercial product Type K) leads to the ready establishment of a gel barrier and this can delay the release of the drugs (Repka et al. 2005, Kumria et al. 2013,) Instead, if there is a

Development of thin film formulations for poorly soluble drugs

uef.fi

Dissertations in Health Sciences

KRISTIINA KORHONEN

DEVELOPMENT OF THIN FILM FORMULATIONS FOR POORLY SOLUBLE DRUGS

KRISTIINA KORHONEN

Development of Thin Film Formulations for

Poorly Soluble Drugs

Development of Thin Film Formulations for Poorly Soluble Drugs

Acknowledgements

List of the original publications

Contents

Abbreviations

1 Introduction

2 Background of the Study