Development of a New Delivery Modality Based on Oral ...€¦ · DRUG DELIVERY » Development of a New Delivery Modality Based on Oral-Soluble Postage Stamp Size Films Zheng Lu, Reza

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Development of a New Delivery Modality Based on Oral-Soluble Postage Stamp Size Films

Zheng Lu, Reza Fassihi*

School of Pharmacy, TemtJie Umversrty, Plu/adelphro, PA

'(ormpondmg author: reta fossrlui}temple.edu

Lb I Ho •\ ll' \ \ I March 2016

Introduction

In recent years, many scientists In the pharmaceutical Industry are

focusing part of their research activity on the development and use

of oral strip technology (OST)'. Medicated oral strips can be used

for local effect2•1, rapid release and absorption as well as controlled­

release systemic drug delivery via mucoadhesive principles•·6 • The

advantages of OST include the ease of administration especially for

pediatric and geriatric patient population who may have the difficulty

of swallowing larger oral dosage forms. It also offers an alternative

platform for molecules that undergo hepatic first-pass metabolism

and avoids the drug degradation and pre-systemic elimination

within the gastrointestinal tract7·8• Table 1 lists some commercially

approved oral strip products for transmucosa l drug delivery. However,

development of oral strip with high drug content uniformity, uniform

appearance and adequate physical and mucoadheslve strength

remains a challenge for pharmaceutical scientists especially when the

drug dose is high. Furthermore, lack of standardized test methods and

monographs in the US Pharmacopeia (USP) makes It more difficult to

develop and compare different oral strip products in terms of their

dissolution performance, formulation differences, excipient effects

and regulatory assessment.

Production of Medicated Oral Str ips

Oral strips are usually prepared by conventional casting methods

in which the solution or emulsion of the polymers, drug and other

exciplents Including plasticizers, sweeteners, surfactants, preservatives,

sa livary stimulating agents etc. are poured into a suitable mold and

allowed it to dry. This process usually consists of six steps including:

preparation of casting solution; deareation of the solution; transfer

of the prepared solution into an appropriate mold with defined

depth and volume; drying the deposited polymeric film; cutting the

- DRUG DELIVERY »

Ondansetron Rai>ldfilm• Labtec Gmbll Ondanse tron 4 mg and 8 mg Prevention of chemotherapy and radiation-Induced nausea and vomiting.

Oonezepll Rapldfltm• Labtec GmbH Oonepezll hyd•ochlo•lde 5 mg and 10 mg Treatmem of mild to moderately severe dementia or the

Alzheimer's tys>c

ChiOJasepttc• Relief St1ipsTM lnnot cn Inc Benzocaine l mg Occasiont~l minor irritat ion. pain. sore throat and sore mouth

Supp1essTM Cough st1ips with Oext•omothOiphan

lnnozen Inc Dexttomethorphan h)ldrobromlde 2.5 mg TempoJtully suppu~sses coughs due to minor throat and Uronchial Irr itation associa ted with cold Inhaled Irrit an ts.

Tliamlnlc TI1in Strlt» ' Cough & llunnyNosc

Novar tis OlphenhydrMllnc I ICI 12.5 rug J Tempowrlly ICiicves cough due to minor throat and bronchial irritation occurring wi th a cold. Temporarily relieves Itchy, watery

eyes cll le to hay rever.

Theraflu• Daytime Thin Strips Novarels Ocxtr(Hl)ethorphan 14.8 mg. Phc nylcptu inc HCI 10 mg Relieves n inal and sinus congC)tlon due to cold. Reduces cough.

Onsolis• BioOelivcry Science lntcmat lonal Fentanyl buccal soluble f1lm Management or breakthrough pal" In opioid-toiNant

cancer patients

j Gunavall' (but>rcnorphlno and naloxone buccal f1im)

BloOcl lvcry Science lntcrn il tlonnl Uuprenorphlrle 6 3 mg

Naloxone I mg

prepared oral film into the desired size; and packaging of the final

oral strip product. When manufacturing the oral strips using the

casting method, particular attention must be given to the rheological

properties of the casting solution, absence of entrapped air bubbles,

film uniformity and content uniformity in the final dosage form.

Oral films can also be prepared by using other technologies such as

direct compression and hot-melt extrusion (HME)9•10

. The advantages

of using the HME technique is that it avoids the use of water or

other organic solvents and therefore expedites the drying process.

However, it is undesirable for heat labile drugs and the mixing is less

homogeneous compared to preparation of a drug-polymer solution.

In-vitro Characterization of Medicated Oral Strips

Characterization of critical properties such as the mechanical strength,

drug content uniformity, dissolution rate and permeation rate

represent some of the major research areas in the design of oral strips.

Content uniformity is a major challenge associated with the

conventional solvent casting method. Historically production of films

have suffered from particle aggregation and non-uniformity due to the

large number of excipients used In their formulation including, soluble

polymers, surfactants, flavors, sweeteners, plasticizers, preservatives

and drugs. Yang et al. indicated that self-aggregation was one of the

main causes of poor uniformity and in particular the relatively long

drying time was found to facilitate intermolecular attractive forces,

convection forces, air bubbles and the like to form such aggregation".

The formed agglomerates randomly distribute inside the cast fi lm and

result in an inaccurate amount of active ingredient Inside each strip

after the cutting process. In order to obtain uniform oral strips, many

attempts have been made such as optimization of film composition,

addition of viscous agents such as gel formers or polyhydric

alcohols' ~· 11, use of controlled drying process for example radiation

drying". Furthermore other techniques for determining drug content

assay, such as X-ray d iffraction, and scanning electron microscopy

can be used to evaluate the content uniformity of oral strips.

28 I Hr•\'lt ' \\ I March 2016

Malntcuance treatment or oploid dcpc11dcnce

Non-aggregating strips are characterized as an amorphous state with

the absence of significant sharp peaks during X-ray diffraction (XRD)

analysis. A rough and uneven surface with lumps In the microscopic or

SEM images of oral strips Is an Indicator of self-aggregation and non­

uniformly dispersed formulation.

The determination of properties of polymeric films including oral strips

is based on standard mechanical testing methods as presented in this

work using textural analyzer (Figure 1 )11• During the tensile testing,

the oral strip was mounted between two clamps and the stress­

strain curve (or load-time profile) was recorded when the strips were

pulled by the top clamp at a fixed rate. From the stress-strain curve,

the tensile strength, percentage elongation at break and the elastic

modulus (also known as Young's modulus) are calculated.

Despite intensive work on oral strip technology, there is no official

standardized method or monograph in the US Pharmacopeia (USP)

for evaluating its "in vitro dissolution" behavior. Most of the studies

have used the paddle over disc method (similar to USP apparatus 5) to

assess the release of drug from the prepared films '0·". Briefly, the film

is fixed on a glass plate and is immersed in the dissolution medium

below the paddle and the paddle is rotated at a fixed rotation per

minute (rpm) speed. Nevertheless, in most of the studies the provision

Figure 1. Texture analyzer equipped with grips for measuring the mechanical properties of oral strip (left) and typical load-time

profile of oral strip under mechanical stress (right).

« DltUl; DEI.IVERY c.

2-side release 1-side release

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Side-view <-""" ..., ,...,..., :==== +- Ot.a rn lwnli)le) ... ""'"'""' XXXXXXXXXlOCXX.XXXX.XXXX me"' xxxxxxxxxxxxxxxxxxxxx ..,.,h

Top-view

Or.- fihh~l t pl.a\lk titm

Figure 2. Modified UPS Apparatus II with double mesh assembly used for dissolution testing of oral-soluble films and illustration of 2-sfde and 1 · side release design.

has been made such that the drug release occurs from a single side of

the strip. This is inconsistent with the real situation "in vivo" where the

drug release can happen from both sides of the oral strip. Therefore,

our lab is proposing a modified UPS Apparatus II with double mesh

assembly to be considered for d issolution testing of ora l-soluble

films. The double mesh design allows the free drug release from both

sides of the oral strip. It also allow allows an easy switch from 2-side

to 1-side release by simply incorporated another plastic film between

the bottom mesh and the oral strip. Th is design offers more flexibility

compared to other methods (Figure 2).

Experin1ental Section

Moteriols nnrf mellwds

In one of the studies, we developed a new postage stamp size oral

strip of water-soluble model drug tramadol HCI using the casting

method according to the formu la shown in Table 2. The aqueous

solutions of each component were thoroughly mixed with the help

of a glass mortar and pestle then poured into the glass/plastic molds

w ith defined depth and dried inside the hood for 14 hours. The

resultant films were cut into stamp size (2.5 cmx1.75 em) oral strips

having fi nal composition (w/w) of 21 .78% API (tramadol HCI), 4.95%

carbopol, 49.5% PEO, 4.95% HPMC, 3.96% glycerol, 9.9% mannitol/

Ingredient Formulation 1 Formulation 2 Function

Carbopol 4.95 4.95 Polymeric matrix

PEO N·80 49.5 49.5 Polymeric matrix

HPMCK4M 4.95 4.95 Vi~cm1s agcut

Glyce•ol 3.96 3.96 Plasuslzcr

Manrlitol 9.9 Sweetening agent

5o•bltol 9.9 Sweetcnmg agent

Citric acid 4.95 4.95 Saliva stimulating i'lgcnt

T•amadol HCI 21.78 21.78 Active ingredient

sorbitol and 4.95% citric acid in the dry form. The dissolution studies

of prepared stamp size oral strips were carried out using modified

UPS apparatus II (paddle with double mesh assembly) (Figure 2) at a

stirring speed of 25 rpm and 50 rpm in 500 ml simulated saliva (pH 6.8)

at 37 oc. The samples were withdrawn at predetermined time intervals

and the percentage dissolved of the drug was determined using a UV

spectrophotometer at 271 nm. The rheological properties of the films

such as tensile strengths, percent elongation, viscoelasticity, structural

recovery were evaluated using a computerized textural analyzer.

Results and Discussion

The resultant stamp-size oral films have an average weight of

0.08g and average thickness of 140 1Jm. On exposure to modified

dissolution testing, the oral strips quick ly hydrated and about 80% of

the drug was released within 15 minutes at a stirring speed of 25 and

50 rpm irrespective of the type of mesh device assembly used (i.e.

2-side or 1-side release) (Figures 3 and 4). More consistent and slower

release was apparent when only one side of the fi lm was exposed to

dissolution medium.

Textural analysis of the prepared oral strips (without tramadoi·HCI)

showed acceptable physica l properties with tensile strength around

• __ s=i

-·-"·~ •o.cn.Jtloh • ,,,,..,.....,a.rp.., , .•• ''~.--~~~~--~~

~-rt,,~ • ....,.,, .• * -rt. pw•I.Or""'· '·~

Figure 3. Dissolution profiles of tramadol-HCI oral strip (Formulation 1) using modified dissolution apparatus II

with Inserted double-mesh assembly at stirring speed of SO rpm and 25 rpm. Drug release was occurring from 2-side and 1·slde

of oral strip.

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DRUG DEI.I VERY »

100

80

'2 60 >

~ i5 40 ~

20 --F1, paddle 50rpm, 1-slde -- F2, paddle 50rpm, 1-slde

0 0 5 10 16 20 26 30

Time (min)

Flgur~ 4. Comparison of dissolution rate of tramadoi-HCI from Formulation 1 and 2 when only one side of film was exposed.

Thickness (mm) 0.100± 0.0 14 0.087.1 0.007

I Tensile >!length (MPa) 5.6h0.77 5.61 :1. 0.56

I %Elongation at break 5.9710.68 8.16 .1 0.78

Clastic Modulus (MPa) 171.26 ± 24.68 162.18' 16.n

Work of Failure (KJ/m') 6.48 i 1.29 9. 11 ± 1.85

5.62 MPa, percent elongation at break of about 5.97% and 8.16%

under studied condition (Table 3).

Conclusion

This study highlights the importance of content uniformity and in vitro

characterization of oral strips using mechanical testing techniques and

proper dissolution methodology. As described in the experimental

section, a stamp-size oral-soluble fi lm with non-self-aggregating

characteristics was successfully developed with acceptable visco­

elasticity, physical strength and release of ~80% of the drug within

1 5 minutes using a casting method. Due to the ease of administration

and avoidance of hepatic first-pass metabolism, oral strip technology

has been explored extensively during the last decades. The goal is to

overcome some of the disadvantages associated with conventional

oral drug delivery where drug and the dosage form is extensively

exposed to the milieu of the gastrointestinal tract with potential d rug

degradation, metabolism, slower onset effect and consequently lower

bioavallabi lity. Oral strips offer an alternative dosage form for patients

~0 I I:,'\ 1< '\\ I March 2016

having difficulty in swallowing of tablets or capsules and exhibit ease

of administration and improved patient compliance. The oral strip

technology is an ideal choice for administration of potent drugs used

to treat acute conditions where rapid onset of action Is required. The

Improvement of manufacturing processes and evaluation of oral strips

presented in this work Is expected to assist pharmaceutical scientists

to produce oral strips with precise dose, better content uniformity and

esthetically more attractive dosage forms for patients.

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