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FORMULACIN Y EVALUACIN DE COMPRIMIDOS SUBLINGUALES CON SULFATO DE TERBUTALINA: ESTUDIOS...

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FORMULATION AND EVALUATION OF A SUBLINGUAL TABLET CONTAINING TERBUTALINE SULPHATE: OPTIMISATION...

Formulacin y evaluacin de comprimidos


sublinguales con sulfato de terbutalina:
estudios de optimizacin e in vivo
Formulation and evaluation of a sublingual tablet containing terbutaline
sulphate: optimisation and in vivo studies

NARENDRA C1,2,*, SRINATH MS1, PRAKASH B RAO2

Department
1
of Pharmaceutics, Government College of Pharmacy, Bangalore-27, India.
Department
2
of Pharmaceutics, Krupanidhi College of Pharmacy, Bangalore-34, India.
Autor de contacto *: C. Narendra, Department of Pharmaceutics, Krupanidhi College of Pharmacy,
# 5, Sarjapur Road, Near kudremukh Building, Koramangala, Bangalore, India. Cdigo PIN: 560 034.
Correo electrnico: narendragcp@rediffmail.com

RESUMEN
La finalidad de este trabajo de investigacin es la formulacin de un comprimido sublingual de sulfato
de terbutalina de accin rpida y mejorar la biodisponibilidad y el cumplimiento de las pautas por parte
del paciente. Para la preparacin de los grnulos se utiliz una tcnica de granulacin hmeda. Se
prepararon formulaciones basadas en el diseo factorial con variables de formulacin 3 2 : la cantidad de
celulosa microcristalina (MCC) (X 1 ) y la crospovidona como componente bioadhesivo (X 2 ). Como
variables de respuesta se evaluaron la resistencia al aplastamiento, la friabilidad y el tiempo de desin-
tegracin (DT). Los principales efectos y trminos de interaccin se evaluaron cuantitativamente median-
te un modelo cuadrtico. Los resultados revelaron que la cantidad de MCC y crospovidona afectaban
significativamente a las variables de respuesta. La formulacin optimizada de comprimidos contiene 31,5
mg de MCC y 4,5 mg de crospovidona, se desintegra en un perodo corto con un ndice DT de 30,2
+ 5,5 seg. y tiene una resistencia al aplastamiento suficiente y una friabilidad aceptable. Las concen-
traciones plasmticas de terbutalina se obtuvieron a los 5 minutos. Los resultados indican que la
crospovidona, un componente bioadhesivo, impide tragar la terbutalina, sin afectar a su liberacin y
absorcin. En conclusin, la formulacin del comprimido sublingual se puede extrapolar a otros frmacos
en los que se desee una absorcin rpida.
PALABRAS CLAVE: Crospovidona. Diseo factorial. Celulosa microcristalina. Optimizacin. Comprimidos sublinguales.
Sulfato de terbutalina.

ABSTRACT
The objective of this research was to formulate a sublingual tablet formulation of terbutaline for rapid
action, and to improve both bioavailability and patient compliance to therapy. A wet granulation technique
was adapted to prepare the granules. Granule formulations were prepared using an adapted wet granulation
technique based on a 3 2 full factorial design. The formulation variables were expressed as follows;
quantity of microcrystalline cellulose (MCC), (X 1 ), and bioadhesive component crospovidone, (X 2 ),
while crushing strength, friability and disintegration time (DT) were determined as response variables.
The main effects and interaction terms were quantitatively evaluated using a quadratic model. The results
obtained showed that the quantity of MCC and crospovidone significantly affect response variables. An
optimised tablet formulation, containing 31.5 mg of MCC and 4.5 mg of crospovidone, provides a short
DT of 30.2 + 5.5 sec with sufficient crushing strength and acceptable friability, while DT for serum
concentrations of terbutaline were obtained within 5 min. The results indicate that the inclusion of
crospovidone, a bioadhesive component, in sublingual tablet formulations, makes the swallowing of

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140 NARENDRA C, SRINATH MS, PRAKASH B RAO

tablets unnecessary, because the release and absorption of the terbutaline in such formulations is
acceptably effective. In conclusion, the developed sublingual tablet formulations is of interest, because
it can be extrapolated to other drugs, where rapid absorption is desirable.
KEY WORDS: Crospovidone. Factorial design. Microcrystalline cellulose. Optimisation. Sublingual tablets. Terbutaline
sulphate.

INTRODUCCIN INTRODUCTION

La cavidad oral se utiliza cada vez ms The oral cavity is increasingly being used
para la administracin de frmacos diseados for administration of drugs, which are mainly
principalmente para la absorcin de medica- designed for the absorption of contained me-
mentos y su introduccin en la circulacin dicines through the oral mucosa into the sys-
sistmica a travs de la mucosa oral. La va temic circulation. The sublingual route of
de administracin sublingual resulta til cuando administration is useful, when immediate drug
se desea conseguir una respuesta inmediata a action is desired. Such a method of adminis-
la accin del frmaco. Esta va de administra- tration provides potential for a rapid onset of
cin tiene un potencial de accin rpida y action with improved bioavailability and avoids
una mayor biodisponibilidad, a la vez que the need for preliminary hepatic elimination1.
permite evitar la primera eliminacin hepti- They also present the advantage of providing
ca1. Estas formas de dosificacin se disuelven fast dissolution or disintegration in the oral
o desintegran en la cavidad oral en un breve cavity, without the need for water or chewing.
perodo de tiempo, sin necesidad de agua ni Asthma is a multifactorial clinical syndro-
masticacin. me characterized by a triad of episodic
El asma es un sndrome clnico multifacto- wheezing, coughing and paroxysmal dyspnoea,
rial caracterizado por una trada episdica de due to an increased resistance to the flow of
resuellos, tos y dispnea paroxsmica debidos air through the narrowed bronchi2. Terbutali-
al aumento de la resistencia al paso del flujo ne sulphate (1-(3, 5-dihydroxyphenyl)-2-ter-
de aire a travs de unos bronquios estrecha- tiary butyl amino ethanol) is a 2 selective
dos2. El sulfato de terbutalina (1-(3, 5-dihi- bronchodilator, which is used for the long term
droxifenil)-2-aminoetanol butil terciario) es un treatment of obstructive airway diseases, and
broncodilatador selectivo 2. Se utiliza para el the treatment of bronchospasm3.
tratamiento a largo plazo de las enfermedades Conventional dosage forms for the mana-
obstructivas de las vas respiratorias y en el gement of asthma include tablets, capsules,
tratamiento del broncoespasmo 3. syrups, injections and metered dose inhalers.
Las formas de dosificacin convencionales Meter dose inhalers provide effective rapid relief,
disponibles para el tratamiento del asma son but at the same time, they present the disad-
comprimidos, cpsulas, jarabes, inyecciones vantage of requiring sophisticated equipment
e inhaladores con dosmetro. Los inhaladores to manufacture, may be harmful to the envi-
con dosmetro tienen la ventaja de la rapidez ronment and are expensive.
de sus efectos, pero sus desventajas son el In this study, an attempt has been made to
elevado grado de sofisticacin de los equipos formulate sublingual dosage formulations of
necesarios para su fabricacin, su elevado coste terbutaline by using experimental design te-
y que pueden ser perjudiciales para el medio- chnique4. A 32 full factorial design was used,
ambiente. where the independent variables were deter-
En este estudio se intenta formular presen- mined as the quantities of microcrystalline
taciones de terbutalina de dosificacin sublin- cellulose (MCC) and crospovidone. Based on
gual mediante una tcnica de diseo experi- the preliminary studies, the ranges for formu-
mental4. Se utiliz un diseo factorial 32, en lation variables were selected. The dependent
el que la variable independiente incluye la (response) variables were determined as; crus-
cantidad de crospovidona y de celulosa mi- hing strength, percentage friability and disin-
crocristalina (MCC). Los rangos de las varia- tegration time (DT). The data obtained were
bles de formulacin se seleccionaron en base fitted to a quadratic model and regression

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FORMULACIN Y EVALUACIN DE COMPRIMIDOS SUBLINGUALES CON SULFATO DE TERBUTALINA: ESTUDIOS... 141
FORMULATION AND EVALUATION OF A SUBLINGUAL TABLET CONTAINING TERBUTALINE SULPHATE: OPTIMISATION...

a los estudios preliminares. Las variables (de analysis was carried out, in order to obtain a
respuesta) dependientes evaluadas incluyen la quantitative relationship between the indepen-
resistencia al aplastamiento, la friabilidad por- dent variables. The optimised sublingual ta-
centual y el tiempo de desintegracin (DT). blet was subjected to pharmacokinetic studies
Los datos obtenidos se ajustaron en un mode- using Rabbits as animal model.
lo cuadrtico y se realiz un anlisis de regre-
sin para obtener una relacin cuantitativa entre
las variables independientes. El comprimido MATERIALS AND METHODS
sublingual optimizado se someti a estudios
farmacocinticos utilizando como modelo Materials
animal al conejo.
A gift sample of Terbutaline sulphate was
received from Astra Zeneca India Pvt. Ltd.
MATERIALES Y MTODOS Bangalore, India. Microcrystalline cellulose
(referred to hereafter as MCC) and crospovi-
Materiales done were supplied by Bangalore Pharmaceu-
tical Research Labs, (Bangalore, India). As-
La muestra de sulfato de terbutalina fue partame was obtained courtesy of Strides Arco
proporcionada gratuitamente por Astra Zene- labs, (Bangalore, India). Other materials were
ca India Pvt. Ltd., Bangalore, India. La celu- purchased from commercial sources; magnesium
losa microcristalina (en adelante denominada stearate from Loba chemicals, Bangalore, In-
MCC) y la crospovidona fueron proporciona- dia, mannitol from Reidel India chemicals,
das por Bangalore Pharmaceutical Research Bangalore, India, and sodium salts of methyl
Labs, (Bangalore, India). La muestra de as- and propyl paraben from Nice chemicals,
partamo fue proporcionada gratuitamente por Bangalore, India.
Strides Arco labs, (Bangalore, India). El resto
de los materiales utilizados se adquirieron a
proveedores comerciales: estearato de mag- Experimental design
nesio (Loba chemicals, Bangalore, India),
manitol (Reidel India chemicals, Bangalore, Factorial design is an experimental design
India), sales de sodio de metil y propil para- technique, from which the factor involved and
bn (Nice chemicals, Bangalore, India). its relative importance can be assessed 4. In
the present study a 32 full factorial design was
employed, containing 2 factors evaluated at 3
Diseo experimental levels (Table 1). The experimental trials were
performed at all 11 possible combinations and
El diseo factorial es una tcnica de dise- the two independent formulation variables eva-
o experimental mediante la cual se puede luated included:
evaluar el factor involucrado y su importan- X1 = amount of MCC.
cia relativa4. En el presente estudio se utiliz X 2 = amount of crospovidone.
un diseo factorial 32 con 2 factores evalua- The response variables tested included:
dos en 3 niveles (Tabla 1), y los ensayos ex- Y 1 = crushing strength.
perimentales se realizaron con las 11 combi- Y2 = disintegration time (DT).
naciones posibles. Las dos variables de Y3 = percentage friability.
formulacin independientes evaluadas son:
X1 = cantidad de MCC.
X 2 = cantidad de crospovidona. Preparation sublingual tablet
Las variables de respuesta analizadas in-
cluyen: Formulations were performed randomly
Y1 = resistencia al aplastamiento. following a 3 2 factorial design as shown in
Y2 = tiempo de desintegracin (DT). (Table 2). All the ingredients were passed
Y 3 = friabilidad porcentual. through a 80 mesh screen. The required quan-

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142 NARENDRA C, SRINATH MS, PRAKASH B RAO

Preparacin de los comprimidos sublinguales tities of mannitol, MCC and crospovidone were
mixed in a suitable stainless steel vessel in a
Las formulaciones se realizaron aleatoria- tumbler mixer (Rimek, Karnavati Engineering
mente segn el diseo factorial 3 2, como se Ltd. Ahmedabad, India) at 100 rpm for 30
indica en la Tabla 2. Todos los ingredientes min. Terbutaline was added to the above mixer
se pasaron por una pantalla de 80 mesh. Las in geometric ratio and mixed at 30 rpm. So-
cantidades requeridas de manitol, MCC y cros- dium salts of methyl and propylparaben were
povidona se mezclaron en un vaso de acero dissolved in water, and water was used as a
inoxidable adecuado en un mezclador de tambor granulating agent. Sufficient cohesiveness was
(Rimek, Karnavati Engineering Ltd. Ahmeda- obtained after thorough mixing of the above
bad, India) a 100 r.p.m. durante 30 min. Se mixture with the granulating agent had been
aadi terbutalina a dicho mezclador en pro- carried out, and the wet mass was subsequen-
porcin geomtrica y se mezcl a 30 r.p.m. tly sieved through 14 mesh screen. The granu-
Las sales de sodio de metil y propil parabn les were dried at 45 0C for 1 hour and the
se disolvieron en agua y se utiliz agua como moisture content was then determined (no
agente granulante. Despus de mezclar bien higher than 3%). The dried granules were
los ingredientes anteriores con agente granu- passed through 20 mesh screens, and were
lante y conseguir un grado de cohesin sufi- finally mixed with aspartame and magnesium
ciente, la masa hmeda se pas por un tamiz stearate. The granules were compressed using
de 14 mesh. Los grnulos se secaron a 45 0C a single-punch tablet compression machine
durante 1 hora y se determin el grado de (Cadmach, Ahmedabad, India) fitted with 5.5
humedad (no superior al 3%). Los grnulos mm standard concave punches. Preparation was
secos se pasaron por tamices de 20 mesh y performed in batches of 100 tablets.
por ltimo se mezclaron con aspartamo y
estearato de magnesio. Los grnulos se com-
primieron mediante una mquina monocom-
primidora (Cadmach, Ahmedabad, India) equi-
pada con troqueles cncavos estndar de 5,5
mm. Se prepararon 100 lotes de comprimi-
dos.

TABLA 1: Niveles de factores seleccionados para el diseo experimental utilizados en la formulacin


de los comprimidos sublinguales.
TABLE 1: Selected factor levels for the experimental design used in the formulation of sublingual tablets.

Factor Niveles
Factor Levels
Bajo Medio Alto
Low Medium High
X 1; celulosa microcristalina
X 1; Microcrystalline cellulose(mg) 10 30 50
X 2; crospovidona (mg)
X 2; Crospovidone (mg) 0.0 2.5 5.0

Evaluacin de los comprimidos Evaluation of tablets

Espesor Thickness

El espesor de los comprimidos sublingua- The thickness of sublingual tablets were


les se determin mediante un micrmetro di- determined using a digital micrometer (Miti-
gital (Mitituo, New Delhi, India). El clculo tuo, New Delhi, India). An average of 5 ta-
se realiz con 5 comprimidos de cada lote. blets from each batch was calculated.

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FORMULACIN Y EVALUACIN DE COMPRIMIDOS SUBLINGUALES CON SULFATO DE TERBUTALINA: ESTUDIOS... 143
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Prueba de variacin de peso Weight variation test

La prueba se realiz segn el mtodo ofi- The test was carried out in accordance with
cial descrito en I.P.5. Se midi la variacin de official method described in I.P. 5. Weight
peso en 20 comprimidos de cada lote y se variation was performed for 20 tablets from
calcularon los valores medios. each batch and average values were calcula-
ted.

Contenido de frmaco Drug content

Se determin el contenido de terbutalina The content of terbutaline in 10 tablets was


de 10 comprimidos mediante espectrofotome- analyzed spectrophotometrically 6. The avera-
tra6. Se calcul el contenido medio de frma- ge drug content was calculated.
co.

Crushing strength
Resistencia al aplastamiento
Crushing strength, the force required to break
La resistencia al aplastamiento de un com- a tablet in diametral direction through com-
primido es la fuerza requerida para partirlo pression, was measured with a Monsanto har-
diametralmente mediante compresin, y se dness tester (Cadmach, Ahmedabad, India).
midi con un medidor de dureza Monsanto
(Cadmach, Ahmedabad, India).
Friability

Friabilidad The friability of the tablets was determined


by using Roche friability apparatus (Campbe-
La friabilidad de los comprimidos se deter- ll Electronics, Mumbai, India) for 4 min. with
min mediante un equipo de friabilidad Ro- the drum rotating at a speed of 25 rpm. The
che (Campbell Electronics, Mumbai, India) test was performed in accordance with Euro-
durante 4 minutos a una velocidad de giro del pean Pharmacopoeia 7. The weight loss of 20
tambor de 25 r.p.m. La prueba se realiz se- tablets before and after measurement was cal-
gn las normas de la European Pharmacopoeia7. culated.
Se calcul la prdida de peso de 20 compri-
midos antes y despus de la medicin.
Drug dissolution

Disolucin del frmaco Dissolution test was performed according


to modified USP paddle method8 (Disso 2000-
La prueba de disolucin se realiz segn Lab India). The paddle rotation rate was 50
el mtodo de palas USP8 (Disso 2000-Lab India). rpm and 100 ml of phosphate buffer PH 6.8
La velocidad de rotacin de las palas fue de was used as dissolution medium maintained
50 r.p.m., y como medio de disolucin se at 370C. Aliquots were withdrawn at different
utilizaron 100 ml de tampn fosfato PH 6.8 time intervals, filtered and analysed spectro-
mantenido a 37 0C. Se extrajeron y filtraron photometrically for terbutaline against appro-
alcuotas a distintos intervalos de tiempo, que priate blank6. A constant volume of dissolu-
se analizaron mediante espectrofotometra para tion was maintained by adding an equal volume
la deteccin de terbutalina con el contraste of fresh medium, immediately on withdrawal
adecuado6. Para mantener un volumen de di- of the sample. The dissolution studies were
solucin constante se aadi un volumen de conducted in triplicates and the mean values
medio fresco igual al de la muestra extrada were plotted verses time with SEM, indicating
inmediatamente despus de la extraccin. Se the reproducibility of the results.

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144 NARENDRA C, SRINATH MS, PRAKASH B RAO

realizaron estudios de disolucin por triplica- Statistical analysis


do y se trazaron los valores medios en rela-
cin al tiempo con ESM, indicando la repro- The effect of formulation variables on the
ducibilidad de los resultados. response variables were statically evaluated
by applying one-way ANOVA at 0.05 level,
using the commercially available software
Anlisis estadstico package Design-Expert , version 6.05 (Stat-
Ease, Inc.). The design was evaluated using a
El efecto de las variables de formulacin quadratic model, which bears the form of
en las variables de respuesta se evalu esta- equation (1).
dsticamente mediante la aplicacin del anli-
sis de varianza unidireccional (ANOVA) en Y = b 0 + b 1 X 1+ b 2 X 2 + b 3 X 1 X 2 + b 4 X 12 + b 5
el nivel 0,05 mediante el paquete de software X2 2 eq-1
comercial Design-Expert versin 6.05 (Stat-
Ease, Inc.). El diseo se evalu mediante un Where y is the response variable, b 0 the
modelo cuadrtico, con una ecuacin de la constant and b1, b2, b3 b5 is the regression
forma (1): coefficient. X1 and X2 represent the main effect;
X 1X 2 are the interaction terms, which show
Y = b 0 + b 1 X 1+ b 2 X 2 + b 3 X 1 X 2 + b 4 how response changes, when two factors are
X 12 + b 5 X2 2 eq-1 simultaneously changed. X12, X22 are quadra-
tic terms of the independent variables used to
En la que y es la variable de respuesta, b0 evaluate no linearity.
la constante y b1, b2, b3 b5 el coeficiente de
regresin. X1 y X2 son el efecto principal; X1X2
son los trminos de interaccin, que muestran Pharmacokinetic studies
los cambios de la respuesta al cambiar simul-
tneamente estos dos factores. X 12, X 22 son Six healthy male albino rabbits weighing
los trminos cuadrticos de las variables inde- between 2.5 3.0 kg were fasted overnight.
pendientes para evaluar la no linealidad. Prior to tablet administration, the Rabbits were
anaesthetized with pentobarbital (25 mg/kg).
The optimised sublingual tablet containing 1.25
Estudios farmacocinticos mg of terbutaline (Table 6) was inserted su-
blingually and positioned in such a way that,
En el estudio se utilizaron seis conejos al- the tablet surfaces came into contact with the
binos macho sanos con un peso de entre 2,5 ventral tongue and the floor of the mouth. At
y 3,0 kg que se haban mantenido en ayuno determined time intervals, 1 ml blood sam-
durante la noche. Los conejos se anestesiaron ples were withdrawn from the marginal ear
con pentobarbital (25 mg/kg) antes de admi- vein. The serum was subsequently separated,
nistrarles los comprimidos. El comprimido and in order to limit degradation, serum sam-
sublingual optimizado con un contenido de 1,25 ples were stored at 0 0C. The samples were
mg de terbutalina (Tabla 6) se insert sublin- analysed through HPLC and the pharmacoki-
gualmente y se coloc de forma que las super- netic data were computed using Kinetica 2000
ficies del contenido estuvieran en contacto con Version 3.0 (InnaPhase Corporation, USA).
la parte ventral de la legua y la base de la
boca. Se extrajeron muestras de sangre de 1 ml
de la vena marginal de la oreja a intervalos Sample analysis
determinados; se separ el suero y las mues-
tras se almacenaron a 0 C para limitar su de- Terbutaline was separated from serum sam-
gradacin. Las muestras se analizaron mediante ples through liquid-liquid extraction, by bu-
HPLC, y los datos farmacocinticos se calcu- ffering with phosphate buffer PH 7.2, extrac-
laron mediante el programa Kinetica 2000 ted with chloroform. The chloroform layer was
Versin 3.0 (InnaPhase Corporation, EE. UU.). separated and mixed with 0.5M hydrochloric

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FORMULACIN Y EVALUACIN DE COMPRIMIDOS SUBLINGUALES CON SULFATO DE TERBUTALINA: ESTUDIOS... 145
FORMULATION AND EVALUATION OF A SUBLINGUAL TABLET CONTAINING TERBUTALINE SULPHATE: OPTIMISATION...

Anlisis de muestras acid. The aqueous layer was then separated


by centrifugation and analysed. The amount
La terbutalina se separ de las muestras de of terbutaline was determined using HPLC
suero mediante extraccin lquido-lquido, con containing hypersil ODS column (4.6 x 150mm)
cloroformo, utilizando tampn fosfato PH 7.2. with UV detector (Waters 2487 dual l absor-
La capa de cloroformo se separ y se mezcl bance detector).
con cido clorhdrico 0.5 M. A continuacin,
se separ la capa acuosa mediante centrifuga-
do y se analiz. La cantidad de terbutalina se RESULTS AND DISCUSSION
determin mediante HPLC conteniendo una
columna Hypersil ODS (4,6 x 150 mm) con Formulation of terbutaline sublingual tablet
un detector de UV (detector de absorcin dual
l Waters 2487). Sublingual tablets were prepared following
a 3 2 full factorial design. The materials and
compositions used are presented in Table 2.
RESULTADOS Y DISCUSIN For rapid drug dissolution, the carrier material
should be highly soluble in the dissolution
Formulacin de los comprimidos sublinguales medium 9, hence, mannitol, which is highly
de terbutalina soluble 10,11 , was chosen as carrier material.
MCC is unlikely to impair the disintegration
Los comprimidos sublinguales se prepara- process, because it belongs to the class of
ron segn un diseo factorial 32. Los materia- moderately deformable binders12. Crospovido-
les utilizados y su composicin se indican en ne, which also presents bioadhesive proper-
la Tabla 2. Para una disolucin rpida del fr- ties, is an effective disintegrant13 and serves to
maco, el material de transporte debe tener un prolong the residence time of the terbutaline
alto grado de solubilidad en el medio de diso- within the sublingual mucosa, thereby increa-
lucin 9, por lo que se eligi manitol como sing its absorption. In this study, the effect of
material de transporte, debido a su gran solu- formulation variables: the amount of MCC and
bilidad10,11. Es improbable que la MCC afecte the presence or absence of crospovidone was
al proceso de desintegracin, ya que pertene- chosen as independent variables. The depen-
ce a la clase de aglutinantes de deformacin dent (response) variables included crushing
moderada 12. Se supone que la crospovidona, strength, percentage friability and DT (Table
un desintegrante eficaz 13 que tambin tiene 3). For the generation of polynomial models,
propiedades bioadhesivas, prolonga el tiempo only coefficients found to be significant
de residencia de la terbutalina en la mucosa (p<0.05) were used.
sublingual, aumentando por tanto la absorcin.
En este estudio, se eligieron como variables
independientes para el efecto de la formula-
cin la cantidad de MCC y la presencia o
ausencia de crospovidona. Las variables de-
pendientes (de respuesta) son la resistencia al
aplastamiento, la friabilidad porcentual y el
tiempo de desintegracin (DT) (Tabla 3). Para
generar los modelos polinmicos slo se utili-
zaron coeficientes significativos (p<0,05).

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146 NARENDRA C, SRINATH MS, PRAKASH B RAO

TABLA 2: Composicin de los comprimidos sublinguales.


TABLE 2: Composition of sublingual tablets.

Ingredientes F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11


Ingredients
Sulfato de terbutalina 1,25 1,25 1,25 1,25 1,25 1,25 1,25 1,25 1,25 1,25 1,25
Terbutaline sulphate
MCC 30 30 10 10 50 30 30 10 30 50 50
MCC
Crospovidona 5 2,5 5 2,5 2,5 2,5 - - 2,5 5 -
Crospovidone
Aspartamo 0,5 0,5 0,5 0,5 0,5 0,5 0,5 0,5 0,5 0,5 0,5
Aspartame
Metil parabn Na 0.012 0,012 0,012 0,012 0,012 0,012 0,012 0,012 0,012 0,012 0,012
Methyl paraben
Propil parabn Na 0.003 0.003 0.003 0.003 0.003 0.003 0.003 0.003 0.003 0.003 0.003
Propyl paraben
Estearato de Mg 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4
Mg stearate
Manitol ----------Cantidad suficiente hasta 60 mg----------
Mannitol ----------Quantity Sufficient to 60 mg----------
Nota: Todas las cantidades estn expresadas en miligramos.
Note: All the quantities are expressed in terms of milligrams.

TABLE 3: Diseo factorial 32 con las respuestas correspondientes de resistencia al aplastamiento,


friabilidad y DT.
TABLE 3: 32 Full factorial design with corresponding responses for crushing strength, friability and DT.

Cdigo de formulacin Resistencia al aplastamiento Friabilidad DT (seg.) (Y 3)


(kg/cm 2) (Y 1 ) (%) (Y 2)
Formulation code Crushing strength Friability DT (sec.) (Y 3)
(kg/cm 2 ) (%) (Y 2)
F1 3,25 0,15 37,4
F2 3,15 0,13 28,6
F3 3,30 0,30 48,6
F4 3,05 0,42 98,8
F5 2,75 0,15 105,8
F6 3,17 0,14 30,2
F7 3,05 0,28 145,0
F8 2,75 0,62 245,0
F9 3,16 0,15 31,2
F10 3,05 0,37 145,0
F11 2,30 0,15 172,4

Contenido de frmaco, variacin de peso y Drug content, weight variation and thickness
espesor
It was considered essential to document the
La determinacin del contenido de frma- drug content, because the amount of terbuta-
co era esencial, ya que la cantidad de terbu- line used in the formulation was relatively low.
talina utilizada en la formulacin era relativa- In all the formulations, the drug content was

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FORMULACIN Y EVALUACIN DE COMPRIMIDOS SUBLINGUALES CON SULFATO DE TERBUTALINA: ESTUDIOS... 147
FORMULATION AND EVALUATION OF A SUBLINGUAL TABLET CONTAINING TERBUTALINE SULPHATE: OPTIMISATION...

mente baja. En todas las formulaciones, el found to be uniform among the different ba-
contenido de frmaco fue uniforme en los tches of tablets, and ranged from 97.54 % to
distintos lotes de comprimidos y se encontra- 101.85 % of the theoretical value. The avera-
ba en el intervalo de 97,54 % a 101,85 % del ge percentage deviation for 20 tablets of each
valor terico. La desviacin porcentual media formula was less than 2%. The thickness of
de 20 comprimidos de cada frmula fue infe- the tablets were found to be 2.30 0.034 to
rior a 2%. El espesor de los comprimidos 2.51 0.045mm.
estaba entre 2,30 0,034 y 2,51 0,045 mm.

Effect of formulation variables on crushing


Efecto de las variables de formulacin en la strength
resistencia al aplastamiento
The quadratic model for Y1 (crushing streng-
El modelo cuadrtico de Y1 (resistencia al th) were found to be significant with an F
aplastamiento) era significativo con un valor value of 183.20 (p< 0.0001).
F de 183,20 (p< 0,0001).
Y1 = 2.55 + 0.025X1 + 0.146X2 6.039X12
Y1 = 2,55 + 0,025X1 + 0,146X2 6,039X1 2
0.01X 22 + 1.00X 1X 2
0,01X 22 + 1,00X 1X 2
In this case, all factors were found to be
En este caso, todos los factores fueron sig- significant with factor X 1 and X 2 showing a
nificativos, y los factores X1 y X2 presentaron positive effect. Increases in quantities of MCC
un efecto positivo. Al aumentar la cantidad and crospovidone gave rise to increases in
de MCC y crospovidona aumenta la resisten- crushing strength, but the effects produced by
cia al aplastamiento, pero el efecto de MCC MCC were found to be minimal. The crushing
observado fue mnimo. La resistencia al aplas- strength of a commercial tablet must be at
tamiento de los comprimidos comerciales debe least 3 kg/cm2 to be practical14, almost all the
ser al menos de 3 kg/cm 2 para que resulten formulations which contain crospovidone met
prcticos14, y casi todas las formulaciones con with this criterion. The relationship between
crospovidona cumplan este criterio. La rela- the variables was further elucidated using
cin entre las variables se dilucid an ms Response surface plot (Figure 1).
mediante el grfico de superficie de respuesta
(Figura 1).

Ars Pharm 2005; 46 (2): 139-158.


148 NARENDRA C, SRINATH MS, PRAKASH B RAO

FIGURA 1: Grfico de superficie de respuesta que muestra el efecto de la cantidad de MCC (X1)
y crospovidona (X2) en la respuesta de resistencia al aplastamiento (Y1).

FIGURE 1: Response surface plot showing the effect of quantities of MCC (X1) and crospovidone (X2)
on response crushing strength (Y1).

Y1= Crushing strength

3.40806
3.13591
2.86376
2.59162
2.31947

50.00
5.00
3.75 40.00

2.50 30.00
1.25 20.00 X1
X2
0.00 10.00

Un nivel alto de X2 (5 mg de crospovido- A high level of X2 (crospovidone-5mg) gave


na) daba un valor alto de resistencia al aplas- a high value of crushing strength, at all the
tamiento con todos los niveles de X1 (1050 levels of X1 (MCC-1050mg) indicating, that
mg de MMC), lo que indica que ambos fac- both factors have a positive effect on crus-
tores tienen un efecto positivo en la resisten- hing strength. The high values for crushing
cia al aplastamiento. En el caso de la crospo- strength in case of crospovidone may be due
vidona, una elevada resistencia al aplastamiento its binding property.
puede deberse a su propiedad aglutinante.

Effect of formulation variables on friability


Efecto de las variables de formulacin en la
friabilidad The terms Y2 of the model were found to
be significant with an F value of 51.25 and a
Los trminos Y2 del modelo eran significa- high R 2 value of 0.9809. This indicates an
tivos con un valor F de 51,25, y un valor alto adequate fit of the quadratic model. In this
de R 2 de 0,9809 indica un ajuste adecuado case, all the factors were found to be signifi-
del modelo cuadrtico. En este caso, todos cant. Thus the model then becomes,
los factores fueron significativos. Por tanto, el
modelo pasa a ser: Y2 = 0.95 - 0.034X 1 - 0.156X 2 + 3.63X 12 +
0.012X 22 + 2.70X 1X 2
Y2 = 0,95 - 0,034X 1 - 0,156X2 + 3,63X 12 +
0,012X 22 + 2,70X 1X 2 As the amount of MCC and crospovidone
increases, the friability of the tablet proportio-
A medida que aumenta la cantidad de MCC nately decreases. The combined effect of X1
y crospovidona, disminuye proporcionalmen- and X2 can be studied with the help of Res-
te la friabilidad del comprimido. El efecto ponse surface plot (Figure 2).

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FORMULACIN Y EVALUACIN DE COMPRIMIDOS SUBLINGUALES CON SULFATO DE TERBUTALINA: ESTUDIOS... 149
FORMULATION AND EVALUATION OF A SUBLINGUAL TABLET CONTAINING TERBUTALINE SULPHATE: OPTIMISATION...

combinado de X1 y X2 se puede estudiar con


ayuda del grfico de superficie de respuesta
(Figura 2).

FIGURA 2: Grfico de superficie de respuesta que muestra el efecto de la cantidad de MCC (X1)
y crospovidona (X2) en la respuesta de friabilidad (Y2).
FIGURE 2: Response surface plot showing the effect of quantities of MCC (X1) and crospovidone (X2)
on response percentage friability (Y2).

Se observ que el mayor valor de friabili- The highest percentage values for friability
dad porcentual tena un efecto muy bajo en coincided with low values for either of the
ambas variables independientes, lo que se puede independent variables. This could be attribu-
deber a la adherencia entre las partculas de ted to weak bonding between the particles in
los grnulos. Un nivel alto de X2 dio un valor the granules. A high level of X2 gave a low
bajo de friabilidad porcentual en todos los value of percentage friability at all the levels
niveles de X 1. De estos resultados se puede of X1. From the results, it can be concluded
concluir que ambas variables tienen efectos that both the variables have negative effects
negativos en la friabilidad porcentual y que el on percentage friability and factor X 2 has a
efecto del factor X2 es ms significativo que more significant effect than that of factor X1.
el del factor X1. Como se ha publicado ante- As reported previously 15 , the hardness of a
riormente 15, la dureza de un comprimido da tablet gives its ability to resist abrasion and
su capacidad de resistencia a la abrasin y al shock, as simulated in the friability machine.
impacto, como se ha simulado en la mquina Conventional compressed tablets that lose less
de friabilidad. Se consideran aceptables los than 1% of their weight are generally consi-
comprimidos convencionales que pierden dered acceptable. In this study, where 10 mg
menos de un 1% de su peso. En este estudio, of MCC was used in the absence of crospovi-
si se utilizaban 10 mg de MCC sin crospo- done, percentage friability was found to be
vidona, la friabilidad porcentual observada fue 0.65, which is more than 1% of tablet weight.
del 0,65, que es superior al 1% del peso del Hence, an optimal amount of MCC with cros-
comprimido. Por tanto, una cantidad ptima de povidone yields a tablet with a lower percen-
MCC con crospovidona proporciona una fria- tage of friability.
bilidad porcentual menos a los comprimidos.

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150 NARENDRA C, SRINATH MS, PRAKASH B RAO

Efecto de las variables de formulacin en el Effect of formulation variables on disintegration


tiempo de desintegracin time

Los coeficientes similares a los de la fria- Similar coefficients to those for percentage
bilidad porcentual, junto con los trminos del friability and along with model terms were
modelo, fueron significativos con un valor F found to be significant with an F value of
de 568,61 (p< 0,0001). 568.61 (p< 0.0001).

Y3 = 348,65 - 11,85X1 - 91,87X2 + 0,166X12 Y3 = 348.65 - 11.85X1 - 91.87X2 + 0.166X12


+ 8,88X22 + 0,845X 1X 2 + 8.88X22 + 0.845X 1X 2

Ambos coeficientes X1 y X2 presentaron un Both the coefficients X1 and X2 are negati-


signo negativo; al aumentar de MCC o cros- ve in sign; as the concentration of either MCC
povidona, se observ una disminucin del DT. or crospovidone increases, DT was found to
Las concentraciones elevadas de MCC dan decrease. High concentrations of MCC lead
como resultado una elevada porosidad y ab- to high porosity and water uptake, which sub-
sorcin de agua, lo que facilita la desintegra- sequently facilitate disintegration. The interac-
cin. El efecto de la interaccin entre X1 y X2 tive effect between X1 and X2 is shown in the
se muestra en el grfico de respuesta de su- Response surface plot (Figure 3). In the ab-
perficie (Figura 3). En ausencia de crospovido- sence of crospovidone, and where 10 mg of
na y si se utilizaban 10 mg de MCC, el DT era MCC was used, a DT value of 245.80 sec was
de 245,80 seg., mientras que si se utilizaba attained, while in presence of crospovidone
crospovidona (5 mg) era de 51,83 seg. De manera (5 mg), this value was reduced to 51.83 sec.
similar, el DT disminua de 172,56 seg. hasta Similarly, DT decreases from 172.56 sec to
146,60 seg. si se utilizaban 50 mg de MCC y 146.60 sec, where 50 mg of MCC was used
se aumentaba la cantidad de crospovidona de and crospovidone was increased from 0 to 50
0 a 50 mg. Nuestra interpretacin de los re- mg. The results lead us to believe that, factor
sultados es que el factor X 2 tiene un efecto X2 has a more significant effect on DT than
ms significativo en el DT que el factor X1. La X1. The presence of a high quantity of cros-
presencia de una elevada cantidad de crospo- povidone facilitates its wicking action. Howe-
vidona facilita el tiempo de desintegracin, y ver, an optimum concentration regarding dis-
se sabe que existe una concentracin ptima14,16. integrating time14,16 is known to exist.
Los valores de ANOVA de la Tabla 4 para The ANOVA in Table 4 for the dependent
las variables (de respuesta) dependientes de- (response) variables demonstrates that the model
muestran que el modelo era significativo para was significant for all response variables. The
todas ellas. Los efectos son los siguientes: los effects are as follows: the amount of MCC
valores de cantidad de MCC y crospovidona and crospovidone were found to be signifi-
eran significativos, junto con sus trminos de cant, along with its quadratic and interaction
interaccin y cuadrticos, para todas las va- terms for all the dependent variables. Hence,
riables dependientes. Por tanto, los resultados the above results lead us to believe that con-
anteriores indican que la concentracin de centrations of disintegrants have an important
desintegrantes desempea una funcin impor- role to play, and optimal concentrations in
tante, y que una concentracin de desintegran- sublingual tablets give rise to rapid disinte-
tes da como resultado comprimidos sublin- gration times, good crushing strength values,
guales que se desintegran en un tiempo corto and sufficiently low friability percentages, in
y con una buena resistencia al aplastamiento order to successfully withstand the mechani-
que puede disminuir la friabilidad porcentual, cal stress, during packing, transportation and
que a su vez permite resistir los esfuerzos handling.
mecnicos durante el embalaje, el transporte
y la manupulacin.

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FORMULACIN Y EVALUACIN DE COMPRIMIDOS SUBLINGUALES CON SULFATO DE TERBUTALINA: ESTUDIOS... 151
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FIGURA 3: Grfico de superficie de respuesta que muestra el efecto de la cantidad de MCC (X1)
y crospovidona (X2) en la respuesta de DT (Y3).

FIGURE 3: Response surface plot showing the effect of quantities of MCC (X1) and crospovidone (X2)
on response DT (Y3).

Y3 = DT

246.797

189.02

131.242

73.4648

15.6873

5.00
50.00
3.75
40.00
2.50
30.00
X2 1.25 20.00
X1
0.00 10.00

TABLA 4: Resumen de la tabla de ANOVA para las variables dependientes del diseo factorial.

TABLE 4: Summary of ANOVA table for dependent variables from full factorial design.

Origen Suma cuadrtica Media cuadrtica Valor F Probabilidad


Source d.f. Sum square Mean square F value Probability
Resistencia al aplastamiento (kg/cm 2)
Crushing strength (kg/cm 2) R2 = 0.9946
X1 1 0.17 0.17 162.12 0.0001
X2 1 0.57 0.57 554.84 0.0001
X 12 1 0.15 0.15 143.81 0.0001
X 22 1 0.01 0.01 10.92 0.0214
X 1X 2 1 1.00 1.00 9.73 0.0263
Friabilidad (%)
Friability (%) R2 = 0.9809
X1 1 0.073 0.073 77.04 0.0003
X2 1 9.048 9.048 9.49 0.0275
X 12 1 0.054 0.054 56.25 0.0007
X2 2
1 0.014 0.014 14.95 0.0118
X 1X 2 1 0.073 0.073 76.43 0.0003
DT (sec) R2 = 0.9982
X1 1 158.11 158.11 8.73 0.0317
X2 1 18304.33 18304.33 1010.24 0.0001
X 12 1 11250.96 11250.96 620.96 0.0001
X 22 1 7815.14 7815.14 431.33 0.0001
X 1X 2 1 7140.25 7140.25 394.08 0.0001

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152 NARENDRA C, SRINATH MS, PRAKASH B RAO

Los datos de error puro y falta de ajuste se The data for pure error and lack of fit are
resumen en la Tabla 5, que puede proporcio- summarized in Table 5, which provides a mean
nar una respuesta media y una estimacin de response and an estimate of pure experimen-
la incertidumbre experimental pura17. Los re- tal uncertainty 17. The residual values shown
siduos son la diferencia entre el valor obser- represent the differences between the obser-
vado y el previsto. Los valores calculados de ved and predicted values, given that compu-
F eran respectivamente inferiores al valor de ted F values were respectively lower than critical
F crtico, lo que denota que la falta ajuste no F values, which denotes non-significance with
es significativa. regard to a lack of fit.

TABLA 5: Resumen de resultados del ANOVA en el anlisis de la falta de ajuste (LOF) y el error puro.
TABLE 5: Summary of ANOVA results in the analysis of Lack of Fit (LOF) and Pure Error.
Origen Suma cuadrtica Media cuadrtica Valor F
Source Sum square df Mean square F value Prob > F
Resistencia al aplastamiento (kg/cm ) 2

Crushing strength (kg/cm 2)


Modelo
Model 0.94 5 0.19 183.20 0.0001*
Residual
Residual 5.14 5 1.02 - -
Total
Total 0.95 10 - - -
Falta de ajuste
Lack of fit 4.94 3 1.64 16.47 0.0578ns
Error puro
Pure error 2.00 2 1.00 - -
Friabilidad (%)
Friability (%)
Modelo
Model 0.24 5 0.049 51.25 0.0003*
Residual
Residual 4.76 5 9.53 - -
Total
Total 0.25 10 - - -
Falta de ajuste
Lack of fit 4.54 3 1.51 13.74 0.0686 ns
Error puro
Pure error 2.20 2 1.10 - -
DT (sec)
Modelo
Model 51512.32 5 10302.46 568.61 0.0001*
Residual
Residual 90.59 5 18.12 - -
Total
Total 51602.91 10 - - -
Falta de ajuste
Lack of fit 87.15 3 29.05 16.89 0.0564 ns
Error puro
Pure error 3.44 2 1.72 - -
Nota: * = significativo (p< 0,05), ns = no significativo.
Note: * = Significant (p< 0.05), ns = non-significant.

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Tiempo de disolucin Dissolution time

Los datos de la cantidad de terbutalina The data for the amount of dissolved ter-
disuelta como funcin del tiempo se muestran butaline as a function of time are presented in
en la Figura 4-5. La formulacin 8, que con- Figure 4-5. Formulation 8, which contains the
tiene la cantidad ms baja (10 mg) de MCC y lowest quantity (10 mg) of MCC and the ab-
en ausencia de crospovidona present el ma- sence of crospovidone, resulted in the highest
yor DT, con una liberacin del frmaco del DT, with a drug release value of 85.53% within
85,53% en 30 minutos. Pero en presencia de a time period of 30 minutes. However, in the
crospovidona, el DT disminuy drsticamente presence of crospovidone, DT was found to
y se observ una liberacin de frmaco del decrease dramatically and drug release was
100% en 30 min. Las formulaciones 2, 6 y 9 found to increase to 100% within the same 30
ilustran los puntos centrales del diseo, que min. period. Formulations 2, 6 and 9 are the
tenan 30 mg de MCC y 2,5 mg de crospovi- most effective alternatives, with formulations
dona y presentaron una liberacin del 100 % of 30 mg of MCC and 2.5 mg of crospovido-
en menos de 20 min. Al aumentar la cantidad ne yielding a 100 % release, in less than 20
de MCC y crospovidona, la disolucin por- min. As the amount of MCC and crospovido-
centual observada disminuy. ne was increased dissolution percentages were
found to decrease.

FIGURE 4: Dissolution profiles of formulations (F1-F5).


FIGURA 4: Perfiles de disolucin de las formulaciones (F1-F5)

120
Terbutaline sulphate released (%)

100

80 F1
F2
60
F3
40 F4

20 F5

0
0 5 10 15 20 25 30
Time (min)

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154 NARENDRA C, SRINATH MS, PRAKASH B RAO

FIGURA 5: Perfiles de disolucin de las formulaciones (F6-F11).

FIGURE 5: Dissolution profiles of formulations (F6-F11).

Optimizacin Optimisation

Para generar los valores ptimos de formu- A numerical optimisation technique, focus-
lacin se utiliz una tcnica de optimizacin sed on the desirability approach, was used to
numrica segn el enfoque de resultado de- generate the optimum settings for the most
seado. El proceso se optimiz para las varia- effective formulation. The objective in the
bles dependientes (de respuesta) Y1 Y3, y se design of the process was to optimise the
lleg a la frmula optimizada minimizando la dependent (response) variables Y 1 Y 3 and
friabilidad y el DT. La resistencia al aplasta- minimize friability and DT. Crushing strength
miento se estableci en el objetivo mximo, was targeted to maximum with independent
con las variables independientes en el rango. variables at range. The optimised results ob-
Los resultados optimizados obtenidos se in- tained were included in Table 6. In order to
cluyeron en la Tabla 6. Para refutar la fiabi- gainsay the reliability of the Response surface
lidad del modelo de superficie de respuesta se model, new optimised formulations were pre-
prepararon nuevas formulaciones segn el pared according to the predicted model and
modelo previsto y se evaluaron las respues- evaluated for their response. The results in
tas. Los resultados de la Tabla 7 presentan Table 7 showed a good relationship between
una buena relacin entre los valores previstos experimental and predicted values, which
y los experimentales, lo que confirma la va- confirms the practicability and validity of the
lidez y practicidad del modelo. model.

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TABLA 6: Composicin de la formulacin optimizada.


TABLE 6: Composition of Optimized formulation

Ingredientes Cantidades (mg)


Ingredients Quantities (mg)
Sulfato de terbutalina
Terbutaline sulphate 1.25
MCC
MCC 31.72
Crospovidona
Crospovidone 4.57
Aspartamo
Aspartame 0.50
Metil parabn Na
Methyl paraben Na 0.012
Propil parabn Na
Propyl paraben Na 0.003
Estearato de Mg
Mg stearate 0.40
Manitol
Mannitol 21.545
TABLA 7: Comparacin entre los valores experimentales (E) y previstos (P) de las formulaciones pti-
mas ms probables.
TABLE 7: Comparison between the Experimental (E) and Predicted (P) values for the most probable
optimal formulations

Variables dependientes Formulacin optimizada


Dependent variables Optimized formulation
E P
Resistencia al aplastamiento (kg/cm 2)
Crushing strength (kg/cm 2) 3.1 0.8 3.35
Friabilidad (%)
Friability (%) 0.14 0.05 0.16
DT (seg.)
DT (sec) 30.2 5.5 28.6

Estudio farmacocintico Pharmacokinetic study

La Figura 6 muestra los niveles sricos medios Figure 6 shows the mean serum level of
de terbutalina obtenidos tras la administracin terbutaline obtained following sublingual ad-
del comprimido sublingual optimizado (Tabla ministration of an optimised sublingual tablet
6) con un contenido en frmaco de 1,25 mg. (Table 6) containing 1.25 mg of drug. The
Los parmetros famacocinticos se resumen en pharmacokinetic parameters are summarized in
la Tabla 8. Las concentraciones sricas se ob- Table 8. Serum concentrations were obtained
tuvieron a los 5 minutos. Esta brevedad se puede within 5 min, such a short time may be attribu-
atribuir a la presencia de crospovidona, que es ted to the presence of crospovidone, which is
un componente bioadhesivo. La crospovidona a bioadhesive component. Crospovidone does

Ars Pharm 2005; 46 (2): 139-158.


156 NARENDRA C, SRINATH MS, PRAKASH B RAO

no dificulta la liberacin y absorcin de terbu- not hamper the release and absorption of ter-
talina, pero promueve la retencin de unidades butaline, and at the same time promotes the
de orden bajo la lengua. retention of order units under the tongue.

FIGURA 6: Perfil concentracin-tiempo de la terbutalina en suero de los comprimidos sublinguales


optimizados. Los valores son medias de n = 6 ESM

FIGURE 6: Serum Terbutaline concentration-time profile of optimized sublingual tablet. The values are
means of n = 6 + SEM

7
Serum drug concentration

6
5
(mcg/ml)

4
3
2
1
0
0 2 4 6 8
Time (hr)

TABLA 8: Parmetros farmacocinticos en conejos de los comprimidos sublinguales optimizados con un


contenido de terbutalina de 1,25 mg. Los valores son medias de n = 6 ESM

TABLE 8: Pharmacokinetic parameters of an optimized sublingual tablet containing 1.25 mg


of Terbutaline in rabbits. The values are means of n = 6 SEM

Parmetros farmacocinticos Formulacin optimizada


Pharmacokinetic parameters Optimized formulation
Cmax (g/ml) 5.15 1.98
Tmax (h) 0.75 0.08
AUC0-8 ( g h/ml) 14.01 4.34
AUCtotal (g h/ml) 16.18 4.72
AUMC0-8 (g h2/ml) 36.94 5.28
AUMC total (g h2/ml) 62.95 12.59
T1/2 (h) 2.76 1.38
Kel (h-1) 0.25 0.097
MRT (h) 3.88 1.26

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CONCLUSIONES CONCLUSIONS

Se realiz un diseo factorial 32 para estu- A 32 full factorial design was performed to
diar el efecto de las variables de formulacin study the effect of formulation variables on
en la resistencia al aplastamiento, la friabili- crushing strength, percentage friability and DT
dad porcentual y el tiempo de desintegracin by applying the computer optimisation tech-
(DT), aplicando la tcnica de optimizacin por nique. The results revealed that, the amount
ordenador. Los resultados revelaron que la of MCC and crospovidone affected significantly
cantidad de MCC y crospovidona afectaban the response variables. Observed responses were
significativamente a las variables de respues- in close accord with the predicted values of
ta. Las respuestas observadas concordaban con the optimised formulation, and consequently
los valores previstos de la formulacin opti- demonstrate the feasibility of the optimisation
mizada, demostrando la viabilidad del proce- procedure in the development of sublingual
dimiento de optimizacin en el desarrollo de tablets. It can be concluded that, sublingual
los comprimidos sublinguales. Se puede con- tablets provide several advantages especially
cluir que los comprimidos sublinguales pre- when administered to children and elderly
sentan diversas ventajas para su administra- patients. Rapid absorption into the systemic
cin a nios y ancianos, y permiten conseguir circulation within a short period time may be
una absorcin y el paso a la circulacin sis- achieved. Dosage forms developed in such a
tmica en un perodo de tiempo muy corto. way provide therefore, an interesting field for
La forma de dosificacin desarrollada es pro- further research, given that the results may be
metedora para estudios posteriores, que se extrapolated to other drugs, for which a rapid
pueden extrapolar a otros frmacos con los onset of effect is a desirable objective.
que se desee conseguir una accin rpida.

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