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FORMULATION AND EVALUATION OF A SUBLINGUAL TABLET CONTAINING TERBUTALINE SULPHATE: OPTIMISATION...
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
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
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-
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.
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
Espesor Thickness
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.
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
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
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.
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).
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
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.
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).
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.
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
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.
120
Terbutaline sulphate released (%)
100
80 F1
F2
60
F3
40 F4
20 F5
0
0 5 10 15 20 25 30
Time (min)
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.
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
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.
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)
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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