31

J Clin Med. 2010; 3(1):31-38

COMPARATIVE BIOAVAILABILITY OF METOCLOPRAMIDE HYDROCHLORIDE AT A DOSE OF 10 MG, ADMINISTERED IN TABLET FORM ORALLY, INTRAVENOUSLY AND THROUGH A NASAL MUCOADHESIVE SPRAYCh. Tzachev1, T. Popov2 1Medical University - Sofia, Faculty of Pharmacy, Department of Technology and Biopharmacy 2Aleksandrovska Hospital, Department of Asthma, Allergology and Clinical Immunology

Keywords: metoclopramide, mucoadhesive spray, comparative bioavailabilityAuthor for contacts: T.A. Popov, Clinic of Allergy & Asthma, 1, Sv. Georgi Sofiyski St., 1431 Sofia, Bulgaria, phone/fax: +359 2 9230397,e-mail: ted.popov@gmail.com

Abstract: Introduction: The advantage of nasal to oral form for administration of antiemetic is obvious. Its efficient administration,

however, depends on the pharmacokinetic characteristics of the form. With the perspective to improve them, a mucoad-

hesive solution of metoclopramide hydrochloride was developed.

Objective: To compare the bioavailability of a mucoadhesive nasal spray containing metoclopramide hydrochloride to

the reference oral and intravenous forms of the same drug.

Design: This was a randomized crossover clinical study comparing the plasma levels of metoclopramide in 18 healthy

volunteers after taking a single dose of 10 mg nasal spray, an intravenous solution and tablets in three periods in random

order. The aim was to evaluate the absolute and relative bioavailability of metoclopramide mucoadhesive nasal spray.

Materials and methods: The mucoadhesive nasal spray contained low concentration of metoclopramide hydrochlo-

ride - 5%, and an overall standard dose of 10 mg was provided by two applications of 100 μl in each nostril. The solution

was isotonic, 310 mOsm/L, and is manufactured in Unipharm AD, Bulgaria. Reference tablet forms were Reglan, tablets

of 10 mg produced by Schwarz Pharma. Reference injection form was Reglan, sol. injection 5 mg/ml produced by Baxter

Healthcare Corp.

Results: Peak plasma levels of metoclopramide were Cmax

= 44.94 (± 3.16) ng/ml, Tmax

= 0.88 (± 0.08) hours for the tablet

forms and Cmax

= 26.99 (± 2.02) ng/ml and Tmax

= 2.17 (± 0.18) hours for nasal form. 60 min. to 210 min after application,

the plasma levels of metoclopramide nasal form remain without significant difference (p [t7, t8, t9, t10, t11, t12]

= 0.95) but with a

tendency for increase. After 60 min the concentration of metoclopramide in tablet forms sharply decreased by 15% and

gradually lowered thereafter. The absolute bioavailability of the nasal spray was 59%, while of the tablets was 80.9%, the

relative bioavailability of the spray was 74%

Conclusion: The mucoadhesive nasal spray provided high bioavailability when administered in low concentration (5%)

and dose (10 mg). Metoclopramide hydrochloride was well-tolerated by patients and no burning, stinging or bitter taste

were reported.

EudraCT number: 2007-006028-36

32

Original Article

Introduction

The nasal mucosa provides access to the absorption

of many substances and is the administration of choice

of drugs with little resistance to gastrointestinal en-

zymes and/or low-absorption in the gastrointestinal

tract. In addition, topical administration of antiemetic

agents has other advantages: avoiding the inconve-

nience of possibly rejecting the dose due to emesis;

avoiding possible direct irritation on the gastrointesti-

nal mucosa, easy and convenient application, as well

as circumvention of the first pass effect through the

liver.

Metoclopramide is a potent antiemetic with well-

studied pharmacological and toxicological profile1-10. It

represents substituted benzamide, antagonist of do-

pamine receptors, with direct effect on the chemo-

receptor trigger zone and in particular the center of

vomiting. It is also antagonist of the serotonin (5-HT3)

receptors. It stimulates the motility of the gastrointes-

tinal tract without affecting the secretion of stomach,

gallbladder, or pancreas and increases gastric peristal-

sis and gastric emptying. The same drug enhances du-

odenal peristalsis and tone of the cardia by reducing

the tone of the pyloric sphincter.

Metoclopramide is rapidly absorbed from the gas-

trointestinal tract after oral administration, but condi-

tions like vomiting or impaired gastric motility may re-

duce absorption. Metoclopramide undergoes hepatic

“first-pass” metabolism with considerable variability in

plasma levels among the individuals. Bioavailability af-

ter oral administration is 80% but ranges from 30% to

100% as peak plasma concentrations were observed

between the first and second hour. Metoclopramide

binds little to plasma proteins - 13% -30%, easily passes

the blood-brain and placental barriers, and is found

in breast milk. It is eliminated mainly through urine

with 4 to 6 hours half-life, 5 percent are eliminated by

the bile11.

Metoclopramide is used in disorders associated with

reduced gastrointestinal motility as gastroparesis, ileus,

reflux, dyspepsia, nausea and vomiting due to migraine,

motion sickness, chemotherapy and other conditions.

For most indications the daily dose does not exceed

500 μg/kg; in the UK the recommended dose for oral,

intramuscular or intravenous administration is 10 mg

three times daily; in the USA the recommended doses

are from 10 to 15 mg four times daily. High doses of

2 to 4 mg/kg are used in the form of intravenous

infusion as preparation for chemotherapy in cancer

patients11.

The interest in creating a nasal dosage form of

metoclopramide is related mainly to the possibility of

avoiding presystemic metabolism and emesis in the

oral form, leading to variability in plasma levels, as well

as the inconvenience in administration of other drug

forms (eg, rectal or injection).

The formulation of the nasal dosage form is asso-

ciated with two major problems on the part of the

nasal mucosa:

- restricted resorption area of 150-180 cm2 with lim-

ited capacity (400 μl) to retain liquids;

- mucocilliary clearance, limiting the layover time of

applied drugs.

Despite the large number of pharmaceutical and

pharmacological studies1-10, 12-22 on the nasal administra-

tion of metoclopramide, only one product is available

on the pharmaceutical market: a highly concentrated

nasal spray13,14, registered in 7 countries in two forms -

20% and 40% water (hypertonic) solutions.

In our previous research12,15 a liquid, non-toxic me-

dium, was created and characterized with excellent

adhesion properties. It also possesses good fluidity to

allow covering large area of mucous membrane, with-

out causing obstruction. It delays mucocilliary clear-

ance long enough, thereby providing optimal absorp-

tion of the active substance. This adhesion medium

is practically inert, with no taste and smell, does not

irritate the mucosa and does not create a sense of

discomfort. Using this medium, a nasal spray form

was developed of metoclopramide hydrochloride 5%

isotonic solution, contained in a dosage spray pump,

providing 5 mg per spray.

Comparative Bioavailability of Metoclopramide

33

J Clin Med. 2010; 3(1):31-38

The purpose of this study was to assess the absolute

and relative bioavailability of metoclopramide muco-

adhesive nasal spray, to compare it to the original in-

jection form and the original oral tablet form: Reglan,

sol. injection 5 mg/ml produced Baxter Healthcare

Corp. and Reglan, tablets of 10 mg produced by

Schwarz Pharma, respectively.

Methods

The test product was produced at Unipharm AD,

Bulgaria, under the rules of Good Manufacturing Prac-

tice and marked in accordance with the Law on Me-

dicinal Products for Human Use. The mucoadhesive

nasal spray contained a low concentration of metoclo-

pramide hydrochloride - 5%, and a standard dose of

10 mg was provided by two applications of 100 μl in

each nostril. The solution was isotonic, 310 mOsm/L.

Reference tablet forms were Reglan, tablets of 10 mg

produced by Schwarz Pharma. Reference injection

form was Reglan, sol. injection 5 mg / ml produced by

Baxter Healthcare Corp.

We conducted a randomized, balanced, single cen-

ter, open, crossover, three period clinical trial, in which

we monitored plasma levels of metoclopramide after

single dose of 10 mg of nasal spray (test formulation),

an intravenous solution (reference formulation) and

tablets (reference formulation).

Eighteen healthy volunteers were included in the

study; all male Caucasians, aged between 18 and 55

years. They all complied with inclusion and exclusion

criteria set out in the clinical protocol.

The volunteers were divided into three random-

ized groups (sequences), according to the route of

administration of metoclopramide (oral, intravenous

and nasal). Each group consisted of 6 volunteers and

received one of the three drugs in each period of the

study (Table 1). After wash-out periods of one week

each group was assigned to the remaining two study

armes.

Metoclopramide concentration in plasma was deter-

mined with High Performance Liquid Chromatogra-

phy (HPLC) according to the requirements of Good

Laboratory Practice (GLP). From each volunteer blood

samples of 8ml was taken before taking metoclo-

pramide, t1 = 0, and at t2 = 10min, t3 = 20min, t4 =

30min, t5 = 40min, t6 = 50min, t7 = 60min, t8 = 1.5h,

t9 = 2h, t10 = 2.5h, t11 = 3h, t12 = 3.5h, t13 = 5h, t14 = 7h,

t15 = 9h, t16 = 12h, t17 = 24h after its administration.

Blood samples were processed immediately after sam-

pling and the obtained plasma was stored at - 20oC

until analysis.

34

Comparative Bioavailability of Metoclopramide

Quantification of plasma levels of metoclopramide

was performed by HPLC-FLD system consisting of a

quaternary pump, model 1050 Hewlett-Packard; auto

sampler, model 1100 Agilent Technologies; degasser

Model 1050 Hewlett-Packard; fluorescent detector,

model 1050 Hewlett-Packard and licensed software

ChemStation, Agilent Technologies. The chromato-

graphic conditions included column Merck - CN

(5μm) 250x4 pre-column and Merck - CN (5μm) 4x4.

Mobile phase consisted of buffer/Acetonitrile (70/30

v/v) flow rate: 1.00ml/min; FL detection: λex=275nm,

λem

=350nm; injected volume: 85 μl.

The method for quantitative analysis of metoclo-

pramide in plasma was validated according to current

guidelines of EMEA23 and FDA24. The chromatography

is a specific and sensitive method and provides a limit

of quantitative detection = 1 ng/ml, limit of detection

= 0.3 ng/ml, precision <20% and accuracy between

80% and 120%.

In the calculation of pharmacokinetic parameters for

determining the absolute and relative bioavailability

was used 90% confidence interval. Statistical analysis

was based on ANOVA. The main pharmacokinetic pa-

rameters for evaluation were:

AUC0-t

,; AUC0-∞

; Cmax

; Tmax

; kel; t

1/2; MRT.

The clinical study was conducted under the guide-

lines of ICH GCP, The Protocol of the clinical study was

approved by the Ethics Committee and Drug Agency,

the Helsinki Declaration and the applicable regulatory

requirements.

Results and discussion

Earlier studies have established peak plasma concen-

trations after oral administration of 10 mg of metoclo-

pramide 50 ng/ml (40 ng/ml to 60 ng/ml) within 0.5

to 2 h. After the IV administration the maximum con-

centrations are 70 ng/ml to 130 ng/ml on the 5th min16.

Systemic bioavailability of metoclopramide after in-

travenous, oral and nasal administration is presented

in Figure 1.

After intravenous administration of metoclopramide,

plasma concentration reached peak value on the 5th

min, which rapidly decreased on the 20th min by 13%,

on the 60th min by 24%, on the 90th min by 29%, on

the 150th min by 38%, and on the 300th min by 55%.

35

J Clin Med. 2010; 3(1):31-38

Peak concentration levels, mean (±SEM), of metoclo-

pramide were higher in oral, Cmax

= 44.94 (3.16) ng/

ml, compared to the nasal form, Cmax

= 26.99 (2.02)

ng/ml. The time for reaching Cmax

for the tablet form

is Tmax

= 0.88 (0.08) hours, and for nasal Tmax

= 2.17

(0.18) hours.

Plasma levels of the tablet forms increased rapidly af-

ter the medication, reaching the highest value on the

60th min, followed by a sharp decrease by 15% until the

90th min and gradual lowering afterwards.

The nasal form provided lower maximum concentra-

tion than the tablets. From the 60th min to 210th min

plasma levels of metoclopramide mucoadhesive spray

remained practically without significant difference (p

[t7, t8, t9, t10, t11, t12] = 0.95). The gradual increase in the con-

centration between t7 and t10 was explained by the

delayed release of metoclopramide from the adhesive

medium. Up to 12h the plasma levels of metoclo-

pramide from the spray reduced slowly, as up to 300

min decreased only by 14% compared to the concen-

tration on the 60th min.

For all volunteers, the ratio AUC0→t

/AUC0→∞

after oral,

nasal and intravenous administration was above 0.80

(except for volunteer #9, respectively, 0.69, 0.69 and

0.70, and volunteer #18 after intravenous administra-

tion, 0.70). (Tables 2, 3 and 4)

The mean values of absolute bioavailability (±SEM) of

metoclopramide, Fabs

of the oral and nasal forms were

respectively 0.8086 (0.0323) and 0.5910 (0.0318). The

value of the absolute bioavailability of oral form was

80.9% and correlated with literature data25 (80%) for

the bioavailability of metoclopramide tablet forms af-

ter oral administration.

The mean relative bioavailability (±SEM) of the nasal

form, compared to the oral was 0.738 (0.039), and

showed that intranasal administration provided 74% of

oral bioavailability. The spray provided 59% of the bio-

availability after intravenous administration of meto-

clopramide hydrochloride. The values of the coefficient

of variability (CV) provide information on low variabil-

ity both of the relative and absolute bioavailability of

(Table 5).

Seven hours after the application of the three forms,

the plasma levels decreased, assuming parallel courses,

which suggested the lack of influence of the dosage

form on the process of elimination of metoclopramide.

The average half-lives after oral, nasal and intrave-

nous forms were similar to values reported in the liter-

ature11. Using the Mann-Whitney method to compare

two dependent samples revealed that mean half-life

values, t1/2

, mean residence time, MRT, and elimination

constant, kel, after PO, N and IV administration did not

differ significantly.

The mucoadhesive nasal spray was well-tolerated by

the patients and no unplrsdnt sensations like burning,

stinging, bitter taste were documented.

Conclusion

High bioavailability of metoclopramide is achieved

through administration of low concentrations (5%)

and dose (10 mg) of this drug mounted on specially

developed mucoadhesive medium, thus outperform-

ing non-mucoadhesive concentrations of 20% and

40% of metoclopramide at doses of 20 mg and higher.

Lower Cmax

values of nasal metoclopramide compared

to the tablet form can be suggested as an advantage

36

Comparative Bioavailability of Metoclopramide

associated with possible reduction of acute side ef-

fects. The lack of a secondary peak plasma concentra-

tion in any of the volunteers is an indication that the

nasal solution is retained and absorbed on the site of

application without outflowing or being swallowed.

Plasma levels are maintained at a plateau after the

60th min with slight tendency to increase to 300th min,

and slow decline thereafter.

Metoclopramide included in a mucoadhesive com-

position of a nasal spray, is an alternative to traditional

routes of administration: it ensures stable plasma con-

centrations and is well tolerated.

The clinical study has been funded by the investor and owner of intellectual property on the product, Fortune Apex Development Ltd., Hong Kong.

Figure 1. Mean plasma concentrations of metoclopramide after single administration of 10 mg as a tablet (T) orally, nasal spray (NS) and injection solution (IS) intravenously

Pla

sma

co

nce

ntr

ati

on

of

me

tocl

op

ram

ide

(n

g/m

l)

time, h

Group T Group NS Group IS

37

J Clin Med. 2010; 3(1):31-38

Declaration of conflict of interest

1. Tzachev Christo: “I declare no conflicts of interest

concerning the submitted clinical study.

2. Todor Popov: “I declare no conflicts of interest

concerning the submitted clinical study.

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Comparative Bioavailability of Metoclopramide