Studies on the in Vitro Dissolution of Insoluble Volatile Drug from Su-Anxin Nasal Inhalant and Its Correlation on the Nose Steady Self-Controllable Expiration and Inspiration at Night

doi:10.4236/pp.2011.22008

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Pharmacology & Pharmacy, 2011, 2, 67-72

doi:10.4236/pp.2011.22008 Published Online April 2011 (http://www.SciRP.org/journal/pp)

Studies on the in Vitro Dissolution of Insoluble

Volatile Drug from Su-Anxin Nasal Inhalant and

Its Correlation on the Nose Steady

Self-Controllable Expiration and Inspiration at

Night

Xiaodong Li 1,2, Guoxiang Xie2, Suyun Li1,3, Chao Hou1,3

1College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, China; 2

Department of Nutrition, University of

North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, USA; 3Nasal preparation institute of traditional Chi-

nese medicine of Fujian province, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, China.

Email: [email protected]

Received February 1st, 2011; revised March 2nd, 2011; accepted March 12th, 2011.

ABSTRACT

In the paper, the in vitro dissolution of borneo l in 12 hou rs from 6 batches of optimized inhalant samples were investi-

gated. As a new dosage form, the in vitro release apparatus of nasal inhalant was invented and a pushing bump was

used accord ing to the simulation of the nose expiration and inspiration. Based on the data of r2 in the profile and simi-

lar factor f2 from 6 linear release tendencies, a good controlled release and a zero order tendency were observed. It can

be suggested that there is a good correlation between the in vitro controlled release and the nose steady self-controllable

expiration and inspira tion, which will contribute to the tren d of insoluble volatile d rug controlled release and the effect

of quick absorption in nasal pulmonary delivery to cure severe or acute cardiovascular or lung diseases at patients’

sleeping, such as angina or breathing obstruction. Also, it was concluded that the prescription composed of insoluble

volatile drugs can be prepared to be nasal inhalant from which drugs can be absorbed through nose steady

self-controllable insp iration to the lung then in to the blood and have a great effectiveness improvement of bioava ilabil-

ity at night timing drug delivery system.

Keywords: Su-Anxin Nasal Inhalants, Insoluble Vola tile Drugs, Timing Drug Delivery System, In Vitro Dissolution,

Controlled Release

1. Introduction

Aromatherapy, a practice of therapeutic use of essential

plant-based oils or other volatile materials for relieving

anxieties and stresses, improving body immunity and

curing some uncertain diseases, has played a great role in

the care of our health and many products of natural es-

sential oil, such as cosmetics, are gaining a pretty good

sale every year. In China, the herbs with essential oils

have been used as traditional Chinese medicine to cure

different kinds of diseases for several thousand years. In

recent literatures , quite a lot of researches were reported

for aromatherapy to have an good effect on Alzheimer’s

disease, anxiety symptoms, stress, supportive care of can-

cer patients, hypertension, cognition and mood modula-

tion, psychiatric disorders, inhalational anaesthetic agents,

cardiovascular disease and so on [1-11].

In this paper a new use mode and dosage form, named

Su-anxin nasal inhalant, was mainly introduced to cure

cardiovascular or pulmonary disease in patients’ sleeping.

As a kind of aromatherapy, this nasal inhalant not only

gave the scientific proofs at its device and in vitro release

test, but also brought a product for healthcare with good

convenience, low cost, steady dose and high bioavail-

ability.

Su-anxin nasal inhalant was defined as an inhaled

preparation which is composed of a kind of equipment

with two sides, one stuck to the middle part, called phil-

trum, under the nose with the help of some stickers, the

Studies on the in Vitro Dissolution of Insoluble Volatile Drug from Su-Anxin Nasal Inhalant and Its Correlation

on the Nose Steady Self-Controllable Expiration and Inspiration at Night

other holding the insoluble volatile drug that are exposed

at atmosphere after discarding the cover, and will be ab-

sorbed through nose inspiration into the lung to cure the

diseases in a systemic or local form [12] (Figure 1). It

consists of some volatile components, such as styrax and

borneol, having an excellent therapy for angina, chest

distress and breathing obstruction especially suddenly

happened at night when a middle or old age patient is in

sleep. Compared with such oral cardiovascular prepara-

tion as Suhexiang pill, Shexiangbaoxin pill and com-

pound dropping pill of Danshen root in China, Su-anxin

nasal inhalant has good merits of quick absorption, high

bioavailability and first metabolism without passing

through the liver. It will be great helpful because it can

avoid the patient’s sudden death induced from these dis-

eases through a good controlled inhalation at the whole

night. Referred to plenty of literatures on inhaled prepa-

ration reported [13-21], it is a good choice for insoluble

volatile drug to be nasal inhalant to cure such diseases,

especially essential oils.

Using the method of gas chromatography, the tests

about the in vitro accumulative release percentage of

(a)

(b)

Figure 1. Real product profile of Su-anxin nasal inhalant.

((a): the whole view of the product; (b): simulated use

under the nose after discarding the cover).

borneol in nasal inhalant were done under the simulation

of nose expiration and inspiration, which will contribute

to the research and development of nasal inhalants for

good nasal inhalants and improving their bioavailability

at night timing drug delivery system.

2．Materials and Methods

2.1. Materials and Agents

Six batches of optimized Su-anxin nasal inhalants were

made by our laboratory colleagues, each piece 0.45 g.

FA2004N type electronic balance (Shanghai Jing-mi

scientific instrument Ltd. Co., China), KQ-500E type ul-

trasonic cleaning(Ultrasonic instrument Ltd. Co. of Kun-

shan, China), standard borneol（National institute for the

control of pharmaceutical and biological products, batch

number 110743-200504）, stearic acid (Tianjin Zhi-yuan

chemical industry Ltd. Co.,China), hydroxypropylmethyl-

cellulose(HPMC, K 15 M, Colorcon Co., U.K.), Starch

(Tianjin Fu-chen chemical reagent company, China), so-

dium lauryl sulfate (SLS, Tianjin Bo-di chemical industry

Ltd. Co.,China), sodium carboxymethycellulose (CMC-

Na, Tianjin Da-mao chemical reagent company, China)

and trolamine (Shanghai Lian-shi chemical reagent Ltd.

Co., China) were needed. All other reagents used were

analytical grade.

2.2. The Preparation of Optimized Su-Anxin

Nasal Inhalants

After 0.075 g stearic acid, 0.075 g trolamine and 0.15 g

petrolatum liquidum were weighed, mixed and melted,

1.5 g HPMC was added to 5 ml water to form gel and

mixed uniformly. Then, prescribed borneol, styrax and

other drugs were weighed and dissolved with 75% alco-

hol to form drug solution. The drug solution was put into

the above mixture and mixed. Then, 3 g starch and 2 g

CMC-Na were added to them again and mixed uniformly

to form Su-anxin nasal inhalant finally.

2.3. The Chromatographic Condition of GC

6890N type gas chromatography and soft work station

were used (Agilent company, USA).The method includes

DB-5 MS type capillary column (30 m × 0.25 mm i.d ×

0.25 μm), a column temperature of 80˚C5Cmin







220˚C

(keeping 25 min at 220˚C), a He carrier gas, a flowing

rate of 1 mL/min, a temperature of sampling entrance at

250˚C, a diffluent rate of 10:1 and a FID detector with a

temperature 280˚C. The sampling size was 1 μL.

2.4. The Preparation of Samples

0.45 g sample was weighed precisely and made it a thin

layer. Then, it was put into 45 ml dehydrated alcohol in

the flask with a glass stopper and shaken for 5 min. After

Studies on the in Vitro Dissolution of Insoluble Volatile Drug from Su-Anxin Nasal Inhalant and Its Correlation 69

on the Nose Steady Self-Controllable Expiration and Inspiration at Night

24 h in a tight state, the solution was ultrasounded 10 min

and filtered into 50 ml measuring flask. Moreover, mod-

erate dehydrated alcohol was added to wash the flask

with a glass stopper and filtered into measuring flask

again. After metered with dehydrated alcohol, the sample

solution was prepared. The total six batches were done.

2.5. The Preparation of Standard Solution

Standard borneol 25 mg was weighed precisely and put it

into 25 mL measuring flask. After dissolved and metered

by dehydrated alcohol, the standard solution at real con-

centration 1.004 mg/mL was obtained.

2.6. The Preparation of Negative Solution

Prescribed styrax and other drugs except borneol were

weighed and negative product was prepared on the basis

of the item 2.2. Then, according to the item 2.4, the nega-

tive solution was obtained.

2.7. Dissolution Studies

Borneol releases from the different 6 batches inhalants

were determined using self-made dissolution apparatus

(Figure 2) designed for simulation of our nose expiration

and inspiration with 50 ml of dehydrated alcohol as dis-

solution medium. The temperature of the dissolution me-

dium was maintained at room temperature. 20 ml dehy-

drated alcohol was added into conical flask and the inha-

lant sample was put in the intubation tube with the drug

surface upwards. One point of intubation tube was set

beneath the liquid of dehydrated alcohol in the conical

flask and, the other was blocked by a glass stopper. There

is an inlet beside the intubation tube near to the stopper,

Figure 2. the test apparatus of the in vitro release for in-

halants.

through which the mild wind was pushed into the tube by

a pushing bump and the gas from insoluble volatile drug

was taken into the liquid and dissolved in the dehydrated

alcohol with the wind while other gases from the atmos-

phere were sent out to atmosphere. When the release

time came, the push bump was turned off and the conical

flask was taken down. Meanwhile, a new conical flask

with 20 ml dehydrated alcohol in it was connected to the

intubation tube quickly to assure the next continual test.

Then, previous about 20 ml dehydrated alcohol was put

into measuring flask and metered. Samples of 20 ml were

withdrawn at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 12.0 hour and

replaced 20.0 ml fresh dissolution media every scheduled

time.Analysis of dissolved borneol in the dehydrated

alcohol solution was conducted by GC method. All ex-

periments were performed in triplicate.

3. Results and Discussion

3.1. The Calibration Curve of Borneol

To determine the linearity of the GC detector response,

calibration standard solutions of borneol at the concen-

tration of 20.08, 40.16, 60.24, 80.32 and 100.4 μg/mL

were prepared on the basis of item 2.5. Linear correlation

was obtained between peak areas versus concentration of

borneol. Each measurement represented the average of

three replicates. The regression equation was A = 4.8582C +

14.809 (r = 0.9998), which indicates a good linear rela-

tion between peaks and borneol concentration at the

range of 20.08 ~ 100.4 μg/ml. Related spectrum can be

seen at Figure 3.

3.2. Accuracy, Reproducibility, Repeatability

and Recovery

Accuracy was performed by running the borneol standard

solution of 60.24 μg/ml for 5 continual times under the

same conditions. Reproducibility was evaluated by ana-

lyzing one sample after diluted 10 times at interval 8

hours. Repeatability was performed by running 5 pieces

of samples after diluted 10 times under the same condi-

tions. Recoveries varied between 99.0% and 104.4%

with RSD 1.96%. The results obtained shows that the

method is very accurate and precise, which were pre-

sented in Tables 1-4.

3.3. Determination of Borneol in Sample

The total 6 batches samples were analyzed by GC method

and average determination were 8.26%, 8.96%, 8.21%,

8.37%, 8.50% and 8.32% respectively, which could be

used as the total quantity of borneol in the test of the in

vitro dissolution.

Studies on the in Vitro Dissolution of Insoluble Volatile Drug from Su-Anxin Nasal Inhalant and Its Correlation

on the Nose Steady Self-Controllable Expiration and Inspiration at Night

3.4. The Release of Borneol from Su-anxin

Inhalants

In order to express the correlation between the controlled

release and the nose expiration and inspiration at night, a

series of our previous screenings of prescription on o/w,

w/o and other excipients’ choice [22] were cancelled and

just the in vitro dissolution release behaviors of borneol

from 6 batches optimized Su-anxin inhalants were done.

The all accumulative releases of borneol from inhalants

were controllable, showing a tendency of zero order re-

lease (the lest r2 = 0.9784). Table 5 and Figure 4 illus-

trated the data and the profile of the release in 12 hours.

However, if the illustration was shown without the point

of the time at 0.5 hour, the tendency of zero order release

was more obvious than that in 12 hours, which could be

seen in Table 6 and Figure 5. From the point at 0.5 hour,

the largest release percentage was observed, showing the

first large concentration of insoluble volatile drug at the

surface of the preparation and a prompt absorption through

nasal lung delivery. The phenomenon was interestingly

accorded with the previous in vivo test which gave a

Cmax of borneol in the blood of rabbits [23].

(a)

(b)

(c)

Figure 3. The GC illustration of borneol in inhalant. ((a)

standard solution; (b) sample solution; (c) negative sample

solution without borneol).

Table 1. The data on the accuracy trial (n = 5).

times 1 2 3 4 5

peak area295.4 298.6 292.1 297.2 294.8

RSD% 1.78

Table 2. The data on the reproducibility trial (n = 6).

time(h) 0.5 1 2 4 6 8

peak area 422.0410.1402.6 400.0 394.2387.1

RSD% 3.04

Table 3. The data on the repeatability trial (n = 5).

times 1 2 3 4 5

peak area 369.1 363.0 359.1 347.8 354.3

RSD% 2.27

Table 4. The data on the recovery trial (n = 6).

samples

(mg)

borneol in

samples

(mg)

added

standard

(mg)

Theoretical

borneol

(mg)

Measured

borneol

(mg)

recovery

(%)

RSD

223.719.9 20.1 40.0 39.8 99.0

219.519.6 20.2 39.8 39.9 100.5

222.919.9 20.2 40.1 40.5 102.0

224.220.0 20.3 40.3 40.6 101.5

223.119.9 19.9 39.8 39.7 99.5

218.619.5 20.3 39.8 40.7 104.4

1.96

Table 5. The data of in vitro accumulative release from 6

batches inhalants.

time(h) 0.5 1 2 4 6 8 12

batch1(%) 2.383.957.4110.43 14.07 16.89 22.1

batch2(%) 2.363.635.378.89 12.07 14.9219.83

batch3(%) 2.033.365.228.89 12.05 15.0120.04

batch4(%) 2.855.217.1511.25 14.93 18.06 23.18

batch5(%) 2.5 4.186.099.86 12.57 15.9820.91

batch6(%) 2.674.527.1511.14 14.14 17.09 22.65

Figure 4. The dissolution release profile of borneol from

inhalants in 12 hours.

Studies on the in Vitro Dissolution of Insoluble Volatile Drug from Su-Anxin Nasal Inhalant and Its Correlation 71

on the Nose Steady Self-Controllable Expiration and Inspiration at Night

Table 6. The linear comparison of r2 between two kind of

release profile.

batches 1 2 3 4 5 6

r2 including 0.5 h 0.9784 0.9922 0.9914 0.9821 0.9893 0.9832

r2 without 0.5 h 0.9836 0.9934 0.9930 0.9890 0.9930 0.9892

Figure 5. The dissolution release profile of borneol from

inhalants in 12 hours without 0.5 hour point.

Also,on the basis of the equation [24] of similar factor

of release curve, 2







250 lg11100

tt t

fnWRT





 







where t is the release of the reference sample at t time,

Tt the release of the test sample at t time, n the number of

the sampling point and t weight factor (here t

W = 1).

After calculation, the 2

values were obtained and the

smallest was 79.16 compared linear tendency of batch 2

and that of batch 4, the largest was 99.61 between batch

2 and batch 3, which indicated a good accordance among

6 batches samples.

3.5. The Elucidation of the Correlation between

Release and Nose Expiration and Inspiration

In the in vitro release at item 2.7, the pushing bump

simulated the nose of human being and modulated to a

mild fixed pushing rate was used. Though the direction

was one way and different from the person’s nose with

two ways by expiration and inspiration. Since Su-anxin

inhalant is used for curing the cardiovascular disease at

night when nose has an expiration and inspiration at a

steady frequency during someone’s sleeping, the total

quantity between accumulative release and nose expira-

tion and inspiration was reckoned to the same for some

extent. However, because there is a very short stop for

nose exchange between expiration and inspiration when a

person’s sleeping, the total quantity of nose expiration

and inspiration will a little larger than that of accumula-

tive release,which can be verified in the near trial. In a

word, it is useful and valuable for the practice of the in-

halants after the elucidation of the correlation between

release and nose expiration and inspiration.

4. Conclusions and Discussion

Analysis results indicated that the determination method

of borneol is sensitive, accurate, and reduplicate, which

can be used to determine borneol from Su-anxin nasal

inhalants. Based on this, the 6 batches of sample inha-

lants showed a good controlled release tendency accord-

ing to r2 in the profile and similar factor 2

, which ex-

plained the excellent preparation of the optimized Su-

anxin inhalant. As a new dosage form, the in vitro release

apparatus was invented and a pushing bump was used

after the simulation of the nose expiration and inspiration,

which confirmed a good correlation between the in vitro

release and the nose expiration and inspiration when used

at the possible same condition. It can be suggested that

the nose, the same as what the pushing bump did, is very

important in bringing the trend of drug controlled release

and the effect of quick absorption when used for the pa-

tients.

For insoluble volatile drugs, it is appropriate to prepare

them for the formulation of nasal inhalant. It will bring a

good drug night timing delivery and improved bioavail-

ability when used. It is very interesting that when the

patient is inhaling the inhalant to cure certain disease, his

or her spouse can also inhale the volatile gas and have a

more quiet and better sleep for the fragrant smell of the

volatile drug.

In the dissolution test, some amount of volatile drug

was possibly lost if dehydrated alcohol could evaporate

with the air. Because the boiling point of alcohol is 78˚C

and the test was done at the room temperature, the real

lost of borneol was very small. It has little effect on the

accumulative release. The test in a low temperature will

be done in our next future tests to check the real value of

volatile drug. Meanwhile,because the mixture of volatile

materials,such as borneol and styrax, had a relatively

similar release tendency when released from the excipi-

ents of the inhalant, the borneol was selected for the in

vitro test model for its simple analytic method.

5. Acknowledgements

Be grateful for the support of grants from Chinese Min-

istry of Education, Fujian Provincial Department of

Education, Fujian Provincial Department of Science and

Technology, and the Foundation of Integrated Traditional

Chinese and Western Medicine from Chen Ke-ji (No.

209064, JA08112, 2005J045 and CKJ2007007).

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