Pharmacology & Pharmacy, 2011, 2, 67-72
doi:10.4236/pp.2011.22008 Published Online April 2011 (http://www.SciRP.org/journal/pp)
67
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.
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 68
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 70
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
f
:
 


12
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
R
W
f
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
f
, 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).
REFERENCES
[1] M. Shakeel, A. Trinidade, S. Jehan and K. W. Ah-See,
“The Use of Complementary and Alternative Medicine by
Patients Attending a General Otolaryngology Clinic: Can
We Afford to Ignore It?” American Journal of Otolaryn-
gology, Vol. 31, No. 4, 2010, pp. 252-260.
doi:10.1016/j.amjoto.2009.02.016

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
72
2.
[2] K. J. Hunt, H. F. Coelho, B. Wider, R. Perry, S. K. Hung,
R. Terry and E. Ernst, “Complementary and Alternative
Medicine Use in England: Results from a National Sur-
vey,” International Journal of Clinical Practice, Vol. 64,
No. 11, 2010, pp. 1496-1502.
doi:10.1111/j.1742-1241.2010.02484.x
[3] D. Jimbo, Y. Kimura, M. Taniguchi, M. Inoue and K.
Urakami, “Effect of Aromatherapy on Patients with Alz-
heimer’s Disease,” Psychogeriatrics, Vol. 9, No. 4, 2009,
pp. 173-179. doi:10.1111/j.1479-8301.2009.00299.x
[4] L. Weinberg, D. Story, J. Nam and L. Mcnicol, “Phar-
macoeconomics of Volatile Inhalational Anaesthetic
Agents: An 11-Year Retrospective Analysis,” Anaesthe-
sia and intensive care, Vol. 38, No. 5, 2010, pp. 849-854.
[5] D. K. Conn and D. P. Seitz, “Advances in the Treatment
of Psychiatric Disorders in Long-Term Care Homes,”
Current Opinion in Psychiatry, Vol. 23, No. 6, 2010, pp.
516-521. doi:10.1097/YCO.0b013e32833efe56
[6] E. Heuberger and J. Llmberger, “The Influence of Essen-
tial Oils on Human Vigilance,” Natural Product Commu-
nications, Vol. 5, No. 9, 2010, pp. 1441-1446.
[7] L. Moss, M. Rouse, K. A. Wesnes and M. Moss, “Dif-
ferential Effects of the Aromas of Salvia Species on
Memory and Mood,” Human Psychopharmacology, Vol.
25, No. 5, 2010, pp. 388-396. doi:10.1002/hup.1129
[8] H. W. Tsang and T. Y. Ho, “A Systematic Review on the
Anxiolytic Effects of Aromatherapy on Rodents under
Experimentally Induced Anxiety Models,” Reviews in the
Neurosciences, Vol. 21, No. 2, 2010, pp. 141-152.
[9] M. H. Hur, M. S. Lee, C. Kim and E. Ernst, “Aromather-
apy for Treatment of Hypertension: A Systematic Re-
view,” Journal of Evaluation in Clinical Practice, Vol. 17,
No. 2, 2010, pp. 1365-2753.
[10] J. Tillett and D. Ames, “The Uses of Aromatherapy in
Women’s Health,” Journal of Perinatal & Neonatal
Nursing, Vol. 24, No. 3, 2010, pp. 238-245.
[11] A. Supoken, T. Chaisrisawatsuk and B. Chumworathayi,
“Proportion of Gynecologic Cancer Patients Using Com-
plementary and Alternative Medicine,” Asian Pacific
Journal of Cancer Prevention, Vol. 10, 2009, pp. 779-
782.
[12] X. D. Li and L. P. Zhang, “The Application Prospect of
Nasal Inhalant of Traditional Chinese Medicine,” Journal
of Fujian College of Traditional Chinese Medicine, Vol.
17, 2007, pp. 56-58.
[13] S. T. Charlton, S. S. Davis and L. Illum, “Evaluation of
Bioadhesive Polymer as Delivery Systems for Nose to
Brain Delivery: In Vitro Characterisation Studies,”
Journal of Controlled Release, Vol. 118, No. 2, 2007, pp.
225-234. doi:10.1016/j.jconrel.2006.12.014
[14] R. Siekmeier and G. Scheuch, “Inhaled Insulin—Does It
Become Reality?” Journal of Physiology and Pharma-
cology, Vol. 59, No. 6, 2008, pp. 81-113.
[15] B. Luppi, F. Bigucci, T. Cerchiara and V. Zecchi,
“Chitosan-Based Hydrogels for Nasal Drug Delivery:
From Inserts to Nanoparticles,” Expert Opinion on Drug
Delivery, Vol. 7, No. 7, 2010, pp. 811-828.
doi:10.1517/17425247.2010.495981
[16] K. W. Spencer, “Isopropyl Alcohol Inhalation as Treat-
ment for Nausea and Vomiting,” Plastic Surgical Nurses,
Vol. 24, No. 4, 2004, pp. 149- 154.
[17] C. Li, C. S. Gao and X. G. Mei, “The Research Develop-
ment of Protain/Polypeptide Drugs in Pulmonary Inhaled
Preparation,” Foreign Medical Sciences Section of Phar-
macy, Vol. 34, 2007, pp. 56-58.
[18] J. P. Zhu and R. S. Zhao, “Inhaled Delivery Drugs and
Their Clinical Application and Evaluation,” Clinical
Medication Journal, Vol. 6, 2008, pp. 49-5
[19] Y. C. Hong and H. W. Huang, “To Cure Chronic Rhinitis
Through a Main Drug Delivery: Chinese Medicine
Aerosol,” Journal of Modern Integrated Medicine, Vol.
11, 2002, p. 1097
[20] Q. L. Yang, “The Treatment of Respiratory Diseases:
Chinese Medicine Aerosol,” Journal of Liaoning Univer-
sity of Traditional Chinese Medicine, Vol. 10, 2008, pp.
103-104.
[21] L. Illum, “Nasal Drug Delivery—Possibilities, Problems
and Solutions,” Journal of Controlled Release, Vol. 87,
No. 1-3, 2003, pp. 187-198.
doi:10.1016/S0168-3659(02)00363-2
[22] X. D. Li and S. Y. Li, “Studies on Improving Absorption of
Insoluble Volatile Drugs from Su-Anxin Nasal Inhalant,”
The Proceedings of 2010 Second Asia Arden Pharmaceu-
Tical Technology Forum, 279.
[23] X. D. Li, Y. Chen and F. H. Wu, “Analysis of in Vitro
And in Vivo Drug Components in Rabbits from Su-
Anxin Nasal Inhalant,” Journal of Chengdu Medical Col-
lege, Vol. 5, No. 2, 2010, pp. 119-121.
[24] P. Costa, “An Alternative Method to the Evaluation of
Similarity Factor in Dissolution Testing,” International
Journal of Pharmaceutics, Vol. 220, No. 2, 2001, pp.
77-83. doi:10.1016/S0378-5173(01)00651-2