CHAPTER 7 RESULTS AND DISCUSSION - a reservoir of Indian...
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CHAPTER 7 RESULTS AND DISCUSSION 122
Transcript of CHAPTER 7 RESULTS AND DISCUSSION - a reservoir of Indian...
CHAPTER 7
RESULTS AND DISCUSSION
122
C:0MPARAT1VE STUDY OF NEW DRUG APPROVAL
PROCESS INDIA V/S U.S.A
EXAMINATI
ON
PARAMETE
ES
Acts and
Rules
Drugs and Cosmetic Act and Rule
In India the new drug is approved under rule
122 A, 122B, 122D, 122DAandthe
requirement for new drug approval is
mentioned in Schedule Y. The guidelines
followed for conducting the clinical research
are ICH-GCP, ICMR-GCP.
U.S.A
Code of Federal Regulation
The new drug is approved under the rules
and regulations laid down under Code of
Federal Regulation, which are as follows:
21CFRPart312
Investigational New Drug Application
21CFR Part 314
INDA andNDA Applications for FDA Approval to Market a New Drug (New Drug Approval)
21CFRPart316 Orphan Drugs
21CFRPart58
Good Lab Practice for Non-clinical Laboratory [Animal] Studies
21CFRPart50
Protection of Human Subjects
21CFRPart56
Institutional Review Boards
21CFR Part 201 Daig Labeling
21CFRPart54
Financial Disclosure by Clinical Investigators
The ICH-GCP guidelines are followed for
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New Drug
Approval
Process
In India, the new drug is approved by the
Drags Controller General India, who heads
the Central Drug Staodard Control
Organization (CDSCO), under the Directed
General of Health Services, Ministry of
Health and Family Welfare. The new drugs
are approved under the drugs and cosmetic
act and rules, 1945-central. In the Act, under
the rule 122-A, 122-B, 122-D, 122-DA the
new drugs pennissions are given by the
central government. Drugs and Cosmetic Act
also provide the comprehensive requirement
of a New Drug Approval and clinical trials
under the Schedule ‘Y’.
The Indian regularion provide various
guidelines for e.g. Good Manufacturing
Practice (GMP), Good Laboratory Practice
(GLP) and Good Clinical Practice (GCP),
applicable to new drug in all aspects viz.
manufacturing, analysis, pharmacology,
toxicology and clinical trials. These
guidelines provide the basic standards of
various operations and processes needed for
drug development and discovery
Schedule Y also provide the details of the
fee, various formats, documentary
requirement etc. which are required for
submitting the new drug application to get its
conducting the clinical trials.
In United States of America, the
designated agency for approving the new
drug in CDER center for drug evaluation
and research, which works under the aegis
of Food and Drug Administration (FDA)
under the Federal Laws. Broadly, CDER
approves the new dmg via few routes;
• IND route
• AN DA route
hivestigational New Drug (IND) route
means when the application is filed by the
inventor or discoverer, along with the pre-
clinical data and the applicant is proposed
to the conduct the early phase of clinical
trial, subsequently the applicant strategize
the whole clinical development plan
(Phase I, II, III, IV) in consultation with
the CDER reviewers and officials. The
whole clinical development is rolled out
in few years and if the drug is found to be
safe and efficacious, then the U.S.F.D.A
approves the drug for the proposed
indications after completing phase III
clinical trial. Then the company conduct
the post-marketing surveillance study
often called as phase IV clinical trial and
collect the huge data (approx. 20,000
patients) on safety of the new drug. If the
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marketing approval in India. Unlike ll.S.A,
India does not have separate definitions for
Investigational New Drug and Abbreviated
New Drag. However, the New Drug
Approval process in India can be divided into
2 broad categories;
3. New Drug Approval for a drug
discovered in India
4. New Drug Approval for a drug
already approved by Regulatory
Authorities of dilferent countries.
New Drug Approval for a drug discovered
in India
The New Drug Approval process for a drug
discovered in India is not very well defined
in Indian Regulation and the regulatory
authorities heavily depends on outside
governmental agencies like ICMR and DBT
for review of proposal and data. The Drug
Controller General India office had an IND
committee, which exclusively deals in
approval process of an investigational new
drug discovered in India. In this process, the
applicant submit the proposal to conduct first
in human study (phase O/I) along with pre-
clinical data, the IND committee examine the
data and the proposal and sends the
recommendation to Drugs Controller General
India (DCGI), based on the recommendation,
DCGI office approve/disapprove the
data is found to be safe enough, then the
sponsor plan to conduct other phase III
clinical trials in different indications and
special population (nursing mother,
pregnant women, paediatrics and
geriatrics) also, the company plan to
develop the new dosage form and drug
delivery system during this phase.
In case, the new drug is indicated for
therapeutic indication, which is rare in
nature (in less than 2 lakh patients in
entire U.S.A population), then the
U.S.F.D.A approve this product as an
orphan drug. From the regulatory
prospective, clearance of any new drug
under the orphan status takes less time as
compared to normal new drug, due to the
reason that less number of patients are
enrolled in phase III clinical trial.
AN DA means Abbreviated New Drug
Application, is applied on those drugs
which are already available in U.S.A. and
are out of patent protecfion. Any U.S.A or
foreign company can take the approval of
these drugs and the main regulatory
requirement to approve such a drug is to
conduct pivotal bioequivalence study,
followed by pilot bioequivalence study
provided these drugs are manufactured in
U.S.F.D.A approved manufacturing
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proposal to carry out planned clinical trials.
Based on the data generated in clinical
studies, and subsequently submitting and
examining by IND committee, the Clinical
Development Program of the new drug
proceeds till the applicant finally gets the
manufacturing and marketing approval after
conducting phase III clinical trial.
It is only in recent past that Indain
Pharmaceutical Company entered into the era
of drug discovery due to the patent
obligations. Only very few drug (10-12)
candidates are there in India as INDs and the
progress of drug discovery in India had been
very significant in past few years and more
and more Indian companies are entering into
their own drug discovery research. So far,
only around 5-6 drugs are successfully
discovered in India since India independence,
inspite of huge infra-structure and resources.
One of the factors responsible for this
situation was unavailability of patent
protection on drug and pharmaceuticals,
which leads to copying of other’s discoveries
in India.
The process of New Drug Approval for
Indian discoveries is shown in schematic
diagram:
New Drug Approval for a drug already
facility in and outside U.S.A.
The pivitol study is conducted in less
number of human volunteers (12-14) in a
cross over randomized design and based
on the variability parameter the sample
size for pilot study is calculated. The pilot
study is usually conducted in 24-30
human volunteer in a cross over
randomized design. The results of pivitol
and pilot study are found to be satisfactory
than U.S.F.D.A. approves the drug for
marketing in U.S.A.
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approved by Megiilatory Aiitlioiities of
different countries
Most of the new drugs are approved under
this process in India provided the new drug is
not available in India. If the new drug is
patented pre-1995 then any company can
apply to Indian Regulatory Authorities and
take its manufacturing and marketing
approval. However, if the new drug is
patented post-1995 and the discoverer has a
patent right in India as well, then in that
condition, only the discoverer can apply for
the new drug approval. This process can be
further sub-divided into the following
category:
® New Drug Approval for a drug (bulk
and formulation) not available in
India, patent status pre-1995.
[Regulatory requirement: phase III
clinical trial, BA/BE study for oral
formulation, CDL testing]
• New Drug Approval for a drug (bulk
and formulation) not available in
India, patent status post-1995.
[Regulatory requirements: phase III
clinical trial, BA/BE study for oral
formulation, CDL testing]
® New Drug Approval for fixed dose
combination.
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[Regulatory requirements: phase III
clinical trial, BA/BE study for oral
formulation, expert consultation]
0 New Drug Approval for r-DNA based
drugs (bulk and formulation).
{Regulatory requirements: phase III
clinical trial, BA/BE study for oral
formulcition, CDL testing]
« New Drug Approval for vaccines
(bulk and formulation).
[Regidatory requirements: phase 111
clinical trial, BA/BE study for oral
formulation, CDL testing]
e New Drug Approval for new
indication.
[Regulatory requirements: phase 111
clinical trial, expert consultation]
® New Drug Approval for new dosage
form.
{Regulatory requirements: phase III
clinical trial, expert consultation]
■ New Drug Approval for new drug
delivery system.
[Regulatory requirements: phase 111
clinical trial, BA/BE study for oral
formulation]
m New Drug Approval for a new
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mcdical device (notified).
[Regulatory requirements: proof o f
concept study, expert consultation]
In most of the above eases, Indian
Regulatory Authority ask the applicant to
conduct a bridge study, specifically phase III
clinical trial and testing of the bulk drug at
government appellate lab. In case of oral
formulation, the India Regulatory Authority
also asks to conduct bio-availability and bio
equivalence study in addition to clinical trial.
DCGi office also consults the outside experts
on various new drag applications, if it is
required. In some special cases, DCGI may
also wave off the clinical trial and
bioequivalence study for e.g. anti-cancer
drugs.
The detailed infonnation is available in
Drugs and Cosmetic Acts and Rules, 1945-
central, Schedule Y, along with amendments
and Good Clinical Practices (GCP)
guidelines, published by CDSCO.
Definitions Indian Drug Regulations clearly defines the
new drug definition, but do not distinguish
between Investigational New Dmg and
Abbreviated New Drug. In Indian legisJation
there in no separate definition of notified
medical devices, hence it is defined under the
Drug Definition. The definitions of a new
U.S.ED.A provide very detailed and clear
definitions of new drugs mainly
Investigational New Drug (IND),
Abbreviated New Drug (AND) and
orphan drag. The legislation also provides
separate authorities, regulations, and
procedures for approving medical devices
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dfug include a!! the recombinant Iherapeutic
products and vaccines as a new drug. The
now drug (other than rDNA product and
vaccines) once approved remains a new drug
for a period of 4 years, after which
manufacturing and marketing license of such
a drug can be obtained front state licensing
authority.
and diagnostic products. U.S.F.D.A works
under federal government due to which
there in no other localized licensing
authority. It means that every
manufacturer needs to take approval by
U.S.F.D.A either for IND or for AND.
Time Line Generally, the time line had been observed
for hidia as follows;
e IND (discovered in India)- 7-9 years
® IND (discovered outside India)- 0.5-
1.5 years
® FDC-0,5-1 year
e New Dosage Form- 0,5-1 year
® New Indication- 0.5-1 year
Generally, the time line had been observed
for U.S.A as follows:
® IND" 3-5 years
® AND-0.5-1.5 years
e FDC- 0.5-1.5 year
e New Dosage Form- 0.5-1 year
• New Indication- 0.5-1 year
Review
Committee/
Reviewer
Drug Controller General India office do have
the following committees consisting of
members from DCGI office and outside
institutions;
® IND committee
« FDC committee
e Medical Device Committee
® Drug Technical Advisory Board
(DTAP)
9 Drug Consultative Committee
Besides these committees Drags Controller
General India also take hefp of independent
reviewers usually working in senior position
at various government and private
The Center for Drug Evaluation and
Research has a vast panel of independent
reviewers who hold the high rank
positions in various government and non
governmental organizations. Beside this
the CDER has its own committees and
sub-committees as per therapeutic
classifications for reviewing the proposal
and data in Drug Development Process.
130
institutions.
Transparency
and Data
Protection
I
Indian regulation does not provide the
adequate mcchanism for the data protection.
Also there is a lack of transparency due to
non-existencc of Standard Operating
Procedures (SOPs) and Regulatory Process
Manuals in Regulatory Authorities.
U.S.F.D.Ahas a full proof medianisin for
the data protection. The work practice
documents are available in U.S.F.D.A
which provides the details of minute to
minute aspects of every regulatory
activity. In most of the regulatory
processes there is a adequate transparency
by U.S.F.D.A.
Fee New drug application fee ranges from 15,000
to 50,000 in INR (Indian Rupees)
New drug application ranges from
100,000 (USD) to 500,000 (USD)
Clinical
Research
Audit
Generally Indian Regulatory Authority do
not conduct any auditing of clinical trial and
clinical research process in India.
CDER in most of occasions do audit the
clinical trial, not only in U.S.A, but
globally also, provided the clinical
development program of the candidate
drug is rolled out globally.
Special
Products
Indian Regulatory Authority sometimes
waive off the clinical trial/ BA and BE/
Bridge study for a critical product meant for
unmet medical need provided the drug is
approved by Regulatory Authorities of other
developed countries.
CDER generally do not waive off any
clinical trial even for a product meant for
unmet medical needs.
Accelerated
Regulatory
Approval
Options
In Indian Drug Regulation, there is no option
of accelerating the regulatory approval
process.
U.S.F.D.A/ CDER provide the option of
accelerated drug approval process by
paying more than normal fee.
Package
Insert
The Drug Controller General India office
approves the package insert at the time of
new drug approval only and if there are
subsequent changes in package insert, then
Indian Regulation do not provide the criteria
In U.S.A once the package insert is
approved by F.D.A, then the subsequent
changes also require approval strictly.
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of approving the same
Post Although there is a provision of conducting
Marketing Post Marketing Surveillance (PMS) Study in
Surveillance Indian rules and regulations, but it is not
Study and monitored and worked upon very thoroughly
Pharmacovigil and professionally. The Indian Regulatory
ance Authority runs the National
Pharmacovigilance Progi'am through their
center, zonal center, regional ccnter and
peripheral centers. But the program is not
implemented and working efficiently.
The PMS studies and phase IV clinical
trials are followed, monitored and studied
by U.S.F.D.A very seriously. U.S.F.D.A
also collect the huge safety data regularly
from their Pharmacovigilance Program,
which is running very professionally in
U.S.A.
132
EVALUATION OF COM[PARATIVE EFFICACY AN» SAFETY OF
INJECTABLE BUTORPHANOL AND INJECTABLE PENTAZOCIN IN THE
TREATMENT OF POST OPERATIVE PAIN AFTER ABDOMINAL SURGERY
Results and discMSsloii
In all 93 patients (47 in the study group (Butorphanol) and 46 in the control group
(Pentazocin) were enrolled in the study.
Table 5: Pemographic Profile
Table 1 shows the demographic profile of the 93 patient who were enrolled in the study.
As evident from the table, majority of them were middle aged patients in the age range of
30 to 40 years. There was a preponderance of male patients in both the group. No
statistically significant difference was observed in the demographic profile o f the patients
ill the two group.
Tables 6: Severity of pain as reported on visHal analogue scale (VAS)
As evident from the mean scores on VAS in the table, most of the patients had severe to
unbearable pain at the baseline in both the groups. A significant reduction was observed
in VAS mean scores, indicating a substantial relief from pain in both the groups within
fist 15 minutes and also subsequently over next 120 minutes. By the end of 45 minutes
and 75 minutes respectively. The reduction in VAS score over a period of 120 minutes
was much more rapid and pronounced in the study group as compared to that in the
control group. This difference between the two groups was found to be statistically
significant at the end of 45 minutes when the reduction in the study group was noted to
be 82.7%from baseline sore as opposed to only 68.1% in the control group. This finding
suggests that Butorphanol may be more patent and may have rapid onset o f action as
compared to Pentazocin as far as the property of pain reduction in the postoperative
period is concemed and Butorphanol may be more effective and better suited for this
purpose.
133
Table 7 shows that at the baseline, most of the patients in both the groups must have had
rating of ‘ T (Drowsy but can be aroused by verbal commands) on the scale used for
rating sedation. The evaluation at the end of 4 hours and subsequently after that at every
4 hours for 48 hours shows that the majority of the patients must have had rating of ‘O'
(Alert) in both the groups. This means that none of these two medications cause
unnecessary long lasting sedation inpatients in the postoperative period and patients
usually remain sedation in patients in the postoperative period and patients usually
remain quite alert and pain free with these medications in the postoperative period.
Table 8: Average number of Iniectioiis (Pose)
Table 8 shows the average number of injections received by the individuals in the 48
hours of postoperative period in each group. On an average patients in butorphanol
group required about 2-3 injections (mean (sd) 263 (1.94) while that in the Pentazocin
group required about 3-4 injection (mean (sd) 3.78 (2.01). This difference was found to
be statistically significant. Thus it seems that butorphanol may be more patent and
effective in pain control and as a result one would require less number of doses of
butorphanol for pain control than that of Pentazocin
Table 9,10,11,12 Safety: vital parameters
Tables 9 to 12 highlight the changes in the vital parameters (pulse, respiratory rate and
systolic and diastolic blood pressure) from baseline at an interval of every 4 hours over a
period of 48 hours. A significant drop in the mean pulse rate, from about 103 pulses per
minute at the baseline to around 90 to 95 pulses per minutes by the end o f 48 hours was
observed in both the gi'oups. This is not very suiprising as due to a variety of factors
pulse rate is expected to be little on the higher side during the surgery and in the
immediate postoperative period. As the patients settle down after the surgery, over a
period of next couple of days, the pulse rate also settles down. The gradual reduction in
Table 7: Pepth of sedation
134
the pulse rate over two days observed in the present study iti both the groups may be
attributed to a variety of factors and is unlikely to be related to the medications in
anyway.
No statistically significant change in respiratory rate or systolic and diastolic blood
pressure was obsei-ved in either of the groups in the postoperative period in the present
study.
These findings are very reassuring and speak about the high safety of using these
medications for this purpose.
Table 12: Adverse events
One of the most common adverse events reported with these medications is nausea and
vomiting. Therefore in the present study all the patients were specifically asked about its
occurrence and these symptoms were also rated on a 3 point scale. (No Nausea or
vomiting = O.Only Nausea = 1, Nausea & Vomiting = 2). Though all the patients reported
nausea none of the patients in the butorphanol group had vomiting as opposed to 2
patients in the Pentazocin group. The feeling of nausea was reported on evaluation at the
end of the first 4 hours and it almost disappeared by the second evaluation at the end of 8
hours in both the groups.
No other adverse event were observed or reported by the any of the patients in either
group.
135
Table 5: DEMOGRAPHY OF PATIENTS
# By Chi-Square Test
This table reveals that mean age of the patients were 40.67 years in Butoq^hanol and
31.54 years among pentazocin treatment group at basal, which was same and difference
was not statistically significant. 56-59% of total cases were made in both the groups.
136
Figure 5:COM PARISON OF CflA N G ES IN SY STO LIC BLOOD
PRESSURE BETW EEN TV?0 GROUPS
120
£ 100mm£a. 80 -nQS.m 60
oto>mc.§
40
20
ButorphanolPentazocin
<?)'/&•
Duration 5n Hours
137
Table 6: COMFARISON OF CHANGES IN SYSTOLIC BLOOD PRESSURE
BETWEEN TWO GROUPS
Duration in hours Mean SB'iP(X + SD)
Biitorpfisinol Pentazocin
Basal 112.48 ±4.33 111.23 ±3.86
4 111.44 ±3.34 111.0 ±6.03
8 112.24 ±4.05 110.50 ±3.71
12 112.24 ±4.05 110.05 ±4.32
16 111.0±5.0 109.77 ±4.03
20 111.20 ±3.32 110.09 ±3.35
24 111.80 ±2.77 110.86 ±4.23
28 111.28±3.31 110.41 ±3.72
32 110.24 ±0.88 110.05 ±5.29
36 110.64 ±2.14 110.45 ±3.02
40 110.72 ±2.30 110.41 ±3.04
44 110.64 ±2.14 110.45 ±3.02
48 110.48 ±3.53 110.45 ±3.02
ByANOVA P > 0.05 Not Significant
Above data shows that mean systohc blood pressure were 112.48 in Butorphanol group
and 111.23 among Pentazocin gi'oup at basal which was same and difference was not
significant. After treatment mean systolic blood pressure did not show any significant
change in both the group till the end of 48 hours.
138
Figure 6 : COM PARISON O F CHANGES IN D IA S'i'O LlC !M-OOjD
PR ESSIJEE B ETW EEN TW O GROUPS
•ooomo
m«5cTO
s
90 1
80 1
70
60 -i
50 :
40
30 ;
20 I
10
0
■ Butorphanol |
Pentazocin
3-'
Duration in Hours
139
Table l i COMPARISON OF CHANGES IN IDIASTOLIC BLOOD PRESSURE
BETWEEN TWO GMOUPS
Duration in hours Mean DBP(X + SD)
Butorphanol Pentazocin
Basal 81.67±3.81 81.20±3.32
4 83.48 + 4.87 83.33 ±4.82
8 82.45 ± 4.27 83.64 ±4.92
12 83.18 ±4.77 84.82 ±5.0
16 82.82 + 4.35 83.64 ±4.92
20 80.67 ±4.88 83.69 ±4.06
24 81.36 ±3.99 84.11 ±4.78
28 81.78 ±3.75 83.36 ±4.79
32 82.0 ±4.11 80.46 ±3.19
36 83.0 ±0.88 81.88 ±3.46
40 82.11 ±3.88 80.49 ±3.77
44 80.49 ± 4.07 81.40 ±4.07
48 81.3±4.53 81.69 ±4.25
By ANOVA P > 0.05N ot Significant
Above data shows that mean diastohc blood pressure were 81.67 in Butorphanol group
and 81.20 among Pentazocin gi'oup at basal which was same and difference was not
significant. After treatment mean diastolic blood pressure did not show any significant
change in both the group till the end of 48 hours.
140
Figure 7: CHANGES IN THE ffiSPIE A T IO N RATE A FTEE THE
TREATM ENT
I >.
r/-(
25
20stsffi
o« I -I, Butorphanol,
^ Pentazocin
cTO«S
Duration in Hours
141
Table 8: CHANGES IN THE RESPIRATION :RATE AFTER THE TREATMENT
Duration in hours Mean Respiratory Rate (X + SD)
Butorphanol Pentazocin
Basal 22.70 ±2.87 21.68 ±2.87
4 22.32 ±2.28 21.48 ±2.37
8 21.64±2.13 21.72 ±2.44
12 21.14 ±2.03 21.08 ±2.20
16 20.82 ±2.14 20.84 ± 1.77
20 20.59 ±2.0 21.28 ±2.07
24 20.77 ± 1.63 20.32 ±1.89
28 20.55 ±.1.69 20.16 ± 1.91
32 20.52 ±1.68 20.24 ± 2.26
36 20.41 ±1.69 19.84 ±2.08
40 20.20 ± 1.42 20.0 ±2.0
44 20.0+1.38 19.84 ± 1.91
48 19.95 ±1.46 19.92 ±1.96
ByANOVA P > 0.05 Not Significant
Mean respiratory rate were 22.70 in Butorphanol group and 21,68 among Pentazocin
group at basal which was same and difference was not significant. After treatment mean
respiratory rate did not show any significant change in both the group till the end of 48
hours.
142
Figure 8:CHANGES IN MEAN PULSE RATE A F T E R THE
TREATMENT
120
100 1 '—--- J
1 80tt
13 60
- Butorphanol
fl. PentazocinC§ 40
20
0
<i?-
Duration in Hours
143
Table 9: CHANGES IN MEAN PULSE RATE AFTER THE TREATM ENT
ByANOVA P > 0.05 Not Significant
In this study group mean pulse rate were 103.68 in Butoiphanol group and 103.92 among
Pentazocin group at basal which was same and difference was not significant. After
treatment at the end of 8-12 hours, mean pulse rate showed a significant fall in both the
groups and if you compare the fall was same. At the end of 48 hours mean pulse rate
were 91.23 in Butorphanol and 94.16 in other groups.
144
Figure 9; COM PARISON O F CHANGES IN M EA N SCO RE O F PAIN
SEVERITY (VAS) BETW EEN TW O G ROUPS
m
100
90
80
70
60o0m 50cra1
30
20
10
0
L3- - Butorphanoi j
Pentazocin i
Basal 15 30 45 60 75 90
Duration in Hours
105 120
145
Table 1(1: COMPARISON OF CHANGES IN M(EAN SCORE OF PAIN SEVERITY
(VAS) BETWEEN TWO GROUPS
Duration in hours Mean Score (X + SD)
Basal
15
30
45
60
75
90
105
120
80.02 + 7.18
*48.34 ± 18.62
*28.07 ± 17.06
*15.45 + 13.15
*9.77+11.20
*6.48 ±11.13
*5.11+ 10.43
*4.66 ± 10.37
*4.77 + 10.37
89.63 + 5.87
*53.60 ±23.34
*38.80+ 19.65
@*28.60 ±20.08
*22.0 ± 18.09
*16.60 ± 15.05
*13.0+14.86
*10.80 ± 11.61
*9.60+ 10.30
ByANOVA(Kruskal) P > 0.05 Not Significant
Between groups @ P < 0.05 Significant
The above table reveals that mean pain score (VAS) were 89.08 and 89.63 in Butorphanol
group and Pentazocin group respectively at basal which was same and difference was not
significant. After the treatment at the end of 15 minutes mean score showed a significant
fall in both the groups i.e. 45.7% in Butorphanol as compared to 40.1% in pentazocin
group. If you compare the fall was more in Butorphanol than pentazocin but difference
was not statistically significant. At the end of 45 minutes the fall was 82.7% in
Butorphanol which was significantly more as compared to 68.1% among the pentazocin.
At the end of 120 minutes mean pain score were 4.77 in Butorphanol which is
significantly low as compared to 9.6 in pentazocin.
146
Figure 1(1: CHANGES IN MEAN SEDATION SCORE A FTER THE
TREATM ENT
1 2
1
£8 0.8
(JO
§S 06■gtoTO 0 4 m§
02
Butorphanol Pentazocin
[ ■ - / 1 / ' / I F K’
12 16 20 24 28 32 36 40 44 48Duration in Hours
147
Table 11: CHANGES IN IVIEAN SEDATION SCORE AFTER THE TREATMENT
This table shows that mean sedation score were 0.98 in Butorphanol group and 0.1
among Pentazocin group at basal which was same and difference was not significant.
After treatment immediately after 4 hours mean sedation score showed a significant fall
in both the groups. If you compare the fall was same and difference was not statistically
significant.
148
Table 12: CHANGES IN MEAN SCORE OF VOMIlflNG AFTER THE
TREATMENT
This table shows that mean sedation score were 0.98 in Butorphanol gi'oup and 0.1
among Pentazocin group at basal which was same and difference was not significant.
After treatment immediately after 4 hours mean sedation score showed a significant fall
in both the groups. If you compare the fall was same and difference was not statistically
significant.
149
EVALUATION OF THE EFFICACY AND SAFETY OF BUTORPHANOL NASAL
SPRAY IN MANAGEMENT OF POST OPERATIVE PAIN
I l l S U O ’S
A total of 105 patients suffering from post operative pain were screened before and
during the study in three centers.
Demograpliic profiles;
The demographic profiles o f the patients enrolled in the study as per inclusion-
exclusiou criteria is shown in the Table. The enrolled patients were in the age group ofl9
to 62 years with the mean age of 40.80 (± 13.88)066.7% of male patients were enrolled.
The weight of the enrolled patients, ranged from 40 kg to 86 kg with tlie mean of 60.11
(± 11.94)
Table 13; Demograpliical Characteristics of Study population.
Param eter Value
Age Mean 40.85
(Yrs.) S.D. 13.88
Range 19-62
Weight Mean 60.11
(Kg) S.D. 11.94
Range 40-86
Sex Male 70(66.7)
(%) Female 35(33.3)
150
Physical examination
Tabie reveals that all the examination like pulse rate, blood pressure and respiratory rate
were within normal limit at baseline.
Table 14: Profile of physical examination
Examination Mean ±SD
Pulse rate 79.82 ± 6.70
mm/Hg
Systolic blood 120.9 ± 13.04
mm/Hg d pressure
Diastolic blood pressure 19.65 ± 70.05
mm/Hg
Respiratory rate 16.67 ±3.35
M in'
Objective efficacy parameters
The reduction in pain intensity was rated by the patients and is shown in table IV. A
statistically fall in the pain score was observed by the end of 15 min. till the end of
treatment (Figure 1). The basal score of pain intensity was 70.06 ± 10.60 which came
down to 19.19 ± 3.71 by the end of 24 hrs. indicating statistically significant decrease in
postoperative pain stimuli.
151
Table 15: Changes in mean score of pain Intensity after the treatment
Duration in hours Mean score (Mean ± SD)
Basal 70.06 ± 10.60
15 mill *59.17 ±9.11
30 min *46.45 ± 8.60j *40.34 ± 8.68
2 *37.33 ± 9.89
4 *30.59 ± 7.98
6 *28.47 ± 7.48
12 *25.35 ±6.36
24 *19.19±3.71
By ANOVA Kruskal Walli’s Test *<0.05 Significant
152
Figure llrCHANGES IN MEAN SCORE OF PAIN INTENSITY
Table shows the rating on overall efficacy by the investigators. Investigators categorized
84.8% patients as either excellent or good improvement while only 15.2% patients fell in
fair and poor category.
Table 16: Overall global efficacy of treatment by investigators.
Assessment No. of Cases Percentage
Excellent 11 10.5
Good 78 74.3
Fair 12 11.4
Poor 04 03.8
Total 105 100.0
153
Figure 12:OVERALL GLOBAL EFFICACY OF TREATMENT
a Excellent■ Good□ Fair□ Poor
Safety and Tolerability
The Butorphanol treatment was observed to be safe and tolerable as 87.6% of the total
study patients had an excellent to good tolerance to the treatment and 12.4% showed fair
or poor tolerance. Not a single patient was withdrawn due to safety and tolerability
concerns.
Table 17: Overall global tolerability of treatment by investigators.
Assessment No. of Cases Percentage
Excellent 76 72.4
Good 16 15.2
Fair 08 07.6
Poor 05 04.8
Total 105 100.0
154
Figure 13: OVERALL GLOBAL TOLERABILITY OF TREATMENT
□ Excellent■ Good□ Fair□ Poor
Adverse events
Out of 105 patients completed the study only 22 patients complained of some minor
problems like Nasal irritation, Nausea/Vomiting, Drowsiness, Taste perversion and
Dizziness. None of the patients experienced serious adverse events during the study
period. Adverse events observed and reported over the study period are listed in Table
Table 18:Profile of adverse events
Assessment No. of Cases Percentage
Nausea/Vomiting 07 06.7
Dizziness 03 02.9
Drowsiness 04 03.8
Taste perversion 04 03.8
Nasal irritation 13 12.4
Hypotension — —
Others — —
Total 22 20.9
155
Figure 14: FREQUENCY OF ADVERSE EFFECTS
j a Nausea/Vomiting*■ Dizziness
I □ Drowsiness□ Taste pen^rsion■ Nasal irritation
156
VALSARTAN
Eesiilts
Administration of the Reference preparation, Capsule STARVAL, as a single dose in the
fasting state produced tlie maximum plasma concentration of 0.92 + 0.09 mcg/ml (C
max) at the time 3.29 + 0.65 hr. (tmax) whereas the Test preparation of Capsule
VALSARTAN, as a single dose in the time 3.96 ± 0.58 hr. (tmax) Administration of the
Reference preparation, Capsule STARVAL, produced the area under plasma
concentration time curve (AUC 0-t) 3.98 + 0.51 meg hr/ml, whereas administration of
Test preparation of Capsule VALSARTAN, produced the area under plasma concentration
time curve 9AUC 0-4) 3.71 ± 0.30 mcg/ml
When administered as a single dose, in the fasting state, the Reference preparation,
Capsule STARVAL, produced the area under plasma concentration time upto infinity
(AUCO-inf) 4.88 + 0.75 meg hr/mi whereas administration of the Test preparation of
Capsule STARVAL, produce the plasma elimination half life (tl/2) 4.37 ± 1.25 hr,
whereas administration o f the Test preparation of Capsule VALSARTAN, produced the
plasma elimination half life (tl/2) 5.29 + 2.76 hr.
Administration of the Reference preparation. Capsule STARVAL, produced the plasma
elimination constant (kel) 0.171 + 0.048 hr, whereas administration of the Test
preparation of Capsule VALSARTAN, produced the plasma elimination constant (kel)
0.205 ± 0,227 hr.
On the basis of comparison of the AUC for VALARTAN 80 mg after single dose
administration the relative bioavailability of the Test preparation, Capsule VALSARTAN
was 93.17% of that of the Reference preparation, Capsule STARVA. 90% confidence
interval (conventional) for Cmax values of Test preparation of Capsule VALSARTAN
were 93.38 - 104.58% of that of the Reference preparation. 90 % confidence interval
(conventional) for AUC-o-t values of Test preparation of Capsule VALSARTAN were
86.83-102.41 % o f that of the Reference preparation 90% confidence interval
(conventional) for AUCO-inf values of Test preparation of Capsule VALSARTAN were
84.67 - 114.72% of that of the Reference preparation. None o f the volunteers complained
of any adverse reaction on the pharmacokinetic profile days.
157-A
BIOEQUI¥ALANCE STUDY OF¥ALSARTAN CAPSULE SOiiig
Table 19
Bioeqiilvalence of Valsarten Capsule
Pemograp h k Date of 12 VolunteersVoi No. SEX ■ AGE(Yre) HEIGHT(cms) W EIGHT(Kg)
1 M 26 160 682 M 20 158 723 M 22 180 724 M 22 158 655 M 20 150 506 M 22 160 587 M 23 165 768 M 21 170 759 M 30 155 7010 M 27 166 5511 M 33 163 7812 M 21 155 52
Mean 23J2 161.67 65.92SD 4.19 7.95 9.79
157
MODE OFTREATMF.NT
Table 20
Bioequivalence of Valsartaii Capsule
Vol No, SESSION I SESSION II1 A B2 A B3 B A4 B A5 A B6 B A7 B A8 A B9 A BMl A B11 B A12 B A
A = Capsule Starval
B = Capsule Valsartan
158
Table 21
Bioequivalciice of Valsartan Capsule
Plasma Concentration (mcg/mi) of the Reference Prep. (A) in 12 volunteer
' Vol. Time (hrs.)
1 No 0 I.O 2.0 3.0 3.5 4.0 5.0 6.0 8.0 10.0 J2.0 16,0 24.0
1 ND 0.139 0.356 0.598 0.811 0.748 0,663 0.608 0,393 0.293 0,187 0.182 ND
2 ND 0.099 0.271 0.414 0.526 0.501 0.814 0.707 0.567 0.363 0.271 0.183 ND')J ND 0.100 0.230 0.347 0.887 0.684 0,512 0.435 0.361 0.271 0,201 0.182 ND
i ^) ......ND 0.203 0.279 0.562 0.783 0.986 0.913 0.410 0.437 0.274 0,211 0.137 ND
5 ND 0.104 0.216 0.280 0.351 0.480 0.808 0.513 0.375 0.275 0,208 0,098 ND
6 ND 0.094 0.189 0.279 0.708 0.980 0.699 0.595 0.566 0.334 0,171 0.127 ND
7 ND 0.010 0.144 0.376 0.519 0.966 0.692 0.416 0.320 0.225 0,095 0.092 ND
8 ND 0.198 0.509 0.125 0.721 0.731 0.580 0.505 0.383 0.206 0.154 0.117 ND
9 ND 0.274 0.396 0.506 0.718 0.907 0.516 0.430 0.275 0.206 0.186 0.124 ND
10 ND 0.263 0.431 0.901 0.688 0.835 0.552 0.431 0.381 0.370 0.276 0.176 ND
11 ND 0.141 0,189 0.583 0.844 0.656 0.591 0,527 0.351 0.197 0.147 0.103 ND
r 12 ND 0.189 0.524 0.746 0.972 0.768 0.605 0.394 0.369 0.268 0.193 0.143 ND
MEAN - 0.151 0.309 0.561 0.711 0.748 0.662 0.497 0.398 0.274 0.192 0.139 -
S,D. 0.077 0.128 0.256 0174 0.181 0.128 0.097 0.088 0.059 0.050 0.034 -
c v.% - 50.91 41.42 45.65 24.44 21.18 19.32 19.59 22.08 21.72 25.97 24.72 -
159
Table 22
Bioequivalence of Valsartan Capsule
Plasma ConceEtratioii (mcg/ml) of the Reference Prep. (B) in 12 volunteer
1Time (Iirs.)
1 No. 0 1,0 2.0 3.0 3.5 4.0 5.0 6.0 8.0 10.0 12.0 16.0 24.0
' 11
ND 0.093 0.261 0.360 0.531 0.747 0.610 0.509 0.442 0.356 0.160 0.196 ND
2 ND 0.139 0.207 0.241 0.354 0.705 0.867 0.615 0.583 0.356 0.208 0.167 ND
3 ND 0.206 0.356 0.726 1.059 0.641 0.491 0.518 0.376 0.141 0.169 0.108 ND
4 ND 0.152 0.180 0.422 0.930 0.525 0.519 0.3636 0.377 0.201 0.175 0.098 ND
5 ND 0.113 0.290 0.354 0.390 0.759 0.590 0.495 0.417 0.228 0.136 0.100 ND
6 ND 0.145 0.281 0.337 0.559 0.884 0.527 0.389 0.393 0.166 0156 0.104 ND
7 ND 0.114 0.449 0.507 0.651 0.872 0.598 0.424 0.248 0.201 0.201 0.149 ND
8 ND 0.208 0.520 0.678 0.674 0.972 0.574 0.567 0.360 0.197 0.141 0.121 ND
9 ND 0.177 0.560 0.998 0.842 0.726 0.497 0.351 0.264 0.210 0.187 0 095 ND
10 ND 0.184 0.285 0.632 0.928 0.568 0.417 0.351 0.338 0.182 0.143 0.096 ND
11 ND 0.094 00.256 0.570 0.755 0.924 0.767 0.358 0.317 0.264 0.177 0.187 ND
12 ND 0.010 0.185 0.262 0.355 0.522 0.894 0.700 0.572 0.368 0.153 0.010 ND
MEAN - 0.136 0.328 0.507 0.669 0.737 0.613 0.472 0.391 0.239 0.167 0.119 -
SD. - 0.056 0.126 0.224 0.240 0.154 0.152 0.114 0.104 0.079 0.023 0.051 -
CV.% - 41.47 38.37 44.08 35.83 20.90 24.73 24.13 26.65 33.00 13.68 42.43 -
160
I. 2
10
|05.5
? 0 6
Figtire 15; Bioequivalence Stiiclv of Valsartan Cap&iilc
Plasma Concentratfon Time Graph (Mean)
T im c {H rs )
- Reference Preparation i Test Preparation
161
PH A RM A CO M N ETIC VARIABLES
Table 23
Bloequivalence of V alsartan Capsule
Cmax (meg/ ml) in 12 volMBteers
W ith the Test and the Reference P reparation
Vol. Reference Test
No. PreparatioKi (A) Preparation (B)1 0.81 0.75
2 0.81 0.87
nJ 0.89 1.06
4 0.99 0.93
5 0.81 0.76
6 0.98 0.88
7 0.97 0.87
8 1.12 0.97
9 0.91 1.00
10 0.90 0.93
11 0.84 0.92
12 0.97 0.89
Mean 0.92 0.90
S.D. 0.09 0.09
C.V.% 10.26 9.89
A= Capsule Starval
B= Capsule Valsartan
162
Bloeqmivaleiice of Valsartan Capsule
Tniax (hr.) in 12 volunteers
With the Test and the Reference Preparation
Table 24
VoL Reference Test
No. Preparation (A) Preparation (B)1 3.50 4.00
2 5.00 5.00
3 3.50 3.50
4 4.00 3.50
5 5.00 4.00
6 4.00 4.00
7 4.00 4.00
8 3.00 4.00
9 4.00 3.00
10 3.00 3.50
11 3.50 4.00
12 3.50 5.00
Mean 3.83 3.96
S.D. 0.65 0.58
c.v.% 16.99 14.71
A= Capsule Starval
B= Capsule Valsartan
163
Bioeqiiivalence of Valsartan Capsule
AUC-t (meg/ ml) ia 12 volunteers
With the Test and the Reference Preparation
Table 25
Vol. Reference Test
No. Preparation (A) Preparation (B)1 4.24 3.84
2 4.43 4.12
3.62 3.88
4 4.32 3.32
5 3.36 3.36
6 4.13 3.29
7 3.03 3.57
8 4.36 3.98
9 3.74 4.06
10 4.64 3.44
11 3.53 3.91
12 4.36 3.71
Mean 3.98 3.71
S.D. 0.51 0.30
C.V.% 12.70 8.14
A= Capsule Starva]
B= Capsule Valsartan
164
Table 26
Bioeqiiivalence of Valsartaii Capsule
AUC-iiif, tl/2 kel in 12 volunteers
With the Test aratl ihe Heference Preparation
V
AUC oinf (meg hr/ ml)
PreparationA
PreparationB
Kel (hr 4 ) Tl/2 (hr.)
Preparation Preparation A B
, 2I
^3It 4
5
6
7
8
9
10
11
12
Mean
S.D,
C.V. %
5.76
5.50
5.44
5,11
3.74
1.66
3.47
5.18
4.72
5.59
4.17
5.27
5,16
5.01
5.49
3.87
4.02
4.19
5.59
4.97
4.54
4.03
6.09
3.72
0.120
0.171
0.100
0.172
0.258
0.242
0.215
0.142
0.126
0.185
0.162
0.157
0.149
0.189
0.067
6.179
0.204
0.116
0.074
0.123
0,200
0.161
0.086
0.909
577
4.04
6.95
4.02
2,69
2.86
3,22
4.88
5.51
3.74
4.29
4.41
4.68
3.67
10.34
3.86
3.39
5.95
9.34
5.63
3.47
4.32
8.05
0.76
4.88
0.75
15.28
4.72
0,77
16,34
0.171
0.48
2821
0.205
0,227
110.85
4.37
1.25
28.65
5.29
2.76
52.11
A = Capsule Starval
B= Capsule Valsartan
165
Table 27
Bioeqnlvsilcnce o f Valsartaii Capsule
Pharsiiacoldiietk Parameter in 12 volunteers
With t ie Test and the Reference Preparation
1: Pharniacokinctic Parameters
Reference Preparation (A)
TestPreparatioii(B)
1Ciiiax
/■'
(mcg/ml) Mean ± SD
0.920.09
0.900.09
{Tiiiax (hr.) Mean 3.83 3.96
ii
± SD 0.65 0.58
AUC 0-t Mean 3.98 3.71(iiicg.hr/ml.) ± SD 0.51 0.30 i:
AUC 0-inf Mean 4.88 4.72 :(mcg.hr/ml.)
■}
± SD 0.75 0.77 i
Kel (hr) Mean 0.171 0.205± SO 0.048 0.227
Tl/2 Mean 4.37 5,29(hr) ± SD 1.25 2.79 1
Relative100% 93.17 j
Bioavailability %
A = Capsule Starval
B = Capsule Valsartan
166
Table 28
Bioeqttlvalemce of Valsartaii Capsule
90% CONFIDENCE INTERVAL
With the Test and the Reference Preparation
Cnia? Untransfornried Data93.38^-104.58%
Ln transformed Date 91.76- 109.54%
AUC 04 Untransformecl Data 86.83- 102.41%
Ln transformed Data 90.02 - 102.07%
AUC 0-t Uiitransformed Data 84.67-114.72%
Ln transformed Data 89.62-108.71%
167
AWO¥A
MFFERNCES & RATIOS
168
Bioecjuivalence of Valsartan Capsule
ANOVA Summary for Cniax Values
IJNTRANSFORMED DATA
Table 29
SOURCE D.F. S. S. M.S.S. F. F.
SUBJECTS 11 0.134 0.012 2.539 N.S.
TREATMENT 1 0.001 0.001 0.238 N.S.
PERIOD 1 0.003 0.003 0.675 N.S.
ERROR 10 0.048 0.005 „ -
TOTAL 23 0.186 - _ -
D.F. = Degree of freedom
S.S. = Sum of square
M.S.S.= Mean sum of square
F= M.S.S./errorM.C.S.
P= Probability
N.S.= Not significant
S.= Significant
169
Bioequivalence of Valsaitan Capsule
ANOVA Summary for Cinax Values
Lii TRANSFORMED DATA
Table 30
SOURCE D .E S. S. M.S.S. F. F.
SUBJECTS 11 0.166 0.015 2.802 N.S.
TREATMENT 1 0.001 0.001 0.254 N.S.
PERIOD J 0.003 0.003 0.601 N.S.
ERROR 10 0.054 0.005 -
TOTAL 23 0.224 - - -
D.F. = Degree of freedom
S.S. = Sum of square
M.S.S.= Mean sum of square
F= M.S.S./error M.C.S.
P= Probability
N.S.= Not significant
S.= Significant
170
Bloeqsilvaleiice of Valsartaii Capsule
ANOVA SuiiMiiary for AUC 04 Values
UNTRANSFORMED DATA
Table 31
SOURCE D.F. S. s. M.S.S. E K
SUBJECTS 11 1.967 0.179 0.985 N.S.
TREATMENT 1 0.443 0.443 2.440 N,S.
PERIOD 1 0.030 0.030 0.167 N.S.
ERROR 10 1.815 0.182 ~ -
TOTAL 23 4.255 - - -
D.F. = Degree of fi-eedom
S.S. == Sum of square
M.S.S.= Mean sum of square
F=M.S.S./error M.C.S.
P= Probabiiity
N.S.= Not significant
S.= Significant
171
Bloequivfllence of Valsartan Capsules
ANOVA SuiMniary for AUC 0-t Values
Lii TRANSFORMEB DATA
Table 32
SOURCE D.F. s.s. M.S.S. E P.
SUBJECTS 11 0.1392 0.0127 1.00 N.S.
TREATMENT 1 0.02609 0.0261 2.07 N.S.
PERIOD 1 0.00250 0.0025 0.20 N.S.
ERROR 10 0.1260 0.0126 -
TOTAL 23 0.2938 - - -
D.F.= Degi-ee of freedom
S.S. = Sum of Squares
M.S.S. - Mean sum of squares
F-M.S.S./error M.C.S.
P = Probability
N.S. = Not significant
S. - Significant
172
Bioeqiiivalence of Valsartan Capsules
ANOVA Summary for AUC 0-Inf Values lii 12 Volunteers with the Test and flieReference Preparation
Table 33
SOURCE D.F. S.S. M.S.S. F. P.
SUBJECTS 11 5.079 0.462 0.610 N.S.
TREATMENT 1 0.157 0.157 0.208 N.S.
PERIOD) I 0.022 0.022 0.029 N.S
EREOR 10 7.574 0.757 -
TOTAL 23 12.832 ~ - -
D.F.= Degree of freedom
S.S. = Sum of Squares
M.S.S. = Mean sum of squares
F = M.S.S./eiTorM.C.S.
P = Probability
N.S. = Not significant
S. = Significant
173
Bioecpivaleiice of Valsaitan Capsules
ANOVA Summary for AUC O-inf Values in 12 Volunteers witii the Test and theReference Preparation
Table 34
SOURCE D.F. S.S. M.S.S. F. P.
SUBJECTS 11 0.23629 0,02148 0.616 N.S.
TREATMENT 1 0.00697 0.00697 0.200 N.S.
PERIOD J 0.0029 0.0029 0.066 N.S
ERROR 10 0.34875 0.03487 -
TOTAL 23 0.59429 - - -
D.F.= Degree of freedom
S.S. = Sum of Squares
M.S.S. - Mean sum of squares
F = M.S.S./eiTor M.C.S.
P = Probability
N.S. =Not significant
S. = Significant
174
Bloequivaleiice of Vsilsartaii Capsules
Differences and Ratios: C max with the Test and the Reference Preparation
Table 35
Vol.
No,
Preparation
(A) (B)
Differences
B-A
Ratio
B/A
1. 0.81 0.75 -0.06 0.921
2. 0.81 0.87 0.05 1.065
3. 0.89 1.06 0.17 i.194
4. 0.99 0.93 -0.06 0.943
5. 0.81 0.76 -0.05 0.940
6. 0.98 0.88 -0.10 0.901
7. 0.97 0.87 -0.09 0.903
8. 1.12 0.97 -0.15 0.855
9. 0.91 1.00 0.09 1.101
10, 0.90 0.93 0.03 1.030
11. 0.84 0.92 0.08 1.095
12. 0.97 0.89 -0.08 0.990
Mean
S.D.
0.92
0.09
0.90
0.09
-0.01
0.10
0.990
0.10
175
Biocqiiivalence of Valsartan Capsules
Differences and Ratios: Lii ,C max with tlie Test and the Reference Preparation
Table 36
Vol.
No.
Preparation
(A) (B)
Differences
B-A
Ratio
B/A
1. -0.21 -0.29 -0.08 1.396
2. -0 .2 ! -0.14 0.06 0.695
3. -0 .12 0.06 0.18 - 0.478
4. - 0.01 - 0.07 -0.06 5.151
5. -0.21 -0.28 -0.06 1.289
6. - 0.02 -0.12 -0.10 6.209
7. -0 .03 -0.14 -0.10 3.917
8. 0.12 -0.03 -0.15 -0.238
9. -0 .1 0 0.00 0.10 0.019
10. -0 .1 0 -0.07 0.03 0.715
11. -0 .17 -0.08 0.09 0.465
12. -0 .03 -0.11 - 0.08 3.908
Mean
S.D.
-0.09
0.10
-0.11
0.10
-0.11
0.10
1.921
2.27
176
Bioeqaivalciace of Valsartaii Capsules
Table 37
177
Bioequivalence of Valsartan Capsules
Table 38
178
BIOEQUIVALANCE STUDY OF BEFLAZACORT TABLET 3«rng
Results of Pharmacokinetic Parameters
The following pharmacokinetic parameters were calculated for 21-OH Deflazacort using
SAS software version 9.1.3.
Cmax: Maximum measured plasma concentration following
treatment of reference and test formulations are 121.42 ± 2.60
(105.60 - 135.60) ng/mL and 126.39 ± 2.68 (111.50 -140.60)
ng/mL respectively. Data arc presented in Table.
Tmax; The time at which maximum concentration of drug achieved by
reference and test foimulations are 1.44 ± 0.03 (1.25 -1.50) hours
and 1.42 ± 0.04 (1.25 - 1.50) hours respectively. Data are presented
in Table.
AUC0-t:The area under the plasma concentration versus time curve from time zero to the
last measurable time achieved by reference and test formulations were 514.95 ± 14.86
(427.49 - 624.66) ng.hr.ml-1 and 512.63 ± 16.74 (438.94 - 597.26) ng.hr.mLt
respectively. Data are presented in table.
AUCO-infThe area under the plasma concentration versus time curve from time zero to
infinity to be calculated as the sum of AUCo-t plus the ratio of the last measurable
concentration to the elimination rate constant achieved by reference and test formulations
were 541.37 ± 15.19 (441.04 - 650.62) ng.hr.ml-1 and 536.21 ± 17.30 (453.68 - 624.89)
ng.hr.mh respectively. Data are presented in table.
Kei; The apparent first-order elimination or terminal rate constant calculated for
reference and test fonnulations are 0.28 ± 0.01 (0.22 - 0.36) hrl and 0.27 ± 0.01 (0.25 -
0.30) hrl respectively. Data are presented in table.
T '/2:The elimination or terminal half-life calculated for reference and test formulation
2.49 ± 0.10 (1.94 -3.13) hours and 2.58 ± 0.05 (2.28 -2.82) hours respectively. Data are
179
Statistical Analysis
A statistical analysis for 21-OH~DefIazacort was performed on the data obtained from all
twelve subjects who completed both treatment periods as per the randomization schedule.
Analysis of Variance
AN OVA model was designed to includc sequence of dosing, subjects nested within
sequences, period of treatment and drug formulations as factors. The untransformed and
log-transformed pharmacokinetic parameters Cmax, Tmax, AUCo-t and AUGo-mr were
subjected to Analysis of variance (ANOVA). Anova Summary for un transformed Cmax,
AUCo* and AUCo-inf are presented in Tables 18, 20, 22. Anova Summary for log
transformed Cmax, AUCo-t and AUCo** are presented in Tables 19, 21, 23, - Any
statistically significant (p <0.05) differences between the pharmacokinetic parameters for
treatments and period of treatment as determined by F-value is reported elsewhere in the
report
Two one-sided tests for bioeqiiivalence
Two one-sided tests for bioequivalcnce, 90% confidence intervals (both Classical and
Westlake) for the difference of means between dmg formulations were calculated for
untransformed data o f C max, I max, AUCo-t and AUCo-inf and log transformed data of
Cmax, AUCw and AUCo-inr. Wilcoxon rank sum test was perfonned to analyze Tmax
arid it was found that P>0.05, which indicated that Tmax, complies with analysis.
Intra-SHbJect variability
Intra-subject variability as indicated by the results of analysis of variance was calculated
for both untransformed and log transformed data. And F-test has determined statistically
significant (p <0.05) differences between some of the phannacokinetic parameters for
treatments and period of treatment which can be attributed to nonlinear pharmacokinetics
and high inter individual pharmacokinetic variability o f Deftazacort 30 mg in human
subjects.
presented in Table 10.
180
Ratio mulysis
Ratio analysis is reported for untransformed and log-transformed Cm ax and AUCo-t and
AUCo-.nf. The geometric mean value is reported for log-transformed data.
In-vitro and in-vlvo correlation
Correlation between the in-vitro and in-vivo results of Deflazacort 30 mg Tablets for
reference and test formulation were detennined by mean percentage released in-vitro at
time, t versus the mean percentage absorbed in-vivo at lime, t. The Wagner-Nelson
method was used to determine the fractional oral absorption of Deflazacort 30 mg. A
slope of 0.9826 and 0.9859 was observed for reference and test formulation for the
percentage dissolved Vs percentage fraction absorbed on ordinate axis indicating a good
in-vitro and in-vivo correlation.
Bioequivalence criteria
Based on the statistical results o f 90% confidence intervals of log-transfoimed
pharmacokinetic parameters Cmax, AUCO-t and AUCO-inf, it is concluded that the Test
Formulation, Deflazacort 30 mg Tablet manufactured by Aristo Phamiaceuticals Pvt Ltd.,
India, administered with 240ml ambient temperature water are bioequivalent to the
reference formulation, Calcort 30 mg Tablet (containing Deflazacort 30 mg) of Aventis
Pharma, Italy, administered with 240ml ambient temperature water under fasting
conditions. The confidence intervals for AUCo-t in the range of 91.75 - 106.44% and log
transformed AUC04 in the range of 98.63 - 101.01% for comparison with Test Vs
reference formulation. For AUCo-inr in the range of 92.23 - 110.15% and log
transformed AUCcwnf in the range of 98.79 - 101.77% for comparison with Test Vs
reference formulation. For Cmax in the range of 98.78 -109.41 % log transformed Cmax
in the range of 99.75 - 101.93 % for comparison with Test Vs reference formulation
which conclude bioequivalence of the two products are within the limit of confidence
interval in the range of 80% to 125%. Therefore it is convincible that the reference
formulation compared with test formulations administered with 240ml ambient
temperature water under fasting condition are bioequivalent.
181
Table 39
Subjects Demographic Data
Subject Name of the sebject No.1 Mr. S.P.
2 Mr. A.D.
3 Mr. M.G.
4 Mr. S.M.
5 Mr. S.S.
6 Mr. A.D.
7 Mr. S.A.
8 Mr. K.K.
9 Mr. D.G,
10 Mr. K.N.
11 Mr. R.P.
12 Mr.A.P.
Mean
S.D
Sex Age(yrs.)
Weight(Kgs)
Height(cms)
M 26 60 171
M 24 58 169
M 20 55 156
M 21 56 166
M 27 62 172
M 30 55 165
M 22 52 159
M 28 58 168
M 24 60 162
M 24 65 173
M 26 56 165
M 25 53 160
24.75 57.5 165.5
2.90 3.78 5.42
182
Table 4
RANDOMIZATION SCHEDULE
ject No TreatiMent Period 1 Period II
1 AB A B
2 BA B A
3 AB A B
4 BA B A
5 BA B A
6 AB A B
7 AB A B
8 BA B A
9 AB A B
10 BA B A11 BA B A
12 AB A B
RefeB’ence Product (A); CALCORT 30 mg Tablet, containing Defiazacort 30 mg (Batch
No.; D006; Exp. Dt: 09/2009) Manufactured by Aventis Pharma, Italy.
Test Product (B).- Dcflazacort 30 mg Tablet (Batch No.: A/RD/1090; Mfg. D t: 06/2005)
Manufactured by Aristo Pharmaceuticals Pvt. Ltd., India.
183
Table 41
Bloequivaknce Study of Defflazacort 30 mg Tablet
Plasma Concentration (iig/ml) of Reference Formulation
In 12 Volunteers
Vol. 0.00 0.50 0.75 1.00 1.25 1.50 2.00 2.50No.
1 0.00 12.30 64.80 90.40 105.30 135.60 112.70 88.80
2 0.00 32.10 69.60 74.20 105.60 96.40 81.40 68.60
3 0.00 47.20 76.80 84.80 93.90 132.50 125.40 110.30
4 0.00 0.00 57.50 66.70 86.20 124.60 112.40 99.70
5 0.00 21.30 72.50 86.40 111.40 101.50 80.40 62.60
§ 0.00 7.80 55.40 68.30 105.20 126.30 104.20 92.50
7 0.00 12.40 64.80 71.80 83.20 116.30 100.90 87.20
8 0.00 26.30 62.40 70.50 93.50 121.20 110.50 94.20
9 0.00 21.50 83.40 94.60 120.40 118.50 102.60 86.40
10 0.00 0.00 61.20 73.40 94.20 130.50 107.50 82.80
11 0.00 20.10 59.40 65.40 87.60 113.20 99.80 87.50
12 0.00 27.40 65.20 79.40 92.50 119.40 106.50 91.40
Mean 0.00 19.03 66.08 77.16 98.25 119.67 103.69 87.67
S.D. 0.00 13.62 8.21 9.77 11.25 11.80 12.65 12.63
!84
Table 42
Bloeqiilvaleiice Study of Deflazacort 30 mg Tablet
Plasma Concentration (ng/iiil) of Reference Foriiiiilatioii
In 12 Voliinteers
VoL 3.00 4.00 6 J0 8.00 10.00 12.00 16.00 24.00No.
1 72.90 51.40 43.70 35.60 12.20 0.00 0.00 0.00
2 54.20 32.80 21.60 15.90 7.20 0.00 0.00 0.00
3 98.30 84.50 64.60 45.20 31.60 13.10 0.00 0.00
4 75.40 58.30 40.20 28.60 14.30 0.00 0.00 0.00
5 50.10 37.40 23.40 17.60 6.10 0.00 0.00 0.00
6 77.40 62.10 50.40 34.80 13.20 0.00 0,00 0.00
7 68.40 55.90 43.50 30.40 11.20 0.00 0.00 0.00
8 82.80 63.40 52.40 37.80 22.60 9.20 0.00 0.00
9 67.50 51.20 37.60 26.40 9.80 0.00 0.00 0.00
10 61.80 48.30 29.40 17.50 6.80 0.00 0.00 0.00
11 74.20 61.40 48.60 30.80 11.80 0.00 0.00 0.00
12 76.20 54.20 40.80 27.60 14.30 6.10 0.00 0.00
Mean 71.60 55.08 41,35 29.02 13.43 2.37 0.00 0.00
S.D. 12.81 13.21 12.35 8.87 7.23 4.54 0.00 0.00
185
Table 43Bloeqiiivaleisce Study of Dellazacort 30 mg Tablet
Plasma Coiiceiiti-atlon (ng/nil) of Test Fornnnilatloii
In 12 Volunteers
Vol.No.
0.00 0.50 0.75 1J§ 1.25 L50 2.0© 2.50
1 0.00 37.20 62.30 92.40 133.20 117.10 90.00 71.10
2 0.00 26.30 47.20 66.50 123.00 115.20 84.10 68.10
3 0.00 22.30 55.10 73.40 103.20 133.60 106.52 85.30
4 0.00 15.00 38.90 63.20 84.70 115.20 85.10 70.60
5 0.00 25,50 53.40 89.70 109.10 140.60 112.40 78.90
6 0.00 29.10 53.40 99.60 109.30 121.50 95.50 64.20
7 0.00 18.20 49.20 63.80 89.40 111.50 92.80 72.40
8 0.00 29.50 50.40 77.60 127.40 110.50 94.30 81.70
9 0.00 17.80 34.20 72.60 104.50 139.50 112.20 83.10
10 0.00 24.60 69.30 79.50 105.20 124.30 102.30 90.40
11 0.00 27.30 53.60 78.10 98.50 129.40 104.20 93.50
12 0.00 32.10 54.50 81.90 117.50 104.20 82.60 71.50
Mean 0.00 25.41 51.79 78.19 108.75 121.88 96.84 77.57
S.D. 0.00 6.38 9.29 11.41 14.60 11.77 10.57 9.29
186
Table 44Bloequivalence Study of Deflazacort 30 mg
Tablet Plasma Concentration (ng/nil) of Test Forniislatioii
In 12 Volunteers
Vol.No.
3 J0 4 M 6 J0 8.00 lOJO 12J0 1 6 J0 24,0*
1 58.20 50.40 40.30 20.20 11.80 0.00 0.00 0.00
2 58.00 55.20 49.40 26.30 22.10 8.50 0.00 0.00
3 71.80 62.60 54.20 28.30 18.10 8.90 0.00 0.00
4 55.40 48.90 40.30 16.40 12.40 5.10 0.00 0.00
5 65.40 60.80 50.70 23.30 13.40 0.00 0.00 0.00
6 56.30 43.40 39.80 18.60 9.20 0.00 0.00 0.00
7 59.80 45.50 35.60 24.10 12.30 0.00 0.00 0.00
8 65.60 58.90 48.30 27.50 20.60 7.40 0.00 0.00
9 60.70 51.90 42.80 21.40 13.20 7.10 0.00 0.00
10 71.50 60.30 49.20 22.50 15.60 9.30 0.00 0.00
11 80.40 64.80 51.20 25.50 20.90 9.80 0.00 0.00
12 60.00 48.90 31.40 21.60 16.10 6.30 0.00 0.00
Mean 63.59 54.30 44.43 22,98 15.48 5.20 0.00 0.00
S.I>. 7.60 7.10 7.06 3.60 4.14 4.05 0.00 0.00
187
160 0
Figure 16; Blocauivaleiice Study of Peflazacort Tablets 30 mg
Mean AUC Graph
E
0 000 4 0 3 12 0 16 0
Tmie h
“ Tesf PrepafBPon on
20 0 24 0
Table 45Bloequivaleiice Study of Deflazacort 3§ mg Tablet
Cmax (ng/iml) in 12 volunteers witli the Test and Reference FornHiIniion
VOL~. NO. TEST Formulation REFERENCEFornm lation
1 133.20 135.60
2 123.00 105.60
3 133.60 132.50
4 115.20 124.60
5 140.60 111.40
6 121.50 126.30
7 111.50 116.30
8 127.40 121.20
9 139.50 120.40
10 124.30 130.50
11 129.40 113.20
12 117.50 119.40
MEAN 126.39 121.42
SD 9.28 8.99
SE 2.68 2.60
C.V (%) 7.34 7.41
189
Table 46Bioequivsaleiice of Deflazacort 30 mg Tablet
Tmax (hr.) In 12 voliissteers witli the Test and Reference Form ulation
VOL. TEST REFEMENCENO. Forniulatioii Foriaiilation
1 1.25 1.502 1.25 1.253 1.50 1.504 1.50 1.505 1.50 1.256 1.50 1.507 1.50 1.508 1.25 1.509 1.50 1.2510 1.50 1.5011 1.50 1.5012 1.25 1.50
MEAN 1.42 1.44SD 0.12 0.11SE 0.04 0.03
C.V(%) 8.69 7.87
190
Table 47Bioeqisivalence of Deflszacort 30 mg Tablet
AUC(o-t) (Mg.hr/ttil) in 12 voliinteers with the Test aacl RefereHce Foriiiwlation
VOL TEST REFERENCE F
NO. FormHlatioii Formwiatiois
1 474.24 536.11
2 535.74 460.65
3 587.95 538.82
4 441.78 515.58
5 536.04 460.65
6 444.43 553.86
7 438.94 502.61
8 556.90 624.66
9 508.94 496.63
10 562.26 427.49
11 597.26 526.89
12 467.09 535.43
MEAN 512.63 514.95
SD 58.00 51.49
SE 16.74 14.86
C.V(% ) . 11.31 10.00
191
Table 48Bioeqiiivakace of Defliizacort 30 mg Tablet
A’UC(O-INF) (ng.lir/ml) in 12 volunteers with the Test and Refen-eiice Form ulation
VOL
NO.
1
2
3
4
5
6
7
8
9
10
11
12
MEAN
SD
SE
C.V (%)
TEST
Fornmlatlon
503.75
559.43
611.85
453.68
569.61
465.42
471.80
576.27
526.28
588.36
624.89
483.13
536.21
59.93
17.30
11.18
REFERENCEFormulatioo
565.95
481.04
544.82
554.48
511.11
588.28
530.80
650.62
520.31
441.04
557.62 ,
550.35
541.37
52.61
15.19
9.72
192
Table 49Bioequivalence of Deflazacort 30 mg Tablet
koi (hr~l) in 12 volunteers with the Test and 'Reference ForiiM latlon
Vol. TEST" REFERENCE
NO. Formiilatiois Form Illation
1 0.28 0.28
2 0.25 0.31
3 0.26 0.36
4 0.30 0.25
5 0.28 0.22
6 0.30 0.27
7 0.26 0.28
8 0.26 0.25
9 0.28 0.29
10 0.25 0.35
11 0.25 0.27
12 0.27 0.28
MEAN 0.27 0.28
SD 0.02 0.04
SE 0.01 0.01
C.V (%) 7.07 13.91
193
Table 50
Bioeqiiivalence of Deflazacort 30 iiig TaMet
TI4 (br) in 12 volunteers with the Test and Reference Form ulation
VOL TEST REFERENCENO. Formulffltlon Forniulation
1 2.50 2.45
2 2.79 2.26
3 2.69 1.94
4 2.33 2.72
5 2.51 3.13
6 2.28 2.61
7 2.67 2.52
8 2.62 2.82
9 2.44 2.42
JO 2.81 1.99
11 2.82 2.60
12 2.55 2.45
MEAN 2.58 2.49
SD 0.18 0.33
SE 0.05 0.10
C.V (%) 6.94 13.37
194
Table 51Pharmacokinetic data for Deflazacort 30 mg
Tablet with Test and Reference Foriiiwlation
Cmax (ng /ml)
T max (hr)
T % (hrs)
Kel
AUC(0~~>t) (iig.hr/ml)
AUC(0~>mt) (ng.lir/ml)
Test Formulation
126.39 ±2.68
1.42 + 0.04
2.58 ±0.05
0.27 ±0.01
512.63 ± 16.74
536.21+17.30
Reference Foriniilatioii
121.42 + 2.60
1.44+_0.03
2.49 ±0.10
0.28J; 0.01
5I4.95±14.86
541.37+15.19
195
Table 52
Bioequlvalence of Deflazacort 30 mg Tablet
Differences and Ratios: Cniax
Ik 12 voltts&teers with the Test and Reference Foriniilatioii
VOL.
NO.
1
2
3
4
5
6
7
8
9
10
11
12
Mean
SD
SE
C.V (%)
Test Reference
FornMiIation Formulation
(B)
133.200
123.000
133.600
115.200
140.600
121.500
111.500
127.400
439.500
124.300
129.400
117.500
126.392
9.283
2.680
7.345
(A)
135.600
105.600
132.500
124.600
111.400
126.300
JI 6.300
121.200
120.400
130.500
113.200
119.400
121.417
8.994
2.596
7.408
Differences(B-A)
-2,400
17.400
1.100
-9.400
29.200
-4.800
-4.800
6.200
19.100
- 6.200
16.200
-1.900
4.975
12.459
3.597
250.436
Ratio
(B/A)
0.982
1.165
1.008
0.925
1.262
0.962
0.959
1.051
1.159
0.952
1.143
0.984
1.046
0.109
0.031
10.410
196
Table 53Bloequivalence of Deflazacort 30 mg Tablet
Differences and Ratios: Ln Cniax
In l2 volunteers with the Test and Reference Formuljitloii
VOL. NO.
1
2
3
4
5
6
7
8
9
10
11
12
Mean
SD
SE
C.V (%)
Test Reference
Formulation Formulation
(B)
4.892
4.812
4.895
4.747
4.946
4.800
4.714
4.847
4.938
4.823
4.863
4.766
4.837
0.074
0.021
1.523
(A)
4.910
4.660
4.887
4.825
4.713
4,839
4.756
4.797
4.791
4.871
4.729
4.782
4.797
0.075
0.022
1.555
Differences
(B-A)
-0.018
0.153
0.008
-0.078
0.233
-0.039
-0.042
0.050
0.147
-0.049
0.134
-0.016
0.040
0.101
0.029
251.542
Ratio
(B/A)
0.996
1.033
1.002
0.984
1.049
0.992
0.991
1.010
1.031
0.990
1.028
0.997
1.009
0.021
0.006
2.116
197
Table54Bioeqiilvalence of Dellazacort 30 mg Tablet
Differences and Ratios; AUCO-t In 12 volunteers with the Test and Reference
Formulation
VOL, Test Reference Differences Ratio
NO. Formulation
(B)
FormulatioM
(A)
(B™A) (B/A)
1 .474.238 536.113 -61.875 0.885
2 535.738 460.650 75.088 1.163
3 587.948 538.818 49.130 1.091
4 441.775 515.575 -73.800 0.857
5 536.038 460.650 75.388 1.164
6 444.425 553.863 -109.438 0.802
7 438.938 502.613 -63,675 0.873
8 556.900 624.663 -67.763 0.892
9 508.938 496.625 12.313 1.025
10 562.263 427.488 134.775 1.315
11 597.263 526.888 70.375 1.134
12 467.088 535.425 -68.338 0.872
Mean 512.629 514.947 -2.318 1.006
SD 58.001 51.492 80.627 0.164
SE 16.743 14.864 23.275 0.047
C V (% ) 11.314 9.999 -3477.780 16.307
198
Table 55Bioeqwivalence of Deflazacort 3§ mg Tablet
Differences and Ratios: Ln-AUCO-t In 12 voliinteers with the Test and Reference
FormHlation
VOL. Test Reference Differences Ratio
NO.
1
2
3
4
5
6
7
8
9
10
11
12
Mean
SD
SE
C.V(%>
Formulation
(B)
6.162
6.284
6.377
6.091
6.284
6.097
6.084
6.322
6.232
6.332
6.392
6.147
6.234
0.114
0.033
1.825
Formjilatioji
(A)
6.284
.6.133
6.289
6.245
6.133
6.317
6.220
6.437
6.208
6.058
6.267
6.283
6.240
0.100
0.029
1.599
(B-A)
-0.123
0.151
0.087
-0.154
0.152
- 0.220
-0.135
-0.115
0.024
0.274
0.125
-0.137
-0.006
0.160
0.046
-2730.846
(B/A)
0.980
1.025
1.014
0.975
1.025
0.965
0.978
0.982
1.004
1.045
1.020
0.978
0.999
0.026
0.007
2.585
199
CHAPTER 8
SUMMIAMY AN© CONCILUSION
200
COMPARATIVE STUDY O F NEW DRUG APPROVAL
PROCESS INDIA V/S U.S.A
Concliislon
The comparative study broadly provides the gaps available in India for the New Drug
Approval Process It is concluded that the New Drug Approval Process for IND
(discovered in India) is the weaker and slower in India. There is a great need to
strengthen the approval process o f Investigational New Drug (IND) and New Chemical
Entity (NCE) discovered in India, enabling India based pharmaceutical companies to
effectively approve their discoveries. The process o f review of proposal and data is very
well defined in U.S.A., even provide the opportunity to applicant company to protect
their data which is not the case in India. Hence there should be a long demanding
provision for pi'otecting the data in Drugs and Cosmetic Act. It will help Indian
pharmaceutical company in the process of globalizing their business and research.
Indian regulation does not provide the option of accelerated regulatory approval whereas
U.S. A has that option. This option will help Indian companies to speed up their approval
of critical therapeutic product specific to Indian market (for e.g. anti-T.B., drugs for kala-
azar). The area o f PMS study and Phannacovigilance is probably the weakest in Indian
Regulatory Authorities and on global scale currently there is a strong focus on drug safety
issues even by international monitoring agencies like WHO. India can provide huge
safety data provided Indian National Phannacovigilance Program runs effectively.
The finding highlights that there is a great need of upgrading the resources required for
New Drug Approval Process. The up-gi'adation can be initiated by;
® Bringing the changes and amendment in Drugs and Cosmetic Acts and Rules.
• Increasing the infrastructure and resources in Drug Regulatory Department
(DCGI) office.
® Formulizing the Standard Operating Procedures and Work Practice Documents in
regulatory department.
® Implementing the latest information and telecom technologies in office.
201
INJECTABLE BUTORPHANOL
In the present study at attempt was made to compare the efficacy and safety of Injectable
butorphanol and injectable Pentazocin in the treatment o f postoperative pain after
abdominal surgery.
The findings of the present study suggest that butorphanol may be more patent and may
have rapid onset o f action as compared to Pentazocin as far as the property of pain
reduction in postoperative period is concerned and butorphanol may be more effective
and better suited for pain reduction in postoperative period.
Neither butorphanol nor Pentazocin cause unnecessary long lasting sedation in patients in
the postoperative period and patients usually remain quite alert and pain free with these
medications in the postoperative period.
It seems that butorphanol may be more patent and effective in pain control and as a result
one would require less number of doses o f butorphanol for pain control than that of
Pentazocin.
Neither any clinically significant alterations in vital parameters nor any major adverse
events were noted with either o f the treatment in the present study.
The findings o f the present study are more or less in agreement with the published
literature on the subject.
ConclMslon
In view of the finding of the present study and the available literature on the subject one
may conclude that butoi'phanol may be more patent and may have rapid onset o f action as
compared Pentazocin and therefore more suited for pain reduction postoperative period.
Discussion
202
BUTORPAHNOL N A S A L SPRAY
DIscsission
In the present study an attempt was made to evaluate the efficacy and safety o f
Butorphanol nasal spray in the management o f postoperative pain. The results o f the
study demonstrate that Butorphanol nasal spray is highly effective in the treatment o f
postoperative pain and is very safe well tolerated by the patients. A significant
improvement in the pain score of patient was observed by the end of 15 min. till the
completion of study. The treatment with Butorphanol nasal spray is associated with very
few adverse events. Further there were no alterations in Hematological and Biochemical
parameters with Butorphanol nasal administration. The tolerability of Butorphanol nasal
spray was reported to be excellent or good in majority o f study population by the
investigators.
Conclusion
The present study concludes that Butorphanol Nasal Spray is highly effective in
postoperative pain management and seems to be good alternative to injectable
Butorphanol treatment. It is also demonstrate that Butorphanol is safe by nasal drug
delivery and is well tolerated by patients.
203
VALSAMTAN
Plscwssioii
The single dose bioequivalence study of Capsule Valsartan 80 mg was conducte in 12
adult healthy human male volunteers with two preparations o f R. Value o f Cm ax, Tmax,
AUCO-t, and AUCO-inf were comparable for reference and test preparation at fasting
state.
VALSARTAN was detected in plasma from 1 hour to about 16 hours in Reference
preparation as well as Test preparation. Peak Plasma levels o f VALSARTAN with the
reference and Test preparation were achieved between three to five hours. The mean peak
plasma levels o f VALSARTAN with Reference preparation, Capsule STARVAL on the
study day ranged between 0.8 -1.2 mcg/ml. while with Test preparation o f Capsule
VALSARTAN ranged between 0.7-1.1 mcg/ml. On the basis o f comparison of AUC(O-t)
For VALSARTAN after single dose administration, the relative bioavailability of the Test
preparation o f VALSARTAN 80 mg was 93.17 % o f that of Reference preparation
STARVAL.
Concltiglon
On the basis o f the Pharmacokinetic parameters studied, it can be concluded that the Test
preparation o f VALSARTAN 80mg mfg by AROSTO PHARMACEUTICALS is bio
equivalent with Reference preparation Capsule STARVAL mfg by RANBAXY
LABORATORIES LTD.
204
DEFLAZACORT
PiscussloM and CoMchisioia
In the present study, it was obsei'ved that the mean values o f various pharmacokinetic
parameters like Cmax, Tmax. AUC<H, AUCo*r, Jm and Lambda_z for both the
formulations were in agreement with the values reported in the literature.
On application of ANOVA to various variables like subjects, sequence of dosing, subjects
nested within sequences, period of treatment and drug foimulations to some extent
significant variation were observed for some of parameters of Cmax, AUCo-t and AUG
cwnr.
Classical Confidence limits (90%) calculated for log-transformed parameters of AUCo-
24 and AUC <,-** values, upper and lower values were within the prescribed limit o f
bioequivalence (80 -125 %) for the test fomiulations.
Deflazacort 30 mg reached mean Cmax of 121.42 & 126.39 ng/ml, Tmax o f 1.44 & 1.42
hour, AUGwenOf 514.95 & 512.63 ng.hr/ml, respectively after administration of
reference and test formulations.
Pharmacokinetic results and statistical evaluation between the investigational Test
products with respect to extent of absorption with the reference product are fall within the
conventional bioequivalence range.
On comparison of AUCCMSH values for Test Fomiulation, dosing done with 240ml
ambient temperature water (Deflazacort 30 mg Tablet) manufactured by Aristo
Pharmaceuticals Pvt. Ltd., India, exhibited a Relative Bioavailability of 99.55 % with
Reference Formulation (Calcort 30 mg Tablets, containing Deflazacort 30 mg)
manufactured by Aventis Pharma, Italy.
Graphical representations of the plasma Deflazacort 30 mg concentrations (including
linear mean data and combined individual graphs of the reference and test products) are
presented.
205
CHAPTER 9
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