Professional Documents
Culture Documents
Jurnal Dipakai - Dienogest Tablet, IJRPBS PDF
Jurnal Dipakai - Dienogest Tablet, IJRPBS PDF
Jurnal Dipakai - Dienogest Tablet, IJRPBS PDF
_____________________________________________________________________Research Paper
___________________________________________________________________________
Abstract
Vaginal delivery is an important route of drug administration for gynecological diseases. The
advantages of vaginal route are large surface area, rich blood supply, avoidance of first pass effect, relatively
high permeability of many drugs and self insertion. The aim of the present work was to develop Dienogest -
containing vaginal tablet for the treatment of endometriosis. Five different formulations were prepared, using
different compositions of Corn Starch, Microcrystalline Cellulose and Crospovidone. The tablets were evaluated
for hardness, friability, disintegration time, drug content and release. Formulation VT6 was found to be the best
among all formulations based on physical properties and in-vitro dissolution profile.
INTRODUCTION
As an important part of health of female being evaluated clinically for treatment of
reproduction system, the vagina, in addition to endometriosis, an estrogen-dependent disease.
being a genital organ with functions related to Dienogest showed therapeutic effect in rats with
conception, serves as a potential route for drug experimental endometriosis as well as amelioration
administration. [1,2] Endometriosis is a debilitating of endometrial implant-induced alteration in the
gynecological medical condition in females in intraperitoneal immune system and maintenance of
which endometrial-like cells appear and flourish in bone mineral density, compared to commonly used
areas outside the uterine cavity, most commonly on drugs for endometriosis. A long-term treatment
the ovaries. The uterine cavity is lined by resulted in lower risk of thrombosis than
endometrial cells, which are under the influence of medroxyprogesterone acetate or danazol in
female hormones. These endometrial-like cells in monkeys. Dienogest should thus serve as a highly
areas outside the uterus are influenced by hormonal safe potent agent for treatment of endometriosis. [4]
changes and respond similarly as do those cells Surgical and endocrine therapies successfully
found inside the uterus. Symptoms often worsen in suppress pelvic pain, but it often recurs after
time with the menstrual cycle. Endometriosis is completion of treatment. The pharmaceutical
typically seen during the reproductive years; it has preparation for treating endometriosis contains at
been estimated that it occurs in roughly 5% to 10% least 28, preferably 30, daily dose units, each of
of women. Symptoms may depend on the site of which contain dienogest, cyproterone acetate, or
active endometriosis. Its main but not universal chlormadinone acetate at a daily dose that is at
symptom is pelvic pain in various manifestations.[3] most twice that required to inhibit ovulation
It has been found desirable to use certain medicinal together with one or more pharmaceutical aids and
agent like progesterone, progestational compounds carriers. The daily dose units are administered in a
via vaginal route in the field of medical practice. method of prophylaxis or therapy of endometriosis
They have been administered in past via oral route continuously during a time interval of at least 169
and found to yield certain undesirable side-effects. days or 25 weeks, preferably more than two years.
These side-effects may be avoided by supplying The method effectively reduces endometriosis and
them directly to uterine wall. associated pain, while undesirable side effects
Dienogest is an orally active synthetic steroid including bone density decrease are reduced or
with prominent progestational activity. It is thus eliminated. [5]
________________________________________ Although the suppositories are easily inserted,
*Address for correspondence: they melt at body temperature and lead to
E-mail: kls.bansal@gmail.com disturbing vaginal discharge. Oral gelatin capsules
seconds among all the formulations. The tablet crospovidone were varied batch to batch. As the
readily absorbs fluid to disintegrate rapidly in the concentration of Crospovidone was increased, the
limited volume of fluid, pH 3.5-4.5, generally disintegration time decreases subsequently.
present in the vagina, by virtue of its ‘wicking In formulation VT1, unmicronized Dienogest API
effect’ that transports water to the tablet’s interior, was employed which shows lower in-vitro
and by virtue of its high surface to volume ratio. dissolution rate while all other formulations (VT2,
The tablet is preferably formulated to erode in the VT3, VT4, VT5 and VT6), developed with
vagina within one hour. In-vitro dissolution data micronized Dienogest API showed good
supports this claim (Table No. 6). The eroding dissolution profile. Out of all the formulations VT6
tablet produces micronized particles of the drug showed best in-vitro release.
which are dispersed in the vagina as a milky Assay of the optimized batch (VT6) was carried
suspension along with the other ingredients in the out by the HPLC method and was found to be
tablet. 99.85%. Stability studies revealed that there was no
The Simulated Vaginal Fluid pH 4.2 [12] was significant change in appearance, assay, and drug
selected to study the release of Dienogest Vaginal release profile at 40⁰C with 75% RH. (shown in
tablets because the prevailing pH of vagina is Table no.7).
maintained by lactobacilli which produce sufficient
lactic acid to acidify vaginal secretions to pH 3.5- CONCLUSION
4.5.[13]
The Active pharmaceutical ingredient Formulation VT6 shows the desired physical
(Dienogest) was micronized in an Air Jet Mill (Fig. parameters, disintegration time and dissolution
3 and Fig. 4) and the particle size of micronized profile. The clinical effectiveness of the prepared
API was found to be 7.36 µ which finally helped in formulation is yet to be performed. However, it
enhancing Dissolution rate (Table No. 3). The would be necessary to conduct more studies like
prepared granules showed good flow properties and long term clinical trials with large number of
the results are shown in Table No. 4. patients, comparative studies with other modes of
All the tablet formulations showed acceptable treatment (oral administration of Dienogest Tablet
phycochemical properties and complied with the 2 mg, vaginal administration of gel of Dienogest
range specified by US Pharmacopeia 33 for Tablet 2 mg) and formulations to assess its
Disintegration, weight variation, friability and therapeutic efficacy. This non-mucoadhesive
hardness (Shown in Table No.5). Dienogest Tablet 2 mg is likely to be well received
The concentration of Povidone was kept by gynecological professionals in future because of
constant in all the formulations while the its non-stickiness and good in-vitro dissolution and
concentration of Lactose monohydrate, Corn likely effectiveness in-vivo.
Starch, Microcrystalline cellulose PH 101 and
TABLES
Table No. 1: Drug Properties
3. Structural Formula
8. Bioavailability 90%
*Unmicronized Dienogest was used.** Micronized Dienogest was used.***Does not appear in the final product.
732
International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
Drug Batch No. Micronization Particle size Particle size Particle size
Substance Status Distribution Distribution Distribution
[D10%] [D 50%] [D 90%]
Dienogest AP/DNG/171 Unmicronized 1.95 µ 10.90 µ 45.97 µ
Formulation Code Average Thickness Diameter (mm) Hardness (N) Friability (At 100 Disintegration Time
Weight (mg) (mm) revolutions)
10 min 68 82 84 87 89 93
15 min 74 84 85 88 90 95
20 min 78 86 87 90 92 96
30 min 82 88 90 92 94 97
45 min 85 90 93 93 95 98
60 min 87 92 94 96 97 99
Dissolution Profile
Time (minutes) 0 0 0 0
10 93 89 89 87
15 95 92 90 88
20 96 94 93 90
30 97 96 95 93
45 98 97 95 94
60 99 98 97 96
100
80
Fig 1: Dissolution profile of all the Formulations in Simulated Vaginal Fluid pH 4.2
100
Cumulative % drug release
80
60
Initial
40 One month
Three month
20
Six month
0
0 10 20 30 40 50 60
Time (min)
Fig 2: Dissolution profile of Formulation VT5 at initial condition compared with Stability at
40⁰C/75%RH for 1 month, 3 months and 6 months.
735
International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
736
International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701