Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITION COMPRISING INSULIN AND HERBAL OIL FOR TRANSDERMAL OR TRANSMUCOSAL
ADMINISTRATION
Field of the Invention
The invention relates to a pharmaceutical composition for transdermal or
transmucosal
administration comprising insulin, insulin analogue or derivatives thereof, an
effective amount
of herbal oil optionally along with one or more pharmaceutically acceptable
excipients. The
invention further provides the process for preparing the said pharmaceutical
composition.
Background of the Invention
Diabetes is a metabolic disorder wherein the human body does not produce or
properly uses
insulin. Diabetes affects approximately 170 million people worldwide. The two
principal
idiopathic forms of diabetes are known as types 1 and type 2 diabetes. Insulin
injections are
prescribed to the patients suffering from diabetes.
Insulin is a natural hormone, which controls the level of the sugar glucose in
the blood. In
healthy people, insulin is released in blood by the pancreas as the
concentration of blood
glucose rises. Increased blood glucose levels, occur after meals and are
rapidly compensated by
a corresponding increase in insulin secretion. Insulin plays major role in
converting the excess
blood glucose into glycogen and storing it in liver.
When insulin is absent (or low), glucose is not taken up by body cells, and
the body begins to
use fat as an energy source. The failure to make insulin or insufficiency of
insulin is termed as
Diabetes mellitus.
Traditionally short acting regular Insulin formulations or its intermediate
acting Insulin
Protamine formulations were used for treating patients with diabetes mellitus.
With time, new
insulin analogues and derivatives were developed. Insulin analogues and
derivatives differ
from human insulin at one or more than one amino acid positions and/or amino
acid chain
length.
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A number of insulin, insulin analogs and derivatives are available in the
market. The
commonly used types of insulin, insulin analogs or insulin derivatives are
categorized as:
Rapid-acting Insulin analogs: For example insulin aspart (Novolog ) or insulin
lispro
(Humalog8). These analogs begin to work within 5 to 15 minutes of
administration and are
active for 3 to 4 hours.
Short-acting insulin: For example Regular insulin (Humulin or Novolie).
Regular insulin
starts working within 30 minutes after administration and duration of action
lasts from about 5
to 8 hours.
Intermediate-acting insulin: For example as Isophane insulin. It starts
working in 1 to 3 hours
after administration. Its duration of action varies between 16 to 24 hours.
Long-acting Insulin: For example Insulin glargine and Insulin detemir. Both
these analogs
starts working within 1 to 2 hours and their duration of action varies from
about 12 to about 24
hours.
Mixed Insulins: For example mixture of NPH and regular insulin. There are
several variations
with different proportions of the mixed insulins. The onset of action of these
mixed
preparations is about 30 minutes.
All the available Insulin formulations are given parenterally to patients
requiring frequent
injections. In a recent survey conducted by University of Pennsylvania School
of Medicine
(Aug., 2008) on behalf of the American Association of Diabetes Educators
(AADE), one-third
of insulin-dependent diabetic patients said the frequent injections were a
source of dread and
were the hardest aspect of their diabetes care. The frequent subcutaneous or
intravenous
injections are associated with adverse effects as including bruises, pain, and
scars as well as
anxiety. Further, these methods of administration have the disadvantage that
when
administered, they cannot be withdrawn, e.g. in the case of development of
hypoglycemia or
other adverse patient reactions.
Noninvasive transdermal or transmucosal insulin delivery could not only
provide diabetic
patients with sustained physiological levels of basal insulin in a pain-free
manner but can also
be withdrawn in case of emergencies. Further, transdermal or transmucosal
administration is
convenient and user friendly, thus leading to patient compliance.
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However, effective insulin absorption via these routes is limited for obvious
reasons.
(1) Effective delivery across the transmucosal or transdermal route is
unlikely because of a
high molecular weight and size of insulin.
(2) Degradation of insulin by enzymes present in dermal layers or Buccal
cavity
(3) Low permeability of transdermal route
(4) Limited stability of peptides during preparation of formulation and
storage
(5) Intra-individual variability, etc.
Attempts have been made to develop transdermal and transmucosal insulin
formulations
usually involving additional excipients such as use of lipophillic compounds
such as
triglycerides, penetration enhancers, etc or delivery methods or devices
inotophoresis, use of
thermal energy, ultrasound etc. to achieve desired absorption.
US Patent No. 5,707,641 US Patent No. 7,033,998 and US 7,291,591 disclose
pharmaceutical
formulations for transdermal administration.
US Patent No. 5,597,796, US Patent No. 6,002,961, US Patent No. 5,814,599 and
US Patent
No. 6,190,315 disclose transdermal delivery of insulin or its analogues using
iontophoresis or
sonophoresis.
US Patent No. 6,274,166 discloses transdermal delivery system comprising an
active
ingredient selected from the group consisting of peptides, proteins and
mixtures thereof and a
pharmaceutically acceptable oxidizing agent.
US Patent No. 5,932,240 disclose multidose transdermal drug delivery assembly,
wherein unit
doses being in the form of a multiphase composition of microspheres.
US Patent No. 6,998,110, US Patent Application No. 20100034880, US Patent
Application No.
20090274758, IN Patent Application No. 2004MU00681 and PCT Patent Application
No.
2008127679 disclose compositions comprising peptide drugs for transmucosal
administration.
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Use of synthetic excipients or artificial methods for delivery of insulin,
insulin analogue or
derivatives, are associated with number of immunogenic reactions and
disturbances in normal
physiological conditions of a body. Thus, there is a need of a system or
composition, which
should be less immunogenic on one hand and on other hand results in achieving
desired insulin
levels from non-invasive methods of delivery.
Summary of the Invention
One of the embodiments of the invention provides a pharmaceutical composition
comprising
insulin, insulin analogue or derivatives thereof, an effective amount of
herbal oil optionally
along with one or more pharmaceutically acceptable excipients.
The term "insulin" used herein includes mammalian insulin, insulin analogues
or derivatives.
By "insulin analogue" (and similar expressions) as used herein is meant human
insulin in
which one or more amino acids have been deleted and/or replaced by other amino
acids,
including non-codeable amino acids, or human insulin comprising additional
amino acids, i.e.
more than 51 amino acids. Examples of insulin analogues are analogues of human
insulin
where the amino acid residue at position B28 is Asp, Lys, Leu, Val, or Ala and
position B29 is
Lys or Pro; or B3 is Lys and B29 is Glu; or A21 is Gly and Arg has been added
to B31 and
B32; or where the amino acid residues in B28-B30 have been deleted; or where
the amino acid
residue at B27 has been deleted; or where the amino acid residue at B30 has
been deleted.
Marketed Insulin analogues include but are not limited to Insulin aspart,
Insulin Lispro, Insulin
glulisine, Insulin glargine, etc.
By" insulin derivative "(and similar expressions) as used herein is meant
human insulin or an
analogue thereof in which at least one organic substituent is bound to one or
more of the amino
acids. Non-limiting examples of a "insulin derivative" are B29-NEmyristoyl-
des(B30) human
insulin (Insulin detemir), B29-1\18-palmitoyl-des(B30) human insulin, B29-1\18-
myristoyl human
insulin, B29-1\18-palmitoyl human insulin, B28-1\18-myristoyl Lys11
28pro11
29 human insulin, B28-
_
1\18-palmitoyl Lys11
28pro11
29 human insulin, B30-NE-myristoylThru29Lysu3o human insulin, B30-
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NE-palmitoy1ThrB29LysB3 human insulin, B29-1\18-(N-palmitoy1-.gamma.-
glutamy1)-des(B30)
human insulin, B29-1\18-(N-lithocholy1-.gamma.-glutamy1)-des(B30) human
insulin, B29-1\18-
(co-carboxyheptadecanoyDdes(B30) human insulin and B29-1\184 co-
carboxyheptadecanoyl)
human insulin.
Non-limiting examples of Insulin, Insulin analogue and derivatives includes
Recombinant
human insulin, Insulin NPH, Insulin Lispro, Insulin Lispro Protamine, Insulin
Glulisine and
Insulin Aspart, Insulin Aspart Protamine, Insulin glargine, insulin detemir or
mixtures thereof.
One of the other embodiment of the present invention provides a pharmaceutical
composition
for transdermal or transmucosal administration comprising insulin, insulin
analogue or
derivatives thereof, an effective amount of herbal oil optionally along with
one or more
pharmaceutically acceptable excipients.
Another embodiment of the present invention provides a pharmaceutical
composition for
transdermal or transmucosal administration comprising insulin, insulin
analogue or derivatives
thereof, an effective amount of herbal oil optionally along with one or more
pharmaceutically
acceptable excipients, wherein the said insulin, insulin analogue or
derivative has not been
subjected to any pretreatment.
Another embodiment of the present invention provides a pharmaceutical
composition for
transdermal or transmucosal administration comprising insulin, insulin
analogue or derivatives
thereof, an effective amount of herbal oil optionally along with one or more
pharmaceutically
acceptable excipients, wherein the composition when administered by the said
routes, insulin is
detectable in blood in less than lh after administration.
Yet another embodiments of the present invention provides a method for
treating diabetes by
administering a pharmaceutical composition comprising insulin, insulin
analogue or
derivatives thereof, an effective amount of herbal oil optionally along with
one or more
pharmaceutically acceptable excipients to a patient in need thereof.
CA 02796567 2015-09-29
50836-34
In a claimed embodiment, the present invention relates to a pharmaceutical
composition for
transdermal or transmucosal administration consisting of insulin, an insulin
analogue, or an
insulin derivative; an herbal oil extracted from a plant species selected from
the group
consisting of brassica junecea, pinus, mentha and ricinus; and one or more
polymeric
ingredients along with one or more pharmaceutically acceptable excipients,
wherein the one
or more polymeric ingredients include a natural gum selected from the group
consisting of
xanthan gum, gum acacia, tragacanth gum, karaya gum, gum arabic, locust bean
gum, gellan
gum and sodium alginate.
In a claimed embodiment, the present invention relates to a pharmaceutical
composition for
transdermal or transmucosal administration consisting of insulin, an insulin
analogue, or an
insulin derivative; an herbal oil extracted from a plant species selected from
the group
consisting of brassica junecea, pinus, mentha and ricinus; and one or more
polymeric
ingredients along with one or more pharmaceutically acceptable excipients,
wherein the one
or more polymeric ingredients include a natural gum selected from the group
consisting of
xanthan gum, gum acacia, tragacanth gum, karaya gum, gum arabic, locust bean
gum, gellan
gum and sodium alginate, and wherein the insulin, the insulin analogue or the
insulin
derivative in the composition is not subjected to any pretreatment.
In a claimed embodiment, the present invention relates to a pharmaceutical
composition for
transdermal or transmucosal administration consisting of insulin, an insulin
analogue, or an
insulin derivative; an herbal oil extracted from a plant species selected from
the group
consisting of brassica junecea, pinus, mentha and ricinus; and one or more
polymeric
ingredients along with one or more pharmaceutically acceptable excipients,
wherein the one
or more polymeric ingredients include a natural gum selected from the group
consisting of
xanthan gum, gum acacia, tragacanth gum, karaya gum, gum arabic, locust bean
gum, gellan
gum and sodium alginate, and wherein when the composition is administered, the
insulin, the
insulin analogue, or the insulin derivative is detectable in blood in less
than lh after
administration.
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50836-34
One of the embodiments of the pharmaceutical composition may include one or
more of the
following features. The pharmaceutical composition may further comprises one
or more
pharmaceutically acceptable excipients selected from the group consisting of
polymeric
ingredient, surfactant, emulsifiers, penetration enhancers, surfactants, pH
modifiers or
buffering agents, thickening or gelling agents, stabilizing agents,
antimicrobials and
preservatives.
Description of drawings
Figure 1 depicts the photomicrographs of the composition of Table 1 at
magnification of 100X
oil immersion. Small globules entrapping Insulin were prominently visible.
Figure 2 graphically compares the results of a biostudies in which
compositions according to
embodiments of the invention were administered transdermally and marketed
regular insulin
compositions were administered subcutaneously to healthy Wistar rats.
Detailed Description of the Invention
While working on development of compositions comprising insulin, insulin
analog and
derivatives suited specially for non-invasive routes such as transdermal or
transmucosal routes,
inventors have surprising found that when herbal oil is added to insulin
solution slowly using
trituration or sonication technique the resulting composition comprising
numerous small
globules entrapping insulin, which when applied on skin results in rapid
systemic absorption,
i.e. less than lh, of insulin across skin. The composition was found to be
stable.
In one of the embodiments of the present invention, herbal oil can be
extracted from the herbs
selected from the group consisting of extracted and processed from brassica
junecea, pinus,
mentha and ricinus species. The invention is not limited to the examples, it
encompass all the
possible related species envisioned by a person ordinary skilled in the art.
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In one of the embodiments of the present invention, one or polymeric
ingredient includes
natural gums selected from the group consisting of Xanthan gum, Gum acacia,
Tragacanth
gum, Karaya gum, Gum Arabic, Locust bean gum, Gellan gum and Sodium alginate.
Suitable surfactants are those known to ordinary skilled in the art and may
include one or more
of amphoteric, non-ionic, cationic or anionic surfactants. Suitable
surfactants comprises one or
more of sodium lauryl sulfate, monooleate, monolaurate, monopalmitate,
monostearate or
another ester of polyoxyethylene sorbitane, sorbitan monostearate, sodium
dioctylsulfosuccinate (DOSS), lecithin, stearylic alcohol, cetostearylic
alcohol, cholesterol,
polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer,
or cremophore
RH 40.
Emulsifiers include one or more of alkyl alcohols, alkyl polyglucosides,
polyglycerol alkyl
esters, C1-C4 esters of alkyl alcohols, C1-C4 esters of alkyl carboxylates,
alkyl amides, alkyl
betaines, and alkyl phosphates or phospholipids, alkyl quaternary amines,
alkyl amine oxides,
polyethoxylated alkyl alcohols, alkyl esters of polyethylene glycol, and
mixtures thereof.
Penetration enhancers can be selected from the group consisting of C8-C22
fatty acids such as
isostearic acid, octanoic acid, and oleic acid, C8-C22 fatty alcohols such as
oleyl alcohol and
lauryl alcohol, lower alkyl esters of C8-C22 fatty acids such as ethyl oleate,
isopropyl myristate,
butyl stearate, and methyl laurate, di(lower)alkyl esters of C6 ¨C8 diacids
such as diisopropyl
adipate, monoglycerides of C8-C22 fatty acids such as glyceryl monolaurate,
tetrahydrofurfuryl
alcohol polyethylene glycol ether, polyethylene glycol, propylene glycol, 2-(2-
ethoxyethoxy)ethanol, diethylene glycol monomethyl ether, alkylaryl ethers of
polyethylene
oxide, polyethylene oxide monomethyl ethers, polyethylene oxide dimethyl
ethers, dimethyl
sulfoxide, glycerol, ethyl acetate, acetoacetic ester, N-alkylpyrrolidone, and
terpenes.
Suitable thickening agents, viscosity modifiers or gelling agents can be
selected from the group
consisting carbomer, carboxyethylene or polyacrylic acid such as Carbopol 980
or 940 NF, 981
or 941 NF, 1382 or 1342 NF, 5984 or 934 NF, ETD 2020, 2050, 934P NF, 971P NF,
974P NF,
Noveon AA-1 USP, etc; cellulose derivatives such as methylcellulose,
ethylcellulose,
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hydroxypropylmethylcellulose (HPMC),
ethylhydroxyethylcellulose
(EHEC),carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC) (Klucel
different
grades), hydroxyethylcellulose (HEC) (Natrosol grades), HPMCP 55, Methocel
grades, etc;
natural gums such as arabic, xanthan, guar gums, alginates, etc;
polyvinylpyrrolidonederivatives such as Kollidon grades; polyoxyethylene
polyoxypropylene
copolymers such as Lutrol F grades 68, 127, etc; chitosan, polyvinyl alcohols,
bentonite,
hectorite, pectins, maltitol, and veegun grades.
Suitable pH modifiers or buffering agents may include one or more of a
bicarbonate salt of a
Group IA metal, an alkali earth metal buffering agent, a calcium buffering
agent, a magnesium
buffering agent, an aluminum buffering agent and the like, sodium bicarbonate,
potassium
bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate,
magnesium
oxide, magnesium aluminate, magnesium carbonate, magnesium silicate, magnesium
citrate,
aluminum hydroxide, aluminum phosphate, aluminum hydroxide/magnesium
carbonate,
potassium carbonate, potassium citrate, aluminum hydroxide/sodium bicarbonate
coprecipitate,
aluminum glycinate, aluminum magnesium hydroxide, sodium citrate, sodium
tartrate, sodium
acetate, sodium carbonate, sodium (polyphosphate, sodium dihydrogen phosphate,
potassium
polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium
hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate,
tripotassium
phosphate, potassium metaphosphate, calcium acetate, calcium glycerophosphate,
calcium
chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium
gluconate, calcium
bicarbonate, calcium citrate, calcium phosphate magnesium phosphate, potassium
phosphate,
sodium phosphate, trihydroxymethylaminomethane, ail amino acid, an acid salt
of an amino
acid, an alkali salt of an amino acid, and combinations of any of the
foregoing.
Moreover, the composition of the invention optionally include usual
auxiliaries known in the
art such as saliva stimulating agents like citric acid, lactic acid, malic
acid, succinic acid,
ascorbic acid, adipic acid, fumaric acid, tartaric acids; cooling sensation
agents like maltitol,
monomenthyl succinate, ultracool; stabilizers like gums, agar; taste masking
agents like acrylic
polymers, copolymers of acrylates, celluloses, resins; zinc, coloring agents
like titanium
dioxide, natural food colors, dyes suitable for food, drug and cosmetic
applications;
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preservatives like alpha-tocopherol, citric acid, butylated hydroxytoluene,
butylated
hydroxyanisole, ascorbic acid, fumaric acid, malic acid, sodium ascorbate or
ascorbic acid
palmitate or effervescing agents like citric acid, tartaric acid, sodium
bicarbonate, sodium
carbonate and the like.
Preservatives or antimicrobials may include one or more of sodium benzoate,
sorbates, such as
potassium sorbate, salts of edetate (also known as salts of
ethylenediaminetetraacetic acid or
EDTA, such as disodium edetate), benzaldionium chloride, parabens, iodine and
its complexed
forms such as povidone/iodine, chlorhexidine salts such as chlorhexidine
digluconate (CHG),
parachlorometaxylenol (PCMX), hexachlorophene, phenols, hydrogen peroxide,
phenols,
silver, silver salts such as silver chloride, silver oxide and silver
sulfadiazine and the like.
The propellant can be chosen from chlorofluorocarbons (CFCs),
hydrochlorofluorocarbons
(HCFCs), hydrofluorocarbons (HFCs), perfluorinated alkanes, and lower alkanes
(CI-CS) as
well as nitrous oxide, dimethyl ether, and other solvent-soluble propellants
In one of the embodiments of the present invention, the pharmaceutical
composition is an
emulsion, dispersion, suspension, film or patch.
In another embodiment of the present invention, the pharmaceutical composition
is an
emulsion, dispersion or suspension.
In another embodiment of the invention, the pH of the composition is from
about 4.5 to about
7.5.
The pharmaceutical compositions of the present invention can be prepared by
the various
processes known in the art.
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Example 1
Table 1: Insulin Composition
Quantity ( %w/v
Sr. No. Ingredients
or v/v)
1 Recombinant Human Insulin 0.1 - 1.0%
2 Xanthan Gum 1.0 - 4.0%
3 Herbal Oil 30 - 50%
4 Purified Water 30 - 50%
Procedure - Xanthan Gum was weighed accurately in requisite amount and
dissolved in herbal
oil using mortar & pestle. Accurately weighed recombinant human insulin or
insulin analogs
was transferred to the above solution in mortar and pestle and mixed slowly
with oil phase for
- 30 min under cold temperature (2-8 C). An equal amount of water was added
drop wise to
the mortar and pestle under constant mixing for 20 - 90 min to prepare a
homogeneous
suspension.
Example 2
For stability studies, the vials containing Insulin composition of Table 1
were stored at a
temperature between 2 C to 8 C for a period of three month. The potency of
insulin was
measured by conducting assay using standard procedure for assaying under
insulin human as
per USP31 NF26. The limit for related impurities like A-21 desamido was
carried out using
standardized procedure mentioned in USP31 NF26. The assay and test for
detecting limit for
related impurities like A-21 desamido were conducted before the initiation of
storage, and after
3 months further studies. The results are shown in Table 2.
Table 2 ¨ Stability data comparison when the composition of Table 1 is
subjected to stability
studies.
S.
Parameters Limits Initial 3 months
No.
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A brownish A brownish A brownish
1. Description
suspension suspension suspension
Between 4.5
2. pH 5.86 5.91
and 7.5
Related impurities
3. NMT 5% 1.95% 1.84%
A21 desamido
Concentration of Between 9.0
4.mg to 11.0 10.86 mg/ml 10.07 mg/ml
Insulin mg per ml
As is clear from Table 2, when the composition of this invention was stored at
a temperature of
2 C to 8 C, it was found to be stable for 3 month. The composition did not
changed in
appearance and was found to be devoid of related A21 desamido impurities. The
active
ingredient recombinant human insulin has not degraded during storage.
Example 3
For in vivo studies, wistar rats were fasted overnight prior to the experiment
but had free
access to water during the study. A total of 06 wistar rats (250-300 g) were
divided in two
experimental groups "A" and "B" with three rats in each group. Pharmaceutical
composition
prepared according to one of the embodiments of the invention comprising 40IU
was applied
on shaved skin of rats of group A for transdermal administration. Regular
insulin marketed
composition (Wosulin0) comprising HU insulin was administered subcutaneously
to rats of
group B. Blood samples were withdrawn at an interval of lh, 2.5h and 5h after
administration.
The results of biostudy were represented in Figure 2.
Around 60% reduction in the blood glucose level was observed within one hour
after the
transdermal application insulin compositions according to present invention in
rats. The effect
of reduction in blood glucose level in rat persisted till 3-4 hours after
transdermal
administration whereas on other hand reduction in blood glucose level after
subcutaneous
injection under the same conditions persisted for 2-3 hours with 57% reduction
in blood
glucose level.
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Figure 1 depicts the photomicrographs of the composition of Table 1 at
magnification of 100X
oil immersion. Small globules entrapping Insulin were prominently visible.
Figure 2 graphically compares the results of a biostudies in which
compositions according to
embodiments of the invention were administered transdermally and marketed
regular insulin
compositions were administered subcutaneously to healthy Wistar rats.
Example 4
Table 3: Insulin Composition
Sr. No. Ingredients Quantity
1 Insulin Human (Recombinant DNA Origin) 0.1 - 1.0% w/v
2 Sorbitan Monostearate (Span 60) 1.0 - 5.0% w/v
3 Herbal Oil 30 - 50% v/v
4 Purified Water 30 - 50% v/v
Procedure - Sorbitan Monostearate (Span 60) was weighed accurately in
requisite amount and
dissolved in herbal oil using mortar & pestle. Accurately weighed recombinant
human insulin
or insulin analogs was transferred to the above oily solution in mortar and
pestle and mixed
slowly with oil phase for 5 - 30 min under cold temperature (2-8 C). An equal
amount of water
was added drop wise to the mortar and pestle under constant mixing for 20 - 90
min to prepare
a homogeneous suspension.
Example 5
For stability studies, the vials containing Insulin composition of Table 3
were stored at a
temperature between 2 C to 8 C for a period of three month. The potency of
insulin was
measured by conducting RP-HPLC method for assay given in monograph entitled
"Insulin
Human" as per U5P32 NF27. Stability testing parameters like Description, pH,
Assay of
Insulin Human & Viscosity (using Brookfield Viscometer) were determined and
recorded
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before the initiation of stability study (Storage Conditions: 5 3 C), and
also after 3 months
of storage at specified conditions. The results are shown in Table 4.
Table 4 ¨ Stability data comparison when the composition of Table 3 is
subjected to stability
studies.
Results
Tests Acceptance Criteria
Initial 3rd Month
A brownish A brownish
A brownish suspension,
suspension, traces of suspension, traces of
Description traces of fine sediment may
fine sediment may be fine sediment may be
be deposited.
deposited. deposited.
pH Between 4.5 and 7.5 5.81 5.86
Not less than 80% and not
Assay of
more than 120% of label 108.65% 100.75%
Insulin Human
claim
Not less than 30 cP and not
Viscosity 37.3 cP 38.5 cP
more than 50 cP.
As is clear from Table 4, when the composition of this invention was stored at
a temperature of
2 C to 8 C, it was found to be stable for 3 month. The composition did not
changed in
appearance. The active ingredient recombinant human insulin has not degraded
during storage.
While the invention has been described in terms of its specific embodiments,
certain
modifications and equivalents will be apparent to those skilled in the art and
are intended to be
included within the scope of the invention.
13
