FIELD OF THE INVENTION
The invention relates to an oral pharmaceutical composition of albendazole
comprising binder and disintegrant, wherein disintegrant is selected from sodium
starch glycolate, crosscarmellose sodium or both.
The invention also relates to pharmaceutical compositions comprising an
oral composition of albendazole and processes for preparation thereof.
BACKGROUND OF THE INVENTION
Albendazole is an orally administered broad-spectrum anthelmintic.
Chemically, it is methyl 5-(propylthio)-2-benzimidazolecarbamate. Its molecular
formula is C12H15N3O2S. Its molecular weight is 265.34. It has the following
chemical structure:
Albendazole is a white to off-white powder. It is soluble in
dimethylsulfoxide, strong acids, and strong bases. It is slightly soluble in methanol,
chloroform, ethyl acetate, and acetonitrile. Albendazole is practically insoluble in
water.
Albendazole is found to inhibit the polymerization of the parasite tubulin
into microtubules. This leads to an impaired uptake of glucose, a depletion of
glycogen stores, and results in the worm's death. There is a higher affinity of
albendazole to the parasite tubulin and so the activity is mediated mainly against
the parasite rather than on the host. The loss of the cytoplasmic microtubules leads
to impaired uptake of glucose by the larval and adult stages of the parasites. The
worm is then unable to maintain energy production, which leads to immobilization
and eventual death (Dayan, 2003). A secondary action of albendazole may be the
(2)
be the inhibition of the enzyme fumarate reductase, which is helminth-specific
(PharmGKB).
Albendazole is a BCS class II molecule i.e. a low solubility and high
permeability molecule. It has pH-dependent solubility, showing poor and erratic
solubility in gastrointestinal tract (GIT), and hence exhibiting extremely low
bioavailability. However, it shows enhanced solubility in strong acids and bases.
Conventional Albendazole formulations are available in the form of filmcoated
tablets and suspensions. Oral liquid formulations of Albendazole such as
suspensions and nanosuspensions, get solubilized in gastric pH, and readily
absorbed in duodenum and jejunum. Although the drug has complete solubility and
permeability with specialized formulations such as nanosuspension and solid
dispersion, the bioavailability of these formulations have been hampered by
extensive first-pass effect of the drug. First pass effect is a phenomenon of drug
metabolism whereby the concentration of drug is greatly reduced during the
absorption process related to liver and gut wall, before reaching systemic
circulation in a patient.
Albendazole is used in the treatment of dog and pork tapeworm-causing
diseases, including hydatid disease and neurocysticercosis. Albendazole may also
be used to treat a variety of other roundworm infections.
Solubilisation of Albendazole doesn't necessarily improve the
bioavailability and hence the solubilisation technology alone will not be sufficient
to improve the therapeutic efficacy. On the other hand, delaying the drug release
from stomach to intestine, may reduce the extent of drug reaching to the liver via
portal circulation and hence improve the drug availability in intestinal mucosa and
lumen. However, the poor solubility of Albendazole in intestinal pH may be the
hurdle to develop enteric release formulation.
Albendazole undergoes extensive first-pass metabolism (i.e. first-pass
effect) in the liver and gut wall, resulting in pharmacologically-active sulfoxide
metabolite in plasma, which then shows the intended anthelmenthic activity.
(3)
However, Albendazole sulfoxide (ABZSO) is comparatively less permeable and
potent than the parent drug 'Albendazole'. The helminths absorb the drug via
passive diffusion through surface rather than via sucked blood. Hence, presence of
luminal Albendazole solution is more desirable than high plasma concentration of
ABZSO, for the treatment of intestinal parasites. Systemic ABZSO is secreted in
intestinal lumen by active transport at a rate of about 0.165 ± 0.05 nmol/cm, and
this secretion renders very small amount of available ABZSO in intestinal lumen,
resulting in low therapeutic efficacy against intestinal helminths. Further, ABZSO
exhibits enantiomerism, and only (+) enantiomer of ABZSO is active in humans.
Hence, first-pass metabolism reduces Albendazole potency by 50%.
Albendazole was approved by U.S. Food and Drug Administration on Jun
11, 1996 for the treatment of parenchymal neurocysticercosis due to active lesions
caused by Taenia solium (larval forms of the pork tapeworm) and also for the
treatment of cystic hydatid disease of the liver, lung, and peritoneum, caused by the
larval form of the dog tapeworm. It is approved in India as a 2.5, 10% w/v
suspension by CDSCO on October 1979 and tablet for 200mg was approved later
on February 1986.
Albendazole and its salts have been disclosed as a novel compound in
US3915986 (SmithKline: Robert J Gyurik et al.). US ‘986 discloses the
benzimidazole and its derivatives indicated for the treatment of gastrointestinal
helminths in pets.
Wang Leibo et al. in CN101288659 discloses a gastric floating pellet
composed of a core, a drug layer, an isolation layer, a sustained-release layer and a
protective layer, and having a density less than 1g/cm3. The drug layer consists of
drugs such as albendazole, and coating materials. The pellet is packaged in capsules
to obtain a gastric floating capsule.
Cheng Liang et al. in CN101007170 discloses a process for preparation of
sustained-release formulation for treating hydatidosis, comprising at least one
(4)
active ingredient including albendazole, and a biocompatible material including
biodegradable and/or non-biodegradable materials.
Sunil Sadanand et al. in IN1360MUM2004 discloses a modified release
dosage form for low dose active ingredient targeted to be delivered in the proximal
part of the gastrointestinal tract, wherein the dosage form is an inlay tablet
comprising an inner portion made of pharmaceutically active ingredient such as
albendazole, release controlling agent(s) and pharmaceutically acceptable
excipients, and an outer portion including hydrophobic nonbiodegradable
material(s), water soluble diluent(s) and other pharmaceutically acceptable
excipients. The application is related to the formation of tablet in tablet for
controlled release of active pharmaceutical ingredients. The dosage form is
fabricated using hydrophobic polymers, which are not suitable for delivery of
poorly soluble drugs. The application fails to describe the intestinal delivery of the
drug using enteric polymer. Intestinal drug concentration is equally important to
achieve the desired therapeutic activity against intestinal worms.
Gérard Soula et al in WO2007036671 discloses microparticulate systems
with modified release of oral active ingredient(s); where the multimicroparticulate
galenic system operates in accordance with a dual time-dependent and pHdependent
release mechanism.
Pascal Prinderre et al in WO2009150514 discloses a process for making
oral solid gastro-retentive forms, comprising the steps of providing a powder
mixture comprising an active ingredient such as albendazole and a hydrophobic
powder, over-granulating the powder mixture with a granulating solution. into an
over granulated paste, and drying the paste into a solid as well as to pharmaceutical
solid dosage forms which are retained in the stomach or upper gastrointestinal tract
for a controlled delivery of a drug. The process disclosed in the application is a
lengthy, tedious process and very difficult to adopt for large scale manufacturing.
Although conventional film-coated tablets prevent Albendazole
solublization in stomach, and ensure the drug release in the intestine by using
(5)
enteric polymers in coating material, the zwitterion nature of Albendazole showing
iso-electric point of 6-6.5, retards the drug solublization in intestinal pH and results
in low therapeutic efficacy of the drug.
In the conventional film-coated tablet of Albendazole, once the coat is
dissolved, the whole drug is dumped in the intestine. Due to low solubility of the
drug and high viscosity of bowel content, only a small fraction of drug gets
dissolved and penetrates the helminth surface, and even smaller amount of drug
gets systemically absorbed. This proves to be a major drawback of conventional
enteric release tablets for their use against intestinal as well as systemic helminths.
The inventor of the present invention also found tablets stable quality, easy
to take, is a basic, the most commonly used formulations. However, for children,
the elderly and patients with dysphagia, ordinary tablets often take difficult, longterm
medication will make it even psychological phenomenon refuse drugs,
chewable tablet can make up the shortfall. Chewable tablet is chewed in the mouth
after swallowing may be a class of tablets, ordinary tablets generally the same size,
can be made as profiled sheet in accordance with different shapes. After swallowing
easy to chew the tablets so that the surface area is increased, can promote
dissolution, absorption of the drug in the body. Advantage with present invention
provides tablets are easy to take medication on time can be even under conditions
of lack of water, especially for children, the elderly poor patients, dysphagia or
gastrointestinal function, drugs can reduce the burden on the gastrointestinal
tract. Therefore, chewable tablets increasingly widespread application up.
Despite several formulations reported in the prior art however, due to
unsuitable tableting properties of albendazole like less adequate release profile and
its reported formulations itself, still there remains need for the
composition/formulation, which are scalable on industrial scale and results in stable
pharmaceutical composition with enhance dissolution profile.
(6)
SUMMARY OF THE INVENTION
Provided herein are simple and easily scalable oral solid pharmaceutical
compositions of albendazole with improved granulating, tabletting properties, and
the process of preparing such composition. The present invention provides a tablet
containing albendazole, which provides enhance release profile of albendazole
within the compositions.
In one aspect of the present invention it relates an oral pharmaceutical
composition of albendazole comprising 30-50% w/w of albendazole, 1-3% w/w of
binder and 5-15% w/w of disintegrant, wherein disintegrant is selected from sodium
starch glycolate, crosscarmellose sodium or both.
In another aspect of the present invention it relates an oral pharmaceutical
composition of albendazole, wherein the composition is prepared using binder as
polyvinylpyrrolidone in aqueous solution.
In another aspect of the present invention it relates a process of preparing
oral pharmaceutical composition of albendazole where the process comprises the
steps of:
a) sifting diluent and filler and third mass of the disintegrant with
surfactant and mixed with albendazole.
b) preparing the sweetening agent with colouring agent aqueous
solution.
c) binder solution prepared using aqueous vehicle at 60-80 C and
mixed with surfactant using organic solvent.
d) sifting the wet mass and dried the granules at 35-45 C
e) drying and sifted the granules.
f) adding rest mass of disintegrant with surfactant and polymer with
flavouring agent as extragranular part.
g) blended the extragranular mass with intragranular mass.
h) lubricated the mass and add glidant by blending for 10-30min.
i) compressed the blend using suitable punch.
(7)
The oral pharmaceutical composition of albendazole according to present
invention may be useful in for the treatment of variety of parasitic worm
infestations.
Various other specific aspects of the invention are further detailed in the
description part of the specification, wherever appropriate.
DETAILED DESCRIPTION
The oral pharmaceutical composition of albendazole according to present
invention may be useful in for the treatment of variety of parasitic worm
infestations.
In one embodiment according to the present invention, it provides an oral
pharmaceutical composition of albendazole comprising 30-50% w/w of
albendazole, 1-3% w/w of binder and 5-15% w/w of disintegrant, wherein
disintegrant is selected from sodium starch glycolate, crosscarmellose sodium or
both.
Albendazole, an orally administered benzimidazole broad-spectrum
anthelmintic that is effective against many diseases. The maximum daily
recommended dose of albendazole is 800mg. It is a white to pale buff, essentially
odorless, powder with freely soluble in formic acid, dimethylfermamide, sparingly
soluble in methanol, chloroform. Albendazole is poorly absorbed from the
gastrointestinal tract due to its low aqueous solubility. Albendazole concentrations
are negligible or undetectable in plasma as it is rapidly converted to the sulfoxide
metabolite prior to reaching the systemic circulation. It is pharmaceutically
compatible with most of the reported adjuvants/excipients. The target population
with uptake the dose of albendazole is delivered to age group upto 15. To deliver
the precise dose there is a need to increase the bioavailability of drug and reduce
the first pass metabolism. The inventors of the present invention found this delivery
to be most convenience in the form of tablet. Thus, in view of the dosage desired
for the therapy and the nature of the active ingredient, there is a further need to
optimize the pharmaceutical dosage forms comprising albendazole so that it is
(8)
convenient to manufacture, administer, and provide the requisite daily dosage of
albendazole.
The pharmaceutical composition of the present invention may be in the form
of oral solid dosage form preferably tablet, capsule, powder, granules, sustained
release, control release, immediate release composition. The inventors of the
present invention came up with the solution as unit solid unit composition in the
form of tablet which is patient compliance and easy to intake as per dosing
frequency.
The pharmaceutical composition of the present invention also provides the
compliance to those group of patient who are not capable to swallow the oral solid
composition. It is required that the pharmaceutical composition of the present
invention provide adequate compaction with desired disintegration time and less
dependency of water to take it as media. Inventors of the present invention
surprisingly found that preparing chewable tablet of albendazole provide patient
compliance and easy to intake having no dependency of water. By preparing the
composition using less starch can improve the self-life of the composition. The
present invention also provides the enhance dissolution profile with improve in
patient compliance.
In pharmaceutical excipients, “binders” are compounds which cause
agglomeration of drug and excipient particles during the manufacturing process and
act to control the release of drug from the dosage form. The agglomeration can be
in the form of a granulation or a powder. The present invention provides the
pharmaceutical composition of albendazole comprising binder selected from
cellulose derivatives e.g. ethyl cellulose, methyl cellulose, guar gum, blende guar
gum and other cellulose e.g. cellulose gums (carboxymethyl cellulose,
hydroxypropyl methylcellulose, and hydroxypropyl cellulose),
polyvinylpyrrolidone (povidone), cross-linked polyvinylpyrrolidone,
pregelatinized starch, acacia, alginic acid, carbomer, dextrin, maltodextrin.
(9)
In a specific embodiment according to present invention the binder used in
the pharmaceutical composition was povidone prepared using aqueous media.
The present invention also provides the pharmaceutical composition of
albendazole comprising disintegrant wherein disintegrant is selected from
mannitol, alginic acid, carboxymethylcellulose, hydroxypropylcellulose,
microcrystalline cellulose, croscarmellose sodium, povidone, polyvinylnpyrrolidone
(crospovidone), magnesium aluminum silicate, methylcellulose,
sodium alginate, starches or modified starches such as sodium starch glycolate, corn
starch, potato starch or pregelatinized starch.
It is required that the pharmaceutical composition of the present invention
provide adequate compaction with desired disintegration time. Inventors of the
present invention surprisingly found that disintegrant play a major role and impact
on pharmaceutical composition when disintegrant is distributed as mixture of one
or more disintegrant. Inventors of the present invention optimise the ratio of
disintegrants to prepare the chewable composition with enhance dissolution profile.
Present invention also provides the pharmaceutical composition of
albendazole comprising mixture of disintegrant as croscarmellose sodium and or
both sodium starch glycolate.
Inventors of the present invention optimised the ratio mixture of
croscarmellose sodium and sodium starch glycolate to give the optimum tabletting
property.
In yet another embodiment of the present invention, it provides a process of
preparing oral pharmaceutical composition of albendazole where the process
comprises the steps of:
a) sifting diluent and filler and third mass of the disintegrant with
surfactant and mixed with albendazole.
b) preparing the sweetening agent with colouring agent aqueous
solution.
(10)
c) binder solution prepared using aqueous vehicle at 60-80 C and
mixed with surfactant using organic solvent.
d) sifting the wet mass and dried the granules at 35-45 C
e) drying and sifted the granules.
f) adding rest mass of disintegrant with surfactant and polymer with
flavouring agent as extragranular part.
g) blended the extragranular mass with intragranular mass.
h) lubricated the mass and add glidant by blending for 10-30min.
i) compressed the blend using suitable punch.
Step a) of sifting the diluent and filler with albendazole and third mass of
disintegrant according to the present invention, carried out in a shifter by
conventional method, however it was found that sifting carried out using mesh size
of ranging between 35-45#.
Premixing the sifted mass using octagonal blender for the time period of 25-
40 min. However, it is preferred that a time of 30-40 min premixing is necessary.
Furthermore, the step b) preparing the sweetening agent and colouring agent
solution by using aqueous media in the temperature ranges between 60-80 C.
Binder solution as per step c) prepared using aqueous media by continue
stirring for 15-30 min at 60-80 C adding the surfactant organic solvent solution by
continue stir for 20-30 min.
Prepared the wet mass as per step d) by using the solution prepared as per
step c). Sifting the wet mass using 10-25# mesh and dried at 35-45 for 20-30
minutes as per step e).
Adding the rest mass of extragranular part of disintegrant with surfactant,
polymer and flavouring agent as per step f).
Mixing the intragranular and extragranular part of mass as per step g) using
blend mixture for 5-20 min. The extragranular and intragranular part gives the
optimum compaction for
(11)
The prepared mixture as per above mixed with lubricant, glidant and as per
present invention in step h) further processed for compression and/or encapsulating
in capsules shell.
In yet another embodiment of the present invention, it provides to prepare
pharmaceutical compositions for oral administration comprising a step of admixing
the albendazole granulate with pharmaceutically acceptable excipients, optionally,
comprising a step of compressing the composition into tablets, and optionally
followed by a film-coating or directly encapsulating in desired capsule size.
The pharmaceutical composition of albendazole according to present
invention involves necessarily use of lubricant, wherein lubricant is selected from
magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl
fumarate, vegetable oil, mineral oil.
It has been observed by present inventors that various composition
discussed in prior art suffer a disadvantage of either less dissolution profile
parameters or making coating process non-uniform and difficult which may results
as blistering, chipping, picking, blushing, cracking (splitting) or the like.
Present invention, provides a process for making the pharmaceutical
composition for oral administration comprising a step of admixing
pharmaceutically acceptable excipients and albendazole, comprising a step of
compressing the composition into tablets, optionally followed by a non-aqueous
film-coating.
The term "oral" administration means that the active agent is in a
formulation designed to be ingested, i.e. designed to be delivered to the
gastrointestinal system for absorption.
The term "oral solid composition" or "oral pharmaceutical composition"
comprises capsule, tablet (film coated tablet, controlled release tablet, modified
release tablet, delayed release etc.), micro tablet, powder, granule and pellets.
(12)
Capsules used as oral dosage form can be soft or hard capsules, though oral dosage
form of the present invention is tablet or capsule.
The term "about" is a value that can be considered ±5% of the given value.
Based on context of discussion, the term "%w/w" refers to the relative value to total
weight of granules or to total weight of pharmaceutical composition and “%v/v”
refer to volume by total volume percentage.
In one of embodiments, the application provides pharmaceutical dosage
forms of albendazole having blend uniformities (CU) from about 98% to about
102% by weight, with relative standard deviations (RSD) of not more than about
5%. In embodiments, the invention relates to pharmaceutical formulations having
a disintegration time of less than about 15 minutes. In embodiments, the invention
relates to pharmaceutical formulations having friability not more than about 1 %
w/w.
Usage of the terms "a" and "an" and "the" and similar referents in the context
of describing the invention (especially in the context of the following claims) are to
be construed to cover both the singular and the plural, unless otherwise indicated
herein or clearly contradicted by context. The terms "comprising," "having,"
"including," and "containing" are to be construed as open-ended terms (i.e.,
meaning "including, but not limited to,") unless otherwise noted. Recitation of
ranges of values herein are merely intended to serve as a shorthand method of
referring individually to each separate value falling within the range, unless
otherwise indicated herein, and each separate value is incorporated into the
specification as if it were individually recited herein. The term wt % refers to
percent by weight. All methods described herein can be performed in any suitable
order unless otherwise indicated herein or otherwise clearly contradicted by
context. The use of any and all examples or exemplary language (e.g. "such as")
provided herein, is intended merely to better illuminate the invention and does not
pose a limitation on the scope of the invention unless otherwise claimed. No
language in the specification should be construed as indicating any non-claimed
element as essential to the practice of the invention.
(13)
The terms “pharmaceutically acceptable excipients”, “pharmaceutically
compatible excipients”, and “excipients” are used interchangeably in this
disclosure. They refer to non-API substances such as disintegrators, binders, fillers,
and lubricants used in formulating pharmaceutical composition. They are generally
safe for administering to humans according to established governmental standards,
including those promulgated by the United States Food and Drug Administration.
Particular embodiments of this invention are described herein, including the
best mode known to the inventors for carrying out the invention. Variations of those
particular embodiments may become apparent to those of ordinary skill in the art
upon reading the foregoing description. The inventors expect skilled artisans to
employ such variations as appropriate, and the inventors intend for the invention to
be practiced otherwise than as specifically described herein. Accordingly, this
invention includes all modifications and equivalents of the subject matter recited in
the claims appended hereto as permitted by applicable law. Moreover, any
combination of the above-described elements in best possible variations thereof is
encompassed by the invention unless otherwise indicated herein or otherwise
clearly contradicted by context.
While the forgoing pages provide a detailed description of the preferred
embodiments of the invention, it is being understood that the summary, description
and examples are illustrative only of the core of the invention and non-limiting.
Furthermore, as many changes can be made to the invention without departing from
the scope of the invention, it is intended that all material contained herein be
interpreted as illustrative of the invention and not in a limiting sense.
(14)
EXAMPLE 01
Tablet 01: Composition of Albendazole
S.No.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Ingredients Name
Albendazole IP
Maize starch BP
Lactose monohydrate BP
Sod. starch glycolate Type-A BP
PVP K-30 BP
Saccharin sodium BP
Polysorbate-80 BP
Croscarmellose sodium BP
Microcrystalline cellulose -102
BP
Dried Orange flavor
Dried Vanilla flavor
Sod. lauryl sulphate BP
Col. Sunset yellow supra
Purified talc BP
Magnesium stearate BP
Colloidal anhydrous silica BP
Isopropyl alcohol
Avg Wt.
Qty mg/tab
400.00
98.000
101.00
80.000
28.000
10.000
2.000
50.000
173.00
7.000
7.000
10.000
4.000
10.000
10.000
10.000
0.2
1000.00
Percentage (%)
40.34
3.5
9.75
8.0
2.8
1.0
0.2
5.0
17.3
0.7
0.7
1.0
0.4
1.0
1.0
1.0
100.0%
Tablets prepared of Examples is packaged in closed HOPE containers,
together with desiccant canister, and stored at three different conditions: 25°C and
60% relative humidity (Condition 1), 30°C and 65% RH (Condition 2) or 40°C and
75% RH (Condition 3) for one month. Dissolution testing results of initial and
stored samples are shown in Table 2. The dissolution study is conducted in 900 ml
(15)
of HCl medium, using Ph. Int. (paddle) apparatus, while stirred at 75 rpm for 30
minutes.
Dissolution testing results of marketed tablet and Examples 01 are shown in
Table 02
Time
(min)
10
20
30
TABLE 02
Cumulative % Drug Dissolved
Trail 03
Avg.
71
87
93
%RSD
01.65
01.95
01.47
ZENTEL
Avg.
64.0
80.0
85.0
% RSD
04.00
02.33
02.73

We Claims:
1. An oral pharmaceutical composition of albendazole comprising 30-50%
w/w of albendazole, 1-3% w/w of binder and 5-15% w/w of disintegrant, wherein
disintegrant is selected from sodium starch glycolate, crosscarmellose sodium or
both.
2. An oral pharmaceutical composition of albendazole according to claim 1,
wherein the composition is prepared using binder as polyvinylpyrrolidone in
aqueous solution.
3. A process for preparing oral pharmaceutical composition according to the
claim 1, wherein the solid oral composition is chewable tablet.
4. A process of preparing oral pharmaceutical composition of albendazole
where the process comprises the steps of:
a) sifting diluent and filler and third mass of the disintegrant with
surfactant and mixed with albendazole.
b) preparing the sweetening agent with colouring agent aqueous
solution.
c) binder solution prepared using aqueous vehicle at 60-80 C and
mixed with surfactant using organic solvent.
d) sifting the wet mass and dried the granules at 35-45 C
e) drying and sifted the .granules.
f) adding rest mass of disintegrant with surfactant and polymer with
flavouring agent as extragranular part.
g) blended the extragranular mass with intragranular mass.
h) lubricated the mass and add glidant by blending for 10-30min.
i) compressed the blend using suitable punch.
5. An oral pharmaceutical composition of albendazole according to claim 1,
used as anti-helminths.