FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. TITLE OF THE INVENTION: – “High Dose Pharmaceutical Composition
Containing Dexamethasone and Its Salt”

2. APPLICANT:
a) NAME : Delnova Healthcare LLP
b) NATIONALITY : Indian
c) ADDRESS : A220, Road No. 16V, Wagle Industrial Estate, Thane
West – 400 604, Maharashtra, India.

(a)
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention and the manner in which it is to be
performed.
2
High Dosed Dexamethasone Compositions
Field of The Invention
5 The invention relates to high dosed Dexamethasone Compositions that are highly
concentrated compositions of Dexamethasone having from 20 % - 40 %
Dexamethasone, more preferably from 25 – 40 % of Dexamethasone.
Dexamethasone herein also includes any derivative, salt, hydrate solvate etc. of
Dexamethasone. The preferred compositions include tablets, granules or powder
10 for oral solution / suspension / for filling into capsules etc. High dosed compositions
preferably contain 40 mg dose of Dexamethasone in not than 200 mg preferably not
more than 180 mg and more preferably not more than 160 mg of a tablet and 20 mg
dose of Dexamethasone in not more than 100 mg preferably not more than 80 mg
of a tablet. The high dosed tablet can be split to deliver smaller doses. Also granules
15 formulation can be titrated to obtain lower doses such as 20 mg and 10 mg doses.
High dosed compositions are high dissolving compositions which provide
Dexamethasone in soluble form and exhibit satisfactory release of Dexamethasone
in media of all pH.
20 Objects of the Invention
A first object of the invention is to provide high dosed highly concentrated
compositions of Dexamethasone. Preferably, the invention provides a dose of 40
mg of dexamethasone in not more than 200 mg of a tablet. The tablet can be split
25 to provide lower doses.
Earlier dexamethasone was only available in lower strengths such as 4 mg tablet or
lower and one needed to take 10 tablets at a time to achieve a dose of 40 mg.
Recently, another brand Hemady is introduced which provides a maximum of 20
mg in a single tablet. Thus, one has to take 2 tablets at a time to achieve a dose of
30 40 mg.
3
No one has achieved accommodating a dose of 40 mg of Dexamethasone in unit
dosage form so far. The present invention achieves the same and enables the patient
to take a single tablet.
Second object is to achieve soluble composition of Dexamethasone which can
5 solubilize a high dose in a highly concentrated form.
Third object is to retain this solubility of soluble composition on shelf and stability.
Thus, third object deals with stable compositions without drop in dissolution on
shelf and stability. Sometimes tablets exhibit solubility in the beginning but
significant drop is solubility is observed after a few months. This object ensures
10 that dexamethasone solubility does not drop with time.
Fourth object of the invention is to achieve soluble composition of Dexamethasone
which exhibits a pH independent In Vitro release of Dexamethasone. For this, high
dosed Dexamethasone compositions are subjected to different dissolution media of
various pH and it is found that high dosed compositions provide rapid to very rapid
15 release of dexamethasone in a media of pH from 1.2 to 6.8. Rapid and very rapid
release means at least 85 % release in 15 – 30 mins.
Fifth object is to provide a sturdy method with low variability to produce soluble
compositions of a high dose Dexamethasone in a highly concentrated form.
20 Summary of the Invention
Under the first aspect the invention provides a high dosed highly concentrated
compositions of Dexamethasone. Preferably, the invention provides a dose of 40
mg of dexamethasone in a single unit dosage form which is provided for the first
25 time ever. Also, this high dose is provided in a highly concentrated form wherein
the amount of Dexamethasone in such unit dosage form is from 20 – 40 %,
preferably, from 25 – 40 %.
This enables client to consume entire dose by consuming a single unit dosage form.
Also, it is taken care that such high dose does not amount to increase in the weight
30 of the unit dosage form. Thus, a tablet not more than 200 mg, preferably not more
4
than 160 mg effectively contains 40 mg of dose. The tablet can be split to provide
lower doses. Thus, a single tablet incorporating 40 mg of Dexamethasone can
efficiently deliver 10 mg or 20 mg.
No one has achieved accommodating a dose of 40 mg of Dexamethasone in unit
5 dosage form so far. The present invention achieves the same and enables the patient
to take a single tablet.
Second aspect is to achieve soluble composition of Dexamethasone which can
solubilize a high dose in a highly concentrated form. This has been achieved by
employing a method of hot melt extrusion. Additionally, solubilizers or solubility
10 enhancers and buffering agents are added.
Dimethylaminoethyl methacrylate-copolymer Eudragit EPO (EPO) has been found
preferably suitable. It plays multiple roles such as plasticizer, solubility enhancer,
stability enhancer and also as a carrier to disperse Dexamethasone preferably in
crystalline form. Another advantage is that it melts or softens well at a temperature
15 of 70°C and above which is above its glass transition temperature (40-48°C) and
aids in hot melt extrusion.
Another solubility enhancer which has been particularly found useful in preparing
compositions of the present invention is a solid solubilizer and compression agent
with a brand name SepitrapTM80. This solid solubilizer has polysorbate 80 (45-
20 65%) adsorbed on the porous mineral carrier Magnesium Aluminometasilicate (35-
55%). Another type SEPITRAP™ 4000 can also be employed which has Polyoxyl
40 hydrogenated castor oil (55-75%) adsorbed on the porous mineral carrier
Magnesium Aluminometasilicate (25-45%).
The buffering agents such as citric acid and other acids such as tartaric acid, benzoic
25 acid, lactic acid, malic acid, maleic acid are also employed.
Hydroxy propyl beta cyclodextrins are also preferably employed for their ability to
enhance solubility as well as stability.
Third aspect is to retain the solubility of soluble composition on shelf and stability.
Thus, third aspect deals with stable compositions without drop in dissolution on
5
shelf and stability. Sometimes tablets may exhibit solubility in the beginning but
significant drop in solubility is observed after a few months. This object ensures
that dexamethasone solubility does not drop with time. Also, in general, stable
compositions are produced with can retain stability on shelf and when subjected to
5 accelerated conditions such as 40°C/75%RH for 6 months. Impurities A, C, D, E,
F, G, J and K are below 0.5 % and preferably below 0.3 %. Single maximum
unknown impurity is below 0.1 % and total impurities are below 1.0 %.
In Vitro release profile of Dexamethasone tablets prepared in accordance with the
present invention at Initial time point, after 1 month storage at 40°C / 75 % RH and
10 after 6 months storage at 40°C / 75 % RH. There is no drop in the dissolution.
Under the fourth aspect, the invention provides soluble composition of
Dexamethasone which exhibits a pH independent solubility. The In Vitro release of
Dexamethasone in various media such as 0.1 N HCl (OGD media), acetate buffer
of pH 4.5 are as below. The pH shift media is also employed which exposes
15 Dexamethasone tablet to acidic pH for first 15 mins and a pH of 6.8 for next 45
minutes.
Table A
Time points /
media (pH)
Batch No. F0106C for dissolution in 0.1N HCl; and Batch
No. F0106I for dissolution in acetate buffer of pH 4.5 and
for pH shift dissolution viz. 0.1 N HCl for 15 mins followed
by 6.8 pH phosphate buffer
0.1 N HCl Acetate buffer of
pH 4.5
pH Shift
Dissolution
5 mins 82 55 95
15 mins 97 88 95
30 mins 101 99 95
60 mins 102 100 96
6
Fifth aspect provides a sturdy method with low variability to produce soluble
composition of a high dose Dexamethasone in a highly concentrated form. The
method employed is such that it causes melting of one or more excipients to produce
extrudates which are milled to produce granules. This solventless process removes
5 variability which is associated with non-uniform wetting during wet granulation
especially when the active ingredient is extremely insoluble.
The present invention employs hot melt extrusion to provide high dosed
compositions of dexamethasone which are fast dissolving and contain at least one
soluble excipient / which melts at a temperature substantially lower than melting
10 point of dexamethasone. The dry blend containing dexamethasone is continuously
and uniformly subjected to same temperatures to cause melting of one or more
excipient ingredient from the composition. The difference in the melting points of
Dexamethasone and soluble ingredient is at least 10-20°C, preferably at least 30 °C,
more preferably at least 40°C and most preferably at least 50°C. The soluble
15 ingredient employed include any one or more of polyethylene glycol, mannitol,
lactose, sorbitol, fructose, sucrose, polyvinyl pyrrolidone, etc. Generally melting
temperature of soluble ingredient is from 50 – 250°C. Preferably, the melting
temperature is from 70 – 210°C. More preferably, the melting temperature is from
110°C to 210°C. Most preferably, the melting temperature is from 110°C to 180°C.
20 Since Dexamethasone is not subjected to its melting temperature, it retains its
polymorphic form. Hence dexamethasone does not get converted into any other
crystal form or amorphous form.
This process thus leads to solid dispersion wherein Dexamethasone at least
substantially in crystal form is suspended in soluble, hydrophilic matrix without
25 getting converted into amorphous form. This is referred as “Solid Crystal
Suspension”. Figure 1 provides process steps in preparing the same.
Finally, even if the present invention adopts a different method to obtain high dosed
highly concentrated compositions of Dexamethasone, the aim is to have same In
Vitro release profile in media of all pH.
30
7
Background of the Invention
Dexamethasone is a synthetic steroidal glucocorticoid that was approved in 1958
under the brand name Decadron (NDA 011664). Decadron was available in five
strengths: 0.5, 0.75 1.5, 4 and 6 mg (withdrawn from the market in 2007).
5 Dexamethasone is highly insoluble in nature. To develop a soluble composition of
Dexamethasone poses challenges. Therefore, it was never available in higher
strengths but was only available in lower strengths such as 4 mg tablet or lower and
one needed to take 10 tablets at a time to achieve a dose of 40 mg.
In 2019, for the first time a brand Hemady was approved having strength of
10 20 mg. Hemady provides a maximum of 20 mg in a single tablet. One has to take
2 tablets at a time to achieve a dose of 40 mg. HEMADY enables patients to take 1
or 2 oral tablets instead of 5 – 10 tablets to achieve the dose of 20 mg or 40 mg and
is frequently used together with other anti-myeloma treatments.
Dexamethasone Immediate Release Tablets, 20 mg is indicated for the treatment of
15 patients with multiple myeloma (MM), as part of combination regimens with antimyeloma drugs. Dexamethasone is approved for the palliative management of
leukemias and lymphomas. The recommended dosing regimen for Dexamethasone
Tablets is 20 or 40 mg orally, once daily, on specific days of the treatment cycle
depending on the treatment protocol.
20 Dexamethasone is a small chiral molecule. It is a white to practically white nonhygroscopic crystalline solid that is practically insoluble in water, sparingly soluble
in acetone, ethanol, and methanol; and slightly soluble in dichloromethane.
Dexamethasone exhibits polymorphic behaviour.
Drug release is usually the rate limiting process for absorption of a
25 Biopharmaceutics Classification System (BCS) Class II compound like
Dexamethasone due to its low solubility. Therefore, the dissolution of the brand
tablets was thoroughly evaluated. Initially, the dissolution method recommended in
the FDA dissolution methods database for this product was utilized (500 mL of 0.1
N HCl using USP apparatus 2 (paddle) at 50 rpm). The temperature of the
8
dissolution medium was maintained at 37 ± 0.5 °C and the drug concentration was
determined using HPLC analysis. The drug release of brand tablets was also
obtained at different strengths (20 mg and 40 mg (20 mg+20 mg) As shown in
Figure 1, RLD tablets exhibited a very rapid dissolution using the FDA5 recommended method. Later dissolution is also tested and compared in other media
such as acetate buffer of pH 4.5 and pH shift media viz. 0.1N HCl for 15 mins and
phosphate buffer of pH 6.8 for next 45 mins.
US patent no. US1053785Β2 covers a high-dose immediate release dexamethasone
tablet or caplet containing 20 mg of Dexamethasone in 100 mg tablet or capsule. It
10 employs wet granulation process which is a variable process for highly insoluble
medicines such as Dexamethasone.
US patent application no. US20200147106A1 covers similar composition having
up to 25 % of dexamethasone. It has binder from 10 – 30 % and at least 45 % filler.
The compositions therein are also prepared by wet granulation process which is a
15 variable process for highly insoluble medicines such as Dexamethasone.
Brief Description of figures
Figure 1 describes process steps of conventional manufacturing and the solid crystal
20 suspension of the present invention.
Figure 2 describes comparative dissolution profiles of RLD, Batch F0106C (20 mg)
and Batch F0106C (40 mg), in 500 mL of medium (strengths as shown) using USP
apparatus 2 at 50 rpm.
Figure 3A describes comparative dissolution profiles of RLD and Batch F0106I, in
25 500 mL of medium in pH 4.5 acetate buffer using USP apparatus 2 at 50 rpm.
Figure 3B describes comparative dissolution profiles of Batch F0106C and Batch
F0106I, in 500 mL of medium in pH 4.5 acetate buffer using USP apparatus 2 at 50
rpm.
9
Figure 4 describes comparative dissolution profiles of Batch F0106C and Batch
F0116C, in 500 mL of medium in 0.1N HCl using USP apparatus 2 at 50 rpm.
Figure 5A describes Multimedia dissolution profiles of Batch F0113A in 500 mL
of medium (different pH as shown) using USP apparatus 2 at 50 rpm
5 Figure 5B describes comparative dissolution profiles of Batch F0113A and Batch
F0113B, in 500 mL of medium in 0.1N HCl using USP apparatus 2 at 50 rpm
Figure 6 describes comparative dissolution profiles of F0106C and Batch F0106G,
in 500 mL of medium in pH 4.5 acetate buffer using USP apparatus 2 at 50 rpm.
10
Definitions:
Brand product and reference listed drug or RLD are used synonymously.
Softening of Eudragit EPO above glass transition temperature is also termed as
5 melting of Eudragit EPO.
Detailed Description of the Invention
Under the first aspect, the present invention provides high dosed and highly
10 concentrated dexamethasone compositions. Preferably, the invention provides high
dosed solid oral compositions of dexamethasone. More preferably, the
compositions of the present invention contain at least 20 %, preferably at least 25
% and more preferably at least 28 % of dexamethasone. Most preferably, the
compositions of the present invention contain from around 28 % to around 40 % of
15 Dexamethasone.
High dosed compositions of the present invention contain around 20 mg or around
40 mg dose of dexamethasone or can be given in as 10 mg or 20 mg or 40 mg dose.
High dosed compositions of the present invention are also high dissolving
compositions. Some of the compositions are fast disintegrating or dispersible
20 compositions.
Preferably the compositions are tablets of Dexamethasone. Another preferred form
is capsules of dexamethasone. Yet another preferred form is dispersible or fast
disintegrating tablets. One more preferred form is powder for oral suspension or
powder for solution.
25 High dosed tablets of dexamethasone of the present invention are preferably with a
dose of 20 mg – 40 mg. More preferably they are with a break line or a score line
that can divide tablets into two or four parts delivering from 5 mg, 10 mg, 20 mg,
and 40 mg of dose.
In an embodiment, dexamethasone is present in an amount of 40 mg in a tablet of
30 100 mg. In few embodiments, dexamethasone is present in an amount of 40 mg in
11
tablets weighing 120 mg, 132 mg, 138 mg and 140 mg. Therefore % dose of these
high dosed formulation varies from about 28 % to about 40 %.
In an embodiment, dexamethasone is present in an amount of 20 mg in a tablet of
50 mg. In few embodiments, dexamethasone is present in an amount of 20 mg in
5 tablets weighing 60 mg, 66 mg, 69 mg and 70 mg. Therefore % dose of these high
dosed formulation varies from about 28 % to about 40 %.
Powder for oral suspension prepared in accordance with the present invention has
a dose of 20 mg or 40 mg of dexamethasone.
Dispersible or fast disintegrating tablets prepared in accordance with the present
10 invention have a dose of 20 mg or 40 mg of dexamethasone.
Highly concentrated high dosed compositions of Dexamethasone provide 40 mg
dose in a relatively smaller tablet. This enables client to consume entire dose by
consuming a single unit dosage form. Also, it is taken care that such high dose does
not amount to increase in the weight of the unit dosage form. Thus, a tablet not
15 more than 200 mg, preferably not more than 160 mg effectively contains 40 mg of
dose. The tablet can be split to provide lower doses. Thus, a single tablet
incorporating 40 mg of Dexamethasone can efficiently deliver 10 mg or 20 mg.
No one has achieved accommodating a dose of 40 mg of Dexamethasone in unit
dosage form so far. The present invention achieves the same and enables the patient
20 to take a single tablet.
High dosed compositions of dexamethasone of the present invention preferably
contain at least one ingredient which exists in substantial amount and which melts
at a temperature lower than melting point of dexamethasone. The substantial
amount is at least about 5 %, preferably at least about 10 % and more preferably, at
25 least about 15 % of the composition. This ingredient is preferably a soluble
ingredient forming soluble part of the composition. Melting of the soluble
ingredient in the blend containing Dexamethasone produces granulate of
dexamethasone without affecting crystal form of dexamethasone making the
composition fast dissolving.
12
The process employed that achieves partial or complete melting of soluble
ingredient is known as hot melt extrusion but is unique process in the present case
because active ingredient is not subjected to melting as in other cases of melt
extrusion.
5 This process thus leads to solid dispersion wherein Dexamethasone at least
substantially in crystal form is suspended in soluble, hydrophilic matrix without
getting converted into amorphous form. This is referred as “Solid Crystal
Suspension”. Figure 1 provides process steps in preparing the same.
During hot melt extrusion, the soluble ingredient, dexamethasone and optionally
10 any other excipient / ingredient are subjected to a first elevated temperature zone.
The soluble ingredient optionally with any other ingredient is blended with
dexamethasone at first elevated temperature zone to form a blend which is subjected
to a second elevated temperature zone higher than the first elevated temperature
zone. The second elevated temperature zone is same as or close to melting
15 temperature of the said soluble ingredient at which dexamethasone does not melt
but the soluble ingredient melts partially or fully / completely. The blend is kneaded
at this second elevated temperature zone and partial or complete melting of soluble
ingredient and kneading together cause granulation of Dexamethasone blend. The
granulate is then subjected to a third elevated temperature zone at same or lower
20 temperature than the second elevated temperature zone to cause solidification of
molten soluble ingredient. Further they are taken to another zone of a temperature
preferably lower than third zone to cause further solidification and drying and taken
out of die as dried extrudates. These extrudates can be like granules or can be
optionally subjected to milling/ crushing/ sizing / sifting etc. to obtain granules of
25 desired size ranges.
Dexamethasone compositions of the present invention are soluble and fast
dissolving in spite of having high dose of dexamethasone which is insoluble in
water. Preferably at least 30 % of the high dosed composition has soluble portion
containing soluble excipient / ingredient. More preferably, at least 40 % of the
13
composition has soluble portion containing soluble ingredient. Most preferably at
least 50 % of the composition has soluble portion containing soluble ingredient.
The soluble or hydrophilic excipient / ingredient can be partially / completely
melted or softened to prepare granulate of Dexamethasone containing soluble mass.
5 The granulate is prepared by a unique process of partial / complete melting of
soluble / hydrophilic ingredient and provides a rapidly dissolving composition of
the present invention.
Soluble ingredient is selected from one or more of sugars, sugar alcohols,
saccharides, polyols and polymers. Soluble ingredient is selected such that its
10 melting point is less than melting point of dexamethasone. Soluble ingredient can
be more than one ingredient wherein at least one of them has melting point lower
than melting point of dexamethasone. Optionally and additionally, insoluble
ingredients can be present in the granulate of Dexamethasone.
In an embodiment, a soluble excipient which is subjected to partial / complete
15 melting is a sugar alcohol. In another embodiment, a soluble excipient which is
subjected to partial / complete melting is a sugar. In yet another embodiment, a
soluble excipient which is subjected to partial / complete melting is a polymer.
In an embodiment sugar alcohol is mannitol. In another embodiment, polyol is
polyethylene glycol. In yet other embodiments polymer is polyvinyl pyrrolidone.
20 In an embodiment, combination of at least two ingredients selected from sugars,
sugar alcohols, saccharides, polyols and polymers are employed as soluble
excipients. In an embodiment, a combination of mannitol and polyvinyl pyrrolidone
are used as soluble excipients. In another embodiment, combination of mannitol
and polyethylene glycol are used as soluble excipients added in granulation. In yet
25 another embodiment, combination of mannitol, polyvinyl pyrrolidone and
polyethylene glycol are used as soluble excipients added in granulation.
The present invention provides high dosed compositions of dexamethasone which
are fast dissolving and contain at least one soluble excipient which melts at a
temperature substantially lower than melting point of dexamethasone. The
14
difference in the melting points of Dexamethasone and soluble ingredient is at least
10-20°C, preferably at least 30 °C, more preferably at least 40°C and most
preferably at least 50°C. The soluble ingredient employed include any one or more
of polyethylene glycol, mannitol, sorbitol, fructose, sucrose, polyvinyl pyrrolidone,
5 etc. Generally melting temperature of soluble ingredient is from 50 – 250°C.
Preferably, the melting temperature is from 70 – 210°C. More preferably, the
melting temperature is from 110°C to 180°C. Since Dexamethasone is not subjected
to its melting temperature, it retains its polymorphic form. Hence dexamethasone
does not get converted into any other crystal form or amorphous form.
10 The granulate produced due to melting of soluble ingredient is subjected to a third
temperature zone at elevated temperature but lower than that of second elevated
temperature zone to cause solidification of molten soluble excipient. This process
of melt extrusion employed in a unique way in the present invention provides
granules after solidification of said granulate. Such granules can be mixed with one
15 or more extragranular materials if needed and further converted into various dosage
forms such as tablets, capsules, fast disintegrating or dispersible tablets, powder for
oral suspension or solution etc.
Once dexamethasone granules containing dexamethasone, soluble excipient which
is subjected to partial / complete melting and optionally one or more other
20 excipients are prepared, they are blended with one or more extra-granular excipients
selected from filler, disintegrant, surfactant, glidant and lubricant and the blend is
ready for compression into a tablet composition or filled in a capsule.
In few embodiments, two soluble ingredients having melting temperatures lower
than dexamethasone are employed. The first soluble ingredient is mannitol. The
25 second soluble ingredient is either polyvinyl pyrrolidone and polyethylene glycol
such as PEG 4000 or both polyvinyl pyrrolidone and polyethylene glycol.
Batch F1 employs mannitol as soluble and intragranular excipient which melts at
around 160-170°C which is substantially lower than melting point of
Dexamethasone (melting point about 262°C). Batch F2 employs two soluble
15
excipients viz. mannitol and PVP K30. Batch F7 employs three soluble excipients
viz. mannitol, PVP K30 and PEG 400.
A non-soluble excipient is also added along with the soluble ingredient / excipient
in melt extrusion process. This non-soluble excipient may or may not melt at a
5 second elevated temperature zone or at any temperature substantially lower than
melting point of Dexamethasone. In an embodiment, microcrystalline cellulose is
added as a non-soluble excipient.
Batch F6 employs around 14.28 % of microcrystalline cellulose.
Additionally, one or more solubilizers or solubility enhancers, carriers / diluents,
10 protective agents are added. These agents are added in an amount of from about 1
% to about 50 %, preferably from about 1 % to about 40 %, more preferably from
about 2 % to about 30 % of the total weight of the composition.
In addition to or alternative to soluble excipient such as mannitol, a hydrophilic
ingredient can be employed. Eudragit EPO is one such ingredient.
15 Dimethylaminoethyl methacrylate-copolymer Eudragit EPO (EPO), a terpolymer
based on N,N-dimethylaminoethyl methacrylate with methylmethacrylate and
butylmethacrylate commonly known by brand name as Eudragit®EPO is found
particularly beneficial. It has reportedly glass transition temperatures (Tg) at 48°C
and 56°C. Temperature higher than Tg such as 70°C and above are employed to
20 soften Eudragit EPO. This softening of Eudragit EPO is termed as melting of
Eudragit EPO.
Eudragit®EPO when added during granulation plays multiple roles. It acts as a
protective agent as well as solubility enhancer. It plays multiple roles such as
plasticizer, solubility enhancer, stability enhancer and also as a carrier to disperse
25 Dexamethasone preferably in crystalline form. Another advantage is that it melts or
softens well at a temperature of 70°C and above which is above its glass transition
temperature (40-48°C) and aids in hot melt extrusion.
Therefore, when Eudragit EPO is added, it is possible to avoid melting of mannitol.
Eudragit EPO melts or sufficiently softens at a temperature of 70°C and above and
16
it is possible to conduct hot melt extrusion at a lower temperature such as from
110°C to 160°C and preferably, from 120°C to 150°C and most preferably at 140°C
+ 10°C . In a batch of Dexamethasone, mannitol and Eudragit EPO, one can employ
a temperature of 170°C to 180°C and cause melting / softening of both mannitol
5 and Eudragit EPO while keeping dexamethasone in crystalline form or one can
employ a temperature of from 120°C to 150°C and most preferably at 140°C + 10°C
to cause melting / softening of only Eudragit EPO.
It is always preferred to cause melting and granulation at lower temperatures.
Although dexamethasone is stable, it is still preferred to employ temperature just
10 sufficient to cause melting / softening of intragranular mass to produce extrudates.
If mannitol is not melted in the process, it will add to increase in the % torque
generated. Melting of major portion of intragranular mass produces lower % torque
such as up to 40 % whereas melting of lesser portion of intragranular mass wherein
major portion is in powder or solid crystalline form enhances % torque.
15 Therefore, a balance is needed between melting at lower temperature and % torque
generated.
In best mode batches, the temperature of 140°C + 10°C to cause melting / softening
of only Eudragit EPO has been employed (Batch No. F0106C). For lower
temperature melting i..e melting / softening at 140°C + 10°C or below, there must
20 be sufficient intragranular melting component which can melt at this temperature
to avoid generation of higher torque. Thus, quantity of Eudragit EPO is important
when it is the only melting component at applied temperatures. The quantity of
Eudragit EPO must be at least 25 % of intragranular mass, preferably at least 30 %
and most preferably from 30 – 60 % of intragranular mass.
In an embodiment, Eudragit® 25 EPO is added in an amount of about 1 – 5 %.
In an embodiment, Eudragit®EPO is added in an amount of from 10-30 %.
In other few preferred embodiments, Eudragit EPO is at least 25 % of intragranular
mass or preferably at least 30 % and more preferably, from 30 % to 60 % of
intragranular mass. In an embodiment, Eudragit EPO is 30 % of intragranular mass
30 (F0109C). In another embodiment, Eudragit EPO is 36 % of intragranular mass
17
(F0116C). In yet another embodiment, Eudragit EPO is 40 % of intragranular mass
(F0106C). In one more embodiment, Eudragit EPO is 60 % of intragranular mass
(F0108C).
However batch with 40 % Dexamethasone and 60 % Eudragit EPO although could
5 be produced successfully with desired torque resulted in tablets with high friability.
This friability is not due to addition of 60 % Eudragit EPO but due to removal of
mannitol completely. This batch however is processed successfully as granules for
oral suspension.
Thus, depending on the melting temperature, Eudragit EPO quantity can be varied.
10 When it is the only melting component such as when lower melting temperatures
are employed, its amount shall be at least 25 % of intragranular mass. Batch No.
F0107C with 20 % intragranular EPO could not be processed as torque raised to
100 % due to non-melting component reaching 80 % of intragranular mass.
15 Torque up to 70 – 75 % is acceptable. When non-melting component of
intragranular mass is 70 % as in case of batch F0109C, torque of 60 % was observed
and acceptable.
If lower than 25 % of intragranular Eudragit EPO is desired, temperature should be
raised to at least 160-165°C to cause melting of mannitol to avoid escalation in %
20 torque.
Tablets of Batches F9 and F10 have Eudragit®EPO in an amount of about 28.5 %.
Powder for oral suspension of Batch F14 has Eudragit®EPO in an amount of about
18 %. Dispersible tablets of Batch F12 have Eudragit®EPO in an amount of about
2.85 %. All compositions containing Eudragit®EPO exhibited at least 85 % release
25 in 15 minutes when tested using 500 ml of 0.1N HCl using USP type II Dissolution
apparatus when used at 50 RPM.
Another solubility enhancer which has been particularly found useful in preparing
compositions of the present invention is a solid solubilizer and compression agent
with a brand name SepitrapTM80. This solid solubilizer has polysorbate 80 (45-
30 65%) adsorbed on the porous mineral carrier Magnesium Aluminometasilicate (35-
18
55%). Another type SEPITRAP™ 4000 can also be employed which has Polyoxyl
40 hydrogenated castor oil (55-75%) adsorbed on the porous mineral carrier
Magnesium Aluminometasilicate (25-45%).
Tablets of batch F13 have around 11.4 % of SepitrapTM80 added during granulation.
5 Solubility enhancers can be added during granulation or in extragranular blend or
both during granulation and in extragranular blend.
In an embodiment, mannitol is used as a soluble excipient. In a melt extrusion
process, a mixture of mannitol and dexamethasone is blended at first elevated
temperature and then subjected to a temperature of around 160 – 170°C to cause
10 partial or complete melting of mannitol. Optionally one or more additional
pharmaceutically acceptable excipients are added. Melting and kneading are done
at second elevated temperature to prepare granulate. Granulate is subjected to a
third elevated temperature lower than second elevated temperature allowing
granulate to solidify and form extrudates. Extrudates are optionally subjected to
15 milling/ crushing/ sizing / sifting if required and granules obtained are further
blended with one or more extra-granular excipients selected from filler,
disintegrant, surfactant, glidant and lubricant and the blend is ready for compression
into a tablet composition or filled in a capsule.
In another embodiment, fast dissolving granules prepared by hot melt extrusion
20 containing dexamethasone and mannitol are blended with extragranular diluent,
disintegrant and lubricant to form a lubricated blend which is further compressed
into tablets.
Under a second aspect there is provided a unique process to carry out hot melt
extrusion of dexamethasone containing blend. The process of hot melt extrusion is
carried out using Pharma 11 Twin-screw Extruder by Thermo ScientificTM 25 . The
extruder has multiple conveying zones which can be maintained at varying
temperatures zones. At least 3 zones of varying temperatures can be employed in
the extruder. At the first zone elevated temperature can be used for blending. In
Second zone, temperature can be used for kneading. This temperature is same as
30 melting temperature of the soluble ingredient or close to its melting point. With
19
Third zone, temperature which may be lower than or similar to the second zone
temperature, is used for solidifying the molten soluble ingredient.
Before subjecting dexamethasone to blending, dexamethasone, soluble ingredient
optionally with one or more other ingredient are subjected to conveying zone which
5 is also maintained at a higher temperature lower than first elevated temperature.
Similarly, after extrudes are formed due to solidifying of soluble ingredient, the
extrudes are exposed to another higher temperature lower than third elevated
temperature zone for further solidification / cooling/ drying etc.
This unique process gradually exposes dexamethasone, soluble and / or hydrophilic
10 ingredient and optionally one or more other ingredient to increasing temperature till
partial / complete melting of soluble / hydrophilic ingredient and similarly
gradually expose granulate to decreasing temperatures till granulate solidify fully
and granules are formed.
As a result of this unique process, dexamethasone high dosed fast dissolving
15 granules are formed which can be further processed into fast dissolving high dosed
compositions of dexamethasone.
High Dosed Highly Concentrated Tablet Compositions with split.
The present invention provides high dosed compositions having a dose of 40 mg
20 and additionally of 20 mg or 10 mg. Preferred compression weights are 140 mg for
40 mg, 70 mg for 20 mg and 35 mg for 10 mg.
Each composition which is compressed into tablet are compressed into split tablets
having one or two breaklines. Such split tablets can be easily cut with tablet cutters.
Thus, 40 mg tablet with a single breakline can give 20 mg dose upon splitting and
25 40 mg tablet with two breaklines can give 10 mg dose upon splitting. Once split,
the unconsumed portion of the tablet can be stored in the same container or in a
separate pharmacy bottle / dispensing bottle.
Dissolution studies / In Vitro Release profiles
20
Even if the present invention adopts a different method to obtain high dosed highly
concentrated compositions of Dexamethasone, the aim is to have same In Vitro
release profile in media of all pH of that of Brand product Hemady.
Hence comparison of In Vitro release profile with this Brand product is also
5 provided in various dissolution media.
Office Of Generic Drugs (OGD), United States has recommended following
dissolution conditions for Dexamethasone Tablets.
Table B
10 OGD recommended dissolution medium:
Drug Name Dosag
e form
USP
apparatu
s
Speed
(RPM
)
Mediu
m
Volum
e (mL)
Samplin
g points
(minutes
)
Dexamethason
e
Tablet II 50 0.1N
HCl 500
5, 10, 20,
30 , 45 &
60
minutes
Three way release criteria is set as follows:
Three-way release criteria in OGD media is set for in-house trials as follows:
Table C
15
Release in 15 mins At least 70 % Dexamethasone is
released - minimum requirement
Release in 15 mins At least 75 % Dexamethasone is
released - preferred requirement
Release in 15 mins At least 85 % Dexamethasone is
released - most preferred requirement
21
Fast dissolving compositions of the present invention release at least 70 % dose of
Dexamethasone in 15 mins in 500 ml of 0.1N HCl using USP type II Dissolution
apparatus when used at 50 RPM. Preferably, fast dissolving compositions release
at least 75 % of the high dose of dexamethasone in 15 mins. More preferably, fast
5 dissolving compositions release at least 85 % of the high dose of dexamethasone in
15 mins.
An embodiment provided in table 5 releases around 88 % of the dose of
Dexamethasone in 15 mins when tested in 0.1 N HCl using USP type II Dissolution
apparatus when used at 50 RPM. Another embodiment releases around 94 % of the
10 dose of Dexamethasone in 15 mins using same test conditions.
It has been noted that all hot melt granulation batches exhibited excellent
Cumulative release profile when tested in 500 ml of 0.1N HCl using USP type II
dissolution apparatus at 50 RPM (OGD dissolution conditions). Each batch
irrespective of composition type exhibited at least 85 % release of the dose of
15 Dexamethasone in 15 minutes which matched the % release of reference product
Hemady (Dexel Pharma) having dose of 20 mg Dexamethasone.
The In Vitro release profile of Dexamethasone high dosed highly concentrated
compositions of the present invention has been tested in various media such as 0.1
N HCl (OGD media), acetate buffer and in the pH shift media is studied. Acetate
20 buffer of pH 4.5 was able to show better discrimination between the batches.
The pH shift media is one which exposes Dexamethasone tablet to acidic pH for
first 15 mins and a pH of 6.8 for next 45 – 60 minutes.
The speed 50 RPM paddles and volume 500 ml is kept same for acetate buffer.
The speed 50 RPM paddles is kept same for pH shift media but volume is increased
25 to 900 ml because 400 ml of phosphate buffer with sufficient sodium hydroxide
which upon addition in 500 ml of 0.1N HCl exhibits pH of 6.8 was necessary. This
led to increase in volume. If volume is reduced, granules would get disturbed.
Hence 6.8 phosphate buffer with sufficient sodium hydroxide maintained at 37°C
22
is cautiously added in volume of 400 ml to OGD media of 500 ml which readily
provides pH of 6.8. has been employed.
In-house pH-shift dissolution protocol is prepared to check dissolution of
5 optimized batch by subjecting it to 0.1N HCl for first 15 mins and then to 6.8
pH phosphate buffer for next 45 – 60 minutes. The conditions are as follows:
Table D
Phase 1 Phase 2
Medium 0.1N HCl pH 6.8 buffer and NaOH
Volume (mL) 500 400
Speed (RPM) 50 50
USP 2 2
Sampling points 15 minutes
20, 25, 30, 35, 45, 60,
and 75 minutes
10 Stability studies
Optimized batch F0106 is subjected to accelerated stability conditions at 40°C and
75 % RH. There is no drop in release of Dexamethasone even after storage at 40°C
and 75 % RH for 6 months. Example 8A provides the detailed results of the same.
Impurity profiling of initial sample and sample stored at 40°C and 75 % RH for 3
15 months is also done and tablets are found to be stable meeting criteria of stability
by ICH.
Failed batches - Examples 9, 10, 11
Batches F16 -F20 prepared with hot melt extrusion failed in In Vitro release profile.
20 None of the batches could release 85 % in 15 mins. Batches 16 and 18 – 20 exhibited
incomplete release even at the end of 60 mins in OGD medium.
23
Example 10 provides that batch F0107C could not be processed due to high torque
when melting component of intragranular mass is 20 %.
Example 10 also provides that batch F0108C with 60 % of melting component
Eudragit EPO of intragranular mass although passed in % torque led to tablets with
5 high friability due to complete removal of mannitol.
Observations and Conclusions
Hot melt granulation / hot melt extrusion is essential to enhance solubility of high
dosed highly concentrated dexamethasone compositions.
10 At least one ingredient which is either soluble excipient like mannitol or hydrophilic
excipient like Eudragit EPO or both are essential for obtaining desired in vitro
release profiles.
The soluble and / or hydrophilic component should melt / soften to produce extrudes
/ extrudates at a temperature lower than melting point of Dexamethasone.
15 Dexamethasone remains dispersed at least substantially in crystal form in soluble
and / or hydrophilic carrier thus leading to solid crystal suspension.
During hot melt granulation, melting component shall be at least 25 % of the
intragranular mass, preferably from 30 – 60 % of intragranular mass.
Melting temperature in the process shall be selected based on selection of
20 ingredients. For melting of mannitol, a temperature of at least 160°C, preferably up
to 180°C is preferred. For melting of Eudraagit EPO, a temperature of from 110°C
– 160°C, preferably from 120°C to 150°C and most preferably from 140°C + 10°C
is preferred.
25 Following examples illustrate the invention but do not limit the scope of the
invention in any way.
Example 1: Batches with one or two intragranular excipients
Table 1:
Ingredient Weight in mg
24
Batch F1 Batch F2 Batch F3 Batch F4
Dexamethasone 40 40.00 40 40
Mannitol 40 17.14 40 40
PVPK30 - 40.86 - 20
Lactose Monohydrate 28 28 13 28
Ac-di-sol 10 10 5 10
Magnesium Stearate 2 2 2 2
Avg Weight 120 138 100 140
Process
1. Dexamethasone, mannitol / mannitol and PVP K30 are added in the
conveying zone of a Twin-screw Extruder which is at a temperature of around 70-
5 80°C;
2. The above ingredients are taken to a mixing / blending zone maintained at
around 110°C (first elevated temperature) and blended together;
3. The blend from step 2 is taken to a kneading and mixing zone maintained at
170°C (second elevated temperature) and kneaded during which melting of
10 mannitol starts and further kneading commences granulation;
4. Granulate from step 3 is taken to another zone maintained at 110°C (third
elevated temperature) where molten mannitol starts solidification and mixing in this
zone produces cooled flakes/ rods/ granulate;
5. Cooled granulate from step 4 is taken to a conveying zone maintained at
15 80°C to cause further cooling / solidification of molten mass and taken out of a die
as extrudates or flakes or rods or dried granules.
6. Extrudes/ flakes/ rods/ granulates from step 5 are crushed/ milled / sifted to
required sizes. These granules are then blended with extragranular materials such
as diluent, disintegrant, glidant and lubricant to produce high dissolving granules
20 which are compressed into tablets.
Example 2: Batches with at least two intragranular excipients
25
Table 2:
Ingredient Compositions from Batches F5 – F10
Batch F5Batch F6Batch F7Batch F8Batch F9Batch
F10
Dexamethasone 40 40 40 40 20 40
Mannitol 40 20 40 40 10 20
PVPK30 - 20 15 20 - -
PEG 4000 20 - - - - -
MCC 102 - 20 - - - -
PEG 400 - - 5 - - -
Eudragit EPO - - - - 20 40
Lactose Monohydrate 20 28 28 18 14 28
Ac-di-sol 10 10 10 10 5 10
Magnesium Stearate 2 2 2 2 1 2
Avg Weight 132 140 140 130 70 140
Process
5 1. Dexamethasone, mannitol and PEG / mannitol and PVP K30 / mannitol and
PVP K30 and microcrystalline cellulose /mannitol and PVP K30 and PEG /
mannitol and PVP K30 and Eudragit®EPO are added in the conveying zone of a
Twin-screw Extruder which is at a temperature of around 70-80°C;
2. The above ingredients are taken to a mixing / blending zone maintained at
10 around 110°C (first elevated temperature) and blended together;
3. The blend from step 2 is taken to a kneading and mixing zone maintained at
170°C (second elevated temperature) and kneaded during which melting of
mannitol starts and further kneading commences granulation;
4. Granulate from step 3 is taken to another zone maintained at 110°C (third
15 elevated temperature) where molten mannitol solidifies and mixing in this zone
produced dried granulate;
26
5. Dried granulate from step 4 is taken to a conveying zone maintained at 80°C
to cause further drying / solidification of molten mass and taken out of a die as dried
extrudates or dried granules.
6. Dried granules are blended with extragranular materials such as diluent,
5 disintegrant, glidant and lubricant to produce high dissolving granules which are
compressed into tablets.
7. Batch F9 was compressed using standard concave punches of diameter 5.5
mm and batch F5-F8 and batch F10 was compressed using standard concave
punches of diameter 7 mm. Hardness of tablets of batch F9 is from 4 – 5 kp and
10 that of tablets of batches F5-F8 and batch F10 is from 7 – 8 kp. Disintegration time
for tablets of batch F9 is 4 – 5 minutes and that of tablets of batches F5-F8 and
batch F10 is less than 3 minutes.
27
Example 3: Batches with solubility enhancers
Table 3:
Ingredients Batch F11 Batch F12 Batch F13 Batch F14
Composition Type Powder
for oral
suspension
Dispersible
tablet
Uncoated
tablet
Powder for
oral
suspension
Dexamethasone 20 20 20 20
Mannitol 10 25 39.3 20
Sepitrap-80 - - 8 -
Eudragit EPO 20 2 - 9
Lactose
monohydrate
9 12 - -
Ac-di-sol - 10 2 -
Magnesium Stearate 1 1 0.7 1
Avg Weight 60 70 70 50
Process
5 1. Dexamethasone, mannitol and Eudragit EPO or Dexamethasone, mannitol
andSepitrap-80are added in the conveying zone of a Twin-screw Extruder which is
at a temperature of around 70-80°C;
2. The above ingredients are taken to a mixing / blending zone maintained at
around 110°C (first elevated temperature) and blended together;
10 3. The blend from step 2 is taken to a kneading and mixing zone maintained at
170°C (second elevated temperature) and kneaded during which melting of
mannitol starts and further kneading commences granulation;
4. Granulate from step 3 is taken to another zone maintained at 110°C (third
elevated temperature) where molten mannitol solidifies and mixing in this zone
15 produced dried granulate;
5. Dried granulate from step 4 is taken to a conveying zone maintained at 80°C
to cause further drying / solidification of molten mass and taken out of a die as dried
extrudates or dried granules.
28
6. Dried granules are blended with extragranular materials such as diluent,
disintegrant and lubricant to produce high dissolving granules which are
compressed into tablets.
Dispersible tablets of batch F12 have hardness of about 4-5kp and disintegration
5 time of less than a minute, preferably less than 30 seconds and more preferably less
than 15 seconds.
Example 4: % Cumulative Release in OGD media
Table 4:
% Cumulative Release
Composi
tion type
Time
Referenc
e
Product
Uncoate
d tablets
Powders
for oral
suspensio
n
Dispersib
le
Tablets
Uncoate
d tablets
Powder
for oral
suspensi
on
Time in
minutes
Batch
F10
Batch
F11
Batch
F12
Batch
F13
Batch
F14
5 71 49.0 62 80 46.0 57
10 86 81.5 84 93 79.5 81
15 90 88.5 94 100 88 90
20 91 90.7 96 - 91.6 93
30 93 92.9 97 - 93 96
45 94 94.6 98 - 95 98
60 97 95.6 99 - 96 99
10
29
Example 5: Best Mode Batches having 40 % melting component Eudragit EPO
Table 5:
F0106C F0106I
HME Ingredients mg/tab % w/w
DEX 40.00 28.57 40.00 28.57
Mannitol (Pearlitol
200 SD)
20.00 14.28 20.00 14.28
Eudragit EPO 40.00 28.57 40.00 28.57
Total Weight of
extrudes
100.00 71.42 100.00 71.42
Observations Off-white color extrudes, smooth extrusion process
Extragranular ingredients
Lactose
monohydrate
(Super Tab 30 GR)
28.00 20.00
- -
mannitol - - 28.00 20.00
Ac-Di-Sol 10.00 7.14 10.00 7.14
Magnesium
stearate
2.00 1.43 2.00 1.43
Total Weight of
Core Tablet
140.00 100.00 140.00 100.00
Punch dimension
7.00 mm, round-shaped
punch, break-line on upper
punch, plain on lower
punch
7.00 mm, round-shaped
punch, break-line on upper
punch, plain on lower
punch
Hardness (kP) 2.90-3.10 3.0-4.0
Thickness 3.80-3.85 3.80-3.90
Disintegration 3:00-4:00 00:50-01:30
30
(mm:ss)
Friablity Non-friable Non-friable
Process
1. Dexamethasone, mannitol and Eudragit EPO are added in the conveying
zone of a Twin-screw Extruder which is at a temperature of around 70-80°C;
2. The above ingredients are taken to a mixing / blending zone maintained at
5 around 110°C (first elevated temperature) and blended together;
3. The blend from step 2 is taken to a kneading and mixing zone maintained at
140°C (second elevated temperature) and kneaded during which melting /softening
of Eudragit EPO starts and further kneading commences granulation;
4. Granulate from step 3 is taken to another zone maintained at 110°C (third
10 elevated temperature) where molten Eudragit EPO starts solidification and mixing
in this zone produces cooled flakes/ rods/ granulate;
5. Cooled granulate from step 4 is taken to a conveying zone maintained at
80°C to cause further cooling / solidification of molten mass and taken out of a die
as extrudates or flakes or rods or dried granules.
15 6. Extrudes/ flakes/ rods/ granulates from step 5 are crushed/ milled / sifted to
required sizes. These granules are then blended with extragranular materials such
as diluent (lactose in batch F0106C and mannitol in batch F0106I), disintegrant,
glidant and lubricant to produce high dissolving granules which are compressed
into tablets.
20
Example 5A: Comparison of In Vitro Release profile of optimized batches with
extragranular lactose (F0106C ) and mannitol (F0106I) in acetate buffer of pH
4.5.
Table 5A
25
40 mg strength
pH 4.5 acetate buffer 500 mL media using USP Type II- Paddle apparatus
at 50 RPM
31
Time (minutes) F0106C F0106I
0 0 0
5 48 55
10 68 76
15 82 88
20 93 95
30 97 99
45 101 100
60 102 100
Recovery 102 100
Example 5B: Comparison of In Vitro Release profile of optimized batch
F0106C and brand product Hemady in OGD medium.
Table 5B:
5
Time
(minutes)
HEMADY
(20 mg)
A6070
HEMADY
(2*20 mg)
A6070
F0106C
(40 mg)
F0106C
(20 mg half
tablet)
0 0 0 0 0
5 64 71 82 91
10 88 86 94 102
15 93 90 97 102
20 95 91 99 102
30 97 93 101 103
45 97 94 102 103
60 97 94 102 103
Recovery 101 100 103 103
Example 5C: pH-shift dissolution data of brand product and F0106C
32
Table 5C
500 ml 0.1 N HCl and 400 ml pH 6.8 phosphate buffer using USP Type IIPaddle apparatus at 50 RPM
Time (minutes)
HEMADY (2*20 mg)
A6070
F0106C
0 0 0
15 91 95
20 93 95
25 94 95
30 94 95
35 95 95
45 96 95
60 98 96
75 100 96
Recovery (%) 100 97
Example 6A: Optimization trials with and without buffering agent citric acid
Table 6A
F0109C F0116C
HME Ingredients mg/tab % w/w mg/tab % w/w
DEX 40.00 28.57 40.00 28.57
Mannitol (Pearlitol 200
SD)
30.00 21.43 20.00 14.28
Eudragit EPO 30.00 21.43 36.00 25.71
Citricacid monohydrate 4.00 2.86
Total Weight of
extrudes
100.00 71.42 100.00 71.42
33
Observations
Off-white color extrudates.
Slightly higher
Torque than batch
F0106C
Higher but acceptable
torque as compared to
batch F0106C
Extragranular ingredients
Lactose monohydrate
(Super Tab 30 GR)
28.00 20.00 28.00 20.00
Ac-Di-Sol 10.00 7.14 10.00 7.14
Magnesium stearate 2.00 1.43 2.00 1.43
Total Weight of Core
Tablet
140.00 100.00 140.00 100.00
Punch dimension
7.00 mm, roundshaped punch, breakline on upper punch,
plain on lower punch
7.00 mm, round-shaped
punch, break-line on
upper punch, plain on
lower punch
Hardness (kP) 3.80-4.40 2.1-2.4
Thickness 3.80-3.90 3.70-3.80
Disintegration
(mm:ss)
03:00-04:20
04:00-06:00; DT
slightly increased.
Friablity Non-friable tablets Friability increased.
Process
1. Dexamethasone, mannitol, Eudragit EPO and optionally citric acid
monohydrate (batch F0116C) are added in the conveying zone of a Twin-screw
5 Extruder which is at a temperature of around 70-80°C;
2. The above ingredients are taken to a mixing / blending zone maintained at
around 110°C (first elevated temperature) and blended together;
3. The blend from step 2 is taken to a kneading and mixing zone maintained at
140°C (second elevated temperature) and kneaded during which melting /softening
10 of Eudragit EPO starts and further kneading commences granulation;
34
4. Granulate from step 3 is taken to another zone maintained at 110°C (third
elevated temperature) where molten Eudragit EPO starts solidification and mixing
in this zone produces cooled flakes/ rods/ granulate;
5. Cooled granulate from step 4 is taken to a conveying zone maintained at
5 80°C to cause further cooling / solidification of molten mass and taken out of a die
as extrudates or flakes or rods or dried granules.
6. Extrudes/ flakes/ rods/ granulates from step 5 are crushed/ milled / sifted to
required sizes. These granules are then blended with extragranular materials such
as diluent, disintegrant, glidant and lubricant to produce high dissolving granules
10 which are compressed into tablets.
Example 6B – In vitro release profile of batch with citric acid and comparison
with best mode batch F0106C.
Table 6B
15
40 mg strength
0.1N HCl 500 mL media using USP Type II- Paddle apparatus at 50 RPM
Time (minutes) F0106C F0116C
0 0 0
5 82 39
10 94 62
15 97 74
20 99 80
30 101 84
45 102 85
35
60 102 86
Batch F0116C which has citric acid does not enhance in vitro release profile over
optimized batch F0106C.
5 Example 7A: Optimization batches with additional solubilizing and stabilizing
agent Hydroxy propyl beta Cyclodextrin in addition to citric acid.
Table 7A
F0113A F0113C F0113B
Without HPBCD With HPBCD
HME Ingredients mg/tab % w/w mg/tab % w/w
DEX 40.00 40.00 40.00 26.31
Mannitol (Pearlitol
200 SD)
10.00 10.00 10.00 6.58
Eudragit EPO 40.00 40.00 40.00 26.31
Citric acid
monohydrate
10.00 10.00 10.00 6.58
Total Weight of
extrudes
100.00 - 100.00 -
Extragranular ingredients
HPBCD (Kleptose) - - 44.00 28.95
SSG - - 6.00 3.95
Magnesium
stearate
- - 2.00 1.31
Weight of
lubricated blend
blend of
F0113B
152.00 100.00
36
Total Weight of
Core Tablet
152.00
Disintegration
time (< 5 mins)
8 mins
Comments
Batch 113A was processed till stage of extrudates. This
was further lubricated adding HPBCD (kleptose), SSG
and magnesium stearate to produce blend 113B.
This blend is compressed to produce tablets 113C.
Process
1. Dexamethasone, mannitol, Eudragit EPO, and citric acid monohydrate are
added in the conveying zone of a Twin-screw Extruder which is at a temperature of
5 around 70-80°C;
2. The above ingredients are taken to a mixing / blending zone maintained at
around 110°C (first elevated temperature) and blended together;
3. The blend from step 2 is taken to a kneading and mixing zone maintained at
140°C (second elevated temperature) and kneaded during which melting /softening
10 of Eudragit EPO starts and further kneading commences granulation;
4. Granulate from step 3 is taken to another zone maintained at 110°C (third
elevated temperature) where molten Eudragit EPO starts solidification and mixing
in this zone produces cooled flakes/ rods/ granulate;
5. Cooled granulate from step 4 is taken to a conveying zone maintained at
15 80°C to cause further cooling / solidification of molten mass and taken out of a die
as extrudates or flakes or rods or dried granules.
6. Extrudes/ flakes/ rods/ granulates from step 5 are crushed/ milled / sifted to
required sizes. These granules are then blended with extragranular materials such
as disintegrant, glidant, lubricant and hydroxy propyl beta cyclodextrin (batch
20 F0113B) to produce high dissolving granules which are compressed into tablets.
Example 7B
37
Since tablets F0113C exhibited disintegration time higher than desired (desired DT
< 5 mins), granules for suspension 113A were directly subjected to In Vitro release
profile in 0.1 N HCl (OGD medium) and phosphate buffer of pH 6.8.
Table 7B
5
F0113A granules (40 mg) and F0113B lubricated blend
500 mL media using USP Type II- Paddle apparatus at 50 RPM
Time (minutes) 0.1N HCl pH 6.8 buffer
113 A 113A 113 B
0 0 0 0
5 68 52 61
10 72 53 66
15 74 53 68
20 76 54 70
30 79 55 73
45 81 56 75
60 83 56 77
Example 7C
Table 7C
10
40 mg strength
0.1N HCl 500 mL media using USP Type II- Paddle apparatus at 50 RPM
Time (minutes) F0113A F0113B
0 0 0
38
5 68 77
10 72 81
15 74 83
20 76 84
30 79 86
45 81 88
60 83 89
These granules did not release 85 % in 15 mins although release is 74 % in 15 mins
and hence comply with the first release criteria.
When granules of batch F0113A are blended with another solubility enhancer
5 hydroxy propyl beta cyclodextrin, sodium starch glycolate and magnesium stearate,
such batch F0113B exhibited better release releasing about 5 – 15 % higher than
release of granules of batch F0113A at each time point. Example 7C provides such
enhanced release.
10 Example 8A: Stability studies - In vitro release profile
Best mode batch F0106C was subjected to accelerated stability studies at 40°C and
75 % RH (accelerated conditions).
Samples initial, 1 month and 6 months accelerated conditions exhibited same in
vitro release profile in ODG medium as below:
15 Table 8A
F0106C (40 mg strength)
0.1N HCl 500 mL media using USP Type II- Paddle apparatus at 50 RPM
Time (minutes) Initial 1M 40°C/75% RH
6M 40°C/75%
RH
39
0 0 0 0
5 82 79 80
10 94 95 91
15 97 100 95
20 99 102 97
30 101 103 99
45 102 104 100
60 102 105 101
Recovery (%) 103 105 103
Assay (%) 102.10 102.60 102.24
Example 8B: Stability studies – Impurity profile
5 Impurities profiling of the F0106C batch
Table 8B
S.N.
Impurities
Name
Initial Results
(%)
1M 40°C/75%
RH (%)
3M
40°C/75%
RH (%)
6M
40°C/75%
RH (%)
1 Imp A 0.03 0.04 0.05 0.01
2 Imp J 0.10 0.08 0.08 0.19
3 Imp C 0.02 0.02 0.03 0.04
4 Imp D 0.01 0.01 0.04 0.10
5 Imp K 0.01 0.01 0.01 0.01
6 Imp E 0.00 0.01 ND 0.01
7 Imp F 0.17 0.15 0.16 0.27
8 Imp G 0.01 0.01 0.01 0.02
40
9
Single
maximum
unknown
impurity
0.05 0.03 0.05
0.03
10
Total
impurities
(allowed limit
is 2.0 %).
0.49 0.45 0.60
0.84
41
Failed batches
Following batches are not part of the invention namely examples 9, 10 and 11.
Example 9A: Comparative batches not part of invention – batches without holt
melt extrusion
5 Table 9A
Ingredients
Batch
F16
Batch
F17
Batch
F18
Batch
F19
Batch
F20
Dexamethasone 20 20 20 20 20
Mannitol - 20 20 20 10
PVPK12 - 10 - - 10
PEG 4000 - - 10 - -
MCC 102 - - - - 10
Sepitrap-80 8 - - - -
Lactose Monohydrate 39.3 14 15 24 14
Ac-di-sol 2 5 5 5 5
Magnesium Stearate 0.7 1 1 1 1
Avg. Weight 70 70 71 70 70
Process:
1. All ingredients except magnesium stearate are blended together in a blender
10 to prepare a blend.
2. The blend is blended with magnesium stearate to prepare lubricated blend.
3. Tablets are compressed at an avg wt. of 70 mg.
Example 9 B: % Cumulative release in 0.1N HCl (500 ml) using paddles (50
15 RPM) for batches without hot melt extrusion
Table 9B
42
Time in
minutes
% Cumulative release in 500 ml 0.1N HCl at 50 RPM
(paddles)
Batch F16 Batch F17 Batch F18 Batch F19 Batch F20
5 29 16.3 10.1 11.7 19.5
10 42 38.6 23.2 22.9 22.3
15 50 59.6 32.1 32.7 24.3
20 54 72.7 39.0 39.3 27.0
30 61 76.0 44.8 47.1 29.3
45 66 91.0 49.5 51.0 31.4
60 70 91.7 52.5 55.2 33.1
Batches 16 -20 prepared without hot melt extrusion failed in In Vitro release profile.
None of the batches could release 85 % in 15 mins. Batches 16 and 18 – 20 exhibited
incomplete release even at the end of 60 mins in OGD medium.
5
Example 10 : Batches with i) melting component 20 % of intragranular mass;
and ii) with 60 % melting component but without mannitol and without
sufficient binding.
Table 10
10
F0107C F0108C
HME Ingredients mg/tab % w/w mg/tab % w/w
DEX 40.00 40.00 40.00 28.57
Mannitol (Pearlitol
200 SD)
40.00 40.00 - -
Eudragit EPO 20.00 20.00 60.00 42.85
Total Weight of
extrudes
100.00 100.00 100.00 71.42
43
Observations
Batch discontinued due
to high torque
generated
Off-white color extrudes,
Extragranular ingredients
Lactose
monohydrate (Super
Tab 30 GR)
- - 28.00 20.00
Ac-Di-Sol - - 10.00 7.14
Magnesium stearate - - 2.00 1.43
Total Weight of
Core Tablet
100.00 100.00 140.00 100.00
Punch dimension Batch discontinued
7.00 mm, round-shaped
punch, break-line on upper
punch, plain on lower punch
Hardness (kP) NA 2.6-3.2
Thickness NA 3.85-3.92
Disintegration
(mm:ss)
NA 01:0-02:00
Friablity NA
Tablets with higher friability;
thus discontinued.
Process
1. Dexamethasone, mannitol, Eudragit EPO, and citric acid monohydrate are
added in the conveying zone of a Twin-screw Extruder which is at a temperature of
5 around 70-80°C;
2. The above ingredients are taken to a mixing / blending zone maintained at
around 110°C (first elevated temperature) and blended together;
3. The blend from step 2 is taken to a kneading and mixing zone maintained at
140°C (second elevated temperature) and kneaded during which melting /softening
10 of Eudragit EPO starts and further kneading commences granulation;
44
4. Granulate from step 3 is taken to another zone maintained at 110°C (third
elevated temperature) where molten Eudragit EPO starts solidification and mixing
in this zone produces cooled flakes/ rods/ granulate;
5. Cooled granulate from step 4 is taken to a conveying zone maintained at
5 80°C to cause further cooling / solidification of molten mass and taken out of a die
as extrudates or flakes or rods or dried granules.
6. Extrudes/ flakes/ rods/ granulates from step 5 are crushed/ milled / sifted to
required sizes. These granules are then blended with extragranular materials such
as disintegrant, glidant, lubricant and hydroxy propyl beta cyclodextrin (batch
10 F0113B) to produce high dissolving granules which are compressed into tablets.
Example 11A: Comparative batches with high amount of Eudragit EPO but
without holt melt extrusion
Table 11A
15
F0106G
Physical mixture
Ingredients mg/tab % w/w
DEX 40.00 28.57
Mannitol (Pearlitol 200 SD) 20.00 14.28
Eudragit EPO 40.00 28.57
Total Weight 100.00 71.42
Extragranular ingredients
Lactose monohydrate (Super Tab
30 GR)
28.00 20.00
Ac-Di-Sol 10.00 7.14
Magnesium stearate 2.00 1.43
Total Weight of Core Tablet 140.00 100.00
Punch dimension
7.00 mm, round-shaped punch, break-line
on upper punch, plain on lower punch
45
Hardness (kP) 2.9-4.4
Thickness 3.80-3.90
Disintegration(mm:ss) 04:30-05:10
Process:
1. Dexamethasone, mannitol and Eudragit EPO are blended.
5 2. Lactose, Ac-di-sol are added and blended again
3. Magnesium stearate is added and blended again.
Example 11B: Comparison of dissolution profile in acetate buffer of pH 4.5 of
10 F0106C (best mode batch 1) and Comparative example batch F0106G (without
hot melt extrusion).
Table 11B
40 mg strength
pH 4.5 acetate buffer 500 mL media using USP Type II- Paddle apparatus
at 50 RPM
Time (minutes) F0106C F0106G
0 0 0
5 48 62
10 68 65
15 82 66
20 93 67
30 97 67
45 101 67
60 102 68
Recovery 102 75
46
Example 12: Marketed Product Evaluation / RLD evaluation
Marketed product Hemady by Dexcel Pharma Technologies is procured and
subjected to various testing including in vitro release profile and to compare it with
5 development batches of Dexamethasone.
The dissolution conditions requirement by Office of Generic Drugs (OGD) are as
follows:
Table 12A
OGD recommended dissolution medium:
Drug Name Dosag
e form
USP
apparatu
s
Speed
(RPM
)
Mediu
m
Volum
e (mL)
Samplin
g points
(minutes
)
Dexamethason
e
Tablet II 50 0.1N
HCl 500
5, 10, 20,
30 , 45 &
60
minutes
10
Table 12B
Marketed / Brand product was evaluated for release profile in OGD media
Time (minutes)
HEMADY (20 mg)
A6070
HEMADY (2*20 mg)
A6070
0 0 0
5 64 71
10 88 86
15 93 90
20 95 91
30 97 93
45 97 94
60 97 94
Recovery 101 100
47
Claims
We claim
5 1. Dexamethasone composition comprising i) Dexamethasone from 20 to 40
%; and ii) a soluble and / or hydrophilic excipient which melts or softens at a
temperature lower than melting temperature of Dexamethasone to produce hot melt
extrudates.
2. The Dexamethasone composition as claimed in claim 1 comprising from 25
10 % - 40 % of Dexamethasone.
3. The Dexamethasone composition as claimed in claim 1 wherein said soluble
and / or hydrophilic excipient melts or softens at a temperature of at least 50°C
lower than the melting temperature of Dexamethasone.
4. The Dexamethasone composition as claimed in claim 1 free of binder.
15 5. The Dexamethasone composition as claimed in claim 1 comprising
dexamethasone extrudates from 50 – 99 %.
6. The Dexamethasone composition as claimed in claim 2 comprising
dexamethasone extrudates from 50 – 85 % and at least 15 % of extragranular
ingredients comprising one or more of diluent, disintegrant and lubricant.
20 7. The Dexamethasone composition as claimed in claim 6 where diluent is
lactose or mannitol.
8. The Dexamethasone composition as claimed in claim 6 where disintegrant
is selected from ac-di-sol and sodium starch glycolate.
9. The Dexamethasone composition as claimed in claim 6 where lubricant is
25 magnesium . stearate.
10. The Dexamethasone composition as claimed in claim 6 comprising from
about 20 – 34 % Dexamethasone, from 30 – 62 % soluble and / or hydrophilic
48
excipient, from 10 – 30 % diluent, from 5 – 10 % disintegrant and from 0.5 – 3 %
lubricant.
11. The Dexamethasone composition as claimed in claim 10 comprising from
about 25 – 30 % Dexamethasone, from 35 – 50 % soluble and / or hydrophilic
5 excipient, from 15 – 25 % diluent, from 5 – 10 % disintegrant and from 0.5 – 3 %
lubricant.
12. The Dexamethasone composition as claimed in claim 10 comprising from
about 27 – 30 % Dexamethasone, from 35 – 50 % soluble and / or hydrophilic
excipient, from 15 – 25 % diluent, from 5 – 10 % disintegrant and from 0.5 – 3 %
10 lubricant.
13. Soluble and / hydrophilic excipient from any of the preceding claims is
selected from the group consisting of mannitol, lactose, Eudragit EPO, polyethylene
glycol, PVP K-30,
14. The Dexamethasone composition as claimed in claim 1 selected from tablet,
15 granules, or powder for oral solution / suspension / for filling into capsule.
15. The Dexamethasone tablet composition as claimed in claim 14 selected
from immediate realease and fast disintegrating tablet.
16. Process of preparing Dexamethasone composition of claim 1 comprising
i) Adding dexamethasone, soluble and / or hydrophilic excipient in the
20 conveying zone of extruder maintained at specific temperature;
ii) Taking above ingredients from step i to mixing / blending zone
maintained at first elevated temperature and blending;
iii) Taking blend from step 2 to a kneading / mixing zone maintained at
second elevated temperature and kneading to commence granulation;
25 iv) Taking granulate from step iii to a zone for solidification maintained at
third elevated temperature to produce dried granulate;
v) Taking dried granulate from step 4 to conveying zone maintained at
lower temperature to cause further drying / solidification and taking
dried extrudates or dried granules out of die;
49
vi) Blending dried granules or extrudates with extragranular material
selected from diluent, disintegrant, lubricant and optionally one more
additional excipient and combination thereof;
vii) Optionally processing or filling or compressing or packaging blend of
5 step vi to produce composition selected from tablet, capsule, granules,
powder for solution or powder for suspension.
17. The process of preparing Dexamethasone composition as claimed in claim
16 wherein
i) First elevated temperature is 110°C + 20°C
10 ii) Second elevated temperature is 150°C + 30°C
iii) Third elevated temperature is 110°C + 20°C
iv) Conveying zone temperature is 80°C + 20°C
18. The process of preparing Dexamethasone composition as claimed in claim
15 16 wherein soluble and / hydrophilic excipient from any of the preceding claims is
selected from the group consisting of mannitol, lactose, Eudragit EPO, polyethylene
glycol, PVP K-30.
19. The process of preparing Dexamethasone composition as claimed in claim
16 wherein diluent is lactose or mannitol.
20 20. The process of preparing Dexamethasone composition as claimed in claim
16 wherein where disintegrant is selected from ac-di-sol and sodium starch
glycolate.
21. The process of preparing Dexamethasone composition as claimed in claim
16 wherein where lubricant is magnesium . stearate.
25 22. The process of preparing Dexamethasone composition as claimed in claim
16 wherein additional excipient is hydroxy propyl beta cyclodextrin.
23. High drug load Dexamethasone composition for Oral administration.