Field of the Invention
The present invention relates to enteric coated didanosine compositions having a subcoat
and process for preparation thereof. The compositions are useful against various retroviral
disorders, particularly HIV related infections.
Background of the Invention
Didanosine or 2', 3'-dideoxyinosine (ddl) is a synthetic purine nucleoside analogue active
against the Human Immunodeficiency Virus (HIV). Intracellularly, didanosine is converted by
cellular enzymes to the active metabolite, dideoxyadenosine S'-triphosphate.
Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse transcriptase both by
competing with the natural substrate, deoxyadenosine S'-triphosphate, and by its
incorporation into viral DNA causing termination of viral DMA chain elongation.
The various didanosine formulations available in the market include chewable/dispersible
buffered tablets, buffered powder for oral solution and enteric coated beadlets filled in
capsules.
Didanosine is unstable in acidic solutions. For example, at pH <3 and 37°C, 10% of
didanosine decomposes to hypoxanthine in less than 2 minutes.
The stability problem associated with acid sensitive compounds is recognized in the prior art,
which teaches enteric coated preparations to prepare stable formulations of these
compounds. One of the approaches utilized to prevent the incompatability of the acid
sensitive compound and the enteric coating material is the use of subcoat between the core
and the enteric coating.
The use of a subcoat between the alkaline core and the enteric coating is described in U.S.
Patent No. 5,225,202, wherein the core includes an acid sensitive drug such as didanosine,
an additional subcoat layer, which acts as a physical barrier between the core and outer
enteric coating layer, and thus prevents interaction of the acid sensitive drug and the acidic
enteric coat. The subcoat disclosed therein is made of water-soluble polymeric substances.
U.S. Patent Application No. 20010051188 teaches a pharmaceutical composition comprising
a core in the form of a spheronized beadlet and an enteric coating for said core, said core
comprising about 80% to about 100% by weight of an acid labile medicament which is 2',
dideoxyinosine, a disintegrant and a binder, said composition being devoid of protective coat
or subcoat between the core and the enteric coating.
It was observed that the presence of a subcoat between the core and the enteric coating
hinders the release of didanosine from the core. We have surprisingly found that
composition of didanosine with subcoat having comparable release profile to that of
didanosine formulations without subcoat can be prepared when the subcoat comprises of
polyvinyl alcohol.
Thus, the present invention relates to pharmaceutical compositions of didanosine comprising
a core, a subcoat comprising polyvinyl alcohol and an enteric coating. The compositions
have acceptable acid resistance and release profile.
Summary Of The Invention
According to one embodiment of the specification there is provided an enteric coated
didanosine composition comprising: a) a core comprising didanosine and optionally one
more pharmaceutically acceptable excipients; b) a subcoat surrounding the core, the
subcoat comprising polyvinyl alcohol and optionally one or more inert pharmaceutically
acceptable additives; and c) an enteric coating surrounding the subcoat.
According to another embodiment of the specification there is provided an enteric coated
didanosine composition comprising: a) a core comprising didanosine and optionally one or
more pharmaceutically acceptable excipients; b) a subcoat surrounding the core, the
subcoat comprising polyvinyl alcohol, xanthan gum, lecithin and optionally one or more inert
pharmaceutically acceptable additives; and c) an enteric coating surrounding the subcoat.
According to further embodiment of the specification there is provided a process for the
preparation of enteric coated didanosine composition, the process comprising the steps of a)
preparing a core comprising didanosine and optionally one or more pharmaceutically
acceptable excipients; b) coating the core obtained in step (a) with a subcoat comprising
polyvinyl alcohol and optionally one or more inert pharmaceutically acceptable additives, and
(c) coating the product of step (b) with an enteric coating.
According to still another embodiment of the specification there is provided a method of
treating one or more HIV infected patients in need thereof, the method comprising
administering an enteric coated didanosine composition comprising: a) a core comprising
didanosine and optionally one or more pharmaceutically acceptable excipients; b) a subcoat
surrounding the core, the subcoat comprising polyvinyl alcohol and optionally one or more
inert pharmaceutically acceptable additives; and c) an enteric coating surrounding the
subcoat.
Detailed Description of the Invention
The enteric coated didanosine composition comprises of a) a core comprising didanosine
and optionally one or more pharmaceutically acceptable excipients; b) a subcoat
surrounding the core, the subcoat comprising polyvinyl alcohol and optionally one or more
inert pharmaceutically acceptable additives; and c) an enteric coating surrounding the
subcoat.
The term "didanosine" as used herein and in the appended claims refers to didanosine or
pharmaceutically acceptable salts thereof.
The "core" as used herein refers to any structure that is enclosed or surrounded by a
subcoat. The core may be in the form of beadlets or pellets.
The "pharmaceutically acceptable excipients" may be selected from one or more of binders,
diluents, disintegrants, lubricants/glidants, solubilizers/wetting agents and such like.
Suitable binders include polymeric substances having sufficient elasticity and structural
stability as a film. Generally the binders may be selected from one or more of cellulose
derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose and
methylcellulose; gums such as xanthan gum, gum acacia and tragacanth; water-soluble
vinylpyrrolidone polymers such as polyvinylpyrrolidone and copolymer of vinylpyrrolidone
vinyl acetate; sugars such as sorbitol and mannitol.
Suitable diluents may be selected from one or more of sugars such as dextrose, glucose and
lactose; sugar alcohols such as sorbitol, xylitol and mannitol; cellulose derivatives such
powdered cellulose and microcrystalline cellulose; starches such as corn starch,
pregelatinized starch and maize starch.
Suitable disintegrants may be selected from one or more of sodium starch glycolate,
croscarmellose sodium, crospovidone and corn starch.
The lubricant/glidants may be selected from one or more of magnesium stearate, talc,
sodium stearyl fumarate, colloidal silicon dioxide and such like.
The solubilizers/wetting agents may be selected from one or more of sodium lauryl sulphate,
polysorbate 80 and such like
The term "subcoat" as used herein refers to the layer that separates the core from the
enteric coating. The subcoat rapidly dissolves upon or after contact with water. The subcoat
comprises polyvinyl alcohol and optionally one or more inert pharmaceutically acceptable
additives.
Polyvinyl alcohol is the film forming agent and has excellent moisture barrier properties.
The inert pharmaceutically acceptable additives include one or more of plasiticizers,
viscosity modifiers, flow aids and colorants.
Plasticizers may include one or more of lecithin, triethylcitrate, glyceryl triacetate, dibutyl
sebacate, diethyl phthalate, polyethylene glycol 400, glycerol and castor oil. Preferably
lecithin is used as a plasticizer. Lecithin, acts as a plasticizer by locking moisture in the
coating so that the coating stays flexible and not brittle.
The viscosity modifier may include one or more of xanthan gum, hydroxypropylmethylcellulose,
alginate, hydroxypropyl cellulose, natural gums, carboxymethylcellulose,
and such like. Preferably xanthan gum is used as a viscosity modifier.
The flow aid may be selected from one or more of talc, fumed silica, lactose and starch.
The colorant may be selected from one or more of any food approved colors, opacifiers, and
dyes. For example, these may be aluminum lakes, iron oxides, titanium dioxide, or natural
colors.
Opadry AMB (aqueous moisture barrier) developed by Colorcon comprising polyvinyl
alcohol, soya lecithin, xanthan gum, talc and titanium dioxide may be used as the subcoat
for didanosine composition.
The "enteric coating" as used herein refers to the layer that surrounds the subcoat. The
enteric coating comprises of enteric polymers, plasticizers, alkalizing agents and, optionally
inert excipients.
The enteric polymers may include one or more of cellulose acetate phthalate,
hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate,
carboxymethylethylcellulose, methacrylic acid methyl esters/methacrylic acid copolymers,
such as for example, compounds known under the tradenames of Eudragit NE30D, Eudragit
L, Eudragit S, Eudragit L 100 55, Eudragit L30 D 55 by Rohm Pharma and mixtures thereof.
In order to reduce the incompatibility between the acid labile didanosine in the core and the
enteric coating, the pH of the enteric coating polymer needs to be raised by using a suitable
alkalizing agent.
The term "alkalizing agent" refers to compounds which are added to the enteric coating to
raise the pH below the point where enteric integrity of the polymer could be lost. Thus they
decrease the instability problem when in contact with acid labile ingredients. The alkalizing
agent may be selected from one or more of sodium hydroxide, potassium hydroxide, calcium
hydroxide, magnesium hydroxide and ammonium hydroxide. Preferably , the alkalizing agent
is sodium hydroxide.
The enteric coating may also contain plasticizers such as triacetin, triethyl citrate, tributyl
sebecate, diethyl phthalate, polyethylene glycol; and inert excipients such as talc, titanium
dioxide, colloidal silicon dioxide, hydroxypropyl methylcellulose, crospovidone and such like.
The core may be in the form of pellets or beadlets, which may be prepared by conventional
processes known to a person skilled in the art, such as by extrusion/ spheronization or by
coating a pharmaceutically acceptable inert core with solution/suspension comprising
didanosine.
The process for the preparation of enteric coated didanosine composition comprises the
steps of a) preparing a core comprising didanosine and optionally one or more
pharmaceutically acceptable excipients; b) coating the core obtained in step (a) with a
subcoat comprising polyvinyl alcohol and optionally one or more inert pharmaceutically
acceptable additives, and (c) coating the product of step (b) with an enteric coating
The following non-limiting examples illustrate the enteric coated didanosine compositions
disclosed in various embodiments of the specification:
(Table Removed)
Manufacturing Process
A. Core pellets
1. Didanosine and Sodium Starch Glycolate were sifted through #18 BSS (850u) to
obtain a mixture.
2. The mixture of step (1) was mixed in a Rapid Mixer Granulator for 10 minutes to
obtain a blend.
3. The blend of step (2) was granulated in Rapid mixer granulator using Purified water
to obtain a wet mass.
4. The wet mass obtained in step (3) was extruded in the extruder fitted with 1.2 mm screen
so as to get extrudates.
5. The extrudates of step (4) were charged to the spheronizer and were operated to get
pellets.
6. The pellets of Step (5) were dried in a suitable drier at 60-70°C till Loss on drying of
pellets was NMT 1.5% w/w.
7. Fraction of pellets between #12 BSS (1405|j) and #18 BSS (850u) were taken for
enteric coating.
B. Enteric coating
8. Diethyl phthalate was added to purified water under mechanical stirring, followed by
methacrylic acid copolymer dispersion under mechanical stirring and was stirred for
15 minutes to obtain a dispersion.
9. 1 %w/v sodium hydroxide solution was added to above dispersion of step (8) and
was stirred for 15 minutes to adjust the pH to 5.0 ±0.1.
10. Talc was added to dispersion of step (9) and stirred for 5 minutes.
11. The pellets of step (7) were coated with dispersion of step (10) to achieve the desired
weight build up to obtain enteric coated pellets.
12. The enteric coated pellets of step (11) were dried at a product temperature of 30-
35°C for 5-10 minutes.
13. The pellets of step (12) were dried in a suitable drier at 35°C-40°C to maintain required
loss on drying of NMT 2.0%w/w
C. Lubrication
14. Fraction of dried enteric coated pellets of step (13) between #12 BSS (1405u) and
#18 BSS (850u) were taken for lubrication.
15. Talc and Colloidal Silicon Dioxide were passed through # 36 BSS (420u) on a
mechanical vibratory sifter and were mixed with the enteric coated pellets of step
(14) in a non-shear blender for 5 minutes.
D. Capsule Filling
16. Enteric coated pellets from step (15) were filled in hard gelatin capsules.
(Table Removed)

*Opadry AMB® is a registered product of Colorcon and contains polyvinyl alcohol, xanthan
gum, talc, titanium dioxide and lecithin
A. Core pellets
1. Didanosine and Sodium Starch Glycolate were sifted through #18 BSS (850u) to
obtain a mixture.
2. The mixture of step (1) was mixed in a Rapid Mixer Granulator for 10 minutes to
obtain a blend.
3. The blend of step (2) was granulated in Rapid mixer granulator using Purified water
to obtain a wet mass.
4. The wet mass obtained in step (3) was extruded in the extruder fitted with 1.2 mm screen
so as to get extrudates.
5. The extrudates of step (4) were charged to the spheronizer and were operated to get
pellets.
6. The pellets of Step (5) were dried in a suitable drier at 60-70°C till Loss on drying of
pellets was NMT 1.5% w/w.
7. Fraction of pellets between #12 BSS (1405u) and #18 BSS (850u) were taken for
sub coating.
B. Sub Coating
8. Polyvinyl alcohol/ opadry AMB was dispersed in purified water under mechanical
stirring to obtain a coating dispersion.
9. The core pellets of step (7) were coated with the dispersion of step (8) to achieve the
desired weight build up.
C. Enteric coating
10. Diethyl phthalate was added to purified water under mechanical stirring, followed by
methacrylic acid copolymer dispersion and was stirred for 15 minutes to obtain a
dispersion.
11. 1%w/v sodium hydroxide solution was added to above dispersion of step (10) and
was stirred for 15 minutes to adjust the pH to 5.0 ±0.1.
12. Talc was added to dispersion of step (11) and stirred for 5 minutes.
13. The sub coated pellets of didanosine of step (9) were coated with dispersion of step (12) to
achieve the desired weight build up to obtain enteric coated pellets.
14. The enteric coated pellets of step (13) were dried at a product temperature of 30-
35°C for 5-10 minutes.
15. The pellets of step (14) were dried in a suitable drier at 35°C-40°C to maintain required
loss on drying of NMT 2.0%w/w
D. Lubrication
16. Fraction of dried enteric coated pellets of step (15) between #12 BSS (1405u) and
#18 BSS (850u) were taken for lubrication.
17. Talc and Colloidal Silicon Dioxide were passed through # 36 BSS (420u) on a
mechanical vibratory sifter and were mixed with the enteric coated pellets of step
(16) in a non-shear blender for 5 minutes.
10
E. Capsule Filling
18. Enteric coated pellets from step (17) were filled in hard gelatin capsules.
Assay, Acid Resistance & Dissolution Profile of the above examples are given below:
Acid resistance test of the enteric-coated pellets in 1000ml 0.1 N HCI at 100rpm for
Dissolution profile in 1000ml 0.1 N HCI, at 100 rpm for 2hrs at 37°C±0.5°C using (Table Removed)

A. Core pellets
1. Didanosine and Sodium Starch Glycolate were sifted through #18 BSS (850u) to
obtain a mixture.
2. The mixture of step (1) was mixed in a Rapid Mixer Granulator for 10 minutes to
obtain a blend.
3. The blend of step (2) was granulated in Rapid mixer granulator using Purified water
to obtain a wet mass.
12
4. The wet mass obtained in step (3) was extruded in the extruder fitted with 1.2 mm screen
so as to get extrudates.
5. The extrudates of step (4) were charged to the spheronizer and were operated to get
pellets.
6. The pellets of Step (5) were dried in a suitable drier at 60-70°C till Loss on drying of
pellets was NMT 1.5% w/w.
7. Fraction of pellets between #12 BSS (1405u) and #18 BSS (850u) were taken for
sub coating.
B. Sub Coating
8. Ingredients 4-10 were dispersed in purified water under mechanical stirring to obtain
a coating dispersion.
9. The core pellets of step (7) were coated with the dispersion of step (8) to achieve the
desired weight build up.
C. Enteric coating
10. Diethyl phthalate was added to purified water under mechanical stirring, followed by
methacrylic acid copolymer dispersion under mechanical stirring and was stirred for
15 minutes to obtain a dispersion.
11.1 %w/v sodium hydroxide solution was added to above dispersion of step (10)
to adjust the pH to 5.0 ±0.1 and was stirred for 15 minutes .
12. Talc was added to dispersion of step (11) and stirred for 5 minutes.
13. The sub coated pellets of didanosine of step (9) were coated with dispersion of step (12) to
achieve the desired weight build up to obtain enteric coated pellets.
14. The enteric coated pellets of step (13) were dried at a product temperature of 30-
35°C for 5-10 minutes.
15. The pellets of step (14) were dried in a suitable drier at 35°C-40°C to maintain required
loss on drying of NMT 2.0%w/w
D. Lubrication
16. Fraction of dried enteric coated pellets of step (15) between #12 BSS (1405u) and
#18 BSS (850u) were taken for lubrication.
17. Talc and Colloidal Silicon Dioxide were passed through # 36 BSS (420u) on a
mechanical vibratory sifter and were mixed with the enteric coated pellets of step
(16) in a non-shear blender for 5 minutes.
E. Capsule Filling
18. Enteric coated pellets from step (17) were filled in hard gelatin capsules.
*0padry AMB is a registered product of Colorcon and contains polyvinyl alcohol, xanthan
gum, talc, titanium dioxide and lecithin
(Table Removed)

Manufacturing Process
A. Core pellets
1. Didanosine and Sodium Starch Glycolate were sifted through #18 BSS (850u) to
obtain a mixture.
2. The mixture of step (1) was mixed in a Rapid Mixer Granulator for 10 minutes to
obtain a blend.
3. The blend of step (2) was granulated in Rapid mixer granulator using Purified water
to obtain a wet mass.
4. The wet mass obtained in step (3) was extruded in the extruder fitted with 1.2 mm screen
so as to get extrudates.
5. The extrudates of step (4) were charged to the spheronizer and were operated to get
pellets.
6. The pellets of Step (5) were dried in a suitable drier at 60-70°C till Loss on drying of
pellets was NMT 1.5% w/w.
7. Fraction of pellets between #12 BSS (1405u) and #18 BSS (850u) were taken for
sub coating.
B. Sub Coating
8. Opadry AMB was dispersed in purified water under mechanical stirring to obtain a
coating dispersion.
9. The core pellets of step (7) were coated with the dispersion of step (8) to achieve the
desired weight build up.
C. Enteric coating
10. Diethyl phthalate was added to purified water under mechanical stirring, followed by
methacrylic acid copolymer dispersion under mechanical stirring and was stirred for
15 minutes to obtain a dispersion.
11. 1 %w/v sodium hydroxide solution was added to above dispersion of step (10)
to adjust the pH to 5.0 ±0.1 and was stirred for 15 minutes
12. Talc was added to dispersion of step (11) and stirred for 5 minutes.
13. The sub coated pellets of didanosine of step (9) were coated with dispersion of step (12) to
achieve the desired weight build up to obtain enteric coated pellets.
14. The enteric coated pellets of step (13) were dried at a product temperature of 30-
35°C for 5-10 minutes.
15. The pellets of step (14) were dried in a suitable drier at 35°C-40°C to maintain required
loss on drying of NMT 2.0%w/w
D. Lubrication
16. Fraction of dried enteric coated pellets of step (15) between #12 BSS (1405u) and
#18 BSS (850u) were taken for lubrication.
17. Talc and Colloidal Silicon Dioxide were passed through # 36 BSS (420u) on a
mechanical vibratory sifter and were mixed with the enteric coated pellets of step
(16) in a non-shear blender for 5 minutes.
E. Capsule Filling
18. Enteric coated pellets from step (17) were filled in hard gelatin capsules.
Assay, acid resistance and dissolution profile of the above examples is given below:
(Table Removed)

Comparative Examples 2, 3 & 4 showed lower acid resistance and a slower drug release in
direct pH 5.0 Acetate buffer when compared to Example 3 (subcoating with opadry AMB)
and comparative example 5 (without subcoat).

WE CLAIM:
1. An enteric coated didanosine composition comprising: a) a core comprising
didanosine and optionally one or more pharmaceutically acceptable excipients; b) a
subcoat surrounding the core, the subcoat comprising polyvinyl alcohol and
optionally one or more inert pharmaceutically acceptable additives; and c) an enteric
coating surrounding the subcoat.
2. The composition according to claim 1, wherein the one or more pharmaceutically
acceptable excipients are selected from one or more of binders, diluents, disintegrants,
lubricants and wetting agents.
3. The composition according to claim 2, wherein the binder is selected from one or
more of cellulose derivatives selected from hydroxypropylmethyl cellulose,
hydroxypropyl cellulose or methylcellulose; gums selected from xanthan gum, gum
acacia or tragacanth; water-soluble vinylpyrrolidone polymers selected from
polyvinylpyrrolidone or copolymer of vinylpyrrolidone vinyl acetate and sugars
selected from sorbitol or mannitol; the diluent is selected from one or more of sugars
selected from dextrose, glucose or lactose; sugar alcohols selected from sorbitol,
xylitol or mannitol; cellulose derivatives selected from powdered cellulose or
microcrystalline cellulose; and starches selected from corn starch, pregelatinized
starch or maize starch; the disintegrant is selected from one or more of sodium starch
glycolate, croscarmellose sodium, crospovidone and corn starch and the lubricant is
selected from one or more of magnesium stearate, talc, sodium stearyl fumarate and
colloidal silicon dioxide.
4. The composition according to claim 1, wherein the inert pharmaceutically acceptable
additives may be selected from one or more of plasticizers, viscosity modifiers, flow
aids and colorants.
5. The composition according to claim 4, wherein the plasticizer is selected from one or
more of lecithin, triethylcitrate, glyceryl triacetate, dibutyl sebacate, diethyl phthalate,
polyethylene glycol 400, glycerol and castor oil

6. The composition according to claim 4, wherein the viscosity modifier is selected from
one or more of xanthan gum, hydroxypropyl-methylcellulose, alginate, hydroxypropyl
cellulose, natural gums and carboxymethylcellulose.
7. The composition according to claim 4, wherein the flow aid is selected from one or
more of talc, fumed silica, lactose and starch.
8. The composition according to claim 1, wherein the subcoat comprises polyvinyl
alcohol, xanthan gum and lecithin.
9. A process for the preparation of enteric coated didanosine composition comprising the
steps of a) preparing a core comprising didanosine and optionally one or more
pharmaceutically acceptable excipients; b) coating the core obtained in step (a) with a
subcoat comprising polyvinyl alcohol and optionally one or more inert
pharmaceutically acceptable additives, and (c) coating the product of step (b) with an
enteric coating.
10. An enteric coated didanosine composition substantially described and exemplified
herein.