Field of the Invention
The present invention relates to high drug load enteric coated pharmaceutical
compositions of didanosine 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). lntracellularly, didanosine is
converted by cellular enzymes to the active metabolite, dideoxyadenosine 5'triphosphate.
Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse
transcriptase both by competing with the natural substrate, deoxyadenosine 5'triphosphate,
and by its incorporation into viral DNA causing termination of viral DNA
chain elongation.
Didanosine is unstable in acidic solutions. For example, at pH <3 and 3rC, 10% of
didanosine decomposes to hypoxanthine in less than 2 minutes. The various
formulations containing didanosine available in the market include chewable/dispersible
buffered tablets, buffered powder for oral solution and enteric coated beadlets filled in
capsules.
The dose of didanosine is very high i.e., 400mg or 250 mg once daily. Thus it would be
desirable to prepare high drug load didanosine compositions for increased patient
acceptance.
Prior art teaches extrusion and spheronization methods to obtain high drug load
pellets.
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', 3'-dideoxyinosine, a disintegrant and a binder, said
composition being devoid of protective coat or subcoat between the core and the
enteric coating.
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U.S. Patent No. 6224910 discloses a process for the preparation of a high drug load
enteric coated pharmaceutical composition of didanosine comprising the steps of:
(a) preparing a dry blend comprising a medicament, a binder, and a disintegrant, and
setting a portion of said dry blend aside; (b) forming a wet mass from the remainder of
said dry blend not set aside in step (a); (c) extruding said wet mass to form an
extrudate and spheronizing said extrudate into high-potency beadlets by dusting said
wet mass extrudate with said portion of said dry blend set aside in step (a); (d) coating
said beadlets with an enteric coating polymer and plasticizer in an aqueous media; and
(e) blending said coated beadlets with an anti-adherent, wherein the process further
comprising the step of separating said spheronized high potency beadlets formed in
step c into 10/18 mesh sized bead lets prior to said coating step (d).
The extrusion /spheronization process is relatively complex and has the disadvantage
of forming pellets with non-uniform shape and widened particle size distribution,
particularly for high drug loaded pellets. Further, these non-uniform pellets are
considered difficult to be provided with a uniform coating, resulting in difficulties in the
manufacture of enteric coated pellets with adequate acid resistance.
Therefore there is a need to prepare uniform shaped high drug load beadlets, for acid
labile drugs, such as didanosine, using simple process like drug layering, wherein the
high drug load bead lets can be further enteric coated.
Thus, the present invention relates to high drug load enteric coated pharmaceutical
compositions of didanosine. The compositions have comparable acid resistance, have
enhanced uniformity of shape and are prepared by a relatively simple process when
compared to prior art compositions.
Summary Of The Invention
According to one embodiment of the specification there is provided a high drug load
enteric coated pharmaceutical composition comprising a core, and an enteric coating
surrounding the core, the core comprising; a) an inert nucleus, and b) a drug layer
surrounding the inert nucleus, the drug layer comprising didanosine and, optionally, one
or more pharmaceutically acceptable excipients.
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According to another embodiment of the specification there is provided a high drug load
enteric coated pharmaceutical composition comprising a core and an enteric coating
surrounding the core, the core comprising; a) an inert nucleus, and b) a drug layer
surrounding the inert nucleus, the drug layer comprising didanosine in an amount of 65
to 95% by weight of the core and, optionally one or more pharmaceutically acceptable
excipients.
According to further embodiment of the specification there is provided a process for the
preparation of a high drug load enteric coated pharmaceutical composition, the process
comprising the steps of; a) preparing a core by coating a drug layer comprising
didanosine in an amount of 65 to 95% by weight of the core, and optionally, one or
more pharmaceutically acceptable excipients onto an inert nucleus, and b) coating the
core of step a) 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 the high drug load enteric coated pharmaceutical compositions of
didanosine disclosed in various embodiments.
Detailed Description of the Invention
The high drug load enteric coated pharmaceutical composition of didanosine comprises
a core, and an enteric coating surrounding the core. The core comprises didanosine in
an amount of 65-95%, more preferably 70-90% by weight of the core.
The term "didanosine" as used herein and in the appended claims refers to didanosine
or salts thereof.
The "core" as used herein refers to any structure that is enclosed or surrounded by an
enteric coating. The core may be in the form of beadlets.
The " inert nucleus" includes sugar spheres, microcrystalline cellulose beads, starch
beads or any combinations thereof. The inert nucleus is enclosed or surrounded by a
drug layer containing didanosine and, optionally, one or more pharmaceutically
acceptable excipients. The pharmaceutically acceptable excipients may be selected
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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 as 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 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 trademarks of Eudragit
NE30D, Eudragit L, Eudragit S, Eudragit L 100 55, Eudragit L30 D 55 by Rohm Pharma
and mixtures thereof.
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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 optionally include a separating layer surrounding the drug layer to
prevent the contact of the acid labile drug and the enteric coating. The separating layer
is made up of water soluble polymers which is capable of dissolving upon or after
contact with water. The water soluble polymers may be selected from one or more of
hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, sodium
carboxymethylcellullose and the like. In the case when a separating layer is included,
the use of alkalizing agent in the enteric coating may be optional.
The process for the preparation of a high drug load enteric coated pharmaceutical
composition comprises the steps of; a) preparing a core by coating a drug layer
comprising didanosine in an amount of 65 to 95% by weight of the core, and optionally,
one or more pharmaceutically acceptable excipients onto an inert nucleus, and b)
coating the core of step a) with an enteric coating.
The inert nucleus is placed in a conventional coating pan, fluidized bed or wurster
coater and then solution/suspension of didanosine along with pharmaceutically
acceptable excipients is sprayed onto the inert nucleus to obtain core beadlets.
Alternatively, the core beadlets may be prepared using powder layering process.
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Enteric coating is applied onto the core beadlets using a suitable coating technique
such as pan coating or fluidized bed coating. The enteric coating layer material may be
dispersed or dissolved in either water or in suitable organic solvents or a combination
thereof or alternatively latex suspensions of the polymers may be used.
The following non-limiting example illustrates the high drug load enteric coated
pharmaceutical composition disclosed in various embodiments of the specification.
Example 1
Quantity (mg/capsules)
125mg 200mg 250mg 400mg
Core beadlets
1.0 Sugar spheres 15.625 25.000 31.250 50.000
(#35-40)
2.0 Didanosine 125.000 200.000 250.000 400.000
3.0 Hydroxypropyl 5.3125 8.500 10.625 17.000
cellulose (HPC-L)
4.0 Hydroxy propyl 7.1875 11.500 14.375 23.000
methyl cellulose
5.0 Purified water gs qs _gs _gs
Enteric coating
6.0 Methacrylic Acid 129.6875 207.500 259.375 415.000
Copolymer
Dispersion 38.90625 62.250 77.8125 124.500
(Eudragit L300 55)
e.q. to dry polymer
7.0 Triacetin 3.28125 5.250 6.5625 10.50
8.0 Triethyl citrate 3.750 6.000 7.500 12.000
9.0 Sodium hydroxide qs qs qs qs
10.0 Purified water qs qs qs qs
Lubrication
11.0 Talc 0.750 1.200 1.500 2.400
12.0 Colloidal silicon 0.21875 0.350 0.4375 0.700
dioxide
Weight of beadlets 200.000 320.000 400.000 640.000
Manufacturing Process
A. Core Beadlets
1. Sugar spheres were sifted through # 35ASTM and # 40 ASTM on a mechanical
sifter and the fraction retained between #35-40 was collected.
2. Hydroxypropyl cellulose and hydroxypropylmethylcellulose were sifted through #
30888 on a mechanical sifter.
3. The material of step (2) was dispersed in purified water under mechanical stirring to
obtain dispersion.
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4. Didanosine was sifted through # 30BSS on a mechanical sifter.
5. Didanosine of step (4) was added into dispersion of step (3) under mechanical
stirring to form a uniform dispersion.
6. Sugar spheres of step (1) were loaded into Wurster coater and were spray coated
with dispersion of step (5) to obtain core beadlets.
B. Enteric Coating
7. Tri ethyl citrate and Triacetin were dissolved in purified water under mechanical
stirring.
8. Dispersion of step (7) was added into methacrylic acid copolymer dispersion under
mechanical stirring for 20-30 min.
9. 1% w/v sodium hydroxide solution was added to above dispersion of step (8) and
stirred for 15 min to adjust the pH.
10. The core bead lets of step (6) were coated with dispersion of step (9) to obtain
enteric coated beadlets.
11. The enteric coated beadlets were dried at a product temperature of 30-35°C for 5-
1 Ominutes in fluid bed coater.
12. The enteric coated beadlets of step (11) were dried in a suitable drier at 35-40°C to
maintain required LOD.
C. Lubrication
13. Talc and Colloidal silicon dioxide were passed through #36 BSS on mechanical
vibrator sifter.
14. The dried enteric coated beadlets of step (12) were lubricated with the material of
step (13).
Acid resistance test of the enteric-coated beadlets was performed using USP-1
apparatus; 1 OOrpm in 1 OOOml of 0.1 N HCI for 2hrs. The result is given in the following
table:
Acid resistance
99%
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Example 2
S.No. Ingredients Quantity
(mg/capsule
)
Core beadlets
1.0 Sugar spheres 50.0
(#35-40)
2.0 Didanosine 400.0
3.0 Hydroxypropyl cellulose (HPC-L) 17.0
4.0 Hydroxy propyl methyl cellulose 23.0
5.0 Purified water qs
Separating layer
6.0 Hydroxy propyl methyl cellulose 18.9
7.0 Polyethylene glycol-400 1.9
8.0 Talc 3.7
9.0 Purified water _gs
Enteric coating
10.0 Methacrylic Acid Copolymer 415.0
dispersion
(Eudragit L30D 55) e.q. to dry 124.5
polymer
11.0 Triacetin 10.5
12.0 Triethyl citrate 12.0
13.0 Purified water qs
Lubrication
14.0 Talc 2.4
15.0 Colloidal silicone dioxide 0.7
Weight of Bead lets 664.5
Manufacturing Process
A. Core Beadlets
1. Sugar spheres were sifted through # 35ASTM and # 40 ASTM on a mechanical
sifter and the fraction retained between #35-40 was collected.
2. Hydroxypropyl cellulose and hydroxypropylmethylcellulose were sifted through #
30BSS on a mechanical sifter.
3. The material of step (2) was dispersed in purified water under mechanical stirring to
obtain dispersion.
4. Didanosine was sifted through # 30BSS on a mechanical sifter.
5. Didanosine of step (4) was added into dispersion of step (3) under mechanical
stirring to form a uniform dispersion.
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6. Sugar spheres of step (1) were loaded into Wurster coater and were spray coated
with dispersion of step (5) to obtain core beadlets.
B. Separating Layer
7. Polyethylene glycol was dissolved in purified water under mechanical stirring to
obtain a solution.
8. Hydroxy propyl methyl cellulose was slowly added to solution of step (7) under
mechanical stirring, to prevent lump formation and was further stirred for 20-30 min.
9. Talc was added to the above solution and stirred for Smin to obtain a uniform
dispersion.
10. The core bead lets obtained in step (6) were coated with dispersion of step (9) to
obtain subcoated bead lets, using bottom spray fluid bed coater.
11. The subcoated bead lets obtained in step (1 0) were dried at a product temperature
of 40°C for 5-10 min.
C. Enteric Coating
12. Triethyl citrate and Triacetin were dissolved in purified water under mechanical
stirring.
13. Dispersion of step (12) was added into methacrylic acid copolymer dispersion
under mechanical stirring for 20-30 min.
14. The subcoated beadlets of step (11) were coated with dispersion of step (13) to
obtain enteric coated bead lets, using bottom spray fluid bed coater.
15. The enteric-coated beadlets were dried at a product temperature of 30-35°C for 5-
1 Ominutes in fluid bed coater.
16. The enteric coated beadlets of step (15) were dried in a suitable drier at 35-40°C to
maintain required LOD.
17. Talc and Colloidal silicon dioxide were passed through #36 BSS on mechanical
vibrator sifter.
18. The dried enteric coated beadlets of step (16) were lubricated with the material of
step (17).

WE CLAIM:
1. A high drug load enteric coated pharmaceutical composition of didanosine
comprising a core, and an enteric coating surrounding the core, the core
comprising; a) an inert nucleus, and b) a drug layer surrounding the inert
nucleus,· the drug layer comprising didanosine and, optionally, one or more
pharmaceutically acceptable excipients.
2. A high drug load enteric coated pharmaceutical composition of didanosine
comprising a core and an enteric coating surrounding the core, the core
comprising; a) an inert nucleus, and b) a drug layer surrounding the inert
nucleus, the drug layer comprising didanosine in an amount of 65 to 95% by
weight of the core and, optionally one or more pharmaceutically acceptable
excipients.
3. The composition according to any of the claims 1 & 2, wherein the one or more
pharmaceutically acceptable excipients are selected from one or more of
binders, diluents, disintegrants, lubricants and wetting agents.
4. The composition according to claim 3, 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.
5. The composition according to claim 3, wherein 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.
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6. The composition according to claim 3, wherein the disintegrant is selected from
one or more of sodium starch glycolate, croscarmellose sodium, crospovidone
and corn starch.
7. The composition according to claim 3, wherein the lubricant is selected from one
or more of magnesium stearate, talc, sodium stearyl fumarate and colloidal
silicon dioxide.
8. The composition according to any of the claims 1 & 2, wherein the enteric
co'ating comprises an alkalizing agent selected from one or more of sodium
hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide and
ammonium hydroxide.
9. The composition according to any of the claims 1 & 2, further comprising a
separating layer surrounding the drug layer.
10. A process for preparing a high drug load enteric coated pharmaceutical
composition of didanosine, the process comprising the steps of; a) preparing a
core by coating a drug layer comprising didanosine in an amount of 65 to 95%
by weight of the core, and optionally, one or more pharmaceutically acceptable
excipients onto an inert nucleus, and b) coating the core of step a) with an
enteric coating.
11. The process according to claim 10, wherein the core of step a) is coated with a
separating layer before the enteric coating.
12. A method of treating one or more HIV infected patients in need thereof, the
method comprising administering a high drug load enteric coated pharmaceutical
composition of didanosine comprising a core, and an enteric coating surrounding
the core, the core comprising; a) an inert nucleus, and b) a drug layer
surrounding the inert nucleus, the drug layer comprising didanosine and,
optionally, one or more pharmaceutically acceptable excipients.
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13. A high drug load enteric coated pharmaceutical composition of didanosine
substantially described and exemplified herein.