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 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 DMA causing termination of viral DNA 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 This patent teaches the use of buffering agents to minimize drug degradation in the core.
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.

Indian Application No. 979/DEL/2006, assigned to Ranbaxy Laboratories, discloses an enteric coated didanosine composition. The composition includes a core comprising didanosine, subcoat comprising polyvinyl alcohol, surrounding the core, and an enteric coating surrounding the subcoat.
PCT application WO06/054175 discloses stable didanosine compositions comprising a core containing didanosine, a seal coat on said core and an enteric coating on said seal coat. The core comprises sodium carboxymethyl cellulose as a binder.
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 hydroxypropyl methylcellulose.
It was further observed that by optimizing the enteric coating percentage in the composition, didanosine compositions having acceptable acid resistance and release profile could be obtained.
Thus, the present invention relates to pharmaceutical compositions of didanosine comprising a core, a subcoat comprising hydroxypropyl methylcellulose and an enteric coating. The core is free of binder or buffering agent. The compositions are stable and have acceptable acid resistance and release profile. Further, the compositions are easy and economical to manufacture.
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 or more pharmaceutically acceptable excipients; b) a subcoat surrounding the core, the subcoat comprising hydroxypropyl methylcellulose and optionally one or more inert pharmaceutically acceptable additives; and c) an enteric coating surrounding the subcoat; wherein the enteric coating ranges from 19 to 25% w/w of composition, and the core is free of binders or buffering agents.
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 hydroxypropyl methylcellulose and optionally one or more inert pharmaceutically acceptable additives; and c) an enteric coating surrounding the subcoat; wherein the enteric coating ranges from 22 to 24% w/w of composition, and the core is free of binders or buffering agents.
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 hydroxypropyl methylcellulose and optionally one or more inert pharmaceutically acceptable additives, and (c) coating the product of step (b) with an enteric coating; wherein the enteric coating ranges from 19 to 25% w/w of composition, and the core is free of binders or buffering agents.
Detailed Description of the Invention
The enteric coated didanosine composition comprises: a) a core comprising didanosine and optionally one or more pharmaceutically acceptable excipients; b) a subcoat surrounding the core, the subcoat comprising hydroxypropyl methylcellulose 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 diluents, disintegrants, lubricants/glidants, solubilizers/wetting agents and mixtures thereof.
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 mixtures thereof.
The "core" is free of any binder or buffering agent.
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 hydroxypropyl methylcellulose and optionally one or more inert pharmaceutically acceptable additives.
The inert pharmaceutically acceptable additives include one or more of plasiticizers, flow aids and colorants.
Plasticizers may include one or more of polyethylene glycol (PEG) 400, lecithin, triethylcitrate, glyceryl triacetate, dibutyl sebacate, diethyl phthalate, glycerol and castor oil. Preferably low molecular weight polyethylene glycols such as PEG 200, PEG 300, PEG 400 and PEG 600 are used as a plasticizer.
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.
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 coating constitutes 19 to 25% w/w of the composition; more preferably the enteric coating constitutes 22-24% w/w of the composition.
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 core is free of any buffering agents or binders.
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 hydroxypropylmethyl cellulose and optionally one or more inert pharmaceutically acceptable additives, and (c) coating the product of step (b) with an enteric coating.
According to one embodiment, the enteric coated composition is bioequivalent to the innovator formulation.
The term "innovator formulation" as used herein refers to capsule formulation of didanosine, commercially available in U.S under the trade name Videx® EC capsules, from Bristol Myers Squibb.
The following non-limiting examples illustrate the enteric coated didanosine compositions disclosed in various embodiments of the specification:

Examples 1-2

(Table Remove) 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. Ingredients 4-7 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 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.
Comparative Example 1 (without subcoat)

(Table Remove)anufacturing 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
enteric coating.
B. Enteric coating
8. Diethyl phthalate was added to purified water under mechanical stirring, followed by
methacrylic acid copolymer 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.
Assay, Acid Resistance & Dissolution Profile of the above examples are given below:
(Table Remove)Acid resistance test of the enteric-coated pellets in 1000ml 0.1N HCI at 100rpm for 120min.

Table 2
Dissolution profile in 1000ml 0.1N HCI, at 100 rpm for 2hrs at 37°C±0.5°C using USP type I method followed by pH 6.8 phosphate buffer.

(Table Remove)The above results show that sub coating with hydroxypropylmethyl cellulose does not delay the release of didanosine in pH 6.8 phosphate buffer. The drug release is comparable to that of the composition without subcoat (comparative example 1).
Bioequivalence results
Enteric coated Didanosine capsules of Example 1 was compared with Videx® EC capsules, from Bristol Myers Squibb under fasted condition. The results are given below:
: BE results of Example 1 Vs Videx EC capsules

As evident from the above data, enteric coated didanosine composition of Example 1, is bioequivalent to Videx® EC capsules.
(Table Remove): Stability data of Example 1
Stability studies of example 1 capsules were conducted for 3 months at 40°C/ 75% RH. The data shows that unknown impurity is below 0.1%w/w and also the Impurity A (Hypoxanthine) is within the specified limits, at 3M 40° C/75%RH conditions. This shows that the enteric coated composition is stable throughout the stability conditions.

(Table Remove)

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 hydroxypropyl methylcellulose and
optionally one or more inert pharmaceutically acceptable additives; and c) an enteric
coating surrounding the subcoat, wherein the enteric coating ranges from 19 to 25%
w/w of the composition, and the core is free of binders or buffering agents.
2. The composition according to claim 1, wherein the one or more pharmaceutically
acceptable excipients are selected from one or more of diluents, disintegrants and
lubricants.
3. The composition according to claim 2, 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, 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, flow aids and colorants.
5. The composition according to claim 4, wherein the plasticizer is selected from one or
more of polyethylene glycol 400, lecithin, triethylcitrate, glyceryl triacetate, dibutyl
sebacate, diethyl phthalate, glycerol and castor oil.
6. The composition according to claim 4, wherein the flow aid is selected from one or more
of talc, fumed silica, lactose and starch.
7. The composition according to claim 1, wherein the enteric coating ranges from 22-24%
w/w of the composition.

8. 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 hydroxypropyl methylcellulose and optionally one or more
inert pharmaceutically acceptable additives, and (c) coating the product of step (b) with
an enteric coating; wherein the enteric coating ranges from 19 to 25% w/w of the
composition, and the core is free of binders or buffering agents.
9. An enteric coated didanosine composition substantially described and exemplified
herein.