WO2006054175A2

WO2006054175A2 - Stable dosage forms of acid labile drug

Info

Publication number: WO2006054175A2
Application number: PCT/IB2005/003535
Authority: WO
Inventors: Sunil Jog Suresh; Pp Yahoo; Vishwanath Lalge Manohar; Premanand Puthli Shivanand; Meenakshisunderam Sivakumaran
Original assignee: Aurobindo Pharma Limited
Priority date: 2004-11-18
Filing date: 2005-11-18
Publication date: 2006-05-26
Also published as: WO2006054175A3

Abstract

A stable dosage forms of didanosine comprising a) core comprising didanosine and one or more pharmaceutically acceptable excipients and is free of buffering agents b) seal coat on the said core, which separates core containing drug and acidic enteric coat and c) an enteric coat on the said seal coat, wherein the amount of the drug present in the core constitutes more than 90% by weight of the core and more than 70% by total weight of the composition.

Description

STABLE DOSAGE FORMS OF ACID LABILE DRUG Field of the invention

The present invention relates to stable dosage forms of acid labile drug, which is sensitive to low pH environment. More particularly, the present invention relates to stable dosage forms of antiviral drug didanosine.

Further more, the invention also relates to a process for preparation of stable dosage forms of didanosine.

Background of the invention

Didanosine is a synthetic purine nucleoside of deoxyadenosine, active against the human immunodeficiency virus (HIV). Chemically, didanosine is

2\3'- dideoxyinosine and is also called as ddl. Didanosine is a white crystalline powder and is unstable in acidic solutions. At pH less than 3 and 37⁰C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes.

Didanosine activity, against HIV virus by inhibiting HTV replication, was first disclosed in US patent No. 4,861,759. Didanosine has become widely used as a component of the therapeutic cocktails for treating AIDS and is generally available in a variety of oral dosage forms, including Chewable/Dispersible Buffered Tablets, Buffered Powder for Oral Solution, Pediatric Powder for Oral Solution, and Delayed release capsules. Chewable/Dispersible Buffered tablet of ddl contains calcium carbonate and magnesium hydroxide as buffering agents and also other excipients such as aspartame, sorbitol, microcrystalline cellulose, Polyplasdone, mandarin-orange flavor, and magnesium stearate.

Buffered Powder for Oral Solution of ddl is supplied as single-dose packets containing citrate-phosphate buffer (composed of dibasic sodium phosphate, sodium citrate, and citric acid) and sucrose.

Didanosine Pediatric Powder for Oral Solution, which is, supplied for oral administration in 4 or 8 ounce glass bottles containing 2 or 4 grams of didanosine respectively, is to be mixed with commercial antacid before oral ingestion.

Didanosine degrades rapidly at acidic pH and hence, ddl in its chewable/dispersible tablet form and its buffered powder for oral solution form, contains buffering agents and is administered with antacids in the pediatric powder form. However, the presence of the large quantities of antacid components in the formulation can lead to significant GI imbalance as noted by severe diarrhea. Hence, there was a need to develop the formulation, which doesn't have these problems and subsequently, delayed release capsules have been developed.

Delayed release capsules of ddl being marketed in the US under the trademark of Videx EC^φ) contain enteric coated pellets of didanosine and the pellets also contain inactive ingredients.

There are few patents/publications which discloses enteric coated didanosine formulations, some of them are as given below:

U.S. Pat. No. 5,026,560 discloses pharmaceutical compositions and methods of making said pharmaceutical compositions, wherein the pharmaceutical composition comprises a Nonpareil seed core produced by coating sucrose with corn starch, spraying the core with an aqueous binder in a solution of water or ethanol and with a spraying powder containing acid labile benzimidazole derivatives and low substituted hydroxypropylcellulose, followed by the application of an enteric coating.

U.S. Pat. No. 5,225,202 discloses enteric-coated pharmaceutical compositions containing hydroxypropyl methylcellulose phthalate polymer (HPMCP) and a enteric polymer coating and the composition comprises a core with an acid labile medicament in an amount within the range of from about 1 to about 60% by weight of the composition, a disinlegrant, one or more buffering agents to provide added gastric protection in addition to the enteric coating, as well as the enteric coating and a plasticizer. US patent No. 6,224,910 and 6,607,747 discloses beadlets composition prepared by spheronization process. The process of spheronisation involves dry blending of active ingredient with the disintegrant like sodium starch glycolate and sodium carboxymethyl cellulose. A portion of this blend containing the active is kept aside for dusting during spheronization. The remaining blend is then granulated with water and this granulate is extruded followed by spheronization to form wet beadlets. During spheronization, the dry blend, which was previously set aside, was used to dust the wet beadlets to prevent beadlet agglomeration. The beadlets thus obtained are enteric coated with polymers. These enteric coated beadlets are further treated with antiadherents and plasticizers prior to filling into capsules.

US patent No. 6,331,316 and 6,569,457 discloses enteric coated composition which is devoid of a protective subcoat between the core and the enteric coating comprising: (a) a core in the form of a tablet consisting of an acid labile medicament, and optionally a binder, a lubricant, a disintegrant, and (b) an enteric coating surrounding said tablet, said enteric coating including an alkalizing agent.

WO 93/07859 discloses a method for producing drug loaded pellets through melt spheronization and pellets are coated with enteric coating.

. Most of the enteric coating materials known in the art are acidic in nature and hence, may cause chemical instability when in contact with acid labile active ingredients especially didanosine. This is especially true under high temperature and humid conditions experienced during an aqueous coating process. The inventors of the present invention found that a protective coat or subcoat between the core in the form- of particles, beadlets, pellets, tablet, and the enteric coat minimizes acid caused instability. This protective coat or seal coat physically separates didanosine from the acidic enteric coat, and hence improves stability of the formulation. Objective of the invention

Accordingly, the main objective of the present invention is to provide stable dosage forms of didanosine. Yet another objective of the present invention is to provide stable dosage forms of didanosine in such a way that it will comply with the reference product in terms of in vitro parameters like dissolution, disintegration, etc and in vivo parameters like bioequivalence.

Summary of the invention According to the main embodiment, the present invention provides stable dosage forms of didanosine comprising a) core comprising didanosine and one or more pharmaceutically acceptable excipients and is free of buffering agents b) seal coat on the said core, which separates core containing drug and acidic enteric coat and c) an enteric coat on the said seal coat, wherein the amount of the drug present in the core constitutes more than 90% by weight of the core and more than 70% by total weight of the composition.

Detailed description of the invention

In an embodiment of the present invention, the composition of core comprises didanosine and one or more pharmaceutically acceptable excipients such as diluents, binders, disintegrants, alkaline substances, antiadherants, and lubricants.

The core used according to the present invention may be pellets, beadlets or a tablet. Suitable diluents used according to the present invention are selected from microcrystalline cellulose, starch, sugar derivatives such as mannitol, lactose, sucrose and the like or a combination thereof.

Suitable binders used according to the present invention are selected from sodium alginate, povidone, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose; sodium carboxymethyl cellulose and the like or a combination thereof.

Suitable disintegrants used according to the present invention are selected from starch or cellulose derivatives like croscarmellose sodium, sodium starch glycolate, crospovidone, pregelatinized starch, cornstarch, sodium carboxymethyl cellulose and the like or a combination thereof.

Suitable antiadherents used according to the present invention are selected from talc, sodium lauryl sulfate, magnesium trisilicate, tribasic calcium phosphate and the like or a combination thereof. Suitable lubricants used according to the present invention are selected from talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, vegetable oil, sodium lauryl sulfate and the like or a combination thereof.

Suitable alkaline substances used according to the present invention are selected from sodium hydroxide, sodium bicarbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate and the like, or a combination thereof.

Seal coat or protective coat, which is applied on the core and is physically separate the core containing acid labile drug from the acidic enteric coat, and improve stability of the formulation. In yet another embodiment of the present invention, the seal coating composition comprises polymers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, xanthan gum or a combination there of.

The seal coating composition may further comprise plasticizer such as polyethylene glycol, dibutyl sebacate, diethyl phthalate, glycerin, glyceryl monostearate, propylene glycol, triacetin and triethyl citrate or a combination there of.

The seal coating composition may further comprise alkaline substances selected from sodium hydroxide, sodium bicarbonate,- magnesium oxide, magnesium hydroxide, magnesium carbonate and the like, or a combination thereof.

In yet another embodiment of the present invention, the enteric coating is applied onto the sub coat to delay the release of the drug from the dosage form and protect the acid labile didanosine and the composition comprises enteric polymers selected from cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polymethacrylates, polyvinylacetate phthalate, and acrylic polymers such as Eudragit and the like or a combination there of.

The enteric coating composition may further comprise one or more plasticizers, antiadherants and opacifiers.

Suitable opacifiers used according to the present invention are selected from titanium dioxide, or carnauba wax.

In yet another embodiment of the present invention, the pH of the enteric coating composition may optionally be adjusted using alkaline substances such as sodium hydroxide, magnesium hydroxide, or sodium bicarbonate.

The stable dosage forms according to the present invention may be in the form of tablets or capsules.

In another embodiment of the present invention there is provide process for the preparation of stable dosage form comprising- didanosine enteric coated pellets, where in the process comprises:

1) sifting and blending didanosine and excipients,

T) wet granulating above blend, and extruding through a gravity fed and /or twin-screw extruder,

3) spheronizing the extmdates in a spheronizer at a desired RPM, and drying to obtain beadlets or pellets,

4) sieving the beadlets or pellets through suitable sieves to remove fines,

5) applying seal coat on the beadlets or pellets in a fluid bed processor, 6) enteric-coating the seal coated pellets or beadlets using enteric coat polymers and

7) blending the enteric-coated pellets with an antiadherant and filling into capsules or compressed into tablets. In yet another embodiment of the present invention, the process for the preparing beadlet or pellets does not contain step of dusting the blend of drug and excipient during spheronization.

In yet another embodiment of the present invention, there is provide process for the preparation of stable dosage form comprising enteric coated pellets of didanosine, where in the process comprises:

1) sifting and blending didanosine and excipients,

2) preparing a suspension or solution of drug with excipients,

3) applying the suspension or solution of step (2) on nonpareil seeds to obtain drug coated pellets and 4) applying seal coat and enteric coat as described in the above process.

The stable dosage forms of the present invention provides excellent protection in acidic environments (pH<3) while not delaying the rapid release in regions of pH greater than 4. The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example 1

Example 2

The processing steps involved in the preparation of enteric coated pellets of didanosine as disclosed in examples 1 and 2 are : 1) sifted and blended didanosine, sodium starch glycolate, and purified talc individually in rapid mixer granulator,

2) granulated the blend of step 1, using a aqueous solution of sodium carboxy methyl cellulose,

3) extruded the granulated mass of step 2, through a gravity fed and /or twin- screw extruder,

4) spheronized the extrudates of step 3, in spheronizer at a desired RPM,

5) dried the spheronized mass of step 4, to obtain beadlets or pellets,

6) seal coated the beadlets or pellets of step 5, with a sealing agent composition in a fluid bed processor, 7) enteric coated the seal coated pellets of step 6, using enteric coating composition, and

8) enteric coated pellets are then lubricated with talc and filled into capsules or compressed into tablets.

Dissolution profile:

The enteric coated capsules were tested for drug release in pH 0.1N HCl for first two hours followed by pH 6.8 phosphate buffer media using USP apparatus 1 with basket speed at 100 rpm. The samples of the media were periodically withdrawn and spectrophotometrically analyzed for didanosine content. The dissolution results are given in Table 1. Table 1

Claims

Claims:

1. Stable dosage forms of didanosine comprising a) core comprising didanosine and one or more pharmaceutically acceptable excipients and is free of buffering agents b) seal coat on the said core, which separates core containing drug and acidic enteric coat and c) an enteric coat on the said seal coat, wherein the amount of the drug present in the core constitutes more than 90% by weight of the core and more than 70% by total weight of the composition.

2. The stable dosage form as claimed in claim 1, wherein the core is in the form of pellets, beadlets or tablet.

3. The core as claimed in claim 2, comprises one ore more pharmaceutically acceptable excipient selected from diluents, binders, disintegrants, alkaline substances, antiadherants, and lubricants.

4. The core as claimed in claim 3, wherein the diluent is selected from microcrystalline cellulose, starch, and sugar derivatives such as mannitol, lactose, sucrose or a combination thereof.

5. The core as claimed in claim 3, wherein the disintegrants is selected from croscarmellose sodium, sodium starch glycolate, crospovidone, pregelatinized starch, cornstarch and sodium carboxymethyl cellulose or a combination thereof.

6. The core as claimed in claim 3, wherein the binder is selected from sodium alginate, povidone, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, and sodium carboxymethyl cellulose or a combination thereof.

7. The core as claimed in claim 3, wherein the antiadherent is selected from talc, sodium lauryl sulfate, magnesium trisilicate and tribasic calcium phosphate or a combination thereof.

8. The core as claimed in claim 3, wherein the lubricant is selected from talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, vegetable oil, and sodium lauryl sulfate or a combination thereof.

9. The seal coat as claimed in claim 1, comprise polymer selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose and xanthan gum or a combination there of.

10. The seal coat as claimed in claim 9, further comprises plasticizer.

1 1. The enteric coat as claimed in claim 1, comprise enteric polymer and one or more plasticizers, antiadherants, and opacifiers.

12. The enteric polymer as claimed in claim 11, is selected from cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polymethacrylates, polyvinylacetate phthalate, and acrylic polymers such as Eudragit or a combination there of.

13. The opacifier as claimed in claim 11, is selected from titanium dioxide, or carnauba wax.

14. The antiadherent as claimed in claim 1 1, is selected from talc, sodium lauryl sulfate, magnesium trisilicate and tribasic calcium phosphate or a combination thereof.

15. The plasticizer as claimed in claims 10 and 11, is selected from polyethylene glycol, dibutyl sebacate, diethyl phthalate, glycerin, glyceryl monostearate, propylene glycol, triacetin and triethyl citrate or a combination there of.

16. The enteric coat as claimed in claim 11, further comprise alkaline substances such as sodium hydroxide, magnesium hydroxide, and sodium bicarbonate to adjust pH of the enteric composition.

17. The dosage forms as claimed in claim 1, in the form of a tablet or capsule.

18. A process for the preparation of stable dosage forms of didanosine comprising a) core comprising Didanosine and one or more pharmaceutically acceptable excipients and is free of buffering agents b) seal coat on the said core, which separates core containing drug and acidic enteric coat and c) an enteric coat on the said seal coat, wherein the amount of the drug present in the core constitutes more than 90% by weight of the core and more than 70% by total weight of the composition, which comprises: i) sifting and blending didanosine and excipients, ii) wet granulating above blend, and extruding through a gravity fed and /or twin-screw extruder, iii) spheronizing the extrudates in a spheronizer at a desired RPM, and drying Io obtain beadlets or pellets, iv) sieving the beadlets or pellets through suitable sieves to remove Fines, v) applying seal coat on the beadlets or pellets in a fluid bed processor, enteric-coating the seal coated pellets or beadlets using enteric coat polymers and vi) blending the enteric-coated pellets with an antiadherant and filling into capsules or compressed into tablets.

19. A process for the preparation of stable dosage forms of didanosine comprising a) core comprising didanosine and one or more pharmaceutically acceptable excipients and is free of buffering agents b) seal coat on the said core, which separates core containing drug and acidic enteric coat and c) an enteric coat on the said seal coat, wherein the amount of the drug present in the core constitutes more than 90% by weight of the core and more than 70% by total weight of the composition, which comprises: i) sifting and blending didanosine and excipients, ii) preparing a suspension or solution of drug with excipients, iii) applying the suspension or solution of step (2) on nonpareil seeds to obtain drug coated pellets and iv) applying seal coat and enteric coat as claimed in claim 18.