WO2008015686A1 - Stable multiparticulate formulations of didanosine - Google Patents

Stable multiparticulate formulations of didanosine Download PDF

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Publication number
WO2008015686A1
WO2008015686A1 PCT/IN2006/000272 IN2006000272W WO2008015686A1 WO 2008015686 A1 WO2008015686 A1 WO 2008015686A1 IN 2006000272 W IN2006000272 W IN 2006000272W WO 2008015686 A1 WO2008015686 A1 WO 2008015686A1
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WIPO (PCT)
Prior art keywords
composition
range
pharmaceutical composition
didanosine
weight
Prior art date
Application number
PCT/IN2006/000272
Other languages
French (fr)
Inventor
Bandi Parthasaradhi Reddy
Swarnkar Ramesh Kumar
Pothireddy Venkateswar Reddy
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Hetero Drugs Limited
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Priority to PCT/IN2006/000272 priority Critical patent/WO2008015686A1/en
Publication of WO2008015686A1 publication Critical patent/WO2008015686A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention produces a stable muliparticulate fast dispersing didanosine formulation when exposed to high pH 6 and above and also reduced inter and intra variability.
  • Didanosine multiparticulate formulation is composed of a spheroid core comprising of didanosine, disintegrant, binding agent and about 1-2% w/w water. Multiparticulate formulations, because of the advantage of tendency of dispersing gastro intestinal tract, which also shows very less effect of food and it provides reduced inter and intra subject variability.
  • European Patent No. EP 206497 disclosed certain 2',3'-dideoxy- nucleosides, pharmaceutically acceptable derivatives thereof, and their use in therapy, particularly for the treatment or prophylaxis of certain viral infections. These compounds are antiviral agents. Among them didanosine, chemically 2',3'-dideoxyinosine is a selective HIV-I inhibitor and can be used as medicaments in the treatment and prophylaxis of viral, especially retroviral infections. Didanosine is represented by the following structure:
  • Didanosine also known as ddl, and marketed by Bristol-Myers Squibb
  • the 759 patent also disclosed the oral administration of these dideoxy purine nucleosides in the form of liquids or tablets containing antacid buffering agents so that the pH of the resultant composition is in the neutral (pH 6 - 8) range.
  • an oral gavage formulation containing 0.1 N acetate buffer with a pH of 6.8 to 7.2.
  • Didanosine is commercially available in a variety of oral dosages, including chewable/dispersible buffered tablets in strengths of 25, 50, 100 or 150 mg of didanosine, buffered powder for oral solution, pediatric powder for oral solution, and delayed release capsules.
  • Chewable/dispersible buffered tablet of didanosine 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.
  • Enteric coatings have been used for many years to arrest the release of the drug from orally ingestible dosage forms. Depending upon the composition and/or thickness, the enteric coatings are resistant to stomach acid for required periods of time before they begin to disintegrate and permit slow release of the drug in the lower stomach or upper part of the small intestines. Numerous enteric coated and/or extended release pharmaceutical compositions comprising a core in the form of a tablet, beadlet, pellet or particle, and the methods of making these compositions have been disclosed in the art.
  • U.S. Patent No. 5,026,560 discloses a pharmaceutical composition and method of making said pharmaceutical composition, 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 a drug and low substituted hydroxypropylcellulose, followed by the application of an enteric coating.
  • U.S. Patent No. 5,225,202 discloses enteric coated pharmaceutical compositions utilizing neutralized hydroxypropyl methylcellulose phthalate polymer (HPMCP) coating and the composition comprises an acid labile medicament core, a disi ⁇ tegrant, 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.
  • HPMCP neutralized hydroxypropyl methylcellulose phthalate polymer
  • U.S. Patent No. 6,224,910 and 6,607,747 discloses beadlets composition prepared by spheronization process.
  • the process of spheronization involves dry blending of medicament with the disintegrant like sodium starch glycolate and sodium carboxymethyl cellulose. A portion of this blend containing the medicament 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.
  • 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.
  • enteric coated beadlets are further treated with antiadherents and plasticizers prior to filling into capsules.
  • U.S. 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.
  • enteric coated composition which is devoid of a protective coat or subcoat between the core and the enteric coating 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.
  • the present formulation is Multi particulate formulation with a different composition. In this Process purified water is added in larger quantity than that of used in the prior art and this process of invention avoids the dusting step.
  • This product has showed unique resistance to disintegration at pH less than 4 and has tendency of dispersing gastro intestinal tract and the release of the drug is faster than the products obtained by the prior art process.
  • This process utilizes low shear during granulation and low temperature during drying for preparation of the multiparticulate. This process contributes to the stability of the core of the multiparticulates.
  • Multi particulate formulations because of their nature of dispersing in the gastro intestinal (Gl) tract, show a reduced food effect and variability in gastric emptying times, thereby providing for reduced inter and intra subject variability, as compared to the innovator.
  • the present invention provides a multiparticulate formulation of didanosine having a unique combination of excipients that are compatible with didanosine. Further, the invention provides a process for the preparation of the multiparticulate formulation of didanosine, wherein the process utilizes low shear during granulation and low temperature during drying for preparation of the multiparticulate. This process contributes to the stability of the core of the multiparticulates of the invention.
  • the composition of the multiparticle and the enteric coat e.g Acryl - EZE MP, allows for reduced release at low pH and fast release at neutral pH.
  • the multiparticulate formulations because of their nature of dispersing in the Gl tract allows for a faster release of Gl tract and prolonged action as compared to the processes disclosed in the prior art.
  • the core comprises of 50 - 100% by the weight of the composition of an acid labile drug (didanosine), the combination of disintegrants pregelatinized starch and sodium starch glycolate, the binder hypromellose and the diluent microcrystalline cellulose.
  • an acid labile drug didanosine
  • disintegrants pregelatinized starch and sodium starch glycolate
  • binder hypromellose the binder hypromellose
  • the diluent microcrystalline cellulose the core comprises of 50 - 100% by the weight of the composition of an acid labile drug (didanosine), the combination of disintegrants pregelatinized starch and sodium starch glycolate, the binder hypromellose and the diluent microcrystalline cellulose.
  • the combination of pregelatinized starch and sodium starch glycolate enhances the faster release of the drug.
  • the coating agent Acryl - EZE MP gives the protection to the particulates at low pH.
  • the acid labile medicament is didanosine.
  • the amount of the drug present in the core is within the range of about 50 - 100% by the weight of the composition.
  • the preferable amount is about 80 - 100% by the weight of the composition.
  • the mean particle size of the didanosine is within the range of 40 - 70 microns and the preferable range is 45 - 55 microns.
  • the core also includes one or more disintegrants in an amount within the range of about 0 - 10% by the weight of the composition.
  • the suitable disintegrants are croscarmellose sodium, pregelatinized starch, crospovidone etc., and the preferred disintegrant is the combination of pregelatinized starch and sodium starch glycolate.
  • the preferable amount of the disintegrants is with in the range of 3 - 6% by the weight of the composition.
  • Binder should be non acidic preferably alkaline because of acid labile drug.
  • the suitable binders are microcrystalline cellulose, corn starch, sodium carboxymethyl cellulose, hydroxyproply methyl cellulose the preferred binder is hypromellose.
  • the amount of the binder present in the core is within the range of about 0 - 5% by the weight of the composition.
  • the preferable amount of the binder is with in the range of 0.5 - 2% by the weight of the composition.
  • the core also includes the filler (diluent) in an amount within the range of about 0 to 5% by the weight of the composition.
  • the preferable amount of the diluent is with in the range of 4 - 5% by the weight of the composition.
  • the suitable diluents are lactose monohydrate, microcrystalline cellulose, carboxymethyl cellulose and the preferred diluent is microcrystalline cellulose.
  • composition disclosed in PCT Patent Publication No. 2006/054175 A2 is required sub coating to the core composition.
  • the use of subcoating is unnessary when the core composition of the present invention is used.
  • the multiparticulates are prepared as follows. A wet mass is formed by granulating didanosine, hypromellose, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose with water. Then the wet mass is extruded. After that is spheronized using a spheronizer. This spheronization is just for 2 minutes. Drying for about 20 minutes in a fluid bed drier. The process is shown in the process flow diagram. In this process dusting step is not necessary and purified water is used in larger quantity than that of prior art to get the uniform shape to the particulates, which gives the better coating to the particulates.
  • the spheroid core contains, w/w based on the dry uncoated core, about 50 - 100% and the preferable is with in the range of 80 - 100% of didanosine, about 0 - 5% and the preferable is with in the range of 4 - 5% of microcrystalline cellulose, about 0 - 5% and the preferable with in the range of 3 - 6% of the disintegrants, about 0 - 5% and the preferable is with in the range of 0.5 - 2% of hypromellose.
  • the dried core is enteric coated with Acryl -
  • EZE MP EZE MP.
  • the amount is within the range of about 0 - 25% by weight of the composition and the preferable is with in the range of 10 - 20%.
  • the dried particulates are coated with an enteric film coating suspension comprising
  • Figure 1 is diagrammatic flow chart generally illustrating the process for manufacturing the enteric coated multiparticulate formulation of the present invention.
  • Example The enteric-coated didanosine capsules are prepared as described below: Didanosine (40 kg), pregletanized starch (0.2 kg), sodiumstarch glycolate (1.5 kg), microcrystalline cellulose (2.2 kg) are placed in rapid Mixture Granulator 600L at 75 rpm for dry mixing for 5 minutes and the dry mix materials are granulated with the binder solution (hypromellose (0.2 kg) + purified water) while mixing at 75 rpm until a suitable mass is achevied for extrusion. The wet mass is extruded using a Extruder EXT-100 (Umang) fitted with 1.0 mm die roller.
  • the extrudate is then transferred to a spherodizer with 1000 rpm, then the little quantity of purified water is added occasionally to give a uniform shape to the particulates and spheronized for 2 minutes.
  • the particulates are dried in a fluid bed dryer at 60° C for 20 minutes then the particles are cured in a tray drier set at 35-4O 0 C till the LOD (at 105 0 C, auto mode) gets in the range of 0.50% w/w to 2.00% w/w.
  • the particulates are passed through mesh # 14.
  • the particulates are retained of mesh # 14 are collected separately and passed into different poly bags.
  • the particulates passed through mesh #14 are passed through mesh #24.
  • the particulates are retained of mesh # 24 are collected separately and passed into different poly bags.
  • the particulates retained of mesh #24 are denoted as #14/24 fraction.
  • the purified water is taken in a S. S vessel container equipped with a propeller stirrer.
  • the particulates are cured in a tray drier at 40 0 C for about 30 minutes.
  • the particulates are passed through mesh # 14.
  • the particulates are retained of mesh # 14 are collected separately and passed into different poly bags.
  • the particulates passed through mesh #14 are passed through mesh #24.
  • the particulates are retained of mesh # 24 are collected separately and passed into different poly bags.
  • the particulates retained of mesh #24 are denoted as #14/24 fraction.
  • the particulates are filled into '0' size capsules. Fill Weight: 520.38 mg. Weight of the capsule: 616.38 mg.
  • the enteric coated capsules were tested for drug release in pH 0.1 N HCI followed by pH 6.8 phosphate buffer media using USP apparatus.
  • the dissolution profiles of the product obtained as per the present invention and product currently marketed by Bristol Myers Squibb (Videx EC) are given in Table 1 & Table 2.

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Abstract

The present invention produces a stable muliparticulate fast dispersing didanosine formulation when exposed to high pH 6 and above and also reduced inter and intra variability. Didanosine muliparticulate formulation is composed of a spheroid core comprising of didanosine, the combination of disintegrants such as pregelatinized starch and sodium starch glycolate, the binding agent hypromellose, the diluent microcrystalline cellulose and about 1 - 2% w/w water.

Description

STABLE MULTIPARTICULATE FORMULATIONS OF DIDANOSiNE
FIELD OF THE INVENTION
The present invention produces a stable muliparticulate fast dispersing didanosine formulation when exposed to high pH 6 and above and also reduced inter and intra variability. Didanosine multiparticulate formulation is composed of a spheroid core comprising of didanosine, disintegrant, binding agent and about 1-2% w/w water. Multiparticulate formulations, because of the advantage of tendency of dispersing gastro intestinal tract, which also shows very less effect of food and it provides reduced inter and intra subject variability.
BACKGROUND OF THE INVENTION
European Patent No. EP 206497 disclosed certain 2',3'-dideoxy- nucleosides, pharmaceutically acceptable derivatives thereof, and their use in therapy, particularly for the treatment or prophylaxis of certain viral infections. These compounds are antiviral agents. Among them didanosine, chemically 2',3'-dideoxyinosine is a selective HIV-I inhibitor and can be used as medicaments in the treatment and prophylaxis of viral, especially retroviral infections. Didanosine is represented by the following structure:
Figure imgf000002_0001
Didanosine (also known as ddl, and marketed by Bristol-Myers Squibb
Co. under the brand name Videx®), is an acid labile drug and is unstable in low pH solutions and undergo rapid acid catalyzed degradation and is relatively stable at neutral or high pH. Didanosine has become widely used as a component of the therapeutic cocktails for treating AIDS. U.S. Patent No. 4,861 ,759 disclosed various compositions containing
2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyinosine (ddl), and 2',3'- dideoxyguanosine (ddG), and their triphosphates for treating retroviral infections. The 759" patent also disclosed the oral administration of these dideoxy purine nucleosides in the form of liquids or tablets containing antacid buffering agents so that the pH of the resultant composition is in the neutral (pH 6 - 8) range. Specifically exemplified and claimed is an oral gavage formulation containing 0.1 N acetate buffer with a pH of 6.8 to 7.2. Didanosine is commercially available in a variety of oral dosages, including chewable/dispersible buffered tablets in strengths of 25, 50, 100 or 150 mg of didanosine, buffered powder for oral solution, pediatric powder for oral solution, and delayed release capsules. Chewable/dispersible buffered tablet of didanosine 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.
Didanosine degrades rapidly at acidic pH and hence, ddl, in its chewable/dispersible form and its buffered powder for oral solution form, contains buffereing agents and is administered with antacids in the pediatric powder form. Nevertheless, the presence of the large quantities of antacid components in the formulation can lead to significant Gl imbalance as noted by severe diarrhea.
Enteric coatings have been used for many years to arrest the release of the drug from orally ingestible dosage forms. Depending upon the composition and/or thickness, the enteric coatings are resistant to stomach acid for required periods of time before they begin to disintegrate and permit slow release of the drug in the lower stomach or upper part of the small intestines. Numerous enteric coated and/or extended release pharmaceutical compositions comprising a core in the form of a tablet, beadlet, pellet or particle, and the methods of making these compositions have been disclosed in the art.
U.S. Patent No. 5,026,560 discloses a pharmaceutical composition and method of making said pharmaceutical composition, 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 a drug and low substituted hydroxypropylcellulose, followed by the application of an enteric coating.
U.S. Patent No. 5,225,202 discloses enteric coated pharmaceutical compositions utilizing neutralized hydroxypropyl methylcellulose phthalate polymer (HPMCP) coating and the composition comprises an acid labile medicament core, a disiήtegrant, 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.
U.S. Patent No. 6,224,910 and 6,607,747 discloses beadlets composition prepared by spheronization process. The process of spheronization involves dry blending of medicament with the disintegrant like sodium starch glycolate and sodium carboxymethyl cellulose. A portion of this blend containing the medicament 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. U.S. 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.
PCT Patent Publication No. 2006/054175 A2 discloses enteric coated composition which is devoid of a protective coat or subcoat between the core and the enteric coating 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. The present formulation is Multi particulate formulation with a different composition. In this Process purified water is added in larger quantity than that of used in the prior art and this process of invention avoids the dusting step. This product has showed unique resistance to disintegration at pH less than 4 and has tendency of dispersing gastro intestinal tract and the release of the drug is faster than the products obtained by the prior art process. This process utilizes low shear during granulation and low temperature during drying for preparation of the multiparticulate. This process contributes to the stability of the core of the multiparticulates. Multi particulate formulations, because of their nature of dispersing in the gastro intestinal (Gl) tract, show a reduced food effect and variability in gastric emptying times, thereby providing for reduced inter and intra subject variability, as compared to the innovator.
DETAILED DESCRIPTION OF THE INVENTION The present invention provides a multiparticulate formulation of didanosine having a unique combination of excipients that are compatible with didanosine. Further, the invention provides a process for the preparation of the multiparticulate formulation of didanosine, wherein the process utilizes low shear during granulation and low temperature during drying for preparation of the multiparticulate. This process contributes to the stability of the core of the multiparticulates of the invention.
According to one aspect of the present invention, the composition of the multiparticle and the enteric coat e.g Acryl - EZE MP, allows for reduced release at low pH and fast release at neutral pH. The multiparticulate formulations, because of their nature of dispersing in the Gl tract allows for a faster release of Gl tract and prolonged action as compared to the processes disclosed in the prior art.
In the present composition, the core comprises of 50 - 100% by the weight of the composition of an acid labile drug (didanosine), the combination of disintegrants pregelatinized starch and sodium starch glycolate, the binder hypromellose and the diluent microcrystalline cellulose.
The combination of pregelatinized starch and sodium starch glycolate enhances the faster release of the drug. The coating agent Acryl - EZE MP gives the protection to the particulates at low pH. The acid labile medicament is didanosine. The amount of the drug present in the core is within the range of about 50 - 100% by the weight of the composition. The preferable amount is about 80 - 100% by the weight of the composition. The mean particle size of the didanosine is within the range of 40 - 70 microns and the preferable range is 45 - 55 microns.
The core also includes one or more disintegrants in an amount within the range of about 0 - 10% by the weight of the composition. The suitable disintegrants are croscarmellose sodium, pregelatinized starch, crospovidone etc., and the preferred disintegrant is the combination of pregelatinized starch and sodium starch glycolate. The preferable amount of the disintegrants is with in the range of 3 - 6% by the weight of the composition.
Binder should be non acidic preferably alkaline because of acid labile drug. The suitable binders are microcrystalline cellulose, corn starch, sodium carboxymethyl cellulose, hydroxyproply methyl cellulose the preferred binder is hypromellose. The amount of the binder present in the core is within the range of about 0 - 5% by the weight of the composition. The preferable amount of the binder is with in the range of 0.5 - 2% by the weight of the composition.
The core also includes the filler (diluent) in an amount within the range of about 0 to 5% by the weight of the composition. The preferable amount of the diluent is with in the range of 4 - 5% by the weight of the composition. The suitable diluents are lactose monohydrate, microcrystalline cellulose, carboxymethyl cellulose and the preferred diluent is microcrystalline cellulose.
The composition disclosed in PCT Patent Publication No. 2006/054175 A2 is required sub coating to the core composition. The use of subcoating is unnessary when the core composition of the present invention is used.
The multiparticulates are prepared as follows. A wet mass is formed by granulating didanosine, hypromellose, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose with water. Then the wet mass is extruded. After that is spheronized using a spheronizer. This spheronization is just for 2 minutes. Drying for about 20 minutes in a fluid bed drier. The process is shown in the process flow diagram. In this process dusting step is not necessary and purified water is used in larger quantity than that of prior art to get the uniform shape to the particulates, which gives the better coating to the particulates.
In one embodiment, the spheroid core contains, w/w based on the dry uncoated core, about 50 - 100% and the preferable is with in the range of 80 - 100% of didanosine, about 0 - 5% and the preferable is with in the range of 4 - 5% of microcrystalline cellulose, about 0 - 5% and the preferable with in the range of 3 - 6% of the disintegrants, about 0 - 5% and the preferable is with in the range of 0.5 - 2% of hypromellose.
Material Quantity (w/w)
Core
Didanosine 90%
Microcrystalline cellulose 4.98%
Pregelatinized starch 0.5%
Sodium starch glycolate 3.4%
Hypromellose 0.5%
In another embodiment, the dried core is enteric coated with Acryl -
EZE MP. The amount is within the range of about 0 - 25% by weight of the composition and the preferable is with in the range of 10 - 20%. The dried particulates are coated with an enteric film coating suspension comprising
Acryl - EZE MP using a suitable coating system such as fluid bed drier.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is diagrammatic flow chart generally illustrating the process for manufacturing the enteric coated multiparticulate formulation of the present invention.
The invention is explained in detail in the examples given below which are provided by the way of illustration only and therefore should not be construed to limit the scope of the invention.
Example The enteric-coated didanosine capsules are prepared as described below: Didanosine (40 kg), pregletanized starch (0.2 kg), sodiumstarch glycolate (1.5 kg), microcrystalline cellulose (2.2 kg) are placed in rapid Mixture Granulator 600L at 75 rpm for dry mixing for 5 minutes and the dry mix materials are granulated with the binder solution (hypromellose (0.2 kg) + purified water) while mixing at 75 rpm until a suitable mass is achevied for extrusion. The wet mass is extruded using a Extruder EXT-100 (Umang) fitted with 1.0 mm die roller. The extrudate is then transferred to a spherodizer with 1000 rpm, then the little quantity of purified water is added occasionally to give a uniform shape to the particulates and spheronized for 2 minutes. The particulates are dried in a fluid bed dryer at 60° C for 20 minutes then the particles are cured in a tray drier set at 35-4O0C till the LOD (at 1050C, auto mode) gets in the range of 0.50% w/w to 2.00% w/w. The particulates are passed through mesh # 14. The particulates are retained of mesh # 14 are collected separately and passed into different poly bags. The particulates passed through mesh #14 are passed through mesh #24. Then the particulates are retained of mesh # 24 are collected separately and passed into different poly bags. Then the particulates retained of mesh #24 are denoted as #14/24 fraction.
The purified water is taken in a S. S vessel container equipped with a propeller stirrer.
Then Acryl - EZE MP (7.938 kg) is added slowly to the purified water while stirring and the contents are stirred for 45 minutes. The particulates are coated with enteric coating suspension in a fluid bed coater with the following coating process parameters.
Sl. No. Process parameters Range
1 Out let Temperature (°C) 34 - 37
2 In let Temperature (°C) 48 - 53
3 Blow Back Dwell 2 - 3
4 Capacity of Fan 2 - 4
5 Atomization (Barr) 1.5 - 3.0
6 Peristaltic Pump speed ' 5 - 20
7 Spray rate (gram / minute) 2 - 4.5 After completion of coating process, the particulates are cured in a tray drier at 40 0C for about 30 minutes. The particulates are passed through mesh # 14. The particulates are retained of mesh # 14 are collected separately and passed into different poly bags. The particulates passed through mesh #14 are passed through mesh #24. Then the particulates are retained of mesh # 24 are collected separately and passed into different poly bags. Then the particulates retained of mesh #24 are denoted as #14/24 fraction. The particulates are filled into '0' size capsules. Fill Weight: 520.38 mg. Weight of the capsule: 616.38 mg.
Material Quantity (mg)
Core
Didanosine 400.00
Microcrystalline cellulose 22.00
Pregelatinized starch 2.00
Sodium starch glycolate 15.00
Hypromellose 2.00
Coating
Acryl-EZE MP 79.38
Purified water q.s
q.s - quantity sufficient
Dissolution profile:
The enteric coated capsules were tested for drug release in pH 0.1 N HCI followed by pH 6.8 phosphate buffer media using USP apparatus. The dissolution profiles of the product obtained as per the present invention and product currently marketed by Bristol Myers Squibb (Videx EC) are given in Table 1 & Table 2.
Videx EC and Didanosine Capsules, 400 mg, 6.8 phosphate buffer as Dissolution Media: TABLE 1
Figure imgf000010_0001
Videx EC and Didanosine Capsules, 400 mg, 0.1 N HCI as Dissolution Media:
TABLE 2
Figure imgf000010_0002

Claims

We claim:
1. An enteric coated pharmaceutical composition comprising a core in the form of a multiparticulate formulation and the said core comprises of didanosine in an amount within the range of about 50 % to 100% by weight of the composition, combination of disintegrants pregelatinized starch and sodium starch glycolate in an amount within the range of about 0 to 10% by weight of the composition.
2. The enteric coated pharmaceutical composition as claimed in claim 1 , wherein the didanosine is within the range of 80 - 100% by the weight of the composition.
3. The pharmaceutical composition as claimed in claim 1 , wherein the combination of pregelatinized starch and sodium starch glycolate is within the range of 3 - 6% by the weight of the composition.
4. The pharmaceutical composition as claimed in claim 1 , wherein the said core is in the form of a multiparticulate formulation.
5. The pharmaceutical composition as claimed in claim 1 , wherein the optional binder hypromellose is used in an amount within the range of about 0 to 5% by weight of the composition.
6. The pharmaceutical composition as claimed in claim 5, wherein the hypromellose is within the range of about 0.5 to 2% by weight of the composition.
7. The pharmaceutical composition as claimed in claim 1 , wherin the optional diluent, microcrystalline cellulose is used in an amount within the range of about 0 to 5% by weight of the composition.
8. The pharmaceutical composition as claimed in claim 7, wherein the microcrystalline cellulose is within the range of about 4 to 5% by weight of the composition.
9. The pharmaceutical composition as claimed in claim 1 , wherein the multiparticulate formulation is enteric coated with the material Acryl-EZE MP.
10. The pharmaceutical composition as claimed in claim 9, wherein the Acryl- EZE MP is within the range of about 0 to 25% by weight of the composition.
11. The pharmaceutical composition as claimed in claim 10, wherein the Acryl- EZE MP is within the range of about 10 to 15% by weight of the composition.
12. The pharmaceutical composition as claimed in claim 1 , wherein the mean particle size of the medicament is within the range of 40 - 70 microns (90% of the particles).
13. The pharmaceutical composition as claimed in claim 12, wherein the mean particle size of the medicament is within the range of 45 - 55 microns (90% of the particles).
14. An enteric-coated didanosine comprising a core in the form of a multiparticulate formulation, which includes didanosine in an amount within the range of about 80 to 100% by weight and an enteric coating which includes Acryl-EZE MP(clorcon).
15. The pharmaceutical composition as claimed in claim 1 , having the following composition:
Material Quantity (mg)
CORE
Didanosine 400.00
Microcrystalline cellulose 22.00
Pregelatinized starch 2.00
Sodium starch glycolate 15.00
Hypromellose 2.00
COATING
Acryl-EZE MP 79.38
Purified water q.s
16. A process for the preparation of an enteric coated pharmaceutical composition comprising the steps of: a) dry mix of medicament, diluent and disintegrant; b) granulation of dry mix with the binder solution; c) extrusion of the granules; d) feed the extrudes into shperodizer to form into high potency Multiparticulates; e) curing the multiparticulates in a tray drier at 35-400C till the LOD gets in the range of 0.5 to 2.00%; and f) coating of the multiparticulates.
17. The process as claimed in claim 16, further comprises the step of sifting and separation of the multiparticulates using a #14 and #24 size mesh to form 14/24 fraction sized multiparticulates.
18. The process as claimed in claim 16, wherein the medicament is didanosine.
19. The process as claimed in claim 16, wherein the disintegrants are sodium starch glycolate and pregelatinized starch.
20. The process as claimed in claim 16, wherein the diluent is microcrystalline cellulose.
21. The process as claimed in claim 16, wherein the binder is hypromellose.
22. The process as claimed in claim 16, wherein the coating material is Acryl- EZE MP (clorcon).
23. The process as claimed in claim 16, wherein the filling of coated multiparticulates into a dissolvable capsule.
PCT/IN2006/000272 2006-08-01 2006-08-01 Stable multiparticulate formulations of didanosine WO2008015686A1 (en)

Priority Applications (1)

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Application Number Priority Date Filing Date Title
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Country Link
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010024660A1 (en) * 1999-09-29 2001-09-27 Ismat Ullah Enteric coated pharmaceutical composition and method of manufacturing
US20020051818A1 (en) * 1998-07-17 2002-05-02 Ismat Ullah Enteric coated pharmaceutical tablet and method of manufacturing
WO2006054175A2 (en) * 2004-11-18 2006-05-26 Aurobindo Pharma Limited Stable dosage forms of acid labile drug

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020051818A1 (en) * 1998-07-17 2002-05-02 Ismat Ullah Enteric coated pharmaceutical tablet and method of manufacturing
US20010024660A1 (en) * 1999-09-29 2001-09-27 Ismat Ullah Enteric coated pharmaceutical composition and method of manufacturing
WO2006054175A2 (en) * 2004-11-18 2006-05-26 Aurobindo Pharma Limited Stable dosage forms of acid labile drug

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