Classifications

• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
• • 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
  • A61K31/12—Ketones
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
  • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• • 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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

• the invention relates to the pharmaceutical field. More specifically it relates to process for preparing solid oral pharmaceutical formulations comprising low dose of entecavir and one or more pharmaceutically acceptable excipient(s).
• Entecavir is an oral antiviral drug used in the treatment of hepatitis B infection (HBV). More specifically, entecavir is a guanosine nucleoside analogue with activity against HBV reverse transcriptase, it inhibits HBV replication by competing with the natural substrate, deoxyguanosine at the viral replication process.
• Entecavir is described chemically as 2-amino-l, 9-dihydro-9-[(l S, 3R, 4S)- 4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, monohydrate. Its molecular formula is C 12 H 15 N 5 0 3 » H 2 0, which corresponds to a molecular weight of 295.3.
• Entecavir is a white to off-white powder. It is slightly soluble in water (2.4 mg/ml), and the pH of the saturated solution in water is 7.9 at 25° ⁇ 0.5° C. Entecavir was introduced into the U.S. market under the brand name of
• Baraclude ® and is available for oral administration in strengths of 0.5 mg and 1 mg.
• Baraclude ® 0.5-mg and 1-mg film-coated tablets contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate.
• the tablet coating contains titanium dioxide, hypromellose, polyethylene glycol 400, polysorbate 80 (0.5-mg tablet only), and iron oxide red (1-mg tablet only). It appears that the marketed tablet Baraclude ® uses povidone as a binder or adhesive.
• 6,627,224 discloses a low dose solid oral formulation containing from about 0.001 mg to about 25 mg entecavir and process for preparing the same, wherein the process comprises the steps of: (a) preparing a solution of the entecavir in a solvent along with an adhesive substance at temperatures ranging from about 25° C.
• the adhesive substance used is preferably, a polymeric material possessing a high degree of tackiness, which acts as a binder, thereby functioning to adhere entecavir to carrier substrate particles and thus prevent the separation of entecavir from the substrate and minimize the loss of entecavir during subsequent processing such as drying and blending, thereby ensuring content uniformity throughout the batch process.
• suitable adhesive substances include povidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, guar gum, and xanthan gum and mixtures thereof. . Prasanth Sai R.V et al., International Journal of Research in
• entecavir tablet composition comprising entecavir, lactose, microcrystalline cellulose, crospovidone and magnesium stearate, wherein said tablet is prepared by employing direct compression method.
• binder or adhesive agent is incorporated in the composition or during the processing steps and preferably spray granulation or spray coating technique is used.
• spray granulation or spray coating technique is used.
• the present inventors have found that the solid oral pharmaceutical formulations of entecavir can be prepared without incorporating or involving the use of any binder in the composition or during the processing step, without compromising or failing in the content uniformity test.
• this advancement helps to reduce additional processing time and the number of ingredients in the composition, while still maintaining the requirement of uniform or acceptable content uniformity.
• the invention relates to processes for preparing solid oral pharmaceutical formulation comprising a low dose of entecavir and one or more pharmaceutical excipient(s), preferably in the form of compressed tablets.
• An objective of the invention is to prepare solid oral pharmaceutical formulation comprising a low dose of entecavir and one or more pharmaceutically acceptable excipient(s), wherein the process does not involve the use of any binder.
• Another objective of the invention is to prepare solid oral tablet formulation comprising a low dose of entecavir and one or more pharmaceutically acceptable excipient(s), wherein the process does not involve the use of any binder.
• Another objective of the invention is to prepare solid oral capsule formulation comprising a low dose of entecavir and one or more pharmaceutically acceptable excipient(s), wherein the process does not involve the use of any binder.
• Another objective of the invention is to prepare solid oral tablet formulation comprising a low dose of entecavir and one or more pharmaceutically acceptable excipient(s), having uniform, or acceptable content uniformity, wherein the process does not involve the use of any binder.
• Another objective of the invention is to prepare solid oral tablet formulation comprising a low dose of entecavir and one or more pharmaceutically acceptable excipient(s) by employing wet granulation process, wherein the process does not involve the use of any binder.
• Another objective of the invention is to prepare solid oral tablet formulation comprising a low dose of entecavir and one or more pharmaceutically acceptable excipient(s) by employing spray granulation or spray coating process, wherein the process does not involve the use of any binder.
• Yet another objective of the invention is to prepare solid oral tablet formulation comprising a low dose of entecavir and one or more pharmaceutically acceptable excipient(s), having comparable in-vitro dissolution profile and in-vivo pharmacokinetic parameters with that of the marketed Baraclude ® tablet, wherein said tablets are prepared employing wet granulation process and said process does not involve the use of any binder.
• the present inventors have developed a wet granulation process of preparing solid oral pharmaceutical formulation comprising low dose of entecavir and one or more pharmaceutically acceptable excipient(s), wherein the process does not involve the use of any binder, and still said solid oral pharmaceutical formulation possess or meets the content uniformity test.
• the solid oral pharmaceutical formulation of a low dose of entecavir preferably includes granules, pellets, mini-tablets, tablets, bi-layered or multi-layered tablets, capsules, lozenges or troches.
• a low dose of entecavir is used in connection with a solid oral formulation containing from about 0.001 mg to about 25 mg of the entecavir, preferably from about 0.01 mg to about 10 mg of entecavir, most preferably from about 0.01 mg to about 5 mg of entecavir .
• entecavir may be present in an amorphous or crystalline form.
• the term "entecavir” is intended to include the active agent itself, as well as its pharmaceutically acceptable salts or derivatives or polymorphs thereof.
• binding is intended to include any pharmaceutically acceptable ingredient that can be used in either dry or wet state to help bind drug and the excipient particle(s) together in a formulation.
• the term, "uniform or acceptable content uniformity” is intended to mean that the percentage relative standard deviation (RSD) of the assay of the composition prepared according to the embodiments of the invention is less than 6.0% and the assay value is within the range of 85% to 115% of the label claim.
• RSS percentage relative standard deviation
• the term "wet granulation" as used herein relates to a process by which powder particles are made to adhere to each other to form agglomeration of particles called as agglomerates or granules by the addition of a granulation liquid onto a powder blend or powder bed comprising other pharmaceutically acceptable excipients.
• the addition of the granulating liquid onto the powder blend or powder bed could be done through spraying and/ or by pouring said granulating liquid on to the powder bed/ blend in a controlled manner, until the granulation end point is reached.
• the process of preparing solid oral pharmaceutical formulation of a low dose of entecavir involves wet granulation process, wherein the process does not involve the use of any binder.
• wet granulation process for preparing solid oral formulation of a low dose of entecavir involves the use of aqueous or non-aqueous or hydro-alcoholic solvent as a granulating liquid.
• non-aqueous solvents for use in granulation process steps include, but are not limited to methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, ethyl acetate, dimethylsulfoxide or their combinations thereof.
• hydro-alcoholic solvents are mixtures of one or more alcohols and water, in various volume ratios.
• entecavir is dissolved in purified water by heating water at a temperature above 70 °C and below 80°C and the resulting entecavir solution maintained at a temperature of 70 ⁇ 5°C is used as granulating liquid for wet granulation process, to be sprayed over the powder bed/ blend until the granulation end-point is reached.
• the wet granulation process of preparing solid oral tablets comprising a low dose of entecavir comprises the step of: a) Dissolving entecavir in water by dispersing it in water and heating the water at a temperature above 70°C and below 80°C to get entecavir solution; b) Sifting one or more pharmaceutically acceptable excipient(s) through size #30 mesh and blending; c) Spray granulating or spray coating the blend obtained in step (b) with the entecavir solution obtained in step (a), which is maintained at temperature 70 ⁇ 5°C, by employing rapid mixer granulator (RMG) or in fluid bed granulator; d) Drying the granules or coated particles of step (c) using fluid bed dryer (FBD) at 50°C to 70°C, and passing or screening the granules through suitable size sieve to get dried granules of desired size; e) Optionally blending the dried a) Dissolving entecavir in water by dispersing it
• the wet granulation process of preparing solid oral tablets comprising a low dose of entecavir comprises the step of: a) Dispersing entecavir in water; b) Sifting one or more pharmaceutically acceptable excipient(s) through size #30 mesh and blending; c) Spray granulating or spray coating the blend obtained in step (b) with the entecavir dispersion obtained in step (a) by employing rapid mixer granulator (RMG) or in fluid bed granulator; d) Drying the granules or coated particles of step (c) using fluid bed dryer (FBD) at 50°C to 70°C, and passing or screening the granules through suitable size sieve to get dried granules of desired size; e) Optionally blending the dried granules or coated particles of step (d) with one or more extra-granular pharmaceutically acceptable excipient(s); f) Compressing the blend of step
• the wet granulation process of preparing solid oral capsule comprising a low dose of entecavir comprises the step of: a) Dissolving entecavir in water by dispersing it in water and heating the water at a temperature above 70°C and below 80°C to get entecavir solution; b) Sifting one or more pharmaceutically acceptable excipient(s) through size #30 mesh and blending; c) Spray granulating or spray coating the blend obtained in step (b) with the entecavir solution obtained in step (a), which is maintained at temperature 70 ⁇ 5°C, by employing rapid mixer granulator (RMG) or in fluid bed granulator; d) Drying the granules or coated particles of step (c) using fluid bed dryer (FBD) at 50°C to 70°C, and passing or screening the granules through suitable size sieve to get dried granules of desired size; e) Optionally blending the dried
• the wet granulation process of preparing solid oral capsule comprising a low dose of entecavir without the use of any binder comprises the step of: a) Dispersing entecavir in water; b) Sifting one or more pharmaceutically acceptable excipient(s) through size #30 mesh and blending; c) Spray granulating or spray coating the blend obtained in step (b) with the entecavir dispersion obtained in step (a) by employing rapid mixer granulator (RMG) or in fluid bed granulator; d) Drying the granules or coated particles of step (c) using fluid bed dryer (FBD) at 50°C to 70°C, and passing or screening the granules through suitable size sieve to get dried granules of desired size; e) Optionally blending the dried granules or coated particles of step (d) with one or more extra-granular pharmaceutically acceptable excipient(s); f) Filling the blend of step (e)
• RMG rapid mixer gran
• the wet granulation process for preparing solid oral pharmaceutical formulation comprising low dose of entecavir does not involve the use of any binder such as povidone, methylcellulose (MC), hydroxymethylcellulose, hydroxypropyl-methylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), gelatin, guar gum, xanthan gum, ethyl cellulose, EudragitTM, starch, pregelatinized starch, alginates and mixtures thereof.
• binder such as povidone, methylcellulose (MC), hydroxymethylcellulose, hydroxypropyl-methylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), gelatin, guar gum, xanthan gum, ethyl cellulose, EudragitTM, starch, pregelatinized starch, alginates and mixtures thereof.
• the tablet or capsule dosage form according to the invention may further contain one or more pharmaceutically acceptable excipient(s) selected from a group comprising diluents, disintegrants, glidants, and/ or lubricants.
• Suitable diluents according to the invention include, but are not limited to, mannitol, xylitol, sorbitol, lactose, sucrose, cellulose, microcrystalline cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate, calcium phosphate tribasic, starch, calcium trisilicate, magnesium trisilicate, cellulose acetate, dextrose, or combinations thereof.
• Suitable disintegrants according to the invention include, but are not limited to, crospovidone, croscarmellose sodium, sodium starch glycolate, low- substituted hydroxypropyl cellulose (L-HPC), pregelatinised starch, starch, microcrystalline cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, polacrilin potassium or combinations thereof.
• Suitable glidants and lubricants according to the invention include, but are not limited to, colloidal silicon dioxide, talc, magnesium stearate, sodium stearyl fumarate, calcium stearate or combinations thereof.
• film coating excipient(s) may be selected from a group comprising of film polymers, plasticizers, opacifiers, and coloring agents, etc.
• Suitable film polymers according to the invention include, but are not limited to, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl acetate (PVAc), methyl cellulose (MC) and ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methacrylic acid copolymer, cellulose acetate phthalate, cellulose phthalate, hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate, and natural gums and resins such as zein, gelatin, shellac and acacia or combinations thereof.
• PVP polyvinylpyrrolidone
• PVA polyvinyl alcohol
• PVAc polyvinyl acetate
• MC methyl cellulose
• EC ethyl cellulose
• HEC hydroxyethyl cellulose
• HPMC
• Suitable plasticizers according to the invention include, but are not limited to, castor oil, polyethylene glycol, propylene glycol, glycerin, triacetin, polysorbates, phthalate esters, dibutyl sebacate, citrate esters, and monoglycerides or combinations thereof.
• Suitable opacifiers according to the invention include, but are not limited to, titanium dioxide and talc or combinations thereof.
• Suitable coloring agents according to the invention include, but are not limited to, FDA approved dyes and lakes such as sunset yellow, tartrazine, erythrosine, iron oxide yellow, and natural colors such as carmine or combinations thereof.
• ready-to-use film coating systems such as Opadry ® and InstacoatTM may also be used for film coating of tablets.
• procedure used to determine the content uniformity test is as follows:
• assay value for entecavir tablets is determined by using following procedure.
• Diluent -2 Degassed mobile phase.
• Diluent as blank Filter a portion of diluent -2 through 0.45 ⁇ PVDF syringe filter.
• LC Label claim of Entecavir as Entecavir in mg, per unit dose.
• the Relative Standard Deviation (RSD) was calculated from content values obtained for each individual tablet samples.
• step (3) Granulating the blend obtained in step (1) by spraying the granulating liquid obtained in step (2) by employing rapid mixer granulator (RMG) to get wet mass or granules.
• RMG rapid mixer granulator
• step (3) Drying the wet mass or granules obtained in step (3) by employing fluid bed dryer (FBD) at 60°C to get LOD of not more than 1.5% at 105°C and sifting or passing dried mass or granules through size #30 mesh to get dried granules.
• BFD fluid bed dryer
• step (4) Sifting microcrystalline cellulose through size #40 mesh and blending with dried granules of step (4).
• Dissolving entecavir in water by dispersing entecavir in water and heating the water at a temperature above 70°C and below 80°C to get granulating liquid.
• step (3) Granulating the blend obtained in step (1) by spraying the granulating solution obtained in step (2) maintained at temperature 70 ⁇ 5°C by employing rapid mixer granulator (RMG) to get wet mass or granules.
• RMG rapid mixer granulator
• step (3) Drying the wet mass or granules obtained in step (3) by employing fluid bed dryer (FBD) at 60°C to get LOD of not more than 1.5% at 105°C and sifting or passing dried mass or granules through size #30 mesh to get dried granules.
• BFD fluid bed dryer
• step (4) Sifting microcrystalline cellulose through size #40 mesh and blending with the granules of step (4).
• step (3) Granulating the blend obtained in step (1) by spraying the granulating solution obtained in step (2) maintained at temperature 70 ⁇ 5°C by employing rapid mixer granulator (RMG) to get wet mass or granules. 4. Drying the wet mass or granules obtained in step (3) by employing fluid bed dryer (FBD) at 60°C to get LOD of not more than 1.5% at 105°C and sifting or passing dried mass or granules through size #30 mesh to get dried granules.
• RMG rapid mixer granulator
• step (4) Sifting microcrystalline cellulose through size #40 mesh and blending with the granules of step (4).
• Entecavir lmg tablets prepared according to Example 1 and 2 were subjected to in-process quality control tests and the resultant data is compiled in Table 1.
• Example 2 shows excellent content uniformity, when compared to Example 1. Stability Study:
• Entecavir tablets prepared according to Example 2 (test product) and Baraclude ® lmg tablets (reference product) were subjected for the in-vivo bioequivalence study in healthy human volunteers under fasting condition and the resultant data is compiled in Table 5 and Table 6.

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Cited By (8)

Citations (2)

• 2012
  • 2012-12-20 WO PCT/IN2012/000833 patent/WO2013114389A1/fr not_active Ceased

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