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WO2005117840A1 - Compositions pharmaceutiques stables comprenant des granules pulverises de nateglinide de forme b - Google Patents

Compositions pharmaceutiques stables comprenant des granules pulverises de nateglinide de forme b Download PDF

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Publication number
WO2005117840A1
WO2005117840A1 PCT/IB2005/051750 IB2005051750W WO2005117840A1 WO 2005117840 A1 WO2005117840 A1 WO 2005117840A1 IB 2005051750 W IB2005051750 W IB 2005051750W WO 2005117840 A1 WO2005117840 A1 WO 2005117840A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
stable pharmaceutical
preparation
nateglinide
composition according
Prior art date
Application number
PCT/IB2005/051750
Other languages
English (en)
Inventor
Romi Barat Singh
Anu Shilpa
Vishnubhotla Nagaprasad
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2005117840A1 publication Critical patent/WO2005117840A1/fr

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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • the present invention relates to stable pharmaceutical compositions comprising nateglinide and processes for making them.
  • Background Art [2] Nateglinide is an amino acid derivative that lowers blood glucose levels by stimulating insulin secretion from the pancreas. It is widely indicated as monotherapy to lower blood glucose in patients with Type 2 diabetes. It is also indicated for use in combination with metformin.
  • nateglinide oral tablets are available in 60 mg or 120 mg strengths and are marketed by Novartis under the trade name STARLIX®.
  • Nateglinide is disclosed in Japanese Patent Application Laid Open No. 63-54321 (equivalent to EP-A-196222 and US 4,816,484) and in J. Med. Chem. 32, 1436.
  • the Japanese application describes how the compound may be crystallized from aqueous methanol to yield crystals having a melting point of 129 °C to 130 °C. These crystals were described as being in a crystalline form and were known as 'B-type' crystals.
  • the known B-type (also known as Form B) crystals suffer from problems of instability, especially when subjected to mechanical grinding. The instability results in conversion of the B-type crystals into other polymorphic forms.
  • U.S. Patent No 5,463,116 discloses a method of producing a crystalline form (H type or Form H) of nateglinide having improved stability, i.e., having an enhanced stability to grinding which is thus said to be more suitable for use in medicines than those of the B-type.
  • U.S. Patent No. 6,559,188 describes compositions of nateglinide which are capable of being granulated without the need for pulverization after the granulation step. All of the examples given in this patent make use of lactose and microcrystalline cellulose as filler. The concentration of lactose is disclosed as being 34 to 46% w/w and micro- crystalline cellulose as being 17 to 23% w/w, the total concentration of filler ranging from 50-70% w/w. [6] In the present invention pharmaceutical compositions comprising nateglinide of Form B, and prepared by pulverizing after the granulation, were found to be stable.
  • compositions which were prepared by using either lactose or microcrystalline cellulose alone as filler did not show comparable dissolution profiles to that of STARLIX®. It was, however, seen that when lactose and microcrystalline cellulose were used in combination as filler in a specific concentration range, a dissolution profile comparable with STARLIX® was obtained.
  • Embodiments of the process may include one or more of the following features.
  • the step of pulverization may be carried out after a granulation step.
  • the granulation step may be carried out in a fluidized bed drier.
  • the step of pulverization may be carried out in a conventional milling instrument, the conventional milling instrument including one or more of an air jet mill, a multi mill and a ball mill.
  • the granulation step may be carried out by wet granulation or dry granulation.
  • the wet granulation process may include blending nateglinide, fillers, surfactant and disintegrant; granulating the blend with a binder solution; drying the granules; pulverizing; lubricating and compressing the lubricated granules.
  • the wet granulation process may include blending nateglinide, fillers, surfactant, disintegrant and binder; granulating the blend with a solvent; drying the granules; pulverizing; lubricating and compressing the lubricated granules.
  • the dry granulation process may include blending nateglinide, fillers, surfactant, disintegrant and binder; compacting or slugging the blend; breaking the slugs to make granules; pulverizing; lubricating and compressing the lubricated granules.
  • the composition may further include one or more pharmaceutically acceptable excipients selected from filler, binder, disintegrant, surfactant, lubricant, coloring agent, and flavoring agent.
  • the filler may be a combination of lactose in the range of 46% to 70% w/w and microcrystalline cellulose in the range of 8% to 17% w/w of the total weight of the pharmaceutical composition.
  • the binder may be one or more of polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and mixtures thereof.
  • the disintegrant may be one or more of crospovidone, sodium starch glycolate, croscarmellose sodium, starch and mixtures thereof.
  • the surfactant may be one or more of sodium lauryl sulphate, poloxamer, Polysorbate 80 and mixtures thereof.
  • the lubricant may be one or more of magnesium stearate, stearic acid, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax and mixtures thereof.
  • a process for the preparation of a stable pharmaceutical composition comprising nateglinide Form B, a filler which is a combination of lactose in the range of 46% to 70% w/w and microcrystalline cellulose in the range of 8% to 17% w/w of the total weight of the pharmaceutical composition, and optionally one or more pharmaceutically acceptable excipients comprising binder, disintegrant, surfactant and lubricant, wherein the process comprises
  • Embodiments of the process may include one or more of the embodiments described above.
  • a stable pharmaceutical composition comprising nateglinide Form B and a combination of lactose and microcrystalline cellulose as filler, wherein the lactose is present in a concentration of 46% to 70% w/w and the microcrystalline cellulose is present in a concentration of 8% to 17% w/w of the total weight of the pharmaceutical composition and is prepared by a process which comprises a step of pulverization.
  • compositions may further include one or more pharmaceutically acceptable excipients selected from binder, disintegrant, surfactant, lubricant, coloring and flavoring agent.
  • the composition may be in the form of a tablet, a coated tablet or a capsule.
  • a medicament for the prevention, delay of progression or treatment of metabolic disorders comprising nateglinide Form B, a combination of lactose and microcrystalline cellulose as filler, and optionally another anti-diabetic compound, wherein the lactose is present in a concentration of 46% to 70% w/w and the microcrystalline cellulose is present in a concentration of 8% to 17% w/w of the total weight of the pharmaceutical composition and the medicament is prepared by a process which comprises a step of pulverization.
  • Embodiments of the medicament may include one or more of the following features or those described above.
  • the metabolic disorder may be type 2 diabetes mellitus or a disease or condition associated with diabetes mellitus.
  • Figure 1 depicts super-imposed X-Ray Diffraction (XRD) patterns of nateglinide Form-H, nateglinide Form-B and an exemplary nateglinide tablet formulation.
  • XRD X-Ray Diffraction
  • the term 'Nateglinide' as used herein includes nateglinide in a free or pharmaceutically acceptable salt form selected from an acid addition salt, for example as a sodium salt or as a maleate.
  • the composition comprises the B- or H-type crystal modification of nateglinide, more particularly the B-type.
  • the active ingredient or the pharmaceutically acceptable salt thereof may also be used in the form of a hydrate or may include other solvents used for crystallization.
  • Nateglinide may be present either substantially in the form of one optically pure enantiomer or as a mixture, racemic or otherwise, of enantiomers. Nateglinide may be administered to a warm-blooded animal in a dosage range of about 5 to 1200, more preferably 10 to 1000 and most preferably 25 to 800 mg/day, especially when the warm-blooded animal is a human of about 70 kg body weight. Nateglinide can be present in an amount of about 5% to about 70% (w/w), and most preferably about 15% to about 40% (w/w), based on the total weight of the composition.
  • Stable refers to little or no evidence of conversion of nateglinide from Form B to Form H, for example, as observed by X-ray diffraction, infrared spectroscopy, or Raman spectroscopy measurements.
  • Filler may be selected from the group comprising corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, starch, starch pregelatinized, sucrose, colloidal silicon dioxide and the like.
  • lactose, microcrystalline cellulose, mannitol or dicalcium phosphate can be used.
  • lactose When a combination of lactose and microcrystalline cellulose is used, lactose may be present in a concentration of 46% to 70% w/w and microcrystalline cellulose may be present in a concentration of 8% to 17% w/w of the total weight of pharmaceutical composition.
  • the total concentration of filler may vary from 40-80% w/w of the total weight of the pharmaceutical composition.
  • lactose and microcrystalline cellulose are used in combination lactose may be present in a concentration range of 46% to 70% w/w, more preferably in the range of 46% to 55% w/w, and microcrystalline cellulose may be present in a concentration range of 8% to 17% w/w more preferably in the range of 9% to 13% w/w of the pharmaceutical composition.
  • compositions as described herein may include other pharmaceutically acceptable excipients in addition to nateglinide and a filler.
  • examples of other pharmaceutically acceptable excipients as used herein include binders, dis- integrants, lubricants, surfactants, glidants, colors and the like.
  • binders include methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
  • disintegrants examples include starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
  • lubricants and glidants include colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax and the like.
  • surfactants include sodium lauryl sulphate, poloxamer, Polysorbate 80 and the like.
  • the coloring agents as described herein may be selected from any FDA approved colors for oral use.
  • the stable pharmaceutical composition can be prepared by processes known in the art selected from wet granulation or dry granulation and may be in the form of a tablet or capsule. Pulverization can be carried out in conventional milling instruments such as air jet mill, multi mill, ball mill or by any other method of particle attrition.
  • nateglinide tablets may be prepared by blending nateglinide, fillers, surfactant and disintegrant; granulating the blend with a binder solution; drying the granules; pulverizing the dried granules; lubricating; and compressing the lubricated granules.
  • nateglinide tablets may be prepared by blending nateglinide, fillers, surfactant, disintegrant and binder; granulating the blend with a solvent; drying the granules; pulverizing the dried granules; lubricating; and compressing the lubricated granules.
  • nateglinide tablets may be prepared by blending nateglinide, fillers, surfactant, disintegrant and binder; compacting or slugging the blend; breaking the slugs to make granules; pulverizing the dried granules; lubricating; and compressing the lubricated granules.
  • the tablets may optionally be coated with film forming agents and/or pharmaceutically acceptable excipients.
  • film forming agents and/or pharmaceutically acceptable excipients.
  • Particularly suitable for use are commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry and Eudragit .
  • the coating layers over the tablet may be applied as solution/dispersion of coating ingredients using conventional techniques known in the art selected from spray coating in a conventional coating pan or fluidized bed processor, dip coating, and the like.
  • PROCEDURE [45] 1. Nateglinide, lactose, a part of the colloidal silicon dioxide and sodium starch glycolate are mixed in a high shear blender to give a uniform dry mixture. 2. 2. Sodium lauryl sulphate is dissolved in about 50% of the purified water and is added slowly to the dry mixture of Step 1 under fast mixing in a rapid mixer granulator (RMG). 3. Polyvinylpyrrolidone is dissolved in the remaining quantity of purified water till a clear solution is formed, this solution is added slowly to the premix of Step 2, and the bulk is then granulated. 4.
  • RMG rapid mixer granulator
  • the wet granules are dried in a fluid bed drier, passed through a screen, and then subjected to a pulverization step. 5.
  • the remaining part of the colloidal silicon dioxide and the crospovidone are mixed, passed through a screen, and blended with the granules of step 4. 6.
  • the magnesium stearate is passed through a screen, blended with the blend of step 5, and the total mixture is compressed into tablets.
  • PROCEDURE [48] 1. Nateglinide, microcrystalline cellulose, a part of the colloidal silicon dioxide, and sodium starch glycolate are mixed in a high shear blender to give a uniform dry mixture. 2. Sodium lauryl sulphate is dissolved in about 50% of the purified water and is added slowly to the dry mixture of Step 1 under fast mixing in a rapid mixer granulator (RMG). 3. Polyvinylpyrrolidone is dissolved in the remaining quantity of purified water till a clear solution is formed, this solution is added slowly to the premix of Step 2, and the bulk is then granulated. 4.
  • RMG rapid mixer granulator
  • the wet granules are dried in a fluid bed drier, passed through a screen, and then subjected to a pulverization step. 5.
  • the remaining part of the colloidal silicon dioxide and the crospovidone are mixed, passed through a screen, and blended with the granules of step 4. 6.
  • the magnesium stearate is passed through a screen, blended with the blend of step 5, and the total mixture is compressed into tablets.
  • PROCEDURE [51] 1. Nateglinide along with lactose, microcrystalline cellulose, a part of the colloidal silicon dioxide, and sodium starch glycolate are mixed in a high shear blender to give a uniform dry mixture. 2. Poloxamer is dissolved in about 50% of the purified water and is added slowly to the dry mixture of Step 1 under fast mixing in a rapid mixer granulator (RMG). 3. Polyvinylpyrrolidone is dissolved in the remaining quantity of purified water till a clear solution is formed, this solution is added slowly to the premix of Step 2, and the bulk is then granulated. 4.
  • RMG rapid mixer granulator
  • the wet granules are dried in a fluid bed drier, passed through a screen, and then subjected to a pulverization step. 5.
  • the remaining part of the colloidal silicon dioxide and crospovidone are mixed, passed through a screen, and blended with the granules of step 4. 6.
  • the magnesium stearate is passed through a screen, blended with the blend of step 5, and the total mixture is compressed into tablets.
  • PROCEDURE [54] 1 Nateglinide, lactose, microcrystalline cellulose, a part of the colloidal silicon dioxide, and sodium starch glycolate are mixed in a high shear blender to give a uniform dry mixture.
  • Sodium lauryl sulphate is dissolved in about 50% of the purified water and is added slowly to the dry mixture of Step 1 under fast mixing in a rapid mixer granulator (RMG).
  • RMG rapid mixer granulator
  • Polyvinylpyrrolidone is dissolved in the remaining quantity of purified water till a clear solution is formed, and this solution is added slowly to the premix of Step 2 and the bulk is then granulated.
  • the wet granules are dried in a fluid bed drier, passed through a screen, and then subjected to a pulverization step. 5.
  • the remaining part of the colloidal silicon dioxide and the crospovidone are mixed, passed through a screen, and blended with the granules of step 4. 6.
  • the magnesium stearate is passed through a screen, blended with the blend of step 5, and the total mixture is compressed into tablets.
  • Table 1 clearly indicates that pharmaceutical compositions comprising combination of lactose (at 46 to 70% w/w) and microcrystalline cellulose (at 8 to 17% w/w) as filler show a comparable dissolution profile to that of STARLIX®, and a better dissolution profile as compared to compositions comprising a single filler. Stability data
  • Figure 1 depicts super-imposed X-Ray Diffraction (XRD) patterns of nateglinide Form-H, nateglinide Form-B and tablets made according to the formulation of Example 4.
  • Figure 1 clearly indicates that pharmaceutical compositions prepared as per the details given in Example 4 remain stable, and there is no conversion of Form B nateglinide to Form H nateglinide.

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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Biophysics (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques stables comprenant des granulés pulvérisés de nateglinide de forme B ainsi que des procédés qui, pour les fabriquer, comportent une opération de pulvérisation.
PCT/IB2005/051750 2004-05-31 2005-05-27 Compositions pharmaceutiques stables comprenant des granules pulverises de nateglinide de forme b WO2005117840A1 (fr)

Applications Claiming Priority (2)

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IN989/DEL/2004 2004-05-31
IN989DE2004 2004-05-31

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5463116A (en) * 1991-07-30 1995-10-31 Ajinomoto Co., Inc. Crystals of N- (trans-4-isopropylcyclohexlycarbonyl)-D-phenylalanine and methods for preparing them
EP0965339A1 (fr) * 1996-11-15 1999-12-22 Ajinomoto Co., Inc. Preparation en comprimes
US6559188B1 (en) * 1999-09-17 2003-05-06 Novartis Ag Method of treating metabolic disorders especially diabetes, or a disease or condition associated with diabetes
WO2005020979A1 (fr) * 2003-09-03 2005-03-10 Ranbaxy Laboratories Limited Procede de preparation de compositions pharmaceutiques a base de nateglinide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5463116A (en) * 1991-07-30 1995-10-31 Ajinomoto Co., Inc. Crystals of N- (trans-4-isopropylcyclohexlycarbonyl)-D-phenylalanine and methods for preparing them
EP0965339A1 (fr) * 1996-11-15 1999-12-22 Ajinomoto Co., Inc. Preparation en comprimes
US6559188B1 (en) * 1999-09-17 2003-05-06 Novartis Ag Method of treating metabolic disorders especially diabetes, or a disease or condition associated with diabetes
WO2005020979A1 (fr) * 2003-09-03 2005-03-10 Ranbaxy Laboratories Limited Procede de preparation de compositions pharmaceutiques a base de nateglinide

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